MEDICINE → NEPHROLOGY

TOPIC 1: HYPOKALEMIA AND

HYPERKALEMIA
SMLE 2026 — Mastery Level 3
Complete Conceptual, Interlinked and Scenario-Based Notes

The Nephrology section of the SMLE 2026 blueprint begins with Hyperkalemia and
Hypokalemia — Mastery Level 3. The blueprint expects understanding of normal renal
physiology, electrolyte homeostasis, clinical manifestations, causes, investigations,
interpretation, acute and chronic management, and complications.

SOURCE FRAMEWORK
Primary source
Approach to Internal Medicine

Used for:

 Normal potassium physiology

 Renal potassium handling
 Causes of hypokalemia and hyperkalemia
 Potassium deficit estimation
 Clinical manifestations
 ECG abnormalities
 Potassium and magnesium replacement
 Hyperkalemia emergency treatment
 Potassium-removal strategies

The source defines hypokalemia as potassium below 3.5 mmol/L, describes muscular,
cardiac, gastrointestinal and renal manifestations, and notes that a 1 mmol/L fall in serum
potassium may represent a total-body potassium deficit of approximately 150–300 mmol.

It defines hyperkalemia as potassium above 5.0 mmol/L and outlines membrane stabilisation
with calcium, intracellular shifting with insulin, glucose, β-agonists and bicarbonate when
acidotic, followed by potassium removal through diuretics, binders or dialysis.

Clinical algorithm source

First Aid Clinical Algorithms for the USMLE Step 2 CK 2024

Used especially for:

 Hypokalemia flowchart
 Oral versus IV potassium decisions
 Magnesium correction
 Pseudohyperkalemia
 ECG-based emergency recognition
 Moderate and severe hyperkalemia treatment
 DKA-related potassium management
 GI and renal potassium-loss scenarios

First Aid recommends oral potassium whenever feasible, IV potassium for ECG
abnormalities or inability to take oral therapy, and magnesium replacement when deficient. It
identifies flattened T waves, U waves and ST depression as classic hypokalemic ECG
abnormalities.

For severe hyperkalemia, First Aid recommends ECG assessment, calcium for myocardial
stabilisation, insulin with glucose ± albuterol and bicarbonate in acidosis, definitive
potassium removal, and dialysis when renal failure or refractory disease is present.

PART 1 — THE CENTRAL CONCEPT

WHAT DOES POTASSIUM ACTUALLY
DO?
Do not begin by memorising:

 Low potassium causes U waves.

 High potassium causes peaked T waves.
 Insulin lowers potassium.

First understand why these facts exist.

Potassium is one of the principal ions controlling:

THE ELECTRICAL STABILITY AND

EXCITABILITY OF CELLS
It is essential for:

 Cardiac conduction
  Cardiac contraction
 Skeletal-muscle contraction
 Nerve conduction
 Gastrointestinal smooth-muscle activity
 Renal tubular function

Almost all potassium is stored:

Inside cells.
Only a very small proportion is present:

Outside cells in blood and extracellular

fluid.
The laboratory measures this very small extracellular portion.

Therefore even a modest change in serum potassium can greatly alter electrical activity
despite representing a small fraction of total-body potassium.

PART 2 — POTASSIUM AS AN
ELECTRICAL GRADIENT
Extra Concept for Concept Building
Imagine every muscle and nerve cell as a battery.

The battery works because:

 Potassium concentration is high inside the cell.

 Potassium concentration is lower outside the cell.
 Sodium concentration is high outside the cell.
 Sodium concentration is lower inside the cell.

Potassium naturally tends to move outward through potassium channels.

As positively charged potassium leaves:

The inside of the cell becomes relatively negative.

This creates:

The resting membrane potential.

The sodium-potassium ATPase maintains this gradient by moving:

 Three sodium ions out

 Two potassium ions in

The gradient permits cells to:

 Depolarise
 Repolarise
 Conduct impulses
 Contract rhythmically

When extracellular potassium becomes abnormal:

The resting membrane potential changes.

Cardiac and skeletal-muscle electrical behaviour becomes unstable.

This is why both hypokalemia and hyperkalemia can cause:

 Weakness
 Paralysis
 Arrhythmias
 Cardiac arrest

PART 3 — SERUM POTASSIUM VERSUS

TOTAL-BODY POTASSIUM
This distinction is essential.

Serum potassium can change because of:

1. A true gain or loss of potassium from the

body
Examples:

 Diarrhea → true potassium loss

 Diuretic therapy → true renal potassium loss
 Renal failure → true potassium accumulation

2. Redistribution between cells and blood

Examples:

 Insulin moves potassium into cells

 β₂-agonists move potassium into cells
 Acidosis may move potassium out of cells
 Cell destruction releases potassium
 Alkalosis moves potassium into cells

Therefore:

Serum potassium does not always equal

total-body potassium status.
A patient may have:

 High serum potassium but depleted total-body stores

 Low serum potassium but nearly normal total-body stores

The classic example is diabetic ketoacidosis.

PART 4 — WHO CONTROLS

POTASSIUM?
Potassium balance is controlled by three interconnected systems.

1. Cellular redistribution
Rapid control occurring over minutes.

Main regulators:

 Insulin
 β₂-adrenergic stimulation
 Acid–base status
  Osmolality
 Cell destruction
 Exercise

2. Renal excretion
The main long-term regulator.

3. Intake and gastrointestinal losses

Usually less important than the kidney unless intake is extremely low or GI losses are severe.

The Approach source notes that daily potassium intake is usually approximately 40–120 mEq
and most potassium is excreted by the kidneys.

PART 5 — HOW THE KIDNEY

HANDLES POTASSIUM
Extra Concept for Concept Building
Potassium is:

 Freely filtered at the glomerulus

 Reabsorbed in the proximal tubule
 Reabsorbed in the loop of Henle
 Finally regulated in the distal nephron and collecting duct

The kidney decides how much potassium leaves the body mainly at the distal nephron.

Distal potassium secretion depends on:

1. Aldosterone
2. Distal sodium delivery
3. Distal tubular flow
4. Serum potassium level
5. Acid–base balance

PART 6 — ALDOSTERONE
Aldosterone acts mainly in the collecting duct.

It increases:

 Sodium reabsorption
 Potassium secretion
 Hydrogen-ion secretion

Mechanism:

Aldosterone increases sodium channels and sodium-potassium ATPase activity.

Sodium enters tubular cells from urine.

Sodium is pumped into blood.

The tubular lumen becomes relatively negative.

Potassium moves into the tubular lumen.

Potassium is lost in urine.

Therefore:

Excess aldosterone → hypokalemia +

metabolic alkalosis.
Deficient aldosterone or aldosterone
resistance → hyperkalemia + metabolic
acidosis.

PART 7 — INSULIN
Insulin stimulates sodium-potassium ATPase.

Potassium moves into cells.

Therefore insulin:

 Lowers serum potassium

 Can worsen hypokalemia
 Is used as temporary emergency therapy in hyperkalemia

Important:

Insulin does not remove potassium from the

body.
It only hides potassium temporarily inside cells.

Unless potassium is removed through urine, stool or dialysis:

Serum potassium can rise again when insulin’s effect wears off.

PART 8 — β₂-ADRENERGIC
STIMULATION
β₂-receptor activation also stimulates cellular potassium uptake.

Therefore:
  Albuterol lowers serum potassium
 High-dose β₂-agonists may cause hypokalemia
 β-blockers may contribute to hyperkalemia by reducing cellular uptake

First Aid identifies insulin, β-agonists and alkalosis as causes of potassium shifting into cells.

PART 9 — ACID–BASE STATUS

Acidosis
Hydrogen ions enter cells.

To maintain electrical neutrality:

Potassium may move out of cells.

Serum potassium rises.

Alkalosis
Hydrogen ions leave cells.

Potassium moves into cells.

Serum potassium falls.

The Approach source lists metabolic acidosis among causes of potassium shifting out of cells
and alkalosis among causes of potassium shifting into cells.

Important clinical point:

Acid–base abnormalities also affect renal potassium excretion, so the final potassium result
may reflect both:

 Cellular shifting
 Kidney handling
PART 10 — MASTER APPROACH TO
ANY ABNORMAL POTASSIUM
Ask three questions:

QUESTION 1
Is the result genuine?
Could it be caused by laboratory error or hemolysis?

QUESTION 2
Is potassium shifting, or has the body truly gained/lost
potassium?

QUESTION 3
Are the kidneys responding appropriately?
This framework prevents random memorisation.

SECTION A — HYPOKALEMIA
PART 11 — DEFINITION
Hypokalemia = serum potassium below 3.5
mmol/L.
A practical clinical classification:

Mild
3.0–3.4 mmol/L

Moderate
2.5–2.9 mmol/L

Severe
Below 2.5 mmol/L

However, treatment urgency also depends on:

 Symptoms
 ECG changes
 Speed of decline
 Cardiac disease
 Digoxin use
 Ongoing losses
 Magnesium deficiency

A symptomatic patient with potassium 3.0 may be more urgent than an asymptomatic patient
with potassium 2.8.

PART 12 — THREE MECHANISMS OF

HYPOKALEMIA
1. Potassium shifts into cells
2. Potassium is lost from the body
3. Intake is reduced
Reduced intake alone rarely causes severe hypokalemia because healthy kidneys can reduce
urinary potassium excretion substantially.

Memory:

SHIFT — LOSS — LOW INTAKE

PART 13 — TRANSCELLULAR SHIFT

INTO CELLS
Causes include:

 Insulin administration
 β₂-agonists
 Metabolic alkalosis
 Refeeding
 Hyperadrenergic states
 Hypothermia
 Hypokalemic periodic paralysis

In redistribution:

 Serum potassium is low

 Total-body potassium may be normal or only mildly reduced

This matters because excessive replacement can later cause hyperkalemia when the shift
reverses.

PART 14 — DKA POTASSIUM

PARADOX
This is one of the most important SMLE concepts.

A patient with DKA may initially have:

Normal or high serum potassium

despite:

Severe total-body potassium depletion.

Why?

Hyperglycemia causes osmotic diuresis.

Water and potassium are lost in urine.

Total-body potassium decreases.

But simultaneously:
Insulin deficiency

Potassium cannot enter cells efficiently.

Acidosis and hyperosmolality

Potassium moves out of cells.

Therefore blood potassium may appear normal or elevated.

When treatment starts:

Insulin is given.

Acidosis improves.

Potassium rapidly enters cells.

Serum potassium falls.

The hidden total-body deficit becomes visible.

First Aid emphasises that potassium should be above approximately 3.3 mmol/L before
insulin is started in DKA because insulin may produce dangerous hypokalemia.

Scenario
A patient with DKA has:

 Glucose 550 mg/dL

 Potassium 4.4 mmol/L
 Severe acidosis

After insulin:

 Potassium falls to 2.9 mmol/L

This is not a new potassium loss caused only by insulin.

It reflects:

Pre-existing urinary depletion + rapid

intracellular shifting.

PART 15 — β₂-AGONIST-INDUCED
HYPOKALEMIA
A patient with severe asthma receives repeated high-dose albuterol.

β₂-receptor activity increases sodium-potassium ATPase function.

Potassium enters skeletal-muscle cells.

Serum potassium falls.

Possible symptoms:

 Tremor
 Palpitations
 Weakness
 Muscle cramps
 Arrhythmia in high-risk patients

Because this is mostly a shift:

Replacement should be monitored carefully.

PART 16 — REFEEDING-RELATED
HYPOKALEMIA
Extra Concept for Concept Building
A severely malnourished patient begins receiving carbohydrate-rich nutrition.

Insulin secretion rises.

Potassium, phosphate and magnesium enter cells.

Serum levels fall.

Possible presentation:

 Weakness
 Arrhythmias
 Respiratory failure
 Confusion

This concept is included because it directly explains an important potassium-shift scenario.

PART 17 — HYPOKALEMIC PERIODIC

PARALYSIS
Extra Concept for Concept Building
Potassium abruptly shifts into skeletal muscle.

The patient develops:

 Sudden flaccid weakness

 Preserved sensation
 Normal consciousness
 Low serum potassium

Possible triggers:

 High-carbohydrate meal
 Rest after strenuous exercise
 Thyrotoxicosis
 Genetic channelopathy
The key concept is:

Redistribution rather than major total-

body loss.
Therefore cautious replacement and treatment of the underlying trigger are necessary.

PART 18 — TRUE POTASSIUM LOSS

Potassium can leave through:

Gastrointestinal tract
or

Kidneys.
To determine which route is responsible, examine:

 History
 Acid–base pattern
 Blood pressure
 Urinary potassium

PART 19 — DIARRHEA
Lower gastrointestinal fluid contains potassium and bicarbonate.

Profuse diarrhea:

Potassium is lost.

Bicarbonate is lost.

Therefore the classic biochemical pattern is:

Hypokalemia + non-anion-gap metabolic
acidosis.
Scenario
A patient has:

 Five days of profuse diarrhea

 Dry mucosa
 Weakness
 Potassium 2.7 mmol/L
 Bicarbonate 16 mmol/L

Think:

GI potassium and bicarbonate loss.

PART 20 — LAXATIVE ABUSE

A patient with an eating disorder may present with:

 Chronic diarrhea
 Low body weight
 Dehydration
 Hypokalemia
 Acid–base abnormalities

First Aid presents a patient with low BMI, concern about weight, diarrhea and hypokalemia
as a laxative-abuse pattern.

Complications include:

 Arrhythmias
 Volume depletion
 Renal dysfunction
 Muscle weakness
 Chronic colonic changes
PART 21 — VOMITING AND
NASOGASTRIC SUCTION
Vomiting causes hypokalemia through several interconnected mechanisms.

Vomiting:

Hydrogen and chloride are lost.

Metabolic alkalosis develops.

Potassium shifts into cells.

At the same time:

Volume falls.

Renin–angiotensin–aldosterone system activates.

Aldosterone increases.

The kidneys excrete potassium.

Therefore vomiting often produces:

Hypokalemia
Hypochloremia
Metabolic alkalosis
Low urinary chloride after vomiting has
stopped
Important:

The main potassium loss may be renal rather than direct loss in gastric fluid.

PART 22 — DIURETICS
Loop and thiazide diuretics increase distal sodium delivery.

More sodium reaches the collecting duct.

More sodium is reabsorbed.

More potassium is secreted.

At the same time:

Volume depletion

Aldosterone increases.

Potassium loss worsens.

The patient may develop:

 Hypokalemia
 Metabolic alkalosis
 Hypomagnesemia
 Weakness
 Cramps
 Arrhythmia
Scenario
A patient with heart failure starts furosemide.

Three days later:

 Potassium 3.1 mmol/L

 Magnesium 1.4 mg/dL
 Muscle cramps

Think:

Renal potassium and magnesium wasting

caused by loop diuretic therapy.
First Aid describes this exact mechanism and recommends replacing both electrolytes.

PART 23 — HYPERALDOSTERONISM
Aldosterone promotes:

 Sodium retention
 Potassium secretion
 Hydrogen secretion

Therefore excess aldosterone produces:

Hypertension
Hypokalemia
Metabolic alkalosis
Scenario
A patient has:

 Resistant hypertension
 Potassium 2.8 mmol/L
 Bicarbonate 34 mmol/L
 No diuretic use
Think:

Primary hyperaldosteronism.
First Aid recommends measuring renin and aldosterone and then adrenal imaging, with
adrenal-vein sampling when required.

PART 24 — PRIMARY VERSUS

SECONDARY
HYPERALDOSTERONISM
Extra Concept for Concept Building
Primary hyperaldosteronism
Aldosterone is produced independently.

Therefore:

 Aldosterone high
 Renin suppressed
 Hypertension common
 Hypokalemia may occur

Secondary hyperaldosteronism
Renin is elevated because the kidney believes perfusion is low.

Examples:

 Renal artery stenosis

 Severe heart failure
 Cirrhosis

Therefore:

 Renin high
 Aldosterone high

This distinction is included because it directly explains the investigation of aldosterone-

related hypokalemia.
PART 25 — BARTTER AND GITELMAN
SYNDROMES
Extra Concept for Concept Building
These inherited disorders cause renal salt wasting.

Bartter syndrome
Mimics loop-diuretic action.

Gitelman syndrome
Mimics thiazide action.

Both may cause:

 Hypokalemia
 Metabolic alkalosis
 Elevated renin
 Elevated aldosterone
 Normal or low blood pressure

First Aid states that Bartter and Gitelman syndromes mimic loop and thiazide diuretics,
respectively.

Key distinction from primary hyperaldosteronism:

Bartter/Gitelman → normal or low BP.

Primary hyperaldosteronism →
hypertension.

PART 26 — RENAL TUBULAR

ACIDOSIS
Type 1 and type 2 renal tubular acidosis can cause:
  Renal potassium wasting
 Hypokalemia
 Non-anion-gap metabolic acidosis

Type 4 RTA causes hyperkalemia and is discussed later.

The detailed classification belongs to acid–base physiology, so only the potassium

relationship is included here.

PART 27 — MAGNESIUM DEFICIENCY

Hypomagnesemia causes persistent renal potassium wasting.

Mechanism:

Low magnesium

Renal potassium channels remain excessively active.

Potassium continues to leave in urine.

Administered potassium is lost.

Therefore:

Potassium may not correct until magnesium

is replaced.
First Aid emphasises that low magnesium prevents successful potassium correction and
should always be considered.

Clinical rule:

Stable patient without ECG changes

Correct magnesium and potassium, often orally.

Symptomatic patient or ECG changes

Replace both promptly, frequently using IV therapy according to severity.

PART 28 — REDUCED INTAKE

Low intake alone rarely causes severe hypokalemia because the kidneys can reduce
potassium excretion.

The Approach source notes that renal potassium excretion may fall to approximately 5–25
mEq/day during hypokalemia.

It becomes clinically important when combined with:

 Diuretics
 Diarrhea
 Vomiting
 Malnutrition
 Alcohol use disorder
 Refeeding
 Chronic illness

PART 29 — PRESENTATION OF
HYPOKALEMIA
Symptoms depend on:

 Potassium level
 Rate of fall
 Underlying cardiac disease
 Magnesium status
 Digoxin use

The source notes symptoms are often absent until potassium is below approximately 2.5
mmol/L, although higher levels may be symptomatic in high-risk patients.

Affected systems:

Skeletal muscle
Heart
GI tract
Kidneys

PART 30 — MUSCLE
MANIFESTATIONS
Low extracellular potassium makes the resting membrane potential more negative.

Cells become harder to depolarise.

Muscle contraction weakens.

Possible symptoms:

 Fatigue
 Muscle cramps
 Proximal weakness
 Flaccid paralysis
 Respiratory-muscle weakness
 Rhabdomyolysis

The Approach source lists weakness, paralysis, cramps, paresthesias, tetany, muscle
tenderness, atrophy and rhabdomyolysis.

Scenario
A patient taking a thiazide develops:

 Difficulty climbing stairs

 Leg cramps
 Potassium 2.4 mmol/L

The weakness is caused by impaired skeletal-muscle excitability.

PART 31 — GASTROINTESTINAL
MANIFESTATIONS
GI smooth muscle also depends on potassium.

Hypokalemia:

Smooth-muscle contraction decreases.

The patient may develop:

 Constipation
 Abdominal distension
 Reduced bowel sounds
 Paralytic ileus
 Nausea

Severe hypokalemia can therefore resemble bowel obstruction.

PART 32 — RENAL MANIFESTATIONS

Hypokalemia can impair the kidney’s concentrating ability.

Urine becomes dilute.

The patient develops:

 Polyuria
 Polydipsia
 Nocturia

The source also lists increased renal ammonia production and chronic hypokalemic
nephropathy.
PART 33 — CARDIAC
MANIFESTATIONS
Hypokalemia delays repolarisation and increases myocardial irritability.

Possible arrhythmias:

 Premature atrial beats

 Premature ventricular beats
 Atrial tachyarrhythmias
 AV block
 Ventricular tachycardia
 Ventricular fibrillation

Risk is particularly high in:

 Ischemic heart disease

 Heart failure
 Digoxin therapy
 Hypomagnesemia

PART 34 — ECG CHANGES IN

HYPOKALEMIA
The typical progression is:

Flattened T waves
↓

ST depression
↓

Prominent U waves
↓

Prolonged QU interval
↓

Atrial or ventricular arrhythmia

First Aid identifies flat T waves, U waves and ST depression as classic findings.

What is a U wave?
A small deflection occurring after the T wave.

It becomes prominent when ventricular repolarisation is delayed.

Memory:

Low K makes a U wave come up.

PART 35 — DIGOXIN AND

HYPOKALEMIA
Extra Concept for Concept Building
Potassium and digoxin compete at the sodium-potassium ATPase.

When potassium is low:

Digoxin binding increases.

Risk of digoxin toxicity rises.

Therefore a patient taking digoxin with hypokalemia is at greater risk of:

 Bradyarrhythmia
 AV block
 Ventricular arrhythmia
 Nausea
 Visual disturbance

This is why even moderate hypokalemia may require urgent correction in a digoxin-treated
patient.
PART 36 — INVESTIGATION OF
HYPOKALEMIA
Start with:

 Repeat serum potassium when unexpected

 ECG
 Magnesium
 Sodium and bicarbonate
 Creatinine and urea
 Glucose
 Calcium and phosphate when relevant
 Medication review
 Acid–base assessment
 Urinary potassium when the cause is unclear

The Approach source recommends electrolytes, magnesium, renal function, glucose, CK,
serum and urine osmolality, urinalysis and urinary electrolytes.

PART 37 — URINARY POTASSIUM: IS

THE KIDNEY WASTING IT?
When serum potassium is low, healthy kidneys should conserve potassium.

Therefore:

Low urinary potassium

Means the kidneys are responding appropriately.

Think:

 Diarrhea
 Poor intake
 Cellular shift

High urinary potassium

Means the kidneys are inappropriately losing potassium.

Think:
  Diuretics
 Hyperaldosteronism
 RTA
 Hypomagnesemia
 Bartter/Gitelman syndrome

A spot urine potassium or urine potassium-to-creatinine ratio may be used depending on the
clinical setting.

PART 38 — ACID–BASE PATTERN AS A

DIAGNOSTIC MAP
Hypokalemia + metabolic acidosis
Think:

 Diarrhea
 Type 1 or type 2 RTA
 Laxative abuse

Then use urinary potassium:

 Low urine potassium → GI loss

 High urine potassium → renal loss

Hypokalemia + metabolic alkalosis

Think:

 Vomiting
 Nasogastric suction
 Diuretics
 Hyperaldosteronism
 Bartter/Gitelman

Then assess:

 Blood pressure
 Urinary chloride
 Medication use
PART 39 — BLOOD PRESSURE AS A
CLUE
Hypokalemia + alkalosis + hypertension
Think:

 Primary hyperaldosteronism
 Secondary mineralocorticoid excess
 Cushing syndrome
 Other mineralocorticoid states

Hypokalemia + alkalosis + normal/low BP

Think:

 Vomiting
 Diuretics
 Bartter syndrome
 Gitelman syndrome

PART 40 — ESTIMATING POTASSIUM

DEFICIT
The Approach source states that each 1 mmol/L decrease in serum potassium may represent
approximately:

150–300 mmol of total-body potassium

deficit.
This is only an estimate.

The relationship varies with:

 Body size
 Muscle mass
 Sex
 Duration of loss
 Acid–base status
 Cellular shifting
Therefore:

Do not attempt to replace the estimated

entire deficit rapidly.
Replace gradually with serial monitoring.

PART 41 — MANAGEMENT
PRINCIPLES OF HYPOKALEMIA
Four objectives:

1. Prevent cardiac complications

2. Replace potassium
3. Correct magnesium
4. Treat the underlying cause

PART 42 — WHO NEEDS URGENT

TREATMENT?
Urgent replacement is required when there is:

 Potassium below approximately 2.5 mmol/L

 ECG abnormalities
 Arrhythmia
 Significant muscle weakness
 Paralysis
 Respiratory compromise
 Rhabdomyolysis
 Ongoing major loss
 Digoxin use
 Acute coronary disease
PART 43 — ORAL POTASSIUM
Oral potassium is preferred whenever
possible.
Why?

 Safer
 Slower absorption
 Lower risk of sudden hyperkalemia
 Easier administration
 Effective in stable patients

First Aid explicitly states that oral replacement is preferred when the patient is stable and able
to take oral medication.

Commonly used form:

Potassium chloride
It is particularly useful when potassium depletion occurs with:

 Chloride depletion
 Metabolic alkalosis
 Diuretic use
 Vomiting

PART 44 — IV POTASSIUM
Use IV replacement when:

 ECG changes are present

 Severe symptoms occur
 Potassium is severely low
 Oral administration is impossible
 GI absorption is unreliable

First Aid recommends IV potassium for ECG abnormalities or inability to take oral
replacement.

Safety principles:
  Never give potassium as an undiluted IV push.
 Use controlled infusion.
 Monitor ECG during rapid or high-dose replacement.
 Check renal function.
 Repeat potassium frequently.
 Correct magnesium.

The exact infusion concentration and speed depend on venous access, setting and institutional
protocol.

PART 45 — WHY DEXTROSE-

CONTAINING FLUID MAY BE
UNHELPFUL
Dextrose:

Stimulates insulin.

Insulin moves potassium into cells.

Serum potassium may fall further.

Therefore potassium replacement is generally not mixed with large glucose loads unless
clinically necessary.

PART 46 — CORRECT THE CAUSE

Diarrhea
 Treat diarrhea cause
 Replace fluids
 Replace potassium and bicarbonate deficits as appropriate

Vomiting
  Stop vomiting
 Replace chloride and volume, usually with saline when appropriate
 Replace potassium

Diuretics
 Reduce dose if possible
 Replace potassium
 Correct magnesium
 Consider a potassium-sparing strategy when clinically appropriate

Hyperaldosteronism
 Unilateral disease → adrenalectomy
 Bilateral disease → mineralocorticoid-receptor antagonist

Redistribution
Treat the precipitating condition and replace cautiously.

PART 47 — COMPLICATIONS OF
HYPOKALEMIA
During the acute episode:

 Ventricular arrhythmia
 Cardiac arrest
 Paralysis
 Respiratory failure
 Rhabdomyolysis
 Ileus

With chronic depletion:

 Hypokalemic nephropathy
 Polyuria
 Glucose intolerance
 Persistent muscle weakness

First Aid notes that severe hypokalemia can cause cardiac arrest.
SECTION B — HYPERKALEMIA
PART 48 — DEFINITION
The Approach source defines:

Hyperkalemia = serum potassium above 5.0

mmol/L.
A practical clinical classification:

Mild
Approximately 5.1–5.9 mmol/L

Moderate
Approximately 6.0–6.4 mmol/L

Severe
6.5 mmol/L or above

But urgency depends on:

 ECG changes
 Symptoms
 Rate of rise
 Renal function
 Ongoing potassium release
 Underlying cardiac disease

A rapidly rising potassium of 6.0 may be more dangerous than a chronically stable potassium
of 6.2.

PART 49 — FIRST QUESTION: IS IT

REAL?
Before treating an unexpected asymptomatic result, consider:
Pseudohyperkalemia.
Common causes:

 Hemolysed sample
 Difficult venepuncture
 Prolonged tourniquet
 Repeated fist clenching
 Extreme thrombocytosis
 Extreme leukocytosis
 Delayed sample processing

First Aid’s algorithm begins by checking whether the sample is hemolysed and repeating
potassium when needed.

Important rule
If the patient has:

 ECG changes
 Severe renal failure
 Muscle weakness
 A very high potassium result

do not delay emergency treatment while waiting for confirmation.

Repeat the test, but treat simultaneously when clinically dangerous.

PART 50 — THREE MECHANISMS OF

HYPERKALEMIA
1. Potassium shifts out of cells
2. Potassium is released from destroyed
cells
3. The kidneys fail to excrete potassium
Excess intake alone rarely causes severe hyperkalemia when renal function is normal.
PART 51 — POTASSIUM SHIFTING OUT
OF CELLS
Causes include:

 Metabolic acidosis
 Insulin deficiency
 β-blockade
 Hyperosmolarity
 Digoxin toxicity
 Succinylcholine in high-risk patients
 Severe exercise

The Approach source identifies acidosis, insulin deficiency and β-blockade as major
redistribution mechanisms.

PART 52 — ACIDOSIS
In acidosis:

Hydrogen ions enter cells.

Potassium leaves cells.

Serum potassium rises.

This is particularly relevant in:

 DKA
 Renal failure
 Severe metabolic acidosis

But again, serum potassium may be high despite total-body depletion in DKA.

PART 53 — INSULIN DEFICIENCY

Without insulin:

Sodium-potassium ATPase activity decreases.

Potassium cannot efficiently enter cells.

Serum potassium rises.

This is why insulin treatment lowers potassium quickly.

PART 54 — HYPEROSMOLARITY
Extra Concept for Concept Building
Severe hyperglycemia increases extracellular osmolality.

Water moves out of cells.

Potassium follows water out.

Serum potassium rises.

This contributes to hyperkalemia in uncontrolled diabetes.

PART 55 — CELL DESTRUCTION

Cells contain large amounts of potassium.

When cells rupture:

↓
Potassium is released into blood.

Causes include:

 Rhabdomyolysis
 Tumor lysis syndrome
 Crush injury
 Severe burns
 Intravascular hemolysis
 Massive tissue necrosis

First Aid lists tumor lysis, hemolysis, rhabdomyolysis and crush injury under cell-lysis
causes.

PART 56 — RHABDOMYOLYSIS
SCENARIO
A patient is trapped under heavy debris.

Hours later:

 Muscle pain
 Dark urine
 CK markedly elevated
 Potassium 6.8 mmol/L
 Peaked T waves

Mechanism:

Muscle-cell destruction

Intracellular potassium enters blood.

Hyperkalemia develops.

At the same time:

Myoglobin injures kidneys.

Renal potassium excretion decreases.

↓

Hyperkalemia worsens.

This can produce rapid cardiac arrest.

PART 57 — TUMOR LYSIS SYNDROME

Extra Concept for Concept Building
Rapid destruction of malignant cells releases:

 Potassium
 Phosphate
 Nucleic acids

Therefore:

 Hyperkalemia
 Hyperphosphatemia
 Hypocalcemia
 Hyperuricemia
 Acute kidney injury

develop together.

The detailed syndrome belongs to oncology, but it is included here because it directly
explains severe hyperkalemia.

PART 58 — REDUCED RENAL

EXCRETION
This is the most common important mechanism in clinical practice.

Causes include:

 Acute kidney injury

 Chronic kidney disease
 Reduced distal tubular flow
 Hypoaldosteronism
 Aldosterone resistance
 Medications
The Approach source identifies renal failure, reduced effective circulating volume,
hypoaldosteronism, ACE inhibitors, ARBs, spironolactone and NSAIDs among causes.

PART 59 — ACUTE KIDNEY INJURY

When filtration falls:

Potassium excretion decreases.

If the patient also has:

 Acidosis
 Cell destruction
 Medications impairing aldosterone

hyperkalemia may become severe.

First Aid presents an AKI patient with hyperkalemia and recommends renal workup, ECG,
fluids where appropriate and electrolyte monitoring.

PART 60 — CHRONIC KIDNEY

DISEASE
In early CKD, surviving nephrons increase potassium secretion.

Therefore serum potassium may remain normal for a long time.

Hyperkalemia becomes more likely when:

 GFR becomes markedly reduced

 Dietary intake is high
 Acidosis develops
 ACE inhibitor or ARB is used
 Potassium-sparing drugs are added
 Diabetes causes hyporeninemic hypoaldosteronism
PART 61 — HYPOALDOSTERONISM
AND TYPE 4 RTA
Type 4 renal tubular acidosis is associated with:

 Reduced aldosterone production

or
 Aldosterone resistance

Therefore:

Potassium secretion decreases.

Hyperkalemia develops.

Hydrogen secretion also decreases.

Non-anion-gap metabolic acidosis develops.

Typical scenario:

A patient with:

 Diabetes
 CKD
 Potassium 5.5 mmol/L
 Bicarbonate 17 mmol/L
 Mildly acidic urine

Think:

Type 4 RTA or hyporeninemic

hypoaldosteronism.
First Aid describes this association with diabetes, CKD, ACE inhibitors, ARBs, NSAIDs and
potassium-sparing drugs.

PART 62 — MEDICATIONS
Important drugs include:

 ACE inhibitors
 ARBs
 Spironolactone
 Eplerenone
 Amiloride
 Triamterene
 NSAIDs
 Trimethoprim
 Heparin
 Calcineurin inhibitors
 β-blockers
 Potassium supplements

Mechanisms differ:

ACE inhibitors/ARBs
Reduce aldosterone.

Spironolactone/eplerenone
Block aldosterone receptor.

Amiloride/triamterene
Reduce distal sodium entry and potassium secretion.

NSAIDs
Reduce renin and renal perfusion.

Trimethoprim
Acts similarly to amiloride in the distal nephron.

The Approach source recommends discontinuing potassium supplements, ACE inhibitors,

ARBs, spironolactone, NSAIDs and trimethoprim when they contribute.

PART 63 — ADRENAL INSUFFICIENCY

Extra Concept for Concept Building
Primary adrenal insufficiency causes aldosterone deficiency.

Therefore:

 Sodium retention decreases

 Potassium excretion decreases
 Hydrogen secretion decreases

The patient may develop:

 Hyperkalemia
 Hyponatremia
 Hypotension
 Non-anion-gap metabolic acidosis
 Hyperpigmentation
 Weight loss

This is included because it directly explains one important hypoaldosterone scenario.

PART 64 — PRESENTATION OF
HYPERKALEMIA
Many patients are asymptomatic until potassium is severe.

Symptoms may include:

 Weakness
 Paresthesias
 Flaccid paralysis
 Palpitations
 Syncope
 Cardiac arrest

The Approach source identifies muscular weakness or paralysis and progressive cardiac
abnormalities.

PART 65 — WHY WEAKNESS OCCURS

Moderate extracellular potassium elevation initially makes the resting membrane potential
less negative.

↓
Cells become easier to depolarise.

But persistent depolarisation inactivates sodium channels.

Cells can no longer generate normal action potentials.

Muscle weakness and paralysis develop.

Therefore hyperkalemia may initially increase excitability but eventually causes electrical
failure.

PART 66 — ECG PROGRESSION IN

HYPERKALEMIA
The classic progression is:

Tall peaked T waves

↓

Shortened QT
↓

PR prolongation
↓

Flattening or loss of P waves

↓

QRS widening
↓
Sine-wave pattern
↓

Ventricular fibrillation or asystole

First Aid lists peaked T waves, flattened P waves, PR prolongation and QRS widening.

Important:

ECG changes do not always correlate

perfectly with the potassium level.
A patient can have severe hyperkalemia with a relatively normal ECG.

Therefore a normal ECG does not make a markedly elevated potassium harmless.

PART 67 — WHY PEAKED T WAVES

APPEAR
Early hyperkalemia accelerates ventricular repolarisation.

The T wave becomes:

 Tall
 Narrow
 Pointed
 Symmetrical

This is usually the earliest classic ECG change.

PART 68 — WHY QRS WIDENS

As potassium rises further:

↓
Persistent membrane depolarisation inactivates sodium channels.

Ventricular conduction slows.

QRS widens.

Eventually:

P waves disappear.

QRS and T wave merge.

Sine-wave pattern develops.

This is a pre-arrest rhythm.

PART 69 — INVESTIGATIONS
Immediately obtain:

 Repeat potassium if pseudohyperkalemia is possible

 ECG
 Creatinine and urea
 Bicarbonate
 Glucose
 Calcium
 Magnesium
 CK if muscle injury suspected
 Phosphate and uric acid if tumor lysis suspected
 Medication review
 Urinalysis
 Urinary studies when hypoaldosteronism is suspected

The Approach source recommends electrolytes, renal function, glucose, CK, serum and urine
osmolality, urinalysis and urinary electrolytes.
PART 70 — WHEN IS HYPERKALEMIA
AN EMERGENCY?
Treat immediately when there is:

 Potassium 6.5 mmol/L or above

 ECG abnormalities
 Rapid rise
 Muscle weakness or paralysis
 Significant renal failure
 Ongoing cell destruction
 Severe acidosis

First Aid categorises potassium above 6.5 mmol/L or any ECG changes as severe
hyperkalemia requiring emergency treatment.

PART 71 — THE FOUR-STEP

EMERGENCY TREATMENT
Emergency hyperkalemia treatment has four separate goals:

1. Protect the heart

2. Shift potassium into cells
3. Remove potassium from the body
4. Treat the cause
Do not confuse these goals.

PART 72 — STEP 1: CALCIUM

PROTECT THE HEART
Give IV calcium when:
  ECG changes are present
 Severe hyperkalemia is producing electrical instability

Options include:

 Calcium gluconate
 Calcium chloride in selected settings

Mechanism:

Calcium stabilises the cardiac membrane.

It raises the threshold potential.

The difference between resting membrane potential and threshold increases.

The myocardium becomes less likely to develop lethal arrhythmia.

Important:

Calcium does not lower potassium.

It protects the heart while other treatments act.

First Aid places calcium first in severe hyperkalemia because it stabilises the myocardium.

PART 73 — CALCIUM GLUCONATE

VERSUS CALCIUM CHLORIDE
Extra Concept for Concept Building
Calcium gluconate
 Safer through a peripheral vein
 Less elemental calcium
 Commonly used in non-arrest situations

Calcium chloride
  Contains more elemental calcium
 More irritating to peripheral tissue
 Often preferred through central access or in cardiac arrest

The exact selection depends on urgency and access.

PART 74 — STEP 2: INSULIN WITH

GLUCOSE
SHIFT POTASSIUM INTO CELLS
Insulin stimulates sodium-potassium ATPase.

Potassium enters cells.

Serum potassium falls within minutes.

Glucose is given to prevent hypoglycemia unless blood glucose is already very high and the
protocol specifies otherwise.

Important:

 Monitor glucose repeatedly.

 Hypoglycemia may occur hours later.
 The effect is temporary.

The Approach source notes a substantial risk of hypoglycemia after insulin treatment and
recommends glucose monitoring.

PART 75 — STEP 3: β₂-AGONIST

High-dose nebulised albuterol/salbutamol:

Stimulates cellular potassium uptake.

↓
Temporarily lowers serum potassium.

It is an adjunct, not a replacement for insulin.

Limitations:

 Variable response
 Tachycardia
 Tremor
 Reduced effect in patients taking β-blockers

PART 76 — STEP 4: BICARBONATE

Sodium bicarbonate may help when:

Significant metabolic acidosis is present.

Correction of acidosis:

Promotes potassium movement into cells.

It is not reliably effective in every normopH hyperkalemic patient.

First Aid recommends bicarbonate particularly when pH is low.

PART 77 — TEMPORARY SHIFTING IS

NOT DEFINITIVE TREATMENT
Insulin, albuterol and bicarbonate:

Move potassium into cells.

They do not remove it.

After several hours:

↓
Potassium may move back into blood.

Therefore every severe hyperkalemia patient also needs:

A potassium-removal plan.

PART 78 — REMOVE POTASSIUM

THROUGH THE KIDNEYS
Loop diuretics increase urinary potassium excretion.

Useful when:

 The patient produces urine

 Volume status permits diuresis
 Renal function is adequate enough to respond

Not useful when:

 The patient is anuric

 Severe renal failure prevents response

PART 79 — POTASSIUM BINDERS

Examples in the supplied sources include:

 Sodium zirconium cyclosilicate

 Patiromer
 Sodium polystyrene sulfonate

They bind potassium in the gastrointestinal tract.

Potassium leaves through stool.

Important:

Most binders are not the sole treatment for

immediately life-threatening hyperkalemia.
They act more slowly than:

 Calcium
 Insulin
 Dialysis

First Aid includes binders as potassium-removal methods after cardiac stabilisation and
intracellular shifting.

PART 80 — DIALYSIS
Dialysis directly removes potassium from blood.

It is the fastest definitive potassium-removal method when renal excretion is severely

impaired.

Indications include:

 Severe hyperkalemia with renal failure

 Refractory hyperkalemia
 Ongoing potassium release
 Anuria
 Recurrent elevation despite medical therapy
 Severe acidosis or volume overload providing additional indication

First Aid recommends hemodialysis when renal failure is present or the patient fails other
treatment.

Definitive treatment in anuric renal failure:

Hemodialysis.

PART 81 — STOP THE CAUSE

Review and stop when possible:

 Potassium supplements
 ACE inhibitors
 ARBs
 Spironolactone
 Eplerenone
 Amiloride
  Triamterene
 NSAIDs
 Trimethoprim
 Other contributing drugs

Treat:

 DKA
 Rhabdomyolysis
 Tumor lysis
 Adrenal insufficiency
 AKI
 Obstruction
 Acidosis

PART 82 — COMPLETE EMERGENCY

ALGORITHM
Potassium elevated
↓

Check for hemolysis and repeat when

appropriate.
At the same time:

Obtain stat ECG.

↓

ECG changes or potassium ≥6.5 mmol/L

↓

1. IV calcium
Protect myocardium.

↓
2. Insulin + glucose
Shift potassium into cells.

3. Nebulised albuterol
Additional intracellular shift.

4. Bicarbonate if significant acidosis

↓

5. Remove potassium
 Loop diuretic if producing urine
 Potassium binder
 Hemodialysis if renal failure, refractory or severe

6. Stop offending drugs and treat cause

↓

7. Repeat ECG, potassium and glucose

frequently

PART 83 — MODERATE
HYPERKALEMIA WITHOUT ECG
CHANGES
First Aid describes moderate hyperkalemia as approximately 5.5–6.5 mmol/L without ECG
abnormalities and recommends confirmation, ECG assessment, removal of the cause and
potassium elimination through binders or diuretics where appropriate.
Management depends on:

 Renal function
 Trend
 Cause
 Symptoms
 Ability to excrete potassium

Do not automatically give IV calcium if there are no ECG changes and no severe instability,
but monitor closely.

PART 84 — COMPLICATIONS OF
HYPERKALEMIA
 Progressive conduction delay
 Bradyarrhythmia
 Ventricular tachycardia
 Ventricular fibrillation
 Asystole
 Cardiac arrest
 Skeletal-muscle paralysis
 Respiratory compromise

First Aid identifies cardiac arrhythmia as the principal untreated complication.

PART 85 — CLINICAL SCENARIOS

Scenario 1 — Diarrheal hypokalemia
A patient develops:

 Profuse diarrhea
 Dehydration
 Potassium 2.8
 Bicarbonate 16

Mechanism

Loss of potassium and bicarbonate in stool.

Diagnosis
GI-loss hypokalemia with non-anion-gap
metabolic acidosis.
Management

 Rehydration
 Oral or IV potassium depending on symptoms
 Treat diarrhea cause
 Check magnesium

Scenario 2 — Vomiting
A patient has:

 Recurrent vomiting
 Potassium 2.9
 Chloride low
 Bicarbonate high
 Low urinary chloride

Diagnosis

Vomiting-induced hypokalemic,
hypochloremic metabolic alkalosis.
Best treatment

Chloride and volume replacement plus

potassium replacement and control of
vomiting.

Scenario 3 — Diuretic-associated hypokalemia

A patient receiving furosemide develops:

 Leg cramps
 Potassium 3.0
  Magnesium low
 Metabolic alkalosis

Mechanism

Distal sodium delivery + aldosterone activation + magnesium loss.

Treatment

 Potassium replacement
 Magnesium replacement
 Review diuretic dose
 Consider potassium-sparing strategy when appropriate

Scenario 4 — Hyperaldosteronism
A patient has:

 Resistant hypertension
 Potassium 2.7
 Bicarbonate 34

Next investigation

Plasma aldosterone and renin.

Definitive treatment

 Unilateral adrenal source → adrenalectomy

 Bilateral adrenal hyperplasia → mineralocorticoid-receptor antagonist

Scenario 5 — DKA
A patient with DKA has initial potassium 5.2.

Interpretation

Serum potassium is high from redistribution, but total-body potassium is depleted.

Key treatment rule

If potassium is dangerously low:

Replace potassium before insulin.
Then monitor frequently during insulin treatment.

Scenario 6 — Pseudohyperkalemia
An asymptomatic patient has potassium 6.2.

The sample is reported as heavily hemolysed.

ECG is normal.

Best next step

Repeat potassium promptly using a

properly collected sample.
Do not label the patient hyperkalemic solely from a hemolysed specimen.

Scenario 7 — Severe hyperkalemia with ECG changes

A CKD patient has:

 Potassium 7.0
 Peaked T waves
 Widening QRS

Immediate treatment

IV calcium first.
Then:

 Insulin + glucose
 Albuterol
 Bicarbonate if acidotic
 Definitive removal, often dialysis
Scenario 8 — Rhabdomyolysis
A patient after crush injury has:

 CK very high
 Potassium 6.8
 Dark urine
 AKI

Mechanism

Cellular potassium release + impaired renal excretion.

Emergency management

 Cardiac stabilisation if ECG abnormalities

 Intracellular shifting
 Aggressive management of rhabdomyolysis
 Dialysis if refractory or renal failure is severe

Scenario 9 — Type 4 RTA

A patient with diabetes and CKD has:

 Potassium 5.7
 Bicarbonate 17
 Normal anion gap

Diagnosis

Hypoaldosteronism/type 4 RTA.
Management principle

 Stop contributing drugs

 Restrict potassium
 Use diuretics when appropriate
 Treat aldosterone deficiency when confirmed
 Correct acidosis where indicated

First Aid describes this exact association.

PART 86 — BEST TEST / GOLD
STANDARD / DEFINITIVE TREATMENT
SUMMARY
Suspected hypokalemia
Most important immediate test in significant disease

ECG.
Best way to distinguish renal from extrarenal loss

Urinary potassium assessment.

Best treatment for stable mild/moderate hypokalemia

Oral potassium chloride.

Best treatment for severe symptomatic hypokalemia or ECG changes

Controlled IV potassium with cardiac

monitoring.
Essential co-treatment in refractory hypokalemia

Magnesium replacement.

Suspected hyperkalemia
First step when an unexpected result may be false

Repeat non-hemolysed potassium.

Most important immediate investigation
ECG.
Best treatment for hyperkalemic ECG changes

IV calcium for myocardial stabilisation.

Best rapid potassium-shifting treatment

Insulin with glucose.

Best definitive potassium-removal treatment in anuric renal failure

Hemodialysis.
Best long-term treatment

Treat the underlying cause and remove

contributing medications.

PART 87 — SMLE EXAM TRAPS

Trap 1
Serum potassium always reflects total-body potassium.

Incorrect.

Redistribution can produce:

 High serum potassium with body depletion

 Low serum potassium without major body loss

Trap 2
A DKA patient with potassium 5.5 has excess total-body potassium.

Incorrect.
Most DKA patients are potassium-depleted despite normal or high initial serum potassium.

Trap 3
Insulin removes potassium from the body.

Incorrect.

Insulin shifts potassium into cells temporarily.

Trap 4
IV calcium lowers serum potassium.

Incorrect.

Calcium stabilises the cardiac membrane.

Trap 5
A normal ECG excludes dangerous hyperkalemia.

Incorrect.

ECG sensitivity is imperfect.

Trap 6
Every elevated potassium result requires emergency treatment.

Incorrect.

First exclude pseudohyperkalemia when clinically appropriate.

But do not delay treatment in an unstable patient.

Trap 7
Potassium should be corrected without checking magnesium.

Incorrect.

Hypomagnesemia may cause refractory renal potassium wasting.

Trap 8
Vomiting causes hypokalemia only because potassium is lost in vomit.

Incomplete.

Volume depletion, aldosterone activation and alkalosis are major mechanisms.

Trap 9
Diarrhea and vomiting produce the same acid–base abnormality.

Incorrect.

 Diarrhea → metabolic acidosis

 Vomiting → metabolic alkalosis

Trap 10
Peaked T waves are the final ECG stage of hyperkalemia.

Incorrect.

They are generally early.

Late findings include:

 Loss of P waves
 Wide QRS
 Sine wave
 Cardiac arrest

Trap 11
Potassium binders alone are sufficient for unstable severe hyperkalemia.

Incorrect.

Emergency instability requires:

 Calcium
 Rapid shifting
 Definitive removal

Trap 12
Oral potassium is inferior to IV replacement.

Incorrect.

Oral replacement is preferred whenever the patient is stable and can absorb it.

PART 88 — MEMORY MAPS

POTASSIUM CONTROL: I-K-A
I — Insulin moves K into cells

K — Kidneys remove K

A — Aldosterone increases K excretion

HYPOKALEMIA CAUSES: SHIFT–GUT–

KIDNEY
SHIFT

 Insulin
 β₂-agonists
 Alkalosis

GUT
  Diarrhea
 Vomiting
 Laxatives

KIDNEY

 Diuretics
 Aldosterone
 RTA
 Low magnesium

HYPOKALEMIA ECG: F-S-U

F — Flat T wave

S — ST depression

U — U wave

HYPERKALEMIA CAUSES: SHIFT–

SPILL–STOP
SHIFT

Potassium moves out of cells.

SPILL

Damaged cells release potassium.

STOP

Kidneys stop excreting potassium.

HYPERKALEMIA ECG: T-P-Q-S

T — Tall T waves

P — PR prolongation/P loss
Q — QRS widening

S — Sine wave

HYPERKALEMIA TREATMENT: C-S-R

C — Calcium protects the heart

S — Shift potassium into cells

R — Remove potassium from body

PART 89 — FINAL MASTER

FLOWCHART
PATIENT HAS ABNORMAL POTASSIUM
↓

Confirm result where appropriate.

↓

Obtain ECG.
↓

Decide whether it is low or high.

IF HYPOKALEMIA
Ask:

Shift into cells?

  Insulin
 β₂-agonist
 Alkalosis
 Periodic paralysis

GI loss?
 Diarrhea
 Vomiting
 Laxatives

Renal loss?
 Diuretics
 Hyperaldosteronism
 RTA
 Hypomagnesemia

Check:

 Magnesium
 Acid–base status
 Urinary potassium
 Blood pressure

Treat:

 Oral potassium when stable

 IV potassium for severe symptoms/ECG changes
 Replace magnesium
 Correct the cause

IF HYPERKALEMIA
Ask:

False result?
 Hemolysis
 Thrombocytosis
 Leukocytosis
Shift out of cells?
 Acidosis
 Insulin deficiency
 β-blockade
 Hyperosmolality

Cell destruction?
 Rhabdomyolysis
 Tumor lysis
 Crush injury

Reduced renal excretion?

 AKI
 CKD
 Hypoaldosteronism
 ACE inhibitor/ARB
 Potassium-sparing drug

If severe or ECG changes:

Calcium
↓

Insulin + glucose ± albuterol

↓

Bicarbonate if acidotic
↓

Remove potassium through urine, stool or

dialysis
↓
Treat cause and repeat
potassium/ECG/glucose.

FINAL MASTER CONCEPT

Potassium disorders are not primarily laboratory-number diseases.

They are disorders of:

Cellular electrical stability.

When potassium is too low:

Cells become excessively negative and difficult to activate.

The patient develops:

 Weakness
 Ileus
 U waves
 Ventricular arrhythmias

When potassium is too high:

Cells remain partly depolarised.

Sodium channels become inactivated.

Conduction slows.

The patient develops:

  Weakness
 Peaked T waves
 QRS widening
 Sine wave
 Cardiac arrest

The SMLE approach is:

Confirm the value

↓

Examine the ECG

↓

Decide whether the problem is

redistribution, true loss/gain or renal
failure
↓

Correct immediate electrical danger

↓

Replace or remove potassium

↓

Treat the underlying cause

↓

Always check magnesium in hypokalemia

and renal function in hyperkalemia.
MEDICINE → NEPHROLOGY
HYPO- AND HYPERNATREMIA
SMLE 2026 — Mastery Level 3
Complete Conceptual, Interlinked, Scenario-Based Notes

This is the second Nephrology topic in the SMLE blueprint, after potassium disorders. The
blueprint expects understanding of fluid and electrolyte homeostasis, clinical presentation,
causes, pathophysiology, laboratory interpretation, imaging where relevant, management, and
complications.

SOURCE LABEL
Reference-book-based
Approach to Internal Medicine, Fifth Edition

Used for:

 Sodium and water physiology

 Volume-status classification
 SIADH diagnostic criteria
 Sodium-correction calculations
 Safe correction limits
 Hypovolemic, euvolemic and hypervolemic treatment
 Hypertonic saline
 Vaptans
 Loop-diuretic use in hyponatremia

First Aid Clinical Algorithms for the USMLE Step 2 CK 2024

Used for:

 Serum-osmolality-first algorithm
 Urine osmolality and urine sodium interpretation
 Primary polydipsia
 Low-solute intake
 SIADH
 Hypovolemic and hypervolemic patterns
 Hypernatremia algorithm
 Central and nephrogenic diabetes insipidus
 DDAVP response
 Osmotic diuresis
 Free-water deficit
 Clinical scenarios and treatment pathways
Any additional physiology included solely to make these algorithms understandable is
labelled:

Extra Concept for Concept Building

THE MASTER CONCEPT

SERUM SODIUM IS MAINLY A
MEASUREMENT OF WATER BALANCE
This is the single most important concept.

A sodium result does not directly tell you how much sodium exists in the whole body.

It tells you:

How concentrated sodium is relative to

body water.
Think of salty water:

 Same amount of salt + more water → lower salt concentration

 Same amount of salt + less water → higher salt concentration

Therefore:

Hyponatremia usually means too much

water relative to sodium.
Hypernatremia usually means too little
water relative to sodium.
This is why:

 A patient with heart failure can be edematous and hyponatremic even though total-
body sodium is increased.
 A patient with diarrhea can be dehydrated and hyponatremic because sodium loss is
greater than water loss.
  A patient with diabetes insipidus becomes hypernatremic because large amounts of
water are lost.

NORMAL WATER AND SODIUM

PHYSIOLOGY
Where is sodium located?
Sodium is the major cation of the:

Extracellular fluid
It is concentrated mainly in:

 Blood plasma
 Interstitial fluid

Potassium is concentrated mainly inside cells.

Because sodium and its associated anions dominate extracellular osmolality, changes in
serum sodium strongly influence movement of water across cell membranes.

Extra Concept for Concept Building

OSMOLALITY VERSUS TONICITY
These terms are closely related but not identical.

Osmolality
The total number of dissolved particles per kilogram of water.

Main contributors in blood include:

 Sodium and associated anions

 Glucose
 Urea

A commonly used calculated serum osmolality is:

2(Na)+glucose18+BUN2.82(\text{Na})+\frac{\text{glucose}}{18}+\frac{\text{BUN}}{2.8}
2(Na)+18glucose+2.8BUN

when glucose and BUN are measured in mg/dL.

Tonicity
The effect of extracellular solutes on water movement across cell membranes.

An effective osmole remains extracellular and pulls water toward it.

Important effective osmoles include:

 Sodium
 Glucose when markedly elevated
 Mannitol

Urea contributes to measured osmolality but crosses cell membranes relatively freely, so it
has less sustained effect on water distribution.

For SMLE reasoning:

Sodium disorders become dangerous

because they change tonicity and therefore
brain-cell volume.

WHY THE BRAIN IS THE MAIN

ORGAN AFFECTED
The skull is rigid.

The brain cannot freely expand or contract without consequences.

When sodium falls

Extracellular fluid becomes hypotonic.

Water enters brain cells.

↓
Brain swelling develops.

Intracranial pressure may rise.

Therefore acute severe hyponatremia causes:

 Headache
 Vomiting
 Confusion
 Seizures
 Coma
 Respiratory arrest
 Herniation

When sodium rises

Extracellular fluid becomes hypertonic.

Water leaves brain cells.

Brain cells shrink.

Cerebral vessels may stretch or rupture.

Therefore acute severe hypernatremia can cause:

 Irritability
 Hyperreflexia
 Confusion
 Seizures
 Coma
 Intracranial hemorrhage

WHY THE SPEED OF CHANGE

MATTERS
A sodium of 120 mmol/L developing over four hours is usually more dangerous than a
sodium of 116 mmol/L developing slowly over several weeks.

Why?

Because the brain adapts.

Extra Concept for Concept Building

BRAIN ADAPTATION IN CHRONIC
HYPONATREMIA
Initially:

Low extracellular sodium

Water enters brain cells.

Brain swelling begins.

To defend itself, the brain removes intracellular osmoles:

 Sodium
 Potassium
 Organic osmolytes

Intracellular osmolality decreases.

Water moves back out.

Brain volume approaches normal.

This adaptation reduces symptoms, but creates a treatment danger.

If sodium is then corrected too rapidly:

Extracellular osmolality rises suddenly.

Water leaves already osmole-depleted brain cells.

Cells shrink and oligodendrocytes are injured.

Osmotic demyelination syndrome

Therefore chronic hyponatremia must be corrected cautiously.

Extra Concept for Concept Building

BRAIN ADAPTATION IN CHRONIC
HYPERNATREMIA
Initially:

High extracellular sodium

Water leaves brain cells.

Cells shrink.

The brain then accumulates intracellular osmoles.

Water re-enters cells.

Brain volume improves.

If chronic hypernatremia is corrected too rapidly:

Extracellular osmolality falls suddenly.

Water rushes into osmole-rich brain cells.

Cerebral edema develops.

Memory:

Chronic low sodium corrected too fast →

demyelination.
Chronic high sodium corrected too fast →
cerebral edema.

NORMAL REGULATION OF WATER

Water balance depends mainly on:

1. Thirst
2. Antidiuretic hormone
3. Renal ability to concentrate and dilute
urine

ANTIDIURETIC HORMONE
ADH is produced in the hypothalamus and released from the posterior pituitary.

The major physiological stimuli are:

  Increased serum osmolality
 Decreased effective circulating volume
 Hypotension
 Nausea
 Pain
 Stress

ADH binds V2 receptors in the collecting duct.

Aquaporin-2 channels are inserted.

Water is reabsorbed.

Urine becomes concentrated.

Serum water increases.

Therefore:

More ADH effect = less urine, concentrated

urine, water retention.
Less ADH effect = more urine, dilute urine,
water loss.
This allows immediate understanding of:

 SIADH
 Hypovolemic hyponatremia
 Heart-failure hyponatremia
 Central diabetes insipidus
 Nephrogenic diabetes insipidus

THE PRIORITY RULE

The body prioritises:

Circulation over sodium concentration.

Suppose a patient loses a large amount of blood or gastrointestinal fluid.

Their serum may already be hypotonic, but low circulating volume stimulates strong ADH
release.

Why?

Because maintaining blood pressure and organ perfusion is more urgent than maintaining
normal osmolality.

Therefore:

ADH can remain high in a hyponatremic

patient if effective circulating volume is low.
This is why patients with:

 Vomiting
 Diarrhea
 Heart failure
 Cirrhosis

can have concentrated urine despite low serum sodium.

SECTION I — HYPONATREMIA
DEFINITION
Serum sodium below 135 mmol/L
Practical classification:

 Mild: 130–134 mmol/L

 Moderate: 125–129 mmol/L
 Profound: below 125 mmol/L

However, the sodium number alone does not determine danger.

Always consider:

 Duration
 Speed of fall
 Symptoms
 Neurological disease
 Hypoxia
 Alcohol use
 Malnutrition
 Hypokalemia
 Liver disease

WHAT ACTUALLY CAUSES

HYPONATREMIA?
In almost every clinically significant case:

Water intake or retention exceeds the

kidney’s capacity to excrete water.
Hyponatremia requires two processes:

Process 1: Water enters the body

Through:

 Drinking
 IV fluids
 Enteral feeding
 Metabolic water

Process 2: The kidneys fail to remove enough water

Because of:

 ADH activity
 Low GFR
 Very low dietary solute
 Excessive water intake overwhelming renal capacity

Therefore hyponatremia is usually not created by sodium loss alone.

Sodium loss stimulates ADH and water intake, which then produces the low sodium
concentration.

CLINICAL PRESENTATION
The presentation is mainly neurological.

Mild or chronic hyponatremia

The patient may have:

 Fatigue
 Poor attention
 Mild headache
 Nausea
 Unsteadiness
 Falls
 Mild confusion
 Cognitive slowing

Older patients may present with recurrent falls rather than dramatic seizures.

Moderate hyponatremia
 Vomiting
 Marked headache
 Disorientation
 Lethargy
 Behavioural change
 Muscle cramps

Severe or rapidly developing hyponatremia

 Seizures
 Obtundation
 Coma
 Respiratory arrest
 Non-cardiogenic pulmonary edema in extreme acute cases
 Brain herniation

WHY NAUSEA AND VOMITING OCCUR

Brain-cell swelling affects central nervous system pathways involved in:

 Nausea
 Vomiting
 Consciousness
 Vestibular stability

Nausea also stimulates ADH.

Therefore a vicious cycle can develop:

Hyponatremia

Nausea

More ADH release

More water retention

Worsening hyponatremia

THE COMPLETE DIAGNOSTIC

APPROACH
Do not start by saying:

“The patient is euvolemic, so this must be SIADH.”

The correct sequence is:

STEP 1 — Is the patient neurologically

unstable?
Look for:

 Seizure
  Coma
 Severe confusion
 Respiratory compromise
 Signs of cerebral edema

If yes:

Treat severe symptomatic hyponatremia

immediately while investigating.

STEP 2 — CONFIRM THAT THE

SODIUM RESULT IS REAL
Repeat sodium if:

 The result is unexpected

 Sample error is possible
 There is a major discrepancy with the clinical picture

Then measure:

Serum osmolality
This divides hyponatremia into:

1. Hypotonic
2. Isotonic
3. Hypertonic

HYPOTONIC HYPONATREMIA
This is the true water-excess state and the most important clinical group.

Serum osmolality is low.

Now ask:

Is ADH absent or active?

To answer this, measure:

Urine osmolality

ISOTONIC HYPONATREMIA
This is usually:

Pseudohyponatremia
Seen with very high concentrations of:

 Triglycerides
 Paraproteins

The sodium concentration in plasma water is normal, but some indirect laboratory methods
report a falsely low sodium because the plasma-water fraction is reduced.

Features:

 Sodium low
 Serum osmolality normal
 No true hypotonicity
 No brain swelling from the sodium result

Possible scenarios:

 Severe hypertriglyceridemia
 Multiple myeloma with marked paraproteinemia

Management:

Do not treat the sodium with hypertonic

saline.
Treat the underlying lipid or protein disorder if clinically necessary.

The Approach framework specifically requires exclusion of pseudohyponatremia before

proceeding with hypotonic-hyponatremia evaluation.
HYPERTONIC HYPONATREMIA
An effective osmole other than sodium pulls water out of cells.

The extracellular compartment gains water.

Sodium becomes diluted.

Common causes:

 Severe hyperglycemia
 Mannitol
 Other retained effective osmoles

Hyperglycemia mechanism
Glucose accumulates extracellularly.

Water leaves cells.

Extracellular volume increases.

Measured sodium falls.

This patient has low sodium but high tonicity.

Therefore:

It is not treated like ordinary hypotonic

hyponatremia.
Treat:

 Hyperglycemia
 Dehydration
 The underlying diabetic emergency

As glucose decreases:
↓

Water returns to cells.

Measured sodium rises.

First Aid explains that glucose or mannitol can create hypertonic hyponatremia through
extracellular osmotic water movement.

CORRECTED SODIUM IN
HYPERGLYCEMIA
First Aid uses an approximate correction of:

Add about 2 mmol/L to sodium for every

100 mg/dL increase in glucose above 100
mg/dL.
Example:

Measured sodium = 126 mmol/L

Glucose = 500 mg/dL

Glucose is 400 above 100.

Approximate sodium correction:

4×2=84 \times 2 = 84×2=8

Corrected sodium:

126+8=134126+8=134126+8=134

Therefore the patient may not have significant true hypotonic hyponatremia.

TRUE HYPOTONIC HYPONATREMIA

Once low serum osmolality is confirmed, measure:
Urine osmolality
This answers:

Is the kidney appropriately excreting dilute water?

URINE OSMOLALITY BELOW 100

mOsm/kg
This means:

ADH is largely suppressed.

The kidney is producing maximally dilute urine.

The renal response is appropriate.

Why is sodium still low?

Because:

 Water intake is extremely high

or
 Dietary solute is extremely low, limiting water excretion

Think mainly:

 Primary polydipsia
 Beer potomania
 Tea-and-toast diet

First Aid places primary polydipsia and low dietary solute in the urine-osmolality-below-100
branch.

URINE OSMOLALITY ABOVE 100

mOsm/kg
This means:
ADH is active.
Now determine whether ADH activity is:

 Appropriate because effective circulating volume is low

or
 Inappropriate, as in SIADH

Use:

 Clinical volume status

 Urine sodium
 Medication history
 Endocrine testing
 Renal function

WHY URINE SODIUM IS IMPORTANT

Urine sodium helps answer:

Is the kidney trying to retain sodium because circulating volume is low?

Urine sodium below approximately 20–30 mmol/L

The kidney is avidly conserving sodium.

This suggests active RAAS.

Think:

 Vomiting
 Diarrhea
 Hemorrhage
 Third spacing
 Heart failure
 Cirrhosis

Urine sodium above approximately 30 mmol/L

The kidney is not avidly conserving sodium or is losing sodium.

Think:

 SIADH
 Diuretic use
  Adrenal insufficiency
 Renal salt wasting
 Kidney disease

Important:

Diuretics can make urine sodium difficult to interpret.

VOLUME-STATUS CLASSIFICATION
True hypotonic hyponatremia is classified into:

1. Hypovolemic
2. Euvolemic
3. Hypervolemic
The Approach source emphasises that volume status narrows the differential diagnosis and
guides treatment.

HYPOVOLEMIC HYPONATREMIA
Core concept
Both sodium and water have been lost.

But:

Sodium loss is proportionally greater than

water loss.
The reduced volume stimulates:

 Renin
 Aldosterone
 ADH
 Thirst
The patient then retains or drinks water.

Water dilutes the remaining sodium.

Hyponatremia develops.

Therefore:

 Total-body sodium is low

 Total-body water is low
 Serum sodium is low

PRESENTATION OF HYPOVOLEMIA
Symptoms and signs may include:

 Thirst
 Orthostatic dizziness
 Tachycardia
 Postural hypotension
 Dry mucous membranes
 Reduced skin turgor
 Low JVP
 Weight loss
 Oliguria
 Delayed capillary refill

Severe disease may cause:

 Shock
 Prerenal AKI
 Lactic acidosis
 Confusion

CAUSES OF HYPOVOLEMIC
HYPONATREMIA
Extrarenal sodium loss
  Vomiting
 Diarrhea
 Burns
 Sweating
 Pancreatitis
 Bowel obstruction
 Third-space loss

The kidney responds appropriately by retaining sodium.

Therefore urine sodium is usually low.

Renal sodium loss

 Thiazide diuretics
 Adrenal insufficiency
 Cerebral salt wasting
 Salt-wasting nephropathy
 Osmotic diuresis
 Tubular disease

The kidney continues losing sodium.

Therefore urine sodium is often high.

CLASSIC SCENARIO: VOMITING AND

DIARRHEA
A 30-year-old develops several days of vomiting and diarrhea.

Examination:

 Dry mouth
 Reduced skin turgor
 Orthostatic hypotension

Investigations:

 Sodium 126 mmol/L

 Serum osmolality low
 Urine osmolality above 100
 Urine sodium below 30

Interpretation:
Volume loss

ADH activation

Concentrated urine

Kidneys retain sodium appropriately

Low urine sodium

Diagnosis:

Hypovolemic hypotonic hyponatremia due

to extrarenal losses.
First Aid uses this exact pattern and recommends isotonic IV fluids plus treatment of the
losses.

BEST TREATMENT OF HYPOVOLEMIC

HYPONATREMIA
Isotonic saline
Why?

Isotonic saline restores circulating volume.

Baroreceptor-driven ADH release stops.

The kidney starts excreting dilute water.

↓
Serum sodium rises naturally.

This treats the mechanism rather than merely giving sodium.

Also:

 Stop diuretics when appropriate

 Treat vomiting
 Treat diarrhea
 Replace corticosteroids in adrenal insufficiency
 Treat bleeding or third spacing
 Monitor urine output and sodium frequently

The Approach source recommends normal saline for hypovolemic hyponatremia.

WHY SODIUM MAY RISE RAPIDLY

AFTER SALINE
Before treatment:

Volume depletion

High ADH

Concentrated urine

After volume restoration:

ADH falls rapidly.

The patient suddenly produces large volumes of dilute urine.

Free water is lost.

Sodium rises quickly.

Therefore even normal saline can cause overcorrection once the cause of ADH release
disappears.

THIAZIDE-INDUCED HYPONATREMIA
Thiazides reduce sodium reabsorption in the distal diluting segment.

Therefore the kidney loses some ability to produce dilute urine.

At the same time:

 Sodium is lost
 Mild hypovolemia stimulates ADH
 Older patients may drink large amounts of water
 Reduced body mass increases susceptibility

Classic scenario:

An older woman recently started hydrochlorothiazide.

She develops:

 Nausea
 Confusion
 Sodium 117 mmol/L

Management:

 Stop thiazide
 Assess symptoms immediately
 Hypertonic saline if severe neurological symptoms
 Restore volume carefully when hypovolemic
 Monitor closely because stopping the thiazide may lead to brisk water diuresis and
rapid correction

ADRENAL INSUFFICIENCY
Adrenal insufficiency must be excluded before diagnosing SIADH.

Why cortisol deficiency causes hyponatremia

Cortisol normally suppresses ADH.
Low cortisol:

ADH increases.

Water is retained.

Sodium is diluted.

Primary adrenal insufficiency

Aldosterone is also deficient.

Therefore:

 Sodium loss
 Volume depletion
 Hyperkalemia
 Hypotension
 Hyponatremia

may occur together.

Clinical clues:

 Weight loss
 Weakness
 Hyperpigmentation
 Abdominal pain
 Vomiting
 Hypotension
 Hyperkalemia

Investigations:

 Morning cortisol
 ACTH
 ACTH stimulation testing where appropriate

Treatment:

Glucocorticoid replacement
and, in primary disease:

Mineralocorticoid replacement

EUVOLEMIC HYPONATREMIA
What does euvolemic mean?
The patient usually has a small increase in total-body water.

However, the increase is not large enough to cause:

 Peripheral edema
 Ascites
 Pulmonary edema

Therefore the patient appears clinically euvolemic.

Main causes:

 SIADH
 Primary polydipsia
 Low-solute intake
 Adrenal insufficiency
 Severe hypothyroidism
 Diuretic effect

SIADH
SYNDROME OF INAPPROPRIATE
ANTIDIURETIC HORMONE ACTIVITY
The problem is not necessarily that ADH concentration is always massively elevated.

The problem is:

ADH effect continues when serum
osmolality is already low and there is no
appropriate circulatory stimulus.
ADH remains active.

Collecting ducts retain water.

Serum sodium is diluted.

Extracellular volume expands slightly.

The body responds to this mild expansion by:

 Suppressing renin
 Suppressing aldosterone
 Increasing natriuretic mechanisms

Sodium is excreted in urine.

Therefore the patient does not usually become visibly edematous.

SIADH LABORATORY PATTERN

 Hyponatremia
 Low serum osmolality
 Urine osmolality above 100 mOsm/kg, often substantially higher
 Urine sodium above approximately 30 mmol/L
 Clinical euvolemia
 Low serum uric acid may support the diagnosis
 Normal renal function sufficient to excrete water
 No adrenal insufficiency
 No major hypothyroidism
 No better diuretic explanation
The Approach source describes SIADH using clinical euvolemia, increased urine osmolality,
urine sodium above 30 mmol/L, low uric acid, and exclusion of thyroid, adrenal, diuretic and
polydipsia causes.

SIADH is a diagnosis of exclusion.

WHY URINE IS CONCENTRATED IN

SIADH
The blood is already dilute.

A normal kidney should suppress ADH and produce very dilute urine.

Instead:

ADH remains active.

Water is reabsorbed.

Urine remains concentrated.

Therefore:

Low serum osmolality + concentrated urine

is the central physiological abnormality.

WHY URINE SODIUM IS HIGH IN

SIADH
Mild water retention slightly expands extracellular volume.

RAAS is suppressed.
↓

The kidneys excrete sodium.

Therefore:

SIADH does not usually have a low urine

sodium.

CAUSES OF SIADH
Use:

C-P-D-M
C — CNS disorders
 Stroke
 Intracranial hemorrhage
 Meningitis
 Encephalitis
 Trauma
 Tumor
 Neurosurgery

P — Pulmonary disorders
 Pneumonia
 Tuberculosis
 Positive-pressure ventilation
 Acute respiratory disease
 Lung malignancy

D — Drugs
 SSRIs
 Carbamazepine
 Oxcarbazepine
 Antipsychotics
 Cyclophosphamide
 Some analgesics
 Other centrally acting drugs
M — Malignancy
Classic:

Small-cell lung carcinoma

which can produce ectopic ADH.

CLASSIC SIADH SCENARIO

A smoker has:

 Weight loss
 Cough
 Confusion

Laboratory results:

 Sodium 118 mmol/L

 Low serum osmolality
 Urine osmolality 480 mOsm/kg
 Urine sodium 55 mmol/L

Examination:

 No edema
 No dehydration

Thyroid, adrenal and kidney function are adequate.

Diagnosis:

SIADH, possibly from small-cell lung

cancer.

WHY NORMAL SALINE MAY FAIL OR

WORSEN SIADH
This is a high-yield concept.
Suppose concentrated urine contains more osmotically active solute than the infused normal
saline.

The kidney may excrete the sodium load in concentrated urine while retaining part of the
infused water.

Net effect:

 Sodium is lost in urine

 Water remains
 Serum sodium fails to rise or may fall

First Aid notes that a fall in serum sodium after isotonic fluids can support SIADH.

Therefore routine normal saline is not the standard chronic treatment for stable SIADH.

TREATMENT OF SIADH
First priority

Treat the cause.

Examples:

 Stop causative drug

 Treat pneumonia
 Treat CNS infection
 Treat malignancy

Stable chronic or mildly symptomatic SIADH

Fluid restriction
Commonly below approximately 1 L/day, adjusted to the patient.

The Approach source recommends free-water restriction below approximately 1 L/day for
euvolemic hyponatremia.

Increase solute excretion capacity

Selected approaches:

 Salt tablets
  Oral urea
 Increased dietary protein/solute

Loop diuretic
May reduce the renal medullary concentration gradient.

Urine becomes more dilute.

It may be used with sodium replacement in selected cases.

Vaptans
V2-receptor antagonists block ADH action.

Free-water excretion increases.

They may be considered in selected euvolemic or hypervolemic cases.

However:

 Require close monitoring

 Can cause rapid correction
 Are generally avoided in acute severe hyponatremia

The Approach source describes vaptans as aquaretics for selected euvolemic or hypervolemic
cases but warns of overcorrection.

Severe neurological symptoms

3% hypertonic saline

PRIMARY POLYDIPSIA
The patient drinks more water than the kidneys can excrete.

Usually a normal kidney can excrete a large amount of free water.

But extremely high intake can overwhelm this capacity.

ADH is appropriately suppressed.

Therefore:

Urine osmolality is below 100 mOsm/kg.

Clinical settings:

 Schizophrenia
 Compulsive water drinking
 Behavioural excess
 Excessive health-related water consumption

Scenario:

A psychiatric patient drinks more than 10 L daily.

Findings:

 Moist mucous membranes

 Normal skin turgor
 Sodium 121 mmol/L
 Low serum osmolality
 Urine osmolality 60 mOsm/kg

Diagnosis:

Primary polydipsia.
Treatment:

 Restrict water
 Treat behavioural or psychiatric cause
 Monitor closely for rapid spontaneous correction

First Aid describes primary polydipsia with urine osmolality below 100, water restriction and
psychiatric evaluation.

LOW-SOLUTE INTAKE
The kidney needs solute to excrete water.

Daily urinary solute includes:

 Urea from protein

  Sodium
 Potassium

The amount of water the kidney can excrete depends partly on:

Daily solute excretionMinimum urine osmolality\frac{\text{Daily solute

excretion}}{\text{Minimum urine
osmolality}}Minimum urine osmolalityDaily solute excretion

If very little protein and salt are consumed:

Very little solute is available for urine.

Even maximally dilute urine cannot carry away enough water.

Hyponatremia develops.

Beer potomania
Beer contains:

 Large amounts of water

 Very little protein
 Very little sodium

A chronic heavy beer drinker may therefore have:

 High water intake

 Low solute intake
 Hyponatremia

Tea-and-toast diet
An older adult consumes mostly:

 Tea
 Bread
 Minimal protein
 Minimal salt

Again:

Low solute
↓

Poor water-excretion capacity

Hyponatremia

First Aid identifies beer potomania and tea-and-toast diet as the classic low-solute
presentations.

WHY LOW-SOLUTE HYPONATREMIA

CAN OVERCORRECT RAPIDLY
Once protein, salt or saline is supplied:

Urinary solute rises.

The kidney can suddenly excrete a large volume of free water.

Sodium may rise extremely rapidly.

Therefore:

 Restore nutrition carefully

 Monitor sodium frequently
 Monitor urine output
 Be prepared to prevent or reverse overcorrection

HYPOTHYROIDISM
Severe hypothyroidism can impair:

 Cardiac output
 Renal blood flow
 Free-water clearance
It may also increase ADH activity.

Therefore hyponatremia may occur, particularly in severe disease such as myxedema.

However:

Mild thyroid abnormalities should not

automatically be blamed for profound
hyponatremia.
Treatment:

Thyroid-hormone replacement
while managing the sodium safely.

HYPERVOLEMIC HYPONATREMIA
In these patients:

 Total-body sodium is increased

 Total-body water is also increased
 Water gain exceeds sodium gain

Therefore the patient is:

Edematous but hyponatremic.

Main causes:

 Heart failure
 Cirrhosis
 Advanced kidney failure
 Nephrotic syndrome

THE CONCEPT OF EFFECTIVE

ARTERIAL CIRCULATING VOLUME
A patient can have excessive total-body fluid but inadequate effective perfusion of the arterial
circulation.

Heart failure
Cardiac output falls.

Kidneys sense reduced perfusion.

RAAS and ADH activate.

Sodium and water are retained.

Because ADH strongly retains water:

Water gain exceeds sodium gain.

Hyponatremia develops.

Meanwhile:

 Edema increases
 Pulmonary congestion worsens

Cirrhosis
Splanchnic vasodilation and portal hypertension reduce effective arterial filling.

RAAS and ADH activate.

Water retention produces dilutional hyponatremia.

Therefore heart failure and cirrhosis are:

High total-body fluid states with low
effective arterial volume.
First Aid explicitly describes heart failure and cirrhosis as states of intravascular underfilling
with increased total-body water.

PRESENTATION OF HYPERVOLEMIC
HYPONATREMIA
Possible findings:

 Peripheral edema
 Raised JVP in heart failure
 Pulmonary crackles
 Orthopnea
 Ascites
 Pleural effusions
 Weight gain
 Oliguria

Urine is usually concentrated because ADH is active.

Urine sodium may be low in:

 Heart failure
 Cirrhosis

because RAAS is active.

It may be higher with:

 Diuretics
 Advanced renal failure

TREATMENT OF HYPERVOLEMIC
HYPONATREMIA
Core principle:
Remove excess water and treat the
underlying disease.
Management may include:

 Fluid restriction
 Sodium restriction
 Loop diuretics
 Optimisation of heart-failure treatment
 Management of cirrhosis
 Dialysis in advanced kidney failure
 Selected vaptan use under specialist monitoring

The Approach source recommends sodium and free-water restriction with treatment of the
underlying cause.

Do not routinely give large volumes of normal saline to an edematous patient.

It can worsen:

 Edema
 Pulmonary congestion
 Ascites

SEVERE SYMPTOMATIC
HYPONATREMIA
This is an emergency.

Examples of severe symptoms:

 Seizure
 Coma
 Severe obtundation
 Respiratory compromise
 Signs of impending herniation

The problem is acute cerebral edema.

The immediate treatment is:

3% HYPERTONIC SALINE
The Approach source identifies seizures as a clear indication for hypertonic saline.

WHY HYPERTONIC SALINE WORKS

3% saline has a very high sodium concentration.

It increases extracellular tonicity.

Water leaves swollen brain cells.

Brain edema decreases.

Seizures and severe neurological symptoms improve.

The goal is not to normalise sodium immediately.

The goal is:

A small controlled increase sufficient to

reverse life-threatening cerebral edema.

INITIAL CORRECTION GOAL

An initial increase of approximately:

4–6 mmol/L
is often enough to improve severe symptoms.

After neurological improvement:

 Stop aggressive correction

 Reassess
 Continue slowly
The Approach source allows a faster initial correction rate for several hours in severe
symptomatic disease while limiting the total daily increase in chronic cases.

SAFE CORRECTION LIMIT

For chronic hyponatremia:

Do not increase serum sodium by more

than approximately 8 mmol/L in 24 hours.
The Approach source specifically gives a daily limit of 8 mmol/L to reduce osmotic
demyelination risk.

In very high-risk patients, clinicians may target an even smaller correction.

High-risk features include:

 Very low starting sodium

 Alcohol use disorder
 Malnutrition
 Advanced liver disease
 Hypokalemia
 Prolonged hyponatremia

WHY POTASSIUM REPLACEMENT

CAN INCREASE SODIUM
Extra Concept for Concept Building
Potassium is also an effective body cation.

When potassium is replaced:

Potassium enters cells.

Water and sodium distribution changes.

↓

Serum sodium may rise.

Therefore a patient with:

 Severe hyponatremia
 Severe hypokalemia

may correct faster than expected when potassium is replaced.

Potassium replacement must be included in the overall correction plan.

OSMOTIC DEMYELINATION
SYNDROME
Rapid correction of chronic hyponatremia:

Water leaves adapted brain cells.

Oligodendrocytes are damaged.

Demyelination develops.

Classically the pons is affected, but extrapontine regions may also be involved.

Clinical course:

The patient may initially improve.

Then after one or several days develops:

 Dysarthria
 Dysphagia
 Quadriparesis
 Behavioural disturbance
 Movement disorders
 Locked-in syndrome
 Coma
Prevention is far more effective than treatment.

WHAT TO DO IF SODIUM IS
OVERCORRECTING
Warning signs:

 Rapid increase in serum sodium

 Sudden high-volume dilute urine
 Correction exceeding planned targets

Specialist-directed management may include:

Desmopressin
to stop excessive water diuresis

and

D5W
to replace water and re-lower sodium.

The aim is to bring the correction back within a safe limit.

COMPLETE HYPONATREMIA
FLOWCHART
Low sodium
↓

Is there seizure, coma or severe neurological compromise?

Yes

 3% hypertonic saline
 Frequent sodium monitoring
  Small initial controlled increase
 Avoid excessive total correction

No

Measure serum osmolality

Normal osmolality
Pseudohyponatremia

 Severe hyperlipidemia
 Paraproteinemia

High osmolality
Translocational hyponatremia

 Hyperglycemia
 Mannitol

Treat the osmotic cause.

Low osmolality
True hypotonic hyponatremia

Measure urine osmolality

Below 100
ADH suppressed

 Primary polydipsia
 Low-solute intake

Above 100
ADH active

↓
Assess volume status and urine sodium
Hypovolemic
 Urine sodium low → extrarenal loss
 Urine sodium high → renal loss

Treatment:

Isotonic saline and correct the cause.

Euvolemic
 SIADH
 Adrenal insufficiency
 Severe hypothyroidism
 Diuretics

Treatment:

Cause-specific; fluid restriction for stable SIADH.

Hypervolemic
 Heart failure
 Cirrhosis
 Renal failure
 Nephrotic syndrome

Treatment:

Fluid restriction, sodium restriction, diuresis and disease-specific therapy.

SECTION II — HYPERNATREMIA
DEFINITION
Serum sodium above 145 mmol/L
Hypernatremia usually means:
Water deficit relative to sodium.
It rarely develops in a healthy alert adult who has:

 Normal thirst
 Normal access to water
 Normal neurological function

Therefore major hypernatremia usually implies:

 Impaired thirst
 Inability to obtain water
 Altered consciousness
 Dependency on caregivers
 Excessive renal or extrarenal water loss

WHO IS AT HIGH RISK?

 Infants
 Frail older adults
 Dementia
 Intubated patients
 Neurological injury
 Patients unable to communicate thirst
 Patients kept NPO
 Diabetes insipidus
 Severe osmotic diuresis
 Fever and burns
 High-output diarrhea
 Inadequate nursing or caregiver water provision

PATHOPHYSIOLOGY
Extracellular sodium rises.

Extracellular tonicity rises.

Water leaves cells.

↓

Cells shrink.

The brain is particularly vulnerable.

Acute brain shrinkage can:

 Stretch cerebral veins

 Cause vascular rupture
 Produce intracranial or subarachnoid bleeding
 Cause neurological dysfunction

CLINICAL PRESENTATION
Early or mild
 Intense thirst
 Dry mouth
 Weakness
 Restlessness
 Irritability

Moderate
 Confusion
 Lethargy
 Hyperreflexia
 Muscle twitching
 Increased tone

Severe or acute
 Seizures
 Coma
 Intracranial hemorrhage
 Death

The volume status determines additional findings.

THREE MECHANISMS OF
HYPERNATREMIA
1. Water loss
2. Reduced water intake
3. Sodium gain
Water loss is the most common.

INITIAL APPROACH TO
HYPERNATREMIA
STEP 1 — Assess circulation
Look for:

 Hypotension
 Tachycardia
 Dry mucosa
 Poor skin turgor
 Oliguria
 Shock

If the patient is hemodynamically unstable:

Restore circulating volume first with

isotonic fluid.
Even though sodium is high.

Why?

Because untreated shock threatens immediate organ perfusion.

After circulation improves:

↓

Replace the free-water deficit.

STEP 2 — Assess urine volume

Is the patient producing:

 Large volumes of urine?

or
 Small concentrated urine volumes?

Polyuria suggests:

 Diabetes insipidus
 Osmotic diuresis

Low urine volume with concentrated urine suggests:

 Extrarenal water loss

 Poor intake

STEP 3 — Measure urine osmolality

This is the major etiological test.

Urine osmolality below approximately 300 mOsm/kg

The urine is inappropriately dilute despite hypernatremia.

Think:

Diabetes insipidus
Urine osmolality approximately 300–600
Think:

 Partial diabetes insipidus

 Osmotic diuresis
 Renal concentrating defect
Urine osmolality above approximately 600
The kidney is appropriately conserving water.

Think:

 Extrarenal loss
 Reduced water intake
 Sodium overload

First Aid uses urine osmolality to distinguish diabetes insipidus, osmotic diuresis and
extrarenal losses.

EXTRARENAL WATER LOSS

Causes:

 Fever
 Sweating
 Burns
 Tachypnea
 Diarrhea
 Vomiting
 Insensible skin and respiratory losses

The kidneys respond appropriately:

ADH rises.

Urine becomes concentrated.

Therefore:

 Urine osmolality usually above 600

 Urine sodium often below 25 when volume depleted

First Aid identifies this pattern and describes extrarenal water loss as the commonest cause of
hypernatremia.
CLASSIC EXTRARENAL-LOSS
SCENARIO
An older patient with dementia develops fever and diarrhea.

Because the patient cannot request water:

 Water intake falls

 Insensible and GI losses continue

Findings:

 Sodium 157 mmol/L

 Dry mucosa
 Tachycardia
 Urine osmolality 750
 Urine sodium 15

Interpretation:

The kidneys are concentrating appropriately.

The cause is:

Extrarenal water loss plus inadequate

replacement.
Management:

 Isotonic resuscitation first if unstable

 Then gradual free-water replacement
 Treat fever and diarrhea
 Replace ongoing losses

DIABETES INSIPIDUS
Diabetes insipidus means:

Excessive loss of dilute urine because ADH

is absent or ineffective.
The patient produces:

 Polyuria
 Polydipsia
 Nocturia
 Dilute urine

If access to water is preserved:

The patient may maintain near-normal sodium by drinking continuously.

If access to water is limited:

Hypernatremia develops rapidly.

CENTRAL DIABETES INSIPIDUS

The hypothalamus or posterior pituitary fails to produce or release enough ADH.

Causes include:

 Traumatic brain injury

 Neurosurgery
 Pituitary or hypothalamic tumor
 Ischemic injury
 Autoimmune disease
 Infiltrative disease
 Idiopathic disease

First Aid specifically associates central DI with pituitary tumors, injury, surgery, autoimmune
disease and ischemia.

CENTRAL DI PRESENTATION
A patient undergoes neurosurgery.

Several hours later:

 Urine output rises markedly

 Urine is very dilute
  Thirst develops
 Sodium rises
 Serum osmolality rises

If unconscious or unable to drink:

Severe hypernatremia may develop.

Laboratory pattern:

 High serum sodium

 High serum osmolality
 Low urine osmolality
 High urine volume

NEPHROGENIC DIABETES INSIPIDUS

ADH is present, but the kidney does not respond appropriately.

Causes:

 Lithium
 Amphotericin
 Demeclocycline
 Hypercalcemia
 Hypokalemia
 Chronic tubulointerstitial disease
 Genetic defects

First Aid lists lithium, amphotericin, demeclocycline, hypercalcemia and hypokalemia as

important causes.

LITHIUM-INDUCED NEPHROGENIC DI
Lithium enters collecting-duct principal cells.

It interferes with ADH signalling and aquaporin function.

↓
The collecting duct cannot reabsorb water effectively.

Polyuria develops.

Scenario:

A patient with bipolar disorder taking lithium develops:

 Constant thirst
 Nocturia
 High-volume urine
 Sodium 160
 High serum osmolality
 Low urine osmolality

ADH is present, but urine remains dilute.

Diagnosis:

Nephrogenic DI.

DISTINGUISHING CENTRAL FROM

NEPHROGENIC DI
The key principle is:

Give desmopressin and observe whether the

kidney concentrates urine.
Central DI
The problem is missing ADH.

Desmopressin replaces the missing hormone.

Urine osmolality rises significantly.

↓
Urine volume falls.

Nephrogenic DI
The kidney cannot respond.

Desmopressin produces little or no meaningful change.

First Aid specifically uses DDAVP response to distinguish central from nephrogenic DI.

WATER-DEPRIVATION TEST
Normal individual or primary polydipsia
Water deprivation increases serum osmolality.

Endogenous ADH rises.

Urine becomes concentrated.

Diabetes insipidus
Urine remains inappropriately dilute despite dehydration.

Then desmopressin is given.

 Concentration rises → central DI

 Minimal response → nephrogenic DI

Important:

Formal water deprivation should be

supervised.
It can be dangerous in a patient who is already severely hypernatremic or dehydrated.
TREATMENT OF CENTRAL DI
Best pharmacological treatment:
Desmopressin
Desmopressin is an ADH analogue.

It increases collecting-duct water reabsorption.

Urine volume falls.

Urine osmolality rises.

Thirst and sodium improve.

Also:

 Replace free water

 Treat the hypothalamic or pituitary cause
 Monitor sodium and urine output

Major treatment complication:

Hyponatremia from excessive desmopressin

plus excessive water intake.

TREATMENT OF NEPHROGENIC DI
Remove the cause
 Stop lithium if possible
 Correct hypercalcemia
 Correct hypokalemia
 Stop other offending medications
Reduce renal solute load
 Low-sodium diet
 Appropriate protein/solute adjustment
 Adequate water intake

Thiazide diuretic
Paradoxically reduces urine output.

Mechanism:

Mild volume contraction

Increased proximal sodium and water reabsorption

Less fluid reaches the collecting duct

Urine volume decreases.

Amiloride
Especially useful in lithium-induced nephrogenic DI.

Amiloride reduces lithium entry into principal cells.

First Aid lists amiloride as first-line for lithium-induced nephrogenic DI and also includes
thiazide and indomethacin.

NSAID in selected cases

Indomethacin reduces prostaglandin-mediated antagonism of ADH and may decrease urine
output.

It must be used cautiously because NSAIDs can damage renal function.

OSMOTIC DIURESIS
In osmotic diuresis, a poorly reabsorbed solute remains inside renal tubules.
The solute holds water in urine.

Urine volume increases.

Examples:

 Glucose
 Mannitol
 Urea

Unlike complete DI, the urine is not extremely dilute because it contains the osmotic solute.

Urine osmolality is often:

Approximately 300–600 mOsm/kg or

higher.
First Aid describes hyperglycemia, mannitol and urea as causes of osmotic diuresis.

HYPERGLYCEMIC OSMOTIC
DIURESIS
Initially, hyperglycemia may cause hypertonic hyponatremia by drawing water out of cells.

If the kidneys can excrete glucose:

Glucose enters urine.

Large amounts of water are lost.

The patient becomes dehydrated.

Sodium may eventually rise.

Therefore severe hyperglycemia can move through:

Initial dilutional low sodium

to

Water-loss-related high sodium.

Treatment:

 Insulin
 Appropriate IV fluids
 Electrolyte monitoring
 Replacement of ongoing water deficit

SODIUM GAIN
Less common causes include:

 Hypertonic saline
 Excess sodium bicarbonate
 Large salt ingestion
 Sea-water ingestion
 Hypertonic feeding

Urine may be concentrated.

Urine sodium is more likely elevated because sodium load is being excreted.

First Aid describes sodium overload after salt ingestion, hypertonic saline or sodium
bicarbonate.

FREE-WATER DEFICIT
The water deficit estimates how much water is required to lower sodium toward a selected
target.

First Aid gives:

Free-water deficit=Total body water×(Measured NaTarget Na−1)\text{Free-water deficit} =

\text{Total body water} \times \left(\frac{\text{Measured Na}}{\text{Target Na}}-
1\right)Free-water deficit=Total body water×(Target NaMeasured Na−1)
Total-body-water estimates:

 Children and adult men: approximately 0.60 × body weight

 Adult women and older men: approximately 0.50 × body weight
 Older women: approximately 0.45 × body weight

FREE-WATER DEFICIT EXAMPLE

A 70-kg adult man has sodium 160 mmol/L.

Estimated total body water:

70×0.6=42 L70 \times 0.6 = 42\,L70×0.6=42L

Using target sodium 140:

42×(160140−1)42 \times \left(\frac{160}{140}-1\right)42×(140160−1) 42×0.1429≈6 L42

\times 0.1429 \approx 6\,L42×0.1429≈6L

Estimated water deficit:

Approximately 6 L
This is only an estimate.

It does not include:

 Ongoing urine loss

 Ongoing diarrhea
 Fever-related losses
 Insensible losses
 Resuscitation fluid needs

MANAGEMENT OF HYPERNATREMIA
The order matters.

STEP 1 — Restore circulation if unstable

If the patient is:

 Hypotensive
  Shocked
 Severely volume depleted

give:

Isotonic saline first.

Why?

Because circulation and organ perfusion must be restored immediately.

After stability:

Switch to free-water replacement.

STEP 2 — REPLACE FREE WATER

Options:

 Oral water
 Enteral water
 IV D5W
 0.45% saline when both sodium and water replacement are needed

D5W behaves as free water after glucose is metabolised.

Choice depends on:

 Volume status
 Glucose
 Ability to drink
 Ongoing losses
 Renal function

STEP 3 — TREAT THE CAUSE

Central DI
 Desmopressin
Lithium nephrogenic DI
 Stop/reduce lithium when possible
 Amiloride
 Low-sodium diet
 Thiazide where appropriate

Other nephrogenic DI
 Correct calcium or potassium
 Stop causative medication
 Thiazide
 Low-solute diet
 Selected NSAID use

Osmotic diuresis
 Treat hyperglycemia
 Stop mannitol where appropriate
 Replace fluid losses

Extrarenal losses
 Treat diarrhea
 Treat fever
 Manage burns
 Replace ongoing water loss

Sodium overload
 Free water
 Stop sodium source
 Specialist management
 Dialysis in selected severe cases, especially with renal impairment or massive load

CORRECTION RATE OF
HYPERNATREMIA
Chronic or unknown-duration hypernatremia
Correct gradually, commonly over:
Approximately 48–72 hours.
The reason:

Brain cells have accumulated osmoles.

Rapid reduction of extracellular sodium:

Water enters brain cells.

Cerebral edema develops.

Acute hypernatremia
If known to have developed over only a few hours from sodium loading, correction may
sometimes be faster under specialist supervision because cerebral adaptation is incomplete.

COMPLICATIONS OF
HYPERNATREMIA
During the disease:

 Severe dehydration
 Hypovolemic shock
 Prerenal AKI
 Rhabdomyolysis
 Seizures
 Intracranial hemorrhage
 Coma
 Death

During treatment:

Cerebral edema from overly rapid

correction.
First Aid lists prerenal AKI and seizures as important consequences of profound
hypernatremia.
COMPLETE HYPERNATREMIA
FLOWCHART
Sodium above 145
↓

Assess circulation
Shock or severe hypovolemia

 Isotonic saline first

 Restore perfusion

Measure urine osmolality

Below 300

Diabetes insipidus

Give supervised desmopressin assessment:

 Urine concentrates → central DI

 No meaningful response → nephrogenic DI

300–600

 Partial DI
 Osmotic diuresis

Check:

 Glucose
 Mannitol
 Urea load
 Drugs

Above 600
Kidney is concentrating appropriately.

Think:

 Extrarenal water loss

 Reduced water access
 Sodium overload

Calculate water deficit

↓

Replace water gradually

↓

Treat cause and monitor:

 Sodium
 Neurological status
 Urine output
 Glucose
 Ongoing losses

HIGH-YIELD COMPARISON
Serum Urine
Disorder Volume status Main clue
osmolality osmolality
Primary polydipsia Low <100 Euvolemic Massive water intake
Beer or tea-and-toast
Low-solute intake Low Often <100 Euvolemic
diet
Urine sodium >30, no
SIADH Low >100 Euvolemic
endocrine cause
Hypovolemic Orthostasis, dry
Low >100 Depleted
hyponatremia mucosa
Heart Low effective arterial
Low >100 Edematous
failure/cirrhosis volume
Central DI High Low Often depleted Responds to DDAVP
Nephrogenic DI High Low Often depleted No DDAVP response
Glucose, mannitol or
Osmotic diuresis Variable/high 300–600+ Depleted
urea
 Serum Urine
Disorder Volume status Main clue
osmolality osmolality
Extrarenal water Kidney concentrates
High >600 Depleted
loss appropriately
Normal/high High urine sodium,
Sodium overload High >600
volume sodium exposure

SMLE CLINICAL SCENARIOS

Scenario 1 — Seizure with acute hyponatremia
A postoperative patient develops:

 Sodium 115 mmol/L

 Generalised seizure
 Low serum osmolality

Best immediate treatment:

3% hypertonic saline
Do not wait to finish the full etiological workup.

Target:

 Small controlled initial increase

 Then slow correction

Scenario 2 — Vomiting and diarrhea

Patient has:

 Dry mucosa
 Orthostatic hypotension
 Sodium 126
 Urine osmolality 450
 Urine sodium 12

Diagnosis:
Hypovolemic hypotonic hyponatremia from
extrarenal losses.
Best treatment:

Isotonic saline.

Scenario 3 — SIADH
Patient with small-cell lung carcinoma:

 Sodium 119
 Serum osmolality low
 Urine osmolality 500
 Urine sodium 60
 Normal volume examination
 Normal adrenal and thyroid assessment

Diagnosis:

SIADH.
Stable treatment:

 Fluid restriction
 Treat malignancy
 Consider increased solute

Seizure:

3% saline.

Scenario 4 — Primary polydipsia

Psychiatric patient:

 Drinks 12 L/day
 Sodium 122
 Urine osmolality 55
Diagnosis:

Primary polydipsia.
Best treatment:

 Water restriction
 Psychiatric management
 Monitor for rapid correction

Scenario 5 — Beer potomania

Chronic alcohol user consumes mainly beer and little food.

Findings:

 Sodium 118
 Low urine osmolality
 Low urinary solute

Mechanism:

Low dietary solute limits water excretion.

Major treatment danger:

Rapid correction after food or saline is

introduced.

Scenario 6 — Heart-failure hyponatremia

Patient has:

 Leg edema
 Raised JVP
 Pulmonary crackles
 Sodium 124
 Concentrated urine

Mechanism:
Low effective arterial filling

ADH-mediated water retention

Dilutional hyponatremia.

Treatment:

 Fluid restriction
 Diuresis
 Heart-failure management

Scenario 7 — Central DI after trauma

After head trauma:

 Urine output 8 L/day

 Sodium 155
 Urine osmolality 90

After DDAVP:

 Urine osmolality rises markedly

Diagnosis:

Central DI.
Best treatment:

Desmopressin plus water replacement.

Scenario 8 — Lithium-induced nephrogenic DI

Patient taking lithium:

 Polyuria
 Polydipsia
 Sodium 158
  Dilute urine
 No meaningful DDAVP response

Diagnosis:

Nephrogenic DI.
Best cause-specific drug:

Amiloride.

Scenario 9 — Hypernatremic shock

Frail older adult:

 Sodium 166
 Severe dehydration
 Hypotension

First treatment:

Isotonic saline.
After circulation improves:

Gradual free-water replacement.

Scenario 10 — Hyperglycemic osmotic diuresis

Patient has:

 Severe hyperglycemia
 Polyuria
 Dehydration
 Urine osmolality 450
 Sodium rising

Diagnosis:

Osmotic diuresis.
Treatment:

 Insulin
 Appropriate fluids
 Electrolyte monitoring

BEST TEST, GOLD-STANDARD AND

DEFINITIVE TREATMENT SUMMARY
Hyponatremia
First classification test

Serum osmolality
Best test to assess whether ADH is active

Urine osmolality
Best practical classification tools

Volume status + urine osmolality + urine

sodium
Best emergency treatment for seizure or coma

3% hypertonic saline
Best treatment for hypovolemic hyponatremia

Isotonic saline
Best initial treatment for stable SIADH

Fluid restriction and treatment of the cause

Major treatment complication
Osmotic demyelination syndrome

Hypernatremia
Most useful initial etiological test

Urine osmolality
Best test to distinguish central from nephrogenic DI

Desmopressin response in a supervised

assessment
Best treatment for central DI

Desmopressin
Best treatment for lithium-induced nephrogenic DI

Remove lithium when possible + amiloride

Best initial fluid in hypernatremic shock

Isotonic saline
Definitive correction

Gradual replacement of the free-water

deficit
Major treatment complication

Cerebral edema
SMLE EXAM TRAPS
Trap 1
Hyponatremia means total-body sodium is always low.

Incorrect.

 Hypovolemic hyponatremia → total sodium low

 SIADH → total sodium near normal
 Heart failure/cirrhosis → total sodium increased

Trap 2
Every low sodium is hypotonic.

Incorrect.

Check serum osmolality.

 Normal → pseudohyponatremia
 High → glucose or another osmole
 Low → true hypotonic hyponatremia

Trap 3
Low sodium in severe hyperglycemia should be treated with hypertonic saline.

Usually incorrect.

Treat the hyperglycemia and volume deficit unless another clear indication for hypertonic
saline exists.

Trap 4
Concentrated urine in hyponatremia always means SIADH.

Incorrect.

ADH is also appropriately active in:

  Hypovolemia
 Heart failure
 Cirrhosis
 Adrenal insufficiency

Trap 5
Urine osmolality below 100 means kidney failure.

Incorrect.

It usually means ADH is suppressed and the kidney is appropriately diluting urine.

Think:

 Polydipsia
 Low-solute intake

Trap 6
SIADH can be diagnosed without excluding cortisol deficiency.

Incorrect.

Adrenal insufficiency must be excluded.

Trap 7
Normal saline always corrects SIADH.

Incorrect.

It can fail or worsen sodium when sodium is excreted in concentrated urine while water is
retained.

Trap 8
The lowest sodium should be corrected the fastest.

Incorrect.
Profound chronic hyponatremia carries the greatest overcorrection danger.

Trap 9
Hypertonic saline should normalise sodium.

Incorrect.

Its immediate purpose is a small rise sufficient to reduce cerebral edema.

Trap 10
Hypernatremia usually means excessive salt intake.

Incorrect.

Most cases result from water deficit.

Trap 11
Give D5W first in hypernatremic shock.

Incorrect.

Restore circulation with isotonic saline first.

Trap 12
All polyuria with hypernatremia is diabetes insipidus.

Incorrect.

Consider osmotic diuresis.

 DI → very dilute urine

 Osmotic diuresis → urine contains solute and is more concentrated
Trap 13
Both central and nephrogenic DI respond to DDAVP.

Incorrect.

 Central responds
 Nephrogenic shows little or no meaningful response

Trap 14
Chronic hypernatremia should be normalised rapidly.

Incorrect.

Rapid correction can produce cerebral edema.

MEMORY MAPS
HYPONATREMIA: O-U-V
O — Serum osmolality

U — Urine osmolality and urine sodium

V — Volume status

TRUE HYPOTONIC HYPONATREMIA:

DRY–NORMAL–SWOLLEN
Dry

Hypovolemic

Normal-looking

Euvolemic
Swollen

Hypervolemic

EUVOLEMIC HYPONATREMIA: SALT

S — SIADH

A — Adrenal insufficiency

L — Low-solute intake/polydipsia

T — Thyroid disease

SIADH: LOW BLOOD, HIGH URINE

 Low serum osmolality
 High urine osmolality
 Urine sodium not suppressed
 Euvolemic examination

SEVERE HYPONATREMIA
“SEIZURE = 3%”

HYPERNATREMIA: WATER LOST,

WATER BLOCKED, OR SALT ADDED
Water lost

 GI/skin
 DI
 Osmotic diuresis

Water blocked
  No access
 Dementia
 Intubation

Salt added

 Hypertonic saline
 Bicarbonate
 Salt ingestion

DI MEMORY
“CENTRAL = SIGNAL ABSENT”
Responds to DDAVP.

“NEPHROGENIC = NEPHRON
IGNORES”
Does not respond meaningfully.

CORRECTION COMPLICATIONS
Low sodium corrected too fast → loss of
myelin.
High sodium corrected too fast → brain
swelling.

FINAL MASTER CONCEPT

Serum sodium disorders are disorders of water distribution.

In hyponatremia:
Water is excessive relative to sodium.

Water enters brain cells.

Symptoms depend mainly on how fast cerebral edema develops.

The diagnostic pathway is:

Serum osmolality
↓

Urine osmolality
↓

Volume status and urine sodium

Treatment then follows the mechanism:

 Hypovolemic → isotonic saline

 Stable SIADH → fluid restriction and treat cause
 Hypervolemic → water restriction, diuresis and disease management
 Severe neurological symptoms → 3% hypertonic saline

In hypernatremia:

Water is deficient relative to sodium.

Water leaves brain cells.

The diagnostic pathway is:

Circulation first
↓

Urine osmolality
↓

DI versus osmotic diuresis versus

extrarenal loss
Treatment follows the cause:

 Shock → isotonic saline first

 Central DI → desmopressin
 Lithium nephrogenic DI → amiloride
 Osmotic diuresis → treat the solute cause
 Water deficit → gradual free-water replacement

The two safety rules that must never be forgotten are:

Correct chronic hyponatremia slowly to

prevent osmotic demyelination.
Correct chronic hypernatremia slowly to
prevent cerebral edema.
MEDICINE → NEPHROLOGY
TOPIC 3: ACUTE KIDNEY INJURY
SMLE 2026 — Mastery Level 2
Complete Conceptual, Interlinked and Scenario-Based Notes

The next Nephrology topic after potassium and sodium disorders is Acute Kidney Injury —
Mastery Level 2. The SMLE blueprint expects understanding of normal renal physiology,
causes and pathophysiology of acute renal disorders, interpretation of clinical signs,
laboratory results and renal imaging, and management of acute kidney disease and its
complications.

SOURCE FRAMEWORK
Reference-book-based
Approach to Internal Medicine, Fifth Edition

Used for:

 Renal blood flow and hemodynamics

 True intravascular volume loss
 Reduced effective circulating volume
 Afferent and efferent arteriolar drug effects
 Initial AKI investigations
 Renal vascular imaging
 General renal-supportive principles

The source groups reduced renal perfusion into true intravascular fluid loss, reduced effective
circulating volume and altered renal hemodynamics. It identifies GI loss, hemorrhage,
diuresis, burns, heart failure, cirrhosis, nephrotic syndrome, sepsis, NSAIDs, ACE inhibitors,
ARBs and calcineurin inhibitors as important causes.

Clinical algorithm source

First Aid Clinical Algorithms for the USMLE Step 2 CK 2024

Used especially for:

 AKI definition
 Prerenal, intrinsic and postrenal algorithm
 BUN/creatinine ratio
 Fractional excretion of sodium and urea
 Urine osmolality
 Urine sediment and casts
 Acute tubular injury
 Acute interstitial nephritis
 Crystal nephropathy
 Vascular AKI
 Obstructive AKI
 Initial treatment
 Complications
 Dialysis and procedural intervention

First Aid defines AKI as an acute, often reversible decline in kidney function, detected by a
creatinine increase of at least 0.3 mg/dL or to at least 1.5 times baseline, and divides it into
prerenal, intrinsic and postrenal causes.

Any physiology added only to make the TOS topic understandable is labelled:

Extra Concept for Concept Building

PART 1 — THE MASTER CONCEPT
AKI IS NOT JUST “HIGH CREATININE”
A high creatinine is evidence of reduced filtration.

But the actual disease is:

A SUDDEN FAILURE OF THE KIDNEYS

TO FILTER BLOOD AND MAINTAIN
INTERNAL BALANCE
The kidneys normally:

 Remove urea and creatinine

 Excrete potassium
 Excrete hydrogen ions
 Regulate sodium and water
 Maintain blood pressure
 Clear drugs and toxins
 Maintain calcium–phosphate balance

When kidney function suddenly declines:

Creatinine and urea accumulate.

Potassium may rise.

Acid accumulates.

Salt and water may accumulate.

Drugs may become toxic.

Therefore AKI can cause:

  Hyperkalemia
 Metabolic acidosis
 Pulmonary edema
 Hypertension
 Uremic symptoms
 Encephalopathy
 Pericarditis
 Bleeding tendency
 Drug toxicity

The creatinine number is important, but the immediate danger usually comes from:

ELECTROLYTES + ACID + FLUID +

UREMIA

PART 2 — NORMAL FILTRATION

FROM ZERO
Blood reaches the kidney through the renal artery.

Blood enters the glomerulus through the:

Afferent arteriole
The glomerulus is a network of capillaries.

Pressure inside these capillaries pushes:

 Water
 Electrolytes
 Small molecules
 Waste products

through the filtration barrier.

The filtrate enters Bowman space.

Blood that remains exits through the:

Efferent arteriole
The amount of plasma filtered per minute is the:

Glomerular filtration rate — GFR

GFR depends mainly on:

1. Blood reaching the kidney

2. Pressure inside the glomerular capillaries
3. Integrity of the glomerulus
4. Integrity of the tubules
5. Free drainage of urine

Failure at any of these levels can produce AKI.

PART 3 — THE THREE-LOCATION

MODEL
Do not memorise dozens of causes separately.

Ask:

Where is the problem?

1. Before the kidney
Blood is not reaching the kidney adequately.

Prerenal AKI
2. Inside the kidney
The kidney tissue itself is damaged.

Intrinsic renal AKI

3. After the kidney
Urine cannot drain because of obstruction.
Postrenal AKI
Memory:

FLOW — FILTER — DRAIN

 Flow problem → prerenal
 Filter/tissue problem → intrinsic
 Drainage problem → postrenal

First Aid uses the same three-part classification.

PART 4 — WHY ALL THREE TYPES

RAISE CREATININE
Prerenal AKI
Less blood reaches the glomerulus.

Less plasma is filtered.

Creatinine stays in blood.

Intrinsic AKI
The glomerulus, tubules, interstitium or renal vessels are damaged.

Filtration and tubular function fall.

Creatinine accumulates.

Postrenal AKI
Urine backs up behind an obstruction.
↓

Pressure rises in the tubules and Bowman space.

This pressure opposes glomerular filtration.

GFR falls.

Therefore the same laboratory abnormality may arise from three completely different
mechanisms.

PART 5 — DEFINITION
The supplied First Aid algorithm defines AKI by either:

 Increase in serum creatinine by at least 0.3 mg/dL

 Increase in serum creatinine to at least 1.5 times baseline

Extra Concept for Concept Building

Modern clinical definitions also use reduced urine output because creatinine may rise late.

Conceptually:

AKI can be present before creatinine has

fully risen.
Why?

Creatinine must accumulate in the blood before the laboratory detects a major change.

Therefore a patient may already have severe renal hypoperfusion with:

 Falling urine output

 Rising potassium
 Worsening acidosis

while creatinine is still only mildly elevated.

PART 6 — URINE-OUTPUT
TERMINOLOGY
Oliguria
Markedly reduced urine output.

Clinically, approximately:

Less than 0.5 mL/kg/hour

Anuria
Near-complete absence of urine.

Approximately:

Less than 100 mL/day

Anuria strongly suggests:

 Complete urinary obstruction

 Severe bilateral renal vascular event
 Severe cortical injury
 Advanced shock
 Catheter blockage

But not every AKI is oliguric.

PART 7 — NON-OLIGURIC AKI

Some patients continue producing apparently reasonable urine volumes despite impaired
filtration.

Examples include:

 Some nephrotoxic tubular injuries

 Acute interstitial nephritis
 Early intrinsic renal injury
 Partial obstruction

Therefore:
Normal-looking urine volume does not
exclude AKI.
Likewise:

Oliguria does not automatically mean

intrinsic renal failure.
A dehydrated patient may have prerenal oliguria with structurally normal kidneys.

PART 8 — WHY CREATININE MAY

MISLEAD YOU
Creatinine production depends partly on muscle mass.

Therefore the same creatinine level has different significance in different patients.

Example
A muscular young adult with creatinine 1.4 mg/dL may have relatively preserved filtration.

A frail older woman with creatinine 1.4 mg/dL may have severe reduction in GFR.

Creatinine may also be deceptively low in:

 Malnutrition
 Amputation
 Advanced liver disease
 Low muscle mass

Therefore always compare with:

The patient’s baseline creatinine.

PART 9 — CLINICAL PRESENTATION

OF AKI
AKI may present in four ways:

1. The cause presents first

Examples:

 Vomiting and diarrhea

 Hemorrhage
 Sepsis
 Heart failure
 Drug exposure
 Urinary retention

2. Reduced urine output

 Oliguria
 Anuria
 Difficulty passing urine

3. Complications present
 Dyspnea from pulmonary edema
 Weakness or arrhythmia from hyperkalemia
 Confusion from uremia
 Nausea from azotemia
 Acidosis
 Pericarditic chest pain

4. Incidental laboratory finding

A hospitalized patient may have a creatinine rise without obvious symptoms.

PART 10 — SYMPTOMS CAUSED BY

UREMIA
Uremia means the clinical syndrome caused by retained renal toxins.

Possible manifestations:

 Nausea
 Vomiting
 Loss of appetite
 Metallic taste
 Fatigue
  Confusion
 Drowsiness
 Asterixis
 Pruritus
 Platelet dysfunction
 Pericarditis

Important:

Uremia is a clinical syndrome, not simply a

high urea number.
A patient with moderate biochemical azotemia but no symptoms does not automatically
require dialysis.

A patient with uremic pericarditis may require dialysis even if the numerical values are not
the highest ever seen.

PART 11 — FIRST ACTION IN A

PATIENT WITH AKI
Before trying to name the exact cause, ask:

IS THE PATIENT UNSTABLE?

Check:

 Airway
 Breathing
 Circulation
 Blood pressure
 Oxygen saturation
 ECG
 Potassium
 Bicarbonate/pH
 Pulmonary edema
 Mental status
 Urine output

Immediate life-threatening complications must be treated first.

Examples:
  Hyperkalemia with ECG changes
 Pulmonary edema with respiratory failure
 Severe acidosis
 Shock
 Uremic pericarditis
 Sepsis

PART 12 — THE MASTER AKI

ALGORITHM
Step 1: Confirm AKI
Compare creatinine with baseline.

Step 2: Look for emergencies

 Potassium
 Acidosis
 Pulmonary edema
 Uremia
 Shock

Step 3: Review the history

 Fluid loss
 Infection
 Heart/liver disease
 Medication exposure
 Contrast exposure
 Urinary symptoms
 Systemic inflammatory symptoms

Step 4: Examine volume status

 Dry
 Edematous
  Septic/vasodilated
 Obstructed bladder

Step 5: Urinalysis and urine microscopy

↓

Step 6: Urine electrolytes when useful

↓

Step 7: Renal ultrasound or bladder

assessment
↓

Step 8: Classify
 Prerenal
 Intrinsic
 Postrenal

Step 9: Treat the cause and complications

SECTION A — PRERENAL AKI

PART 13 — WHAT PRERENAL MEANS
Prerenal AKI means:

The kidney tissue is initially structurally

intact, but effective renal blood flow is
inadequate.
Because less blood reaches the glomerulus:

Glomerular pressure falls.

Filtration falls.

Creatinine rises.

The kidney responds by conserving:

 Sodium
 Water
 Urea

This adaptive response produces the classic prerenal laboratory pattern.

PART 14 — THREE MECHANISMS OF

PRERENAL AKI
1. True volume loss
The body genuinely lacks circulating fluid.

2. Reduced effective arterial circulating volume

Total-body fluid may be normal or increased, but renal perfusion is inadequate.

3. Altered renal vascular tone

Drugs or vascular disease interfere with afferent or efferent arteriolar regulation.

The Approach source uses the same conceptual grouping.

PART 15 — TRUE VOLUME LOSS

Causes include:

 Hemorrhage
 Vomiting
 Diarrhea
 Diuretic overuse
 Osmotic diuresis
 Burns
 Sweating
 Fever
 Poor oral intake

Clinical signs:

 Dry mucous membranes

 Reduced skin turgor
 Orthostatic hypotension
 Tachycardia
 Low JVP
 Narrow pulse pressure
 Weight loss
 Oliguria

First Aid’s prerenal algorithm highlights reduced skin turgor, postural hypotension and low
effective renal perfusion.

PART 16 — VOLUME-DEPLETION
SCENARIO
An older patient has three days of vomiting and diarrhea.

Findings:

 Dry mouth
 Orthostatic dizziness
 Tachycardia
 Reduced urine output
 Creatinine increased from 0.9 to 1.8 mg/dL
 Bland urinalysis

Mechanism:

GI fluid loss

↓
Reduced circulating volume

Reduced renal blood flow

Reduced GFR

Prerenal AKI

Best initial treatment

Isotonic fluid resuscitation

plus:

 Treat vomiting/diarrhea
 Stop contributing drugs
 Monitor electrolytes
 Monitor urine output
 Recheck creatinine

PART 17 — REDUCED EFFECTIVE

CIRCULATING VOLUME
The body may contain excess total fluid but the kidneys still receive insufficient effective
perfusion.

Examples:

 Heart failure
 Cirrhosis
 Nephrotic syndrome
 Sepsis
 Third spacing

Heart failure
Cardiac output falls.
↓

Renal perfusion falls.

RAAS and ADH activate.

Salt and water are retained.

The patient becomes:

 Edematous
 Congested
 Renally underperfused

Giving large amounts of fluid may worsen pulmonary edema.

Therefore treatment is not automatically “give IV fluids.”

PART 18 — CARDIORENAL SCENARIO

A patient with severe heart failure has:

 Orthopnea
 Raised JVP
 Crackles
 Leg edema
 Rising creatinine
 Low urine sodium

The kidneys are underperfused because cardiac output is low.

But total body fluid is high.

Diagnosis:

Prerenal AKI from low effective arterial

volume in heart failure.
Management may require:

 Treatment of acute heart failure

  Careful diuresis for congestion
 Optimisation of cardiac output
 Avoidance of nephrotoxins
 Monitoring renal function and electrolytes

Important:

Do not assume rising creatinine in an

edematous heart-failure patient means they
need fluid.

PART 19 — CIRRHOSIS AND

HEPATORENAL PHYSIOLOGY
Advanced cirrhosis causes:

 Marked splanchnic vasodilation

 Reduced effective arterial filling
 Activation of RAAS and sympathetic tone
 Renal vasoconstriction

The kidneys may be structurally normal but severely underperfused.

Clinical clues:

 Advanced cirrhosis
 Ascites
 Low blood pressure
 Low urine sodium
 Rising creatinine
 Bland urine sediment
 No improvement after ordinary reversible causes are corrected

First Aid’s prerenal pathway includes hepatorenal syndrome and focuses treatment on
restoring effective renal blood flow and managing the underlying liver disease.

Detailed cirrhosis treatment was covered under the hepatology TOS and is not repeated here.

PART 20 — SEPSIS
Sepsis can cause AKI through several mechanisms:

 Systemic vasodilation
 Reduced effective perfusion
 Microcirculatory dysfunction
 Inflammation
 Tubular injury

Initially it may resemble prerenal AKI.

If prolonged:

Tubular cells become injured.

The patient develops intrinsic acute tubular injury.

Therefore sepsis can create a continuum:

Prerenal hypoperfusion → acute tubular

injury

PART 21 — RENAL AUTOREGULATION

Extra Concept for Concept Building
The kidney tries to maintain glomerular pressure when systemic blood pressure changes.

Two vessels are crucial:

Afferent arteriole
Brings blood into the glomerulus.

Efferent arteriole
Carries blood away.

When renal perfusion falls:

  The afferent arteriole dilates
 The efferent arteriole constricts

This helps preserve pressure inside the glomerulus.

Two major systems support this:

 Prostaglandins dilate the afferent arteriole

 Angiotensin II constricts the efferent arteriole

This explains major drug-induced AKI patterns.

PART 22 — NSAIDs AND THE

AFFERENT ARTERIOLE
NSAIDs inhibit prostaglandin synthesis.

The afferent arteriole cannot dilate adequately.

Blood entering the glomerulus decreases.

Glomerular pressure falls.

GFR falls.

This is especially dangerous in patients who depend on prostaglandins:

 Dehydration
 Older age
 CKD
 Heart failure
 Cirrhosis
 Diuretic use

The Approach source lists NSAIDs and calcineurin inhibitors among causes of altered
afferent renal hemodynamics.
PART 23 — ACE INHIBITORS AND THE
EFFERENT ARTERIOLE
Angiotensin II normally constricts the efferent arteriole.

ACE inhibitors and ARBs reduce this effect.

The efferent arteriole dilates.

Pressure inside the glomerulus falls.

GFR decreases.

This is especially important in:

 Bilateral renal artery stenosis

 Stenosis of a solitary functioning kidney
 Severe volume depletion
 Advanced heart failure

The Approach source identifies ACE inhibitors and ARBs as causes of altered efferent renal
hemodynamics.

PART 24 — THE “TRIPLE WHAMMY”

Extra Concept for Concept Building
A high-risk combination is:

 Diuretic
 NSAID
 ACE inhibitor or ARB

Mechanism:

Diuretic

↓
Reduces circulating volume

NSAID

Constrains afferent blood entry

ACE inhibitor/ARB

Dilates efferent exit

Therefore:

 Less blood enters

 Blood leaves the glomerulus more easily
 Filtration pressure collapses

This combination can precipitate AKI, especially during dehydration.

PART 25 — BILATERAL RENAL

ARTERY STENOSIS
Renal arteries are narrowed.

Perfusion pressure reaching both kidneys falls.

The kidneys depend on angiotensin-II-mediated efferent constriction to maintain GFR.

ACE inhibitor or ARB is started.

Efferent constriction is removed.

GFR falls sharply.

Clinical clue:
Significant creatinine rise after starting an
ACE inhibitor or ARB
especially with:

 Resistant hypertension
 Abdominal bruit
 Atherosclerotic vascular disease
 Flash pulmonary edema

First Aid identifies AKI after ACE inhibitor/ARB exposure as a clue to significant
renovascular disease.

PART 26 — PRERENAL LABORATORY

PATTERN
The kidney is structurally intact and tries to conserve sodium and water.

Therefore typical findings include:

 BUN/creatinine ratio above approximately 20

 Urine sodium low
 Fractional excretion of sodium below 1%
 Concentrated urine, often above 500 mOsm/kg
 Bland urine sediment
 Hyaline casts may be present

First Aid’s AKI algorithm contrasts prerenal disease—BUN/Cr above 20, FeNa below 1%
and urine osmolality above 500—with intrinsic disease.

PART 27 — WHY BUN/CREATININE

RATIO RISES
In prerenal AKI:

Slow tubular flow

More water is reabsorbed.

↓

More urea is passively reabsorbed with water.

Creatinine is not reabsorbed to the same degree.

Therefore:

BUN rises disproportionately to creatinine.

Typical prerenal ratio:

Above approximately 20:1

But this is not perfect.

BUN may also rise with:

 Upper GI bleeding
 Corticosteroids
 High-protein intake
 Catabolic states

BUN may be relatively low in:

 Liver disease
 Malnutrition

Therefore never diagnose solely from the ratio.

PART 28 — FRACTIONAL EXCRETION

OF SODIUM
FeNa estimates what percentage of filtered sodium is excreted.

FeNa=Urine Na×Plasma CrPlasma Na×Urine Cr×100FeNa = \frac{Urine\,Na \times

Plasma\,Cr} {Plasma\,Na \times Urine\,Cr} \times
100FeNa=PlasmaNa×UrineCrUrineNa×PlasmaCr×100

Prerenal AKI
The intact kidney retains sodium.
Therefore:

FeNa usually below 1%

Acute tubular injury
Damaged tubules cannot retain sodium effectively.

Therefore:

FeNa often above 1–2%

First Aid uses FeNa below 1% to support prerenal AKI.

PART 29 — LIMITATIONS OF FeNa

FeNa may be misleading when:

 Diuretics increase urine sodium

 CKD impairs sodium conservation
 Contrast injury is early
 Glomerulonephritis is present
 Pigment nephropathy is present
 Sepsis alters tubular handling

Therefore FeNa supports the diagnosis but does not replace clinical reasoning.

PART 30 — FRACTIONAL EXCRETION

OF UREA
In a patient receiving diuretics, urine sodium may be artificially high.

Urea handling is less directly altered by many diuretics.

Therefore:

FeUrea may be more useful when diuretics

are being used.
First Aid’s algorithm states that low FeUrea supports prerenal AKI in patients receiving
diuretics.

The supplied First Aid text uses a value below approximately 20%; other clinical references
may use different cutoffs. For these notes, the source-based value is retained.

PART 31 — TREATMENT OF
PRERENAL AKI
The unifying goal is:

RESTORE EFFECTIVE RENAL

PERFUSION
But the method depends on the cause.

True volume depletion

 Isotonic fluids
 Blood products for major hemorrhage
 Control GI losses
 Stop excessive diuretics

Sepsis
 Appropriate fluids
 Early antibiotics
 Source control
 Vasopressors if shock persists

Heart failure
 Treat congestion and low cardiac output
 Do not reflexively give large fluid boluses

Cirrhosis-related underfilling
 Cause-specific cirrhosis management
 Avoid nephrotoxins
 Selected albumin/vasoconstrictor strategies under specialist care
Drug-induced hemodynamic AKI
 Stop NSAIDs
 Hold ACE inhibitor/ARB temporarily when clinically appropriate
 Correct volume depletion

First Aid emphasises that all prerenal causes are treated by improving effective renal blood
flow.

PART 32 — COMPLICATION OF
UNTREATED PRERENAL AKI
If renal hypoperfusion persists:

Tubular cells become ischemic.

Tubular injury develops.

Prerenal AKI becomes intrinsic AKI.

Prolonged prerenal AKI → acute tubular

injury
First Aid explicitly identifies this progression.

SECTION B — INTRINSIC RENAL AKI

PART 33 — WHAT INTRINSIC AKI
MEANS
Intrinsic AKI means:
The kidney tissue itself has been damaged.
The injured compartment may be:

 Tubules
 Interstitium
 Glomeruli
 Renal vessels

Memory:

T-I-G-V
T — Tubules

I — Interstitium

G — Glomeruli

V — Vessels

PART 34 — URINE SEDIMENT AS A

“RENAL BIOPSY IN A CUP”
Urine microscopy can reveal where injury is occurring.

Muddy brown granular casts

Think:

Acute tubular injury

White blood cell casts
Think:

 Acute interstitial nephritis

 Pyelonephritis

Red blood cell casts

Think:

Glomerulonephritis or renal vasculitis

Crystals
Think:

Crystal nephropathy
Bland sediment
Think:

 Prerenal AKI
 Early obstruction
 Some vascular causes

First Aid directly connects muddy brown casts with tubular injury, WBC casts with AIN or
pyelonephritis, and RBC casts with glomerular disease.

PART 35 — ACUTE TUBULAR INJURY

Acute tubular injury is commonly called acute tubular necrosis, although not every case
involves widespread tissue necrosis.

It occurs when tubular cells are injured by:

Ischemia
or

Toxins

PART 36 — ISCHEMIC TUBULAR

INJURY
Causes:
  Prolonged shock
 Severe sepsis
 Major hemorrhage
 Prolonged dehydration
 Major surgery
 Severe hypotension

Mechanism:

Reduced oxygen delivery

Tubular epithelial cells lose ATP.

Ion pumps fail.

Cells swell and detach.

Dead and injured cells enter tubular lumen.

Casts form and obstruct flow.

Filtrate may leak backward through damaged tubules.

GFR falls further.

PART 37 — WHY THE PROXIMAL

TUBULE AND THICK ASCENDING
LIMB ARE VULNERABLE
Extra Concept for Concept Building
These tubular segments have high energy requirements because they perform active transport.

Therefore they require substantial oxygen.

During ischemia:

ATP production falls.

High-demand cells are injured early.

This explains why severe hypoperfusion can initially be prerenal but later becomes tubular
injury.

PART 38 — NEPHROTOXIC TUBULAR

INJURY
Causes in the supplied First Aid source include:

 Aminoglycosides
 Amphotericin B
 Sulfonamides
 Acyclovir
 Calcineurin inhibitors
 Cisplatin
 Radiocontrast
 Myoglobin from rhabdomyolysis
 Hemoglobin from intravascular hemolysis

Different toxins injure the kidney through different mechanisms:

 Direct tubular toxicity

 Vasoconstriction
 Crystal precipitation
 Oxidative injury
 Tubular obstruction

PART 39 — RHABDOMYOLYSIS-
RELATED AKI
Muscle cells break down.

Myoglobin enters blood.

Myoglobin is filtered by the kidney.

In dehydration or acidic urine:

Pigment damages tubular cells and may obstruct tubules.

Clinical scenario:

 Crush injury
 Prolonged immobilisation
 Severe muscle pain
 Dark urine
 Very high CK
 Dipstick positive for blood but few RBCs on microscopy
 Hyperkalemia
 Rising creatinine

Management:

 Early isotonic fluids where appropriate

 Treat cause
 Monitor potassium and calcium
 Avoid nephrotoxins
 Dialysis if severe complications develop

PART 40 — PHASES OF ACUTE

TUBULAR INJURY
Extra Concept for Concept Building
Initiation phase
Initial ischemic or toxic injury.
Maintenance phase
GFR remains low.

Possible features:

 Oliguria
 Hyperkalemia
 Acidosis
 Fluid overload
 Rising creatinine

Recovery phase
Tubular cells recover.

Urine output may increase dramatically.

But early recovering tubules cannot fully concentrate urine or retain electrolytes.

Therefore the patient may develop:

 Polyuria
 Dehydration
 Hypokalemia
 Hypomagnesemia

Clinical lesson:

Increased urine output during recovery

does not mean monitoring can stop.

PART 41 — LABORATORY PATTERN

OF TUBULAR INJURY
Common findings:

 BUN/creatinine ratio often below 20

 FeNa often above 1–2%
 Urine osmolality often below 500
 Urine sodium elevated
 Muddy brown granular casts
 Renal tubular epithelial cells
First Aid contrasts this intrinsic pattern with prerenal disease.

PART 42 — TREATMENT OF ACUTE

TUBULAR INJURY
There is usually no single drug that immediately repairs damaged tubules.

Management is:

SUPPORTIVE + REMOVE THE CAUSE +

TREAT COMPLICATIONS
 Stop nephrotoxic drugs
 Treat sepsis or shock
 Optimise volume status
 Avoid further renal insults
 Adjust drug doses
 Monitor potassium
 Monitor acid–base status
 Monitor fluid balance
 Provide nutritional support
 Dialyse when indicated

First Aid recommends supportive care, stopping nephrotoxins and treating the underlying
shock or sepsis.

PART 43 — ACUTE INTERSTITIAL

NEPHRITIS
AIN is inflammation of the renal interstitium, commonly due to a drug hypersensitivity
reaction.

Common causative groups include:

 Antibiotics
 NSAIDs
 Proton-pump inhibitors
 Some diuretics
 Other medications
The inflammation surrounds and disrupts renal tubules.

Tubular function declines.

Creatinine rises.

PART 44 — CLASSIC AIN

PRESENTATION
Traditional triad:

 Fever
 Rash
 Eosinophilia

But the complete triad is often absent.

Possible findings:

 Recent new medication

 AKI
 Fever
 Maculopapular rash
 Arthralgia
 Peripheral eosinophilia
 Sterile pyuria
 WBC casts
 Mild proteinuria
 Hematuria

NSAID-related disease may have:

 Less fever/rash
 More proteinuria

First Aid gives an AIN scenario with NSAID exposure, WBCs, eosinophils and WBC casts.
PART 45 — BEST MANAGEMENT OF
AIN
Stop the offending drug.
Then:

 Supportive care
 Correct fluid/electrolyte abnormalities
 Avoid further nephrotoxins

Corticosteroids may be considered in selected persistent or severe drug-induced cases after

appropriate specialist evaluation.

Definitive diagnosis

Kidney biopsy
when the diagnosis remains uncertain or renal function fails to improve.

But biopsy is not required in every classic medication-associated case that improves after
drug withdrawal.

PART 46 — ACUTE PYELONEPHRITIS

AS INTRINSIC AKI
Pyelonephritis affects the renal parenchyma and interstitium.

Presentation:

 Fever
 Chills
 Flank pain
 Costovertebral-angle tenderness
 Dysuria/frequency
 Pyuria
 WBC casts

Treatment:
Appropriate antibiotics
plus:

 Fluids where needed

 Relief of obstruction if present
 Sepsis management

First Aid distinguishes pyelonephritis from other intrinsic causes by fever, flank pain and
WBC casts.

Detailed UTI management belongs to the Infectious Diseases TOS and is not expanded here.

PART 47 — CRYSTAL NEPHROPATHY

Some substances precipitate inside renal tubules.

Crystals obstruct urine flow and injure tubular cells.

Causes in the supplied source include:

 Acyclovir
 Methotrexate
 Sulfonamides
 Ethylene glycol

Risk is greater with:

 Dehydration
 High drug dose
 CKD
 Acidic or alkaline urine depending on crystal type

Urinalysis may show:

 Crystals
 Hematuria
 Pyuria

First Aid recommends stopping the causative agent and correcting volume depletion.
PART 48 — CRYSTAL NEPHROPATHY
SCENARIO
A patient starts high-dose acyclovir.

Several days later:

 Creatinine rises
 Urinalysis shows crystals
 Patient is dehydrated

Diagnosis:

Acyclovir-associated crystal nephropathy.

Best management:

 Stop or adjust acyclovir

 Isotonic hydration
 Review all nephrotoxic drugs
 Monitor renal function

Possible complications:

 Acute tubular injury

 Temporary dialysis
 CKD

PART 49 — GLOMERULAR AKI

Glomerular inflammation damages the filtration barrier.

Clinical pattern:

Nephritic syndrome
Possible findings:

 Hematuria
 Cola-coloured urine
 Dysmorphic RBCs
 RBC casts
 Proteinuria
  Hypertension
 Edema
 Reduced GFR

First Aid links RBC casts, dysmorphic RBCs and proteinuria with glomerular disease.

The individual glomerulonephritis syndromes are not separately listed in this adult SMLE
Nephrology TOS, so they are not expanded here beyond what is needed to recognise an
intrinsic AKI pattern.

PART 50 — RAPIDLY PROGRESSIVE

PRESENTATION
A patient may develop over days to weeks:

 Rapid creatinine rise

 Hematuria
 RBC casts
 Proteinuria
 Hypertension
 Edema
 Pulmonary symptoms in pulmonary–renal syndromes

This requires urgent nephrology review.

Possible investigations:

 Complement
 ANA and anti-dsDNA
 ANCA
 Anti-GBM antibodies
 Hepatitis testing
 Other cause-specific serology

Gold standard for defining glomerular pathology

Kidney biopsy
when safe and clinically indicated.

PART 51 — VASCULAR AKI

Intrinsic vascular causes include:

 Atheroembolic disease
 Renal artery occlusion
 Renal vein thrombosis
 Thrombotic microangiopathy
 Malignant hypertension
 Scleroderma renal crisis
 Vasculitis

PART 52 — CHOLESTEROL
ATHEROEMBOLI
Usually follows a vascular procedure or anticoagulation in a patient with severe
atherosclerosis.

Cholesterol debris travels to small renal vessels.

Possible presentation:

 Rising creatinine after angiography

 Livedo reticularis
 Blue or painful toes
 Eosinophilia
 Low complement
 Systemic embolic findings

First Aid gives this classic post-PCI presentation and notes progression to CKD or ESRD can
occur.

Treatment is mainly:

 Supportive care
 Cardiovascular risk management
 Avoiding further embolic insult

PART 53 — THROMBOTIC
MICROANGIOPATHY
Small renal vessels become obstructed by platelet-rich thrombi.

Think of this when AKI is accompanied by:

  Thrombocytopenia
 Microangiopathic hemolytic anemia
 Schistocytes
 Elevated LDH
 Low haptoglobin
 Neurological or systemic features

Treatment depends on the underlying syndrome and requires urgent specialist management.

Only the AKI recognition principle is included here because the full hematologic syndromes
belong elsewhere in the TOS.

SECTION C — POSTRENAL AKI

PART 54 — WHAT POSTRENAL MEANS
Postrenal AKI occurs because:

Urine cannot leave the urinary tract.

Urine accumulates behind the obstruction.

Tubular pressure rises.

Pressure is transmitted back toward Bowman space.

The pressure opposing filtration increases.

GFR falls.

If prolonged:

Tubular atrophy and interstitial fibrosis develop.

Therefore obstruction should be relieved promptly.

PART 55 — WHEN OBSTRUCTION
CAUSES AKI
A unilateral ureteric obstruction usually does not cause major AKI if the other kidney
functions normally.

Significant postrenal AKI usually requires:

 Bilateral ureteric obstruction

 Bladder outlet obstruction
 Urethral obstruction
 Obstruction of a solitary functioning kidney

PART 56 — CAUSES OF POSTRENAL

AKI
Bladder outlet or urethral obstruction
 Benign prostatic hyperplasia
 Prostate cancer
 Urethral stricture
 Neurogenic bladder
 Anticholinergic medications
 Blocked or kinked catheter

Bilateral ureteric obstruction

 Pelvic malignancy
 Retroperitoneal fibrosis
 Bilateral stones
 Blood clots
 External compression

First Aid’s postrenal algorithm includes BPH, stricture, neurogenic bladder, medication
effects, kinked Foley, malignancy and nephrolithiasis.
PART 57 — CLINICAL PRESENTATION
OF OBSTRUCTION
Possible symptoms:

 Difficulty starting urine

 Weak urinary stream
 Hesitancy
 Straining
 Incomplete emptying
 Dribbling
 Suprapubic pain
 Flank pain
 Intermittent urine output
 Anuria

Examination:

 Palpable distended bladder

 Enlarged prostate
 Pelvic mass
 Costovertebral-angle tenderness

Important:

Chronic obstruction may be painless.

Therefore absence of pain does not exclude it.

PART 58 — CLASSIC BPH SCENARIO

An older man has:

 Hesitancy
 Weak stream
 Nocturia
 Suprapubic discomfort
 Reduced urine output
 Rising creatinine
 Large postvoid residual

Diagnosis:
Postrenal AKI from bladder outlet
obstruction.
Immediate treatment:

Bladder catheterisation
unless contraindicated by suspected urethral injury.

Then:

 Monitor urine output

 Monitor electrolytes
 Treat BPH
 Obtain urologic assessment when needed

PART 59 — BLADDER SCAN AND

POSTVOID RESIDUAL
A bedside bladder scan estimates retained urine.

A high postvoid residual supports:

Bladder outlet obstruction or impaired

bladder emptying.
First Aid’s algorithm uses a postvoid residual above approximately 300 mL as a significant
clue before renal imaging.

PART 60 — RENAL ULTRASOUND

Renal ultrasound is useful for identifying:

 Hydronephrosis
 Bladder distension
 Kidney size
 Some structural abnormalities
Best initial imaging for suspected obstruction

Renal and bladder ultrasound

Advantages:

 No radiation
 No iodinated contrast
 Rapid
 Detects hydronephrosis

First Aid recommends renal ultrasound when postrenal AKI is suspected.

PART 61 — CAN OBSTRUCTION EXIST

WITHOUT HYDRONEPHROSIS?
Yes.

Hydronephrosis may be absent in:

 Very early obstruction

 Severe dehydration
 Retroperitoneal fibrosis
 Some infiltrative malignancies
 Technical limitations

Therefore if suspicion remains high despite a negative ultrasound:

 Reassess bladder
 Consider CT
 Seek urologic input

PART 62 — DEFINITIVE
MANAGEMENT OF POSTRENAL AKI
Remove or bypass the obstruction.
Examples:
Bladder outlet obstruction
 Foley catheter
 Suprapubic catheter when required
 BPH therapy
 Surgical management

Ureteric obstruction
 Ureteric stent
 Percutaneous nephrostomy
 Stone removal
 Tumor treatment

First Aid notes that postrenal AKI may require procedures such as nephrostomy or tumor-
related intervention.

PART 63 — POSTOBSTRUCTIVE
DIURESIS
After obstruction is relieved, the patient may produce a very large volume of urine.

Why?

The kidneys excrete:

 Retained salt
 Retained water
 Accumulated urea

Tubules may also temporarily have poor concentrating ability.

Possible complications:

 Dehydration
 Hypotension
 Hypokalemia
 Hypernatremia
 Hypomagnesemia

Therefore monitor:

 Hourly urine output

 Blood pressure
 Sodium
  Potassium
 Magnesium
 Volume status

Replacement should be careful; blindly matching every millilitre may perpetuate diuresis,
while inadequate replacement may cause shock.

PART 64 — COMPLETE AKI

INVESTIGATIONS
Immediate laboratory tests
 Serum creatinine
 Urea/BUN
 Sodium
 Potassium
 Bicarbonate
 Calcium
 Magnesium
 Phosphate
 Glucose
 CBC

Urine tests
 Urinalysis
 Urine microscopy
 Urine protein
 Urine sodium
 Urine creatinine
 Urine osmolality
 Culture when infection suspected

Other tests according to scenario

 CK for rhabdomyolysis
 Hemolysis screen
 Blood cultures
 Autoimmune and glomerular serology
 Drug levels
 Serum and urine electrophoresis where indicated

The First Aid source recommends history, examination, electrolytes, BUN, creatinine, urine
electrolytes, urinalysis, urine-output assessment and renal imaging.
PART 65 — HISTORY CHECKLIST
Use the mnemonic:

VOMIT–DRUG–BLOCK–SYSTEM
VOMIT
Volume loss:

 Vomiting
 Diarrhea
 Bleeding
 Poor intake
 Fever
 Burns

DRUG
 NSAIDs
 ACE inhibitors
 ARBs
 Diuretics
 Antibiotics
 PPIs
 Contrast
 Chemotherapy
 Herbal medicines

BLOCK
 Weak stream
 Retention
 Stones
 Cancer
 Pelvic surgery
 Neurogenic bladder

SYSTEM
 Sepsis
 Heart failure
 Cirrhosis
 Rash
  Arthritis
 Hemoptysis
 Hemolysis
 Vascular procedure

PART 66 — PHYSICAL EXAMINATION

Volume depletion
 Dry mucosa
 Orthostasis
 Low JVP
 Tachycardia
 Reduced skin turgor

Volume overload
 Raised JVP
 Crackles
 Edema
 Ascites
 Hypertension

Sepsis
 Fever
 Warm extremities early
 Hypotension
 Altered mentation

Obstruction
 Palpable bladder
 Enlarged prostate
 Pelvic mass
 Flank tenderness

Systemic renal disease

 Rash
 Purpura
 Joint swelling
 Livedo reticularis
 Blue toe
  Pulmonary hemorrhage features

PART 67 — BLAND VERSUS ACTIVE

URINE SEDIMENT
Bland sediment
Few cells or casts.

Think:

 Prerenal AKI
 Postrenal AKI
 Some vascular causes

Active sediment
Contains:

 RBC casts
 WBC casts
 Granular casts
 Dysmorphic RBCs
 Significant protein
 Crystals

Think:

Intrinsic renal injury

This is one of the highest-yield SMLE distinctions.

PART 68 — ROLE OF KIDNEY BIOPSY

Kidney biopsy is not required for routine dehydration or obvious obstruction.

Consider it when:

 Cause remains unclear

 Glomerulonephritis is suspected
 Vasculitis is suspected
  AIN diagnosis remains uncertain
 AKI is prolonged or atypical
 Treatment depends on pathology

Gold standard for defining intrinsic renal pathology

Kidney biopsy
But only when clinically appropriate and safe.

PART 69 — GENERAL MANAGEMENT

OF ALL AKI
Regardless of cause:

1. Treat the underlying cause

2. Optimise volume status
Avoid both:

 Hypovolemia
 Fluid overload

3. Stop nephrotoxins
4. Adjust medication doses
Renally cleared drugs may accumulate.

5. Monitor urine output

6. Monitor electrolytes and acid–base status
7. Manage nutrition
8. Prevent complications
9. Dialyse when indicated
PART 70 — FLUID MANAGEMENT
Do not give IV fluids automatically to every AKI patient.

Give fluids when:

 True volume depletion
 Hemorrhage
 GI losses
 Sepsis with fluid responsiveness
 Poor intake

Avoid unnecessary fluids when:

 Pulmonary edema
 Heart failure
 Cirrhosis with severe overload
 Oliguric intrinsic AKI with congestion

Clinical principle:

Treat the patient’s volume state, not the

creatinine alone.

PART 71 — ROLE OF DIURETICS

Loop diuretics may help control:

 Pulmonary edema
 Peripheral edema
 Severe volume overload

But:

Diuretics do not directly cure intrinsic AKI.

They may increase urine volume without improving GFR.

Do not use them simply to make the urine output look better.
PART 72 — DRUG MANAGEMENT
Review and temporarily stop or adjust when appropriate:

 NSAIDs
 ACE inhibitors
 ARBs
 Diuretics
 Metformin in severe renal dysfunction
 Nephrotoxic antibiotics
 Contrast exposure
 Renally excreted sedatives
 Anticoagulants requiring renal adjustment

The exact choice depends on:

 Cause of AKI
 Potassium
 Blood pressure
 Volume status
 Clinical indication

PART 73 — CONTRAST-ASSOCIATED
RENAL INJURY
Risk is greater with:

 CKD
 Diabetes with CKD
 Dehydration
 Older age
 Heart failure
 Large contrast volume
 Concurrent nephrotoxins

Prevention principles:

 Avoid unnecessary contrast

 Use the lowest necessary dose
 Correct dehydration
 Avoid concurrent nephrotoxins where possible
 Monitor high-risk patients
The supplied First Aid source lists radiocontrast among causes of acute tubular injury.

PART 74 — ELECTROLYTE
COMPLICATIONS
Hyperkalemia
Reduced potassium excretion.

Can cause:

 Peaked T waves
 QRS widening
 Arrhythmia
 Cardiac arrest

Treat using the hyperkalemia emergency algorithm already covered.

Hyponatremia
May develop from water retention.

Hyperphosphatemia
Reduced phosphate excretion.

Hypocalcemia
May result from phosphate retention and reduced vitamin-D activation, particularly with
more prolonged renal dysfunction.

PART 75 — ACID–BASE
COMPLICATION
The kidney cannot adequately excrete:

 Hydrogen ions
 Ammonium

↓
Metabolic acidosis develops.

Possible consequences:

 Tachypnea
 Reduced cardiac contractility
 Hyperkalemia
 Hypotension
 Altered consciousness

Severe refractory acidosis is an indication for dialysis.

PART 76 — FLUID OVERLOAD

Salt and water retention may cause:

 Peripheral edema
 Hypertension
 Pleural effusions
 Pulmonary edema
 Hypoxemia

Management:

 Fluid and sodium restriction

 Loop diuretic if responsive
 Oxygen/ventilatory support
 Dialysis if refractory

PART 77 — UREMIC COMPLICATIONS

Uremic encephalopathy
 Confusion
 Drowsiness
 Asterixis
 Seizures

Uremic pericarditis
 Pleuritic chest pain
 Pericardial rub
 Possible effusion
Platelet dysfunction
 Easy bruising
 Mucosal bleeding
 Procedure-related bleeding

These are important indications for renal replacement when clinically significant.

PART 78 — INDICATIONS FOR

DIALYSIS
Use the mnemonic:

AEIOU
A — Acidosis
Severe metabolic acidosis refractory to medical treatment.

E — Electrolytes
Especially refractory or life-threatening hyperkalemia.

I — Intoxications
Selected dialysable toxins.

O — Overload
Pulmonary edema or severe volume overload refractory to diuretics.

U — Uremia
 Encephalopathy
 Pericarditis
 Significant bleeding
 Severe persistent symptoms

Dialysis decisions depend on complications, not creatinine alone.

First Aid notes that AKI may require dialysis when supportive treatment is insufficient or
severe complications are present.
PART 79 — GOLD STANDARD AND
DEFINITIVE TREATMENT
There is no single definitive treatment for all AKI.

The definitive treatment is:

Correction of the underlying mechanism.

Prerenal volume loss
Definitive treatment:

Restore circulating volume and stop losses.

Drug-hemodynamic AKI
Definitive treatment:

Stop the causative drug and restore

perfusion.
Acute tubular injury
No instant curative drug.

Best treatment:

Supportive care while tubules recover.

Acute interstitial nephritis
Definitive treatment:

Remove the offending agent.

Pyelonephritis
Definitive treatment:

Appropriate antibiotics and relief of any

obstruction.
Glomerulonephritis
Definitive treatment:

Cause-specific immunologic therapy guided

by biopsy and serology.
Postrenal AKI
Definitive treatment:

Relieve obstruction.
Life-threatening complications
Definitive organ-support treatment:

Dialysis when indicated.

PART 80 — CLINICAL SCENARIOS

Scenario 1 — Gastroenteritis
Patient:

 Vomiting and diarrhea

 Orthostasis
 Dry mucosa
 Creatinine doubled
 BUN/Cr above 20
 FeNa below 1%
 Bland urine

Diagnosis:
Prerenal AKI from volume depletion.
Best treatment:

Isotonic fluids and treatment of GI losses.

Scenario 2 — NSAID-associated AKI

Older patient with CKD and dehydration takes ibuprofen.

Creatinine rises.

Mechanism:

NSAID blocks prostaglandins.

Afferent arteriole constricts.

Glomerular blood flow falls.

Management:

 Stop NSAID
 Correct dehydration
 Monitor renal function and potassium

Scenario 3 — ACE inhibitor after bilateral renal artery

stenosis
Patient with resistant hypertension starts ACE inhibitor.

Creatinine rises sharply.

Think:

Bilateral renal artery stenosis.

Mechanism:

Loss of efferent arteriolar constriction.

Next steps:

 Hold ACE inhibitor

 Renal vascular assessment
 Specialist management

Scenario 4 — Septic shock

Patient has:

 Fever
 Hypotension
 Elevated lactate
 Oliguria
 Rising creatinine

Initially:

Prerenal/septic hypoperfusion.
If prolonged:

Acute tubular injury.

Treatment:

 Antibiotics
 Source control
 Appropriate fluid resuscitation
 Vasopressors where required
 Renal monitoring

Scenario 5 — Muddy brown casts

ICU patient after prolonged hypotension develops:

 Rising creatinine
 FeNa above 1%
 Urine osmolality below 500
  Muddy brown casts

Diagnosis:

Ischemic acute tubular injury.

Treatment:

 Supportive care
 Treat shock
 Avoid nephrotoxins
 Dialysis if complications occur

Scenario 6 — Drug-induced AIN

Patient started an antibiotic two weeks ago.

Now:

 Fever
 Rash
 Eosinophilia
 AKI
 WBC casts

Diagnosis:

Acute interstitial nephritis.

Best treatment:

Stop the drug.

Consider biopsy or steroids if severe or not improving.

Scenario 7 — Rhabdomyolysis
Patient after crush injury:

 Muscle pain
 Dark urine
 CK extremely high
  Hyperkalemia
 Dipstick blood positive with few RBCs
 Rising creatinine

Diagnosis:

Pigment-associated tubular injury.

Management:

 Early isotonic fluids when appropriate

 Treat hyperkalemia
 Monitor renal function
 Dialysis if indicated

Scenario 8 — Atheroembolic disease

After coronary angiography:

 Creatinine rises
 Blue toe
 Livedo reticularis
 Eosinophilia
 Low complement

Diagnosis:

Cholesterol atheroembolic renal disease.

Management:

Supportive care and prevention of further

vascular injury.

Scenario 9 — BPH obstruction

Older man:

 Weak stream
 Hesitancy
 Suprapubic fullness
  Large postvoid residual
 Bilateral hydronephrosis
 Rising creatinine

Diagnosis:

Postrenal AKI.
Immediate treatment:

Urinary catheterisation.
Definitive treatment:

Relief of bladder outlet obstruction.

Scenario 10 — Postobstructive diuresis

After catheterisation:

 Several litres of urine produced

 Blood pressure falls
 Potassium falls

Diagnosis:

Postobstructive diuresis.
Management:

 Careful fluid replacement

 Frequent electrolyte checks
 Monitor urine output and blood pressure

PART 81 — HIGH-YIELD COMPARISON

Feature Prerenal AKI Acute tubular injury Postrenal AKI
Reduced
Primary problem Tubular damage Obstruction
perfusion
 Feature Prerenal AKI Acute tubular injury Postrenal AKI
Kidney structure
Intact Injured Initially intact
initially
BUN/Cr Often >20 Often <20 Variable
FeNa Usually <1% Often >1–2% Variable
Urine osmolality Often >500 Often <500 Variable
Urine sediment Bland/hyaline Muddy brown casts Bland, crystals or blood
Supportive, remove
Main treatment Restore perfusion Relieve obstruction
cause
Major progression Tubular injury CKD or dialysis need Hydronephrosis/fibrosis

These laboratory distinctions are presented in the First Aid AKI algorithm.

PART 82 — BEST TEST SUMMARY

First laboratory comparison

Current creatinine versus baseline

creatinine
Best initial urine investigation

Urinalysis with urine microscopy

Best test for suspected bladder retention

Bladder scan/postvoid residual

Best initial imaging for obstruction

Renal and bladder ultrasound

Best test for defining uncertain intrinsic pathology

Kidney biopsy
Best clue for prerenal physiology

Clinical hypoperfusion with sodium and

water conservation
Best clue for acute tubular injury

Muddy brown granular casts

Best clue for glomerular disease

Dysmorphic RBCs and RBC casts

Best clue for AIN

New drug exposure with sterile

pyuria/WBC casts ± eosinophilia

PART 83 — COMPLICATIONS DURING

AKI
 Hyperkalemia
 Metabolic acidosis
 Pulmonary edema
 Hypertension
 Uremic encephalopathy
 Uremic pericarditis
 Platelet dysfunction
 Infection
 Drug accumulation
 Malnutrition
 Arrhythmia
 Respiratory failure
 Death
PART 84 — COMPLICATIONS AFTER
AKI
Even if creatinine improves, patients may have increased risk of:

 Recurrent AKI
 Chronic kidney disease
 Hypertension
 Cardiovascular disease
 Future dialysis
 Mortality

Therefore follow-up may include:

 Repeat creatinine
 Urinalysis
 Proteinuria assessment
 Blood-pressure monitoring
 Medication review
 Avoidance of nephrotoxins

PART 85 — SMLE EXAM TRAPS

Trap 1
AKI always causes oliguria.

Incorrect.

AKI may be non-oliguric.

Trap 2
A high creatinine alone tells you the cause.

Incorrect.

You need:

 History
 Volume status
 Urinalysis
  Urine microscopy
 Urine electrolytes
 Imaging

Trap 3
Every AKI patient should receive IV fluids.

Incorrect.

Fluids may worsen:

 Heart failure
 Pulmonary edema
 Hypervolemic renal failure

Trap 4
Edema means the kidneys are well perfused.

Incorrect.

Heart failure and cirrhosis may cause edema with low effective renal perfusion.

Trap 5
FeNa below 1% always proves prerenal AKI.

Incorrect.

It is supportive, not absolute.

Trap 6
FeNa is reliable during diuretic therapy.

Less reliable.

FeUrea may be more useful in this setting.

Trap 7
Muddy brown casts suggest glomerulonephritis.

Incorrect.

They suggest acute tubular injury.

Trap 8
WBC casts mean only pyelonephritis.

Incorrect.

They may also occur in acute interstitial nephritis.

Trap 9
RBC casts are caused by lower urinary tract bleeding.

Incorrect.

RBC casts form inside renal tubules and strongly indicate glomerular inflammation.

Trap 10
AIN always presents with fever, rash and eosinophilia.

Incorrect.

The full triad is often absent.

Trap 11
Unilateral ureteric obstruction usually causes severe AKI.

Not when the other kidney is functioning normally.

Severe postrenal AKI usually requires bilateral obstruction, bladder outlet obstruction or a
solitary kidney.

Trap 12
A normal ultrasound completely excludes obstruction.

Incorrect.

Early or infiltrative obstruction may lack obvious hydronephrosis.

Trap 13
Diuretics cure intrinsic AKI.

Incorrect.

They may manage volume overload but do not repair damaged tubules.

Trap 14
Dialysis is started based only on a high creatinine.

Incorrect.

Dialysis is based mainly on:

AEIOU complications.

PART 86 — MEMORY MAPS

AKI LOCATION: FLOW–FILTER–
DRAIN
Flow
Prerenal

Filter/tissue

Intrinsic

Drain

Postrenal

PRERENAL CAUSES: EMPTY–PUMP–

PIPE
EMPTY

True volume loss

PUMP

Heart failure/low effective circulation

PIPE

Renal vascular tone or renal artery disease

INTRINSIC AKI: TIGV

T — Tubules

I — Interstitium

G — Glomeruli

V — Vessels

CASTS: M-W-R
M — Muddy brown = tubular injury
W — WBC casts = interstitial infection/inflammation

R — RBC casts = glomerular disease

POSTRENAL: PROSTATE–PELVIS–PIPE
Prostate/bladder outlet

Pelvic mass

Pipe blockage: ureter, urethra or catheter

DIALYSIS: AEIOU
A — Acidosis

E — Electrolytes

I — Intoxications

O — Overload

U — Uremia

PART 87 — FINAL MASTER

FLOWCHART
Creatinine rises or urine output falls
↓

Check immediately:
 Potassium
 ECG
 Acidosis
 Pulmonary edema
  Uremia
 Shock

Review:
 Fluid loss
 Infection
 Heart/liver disease
 Drugs
 Contrast
 Urinary symptoms
 Systemic disease

Examine volume status

Dry

Think prerenal volume loss.

Edematous

Think heart failure, cirrhosis, nephrotic state or intrinsic fluid retention.

Distended bladder

Think postrenal obstruction.

Urinalysis and microscopy

Bland

Prerenal or postrenal.

Muddy brown casts

Acute tubular injury.

WBC casts

AIN or pyelonephritis.
RBC casts

Glomerular disease.

Crystals

Crystal nephropathy.

Assess urinary indices when useful

 BUN/Cr
 FeNa
 FeUrea
 Urine osmolality

Ultrasound/bladder scan
Hydronephrosis or retention?

Yes

Relieve obstruction.

No

Continue prerenal/intrinsic evaluation.

Treat the mechanism

 Restore perfusion
 Stop nephrotoxins
 Treat sepsis
 Support tubular recovery
 Stop AIN drug
 Treat glomerular/vascular cause
 Relieve obstruction

↓
Monitor complications
 Potassium
 Acidosis
 Fluid overload
 Uremia

Dialysis if AEIOU indication develops.

FINAL MASTER CONCEPT

Acute kidney injury becomes understandable when you ask one question:

Is the kidney not receiving blood, is the

kidney tissue damaged, or is urine unable to
leave?
Prerenal
The kidney is structurally intact but underperfused.

It responds by conserving:

 Sodium
 Water
 Urea

Best treatment:

Restore effective renal blood flow.

Intrinsic
The kidney tissue is damaged.

Urine sediment reveals the injured compartment:

 Muddy brown casts → tubules

  WBC casts → interstitium
 RBC casts → glomeruli
 Crystals → tubular precipitation

Best treatment:

Remove the cause, provide renal support

and treat complications.
Postrenal
Urine is blocked.

Back pressure suppresses filtration.

Best treatment:

Relieve obstruction urgently.

Throughout every AKI case, the immediate priorities are:

Potassium
Acid–base status
Fluid balance
Uremic complications
The creatinine helps diagnose and monitor AKI, but the patient’s danger and need for dialysis
are determined mainly by:

AEIOU—not by the creatinine number

alone.
MEDICINE → NEPHROLOGY
TOPIC 4: CHRONIC KIDNEY DISEASE
SMLE 2026 — Mastery Level 2
Complete Conceptual, Interlinked and Scenario-Based Notes

The next adult Nephrology topic after Acute Kidney Injury in the SMLE 2026 blueprint is:

CHRONIC KIDNEY DISEASE —

MASTERY LEVEL 2
The blueprint expects you to understand renal physiology, recognize clinical manifestations,
explain the causes and pathophysiology, interpret laboratory and imaging findings, and
manage chronic renal disease and its complications.

SOURCE FRAMEWORK
Reference-book-based
Approach to Internal Medicine, Fifth Edition

Used for:

 Definition of CKD
 GFR and albuminuria staging
 CKD progression
 Clinical manifestations
 Differentiation of CKD from AKI
 Anemia
 Hyperkalemia
 Metabolic acidosis
 CKD–mineral and bone disorder
 Proteinuria reduction
 ACE-inhibitor mechanism
 Diabetic kidney disease
 Renal replacement therapy
 Dialysis indications

The supplied source defines CKD as abnormal renal function persisting for more than three
months and stages it according to GFR and albuminuria.

Clinical algorithm source

First Aid Clinical Algorithms for the USMLE Step 2 CK 2024
Used especially for:

 Recognition of chronic renal dysfunction

 Diabetic nephropathy
 Nephrotic protein loss as a cause of progression
 CKD-associated hypocalcemia
 Secondary hyperparathyroidism
 Renal osteodystrophy
 Complication-based management

First Aid links CKD with phosphate retention, reduced active vitamin D, hypocalcemia,
secondary hyperparathyroidism and renal bone disease.

Any additional physiology included only to build understanding is labelled:

Extra Concept for Concept Building

PART 1 — THE MASTER CONCEPT

CKD IS PROGRESSIVE LOSS OF
FUNCTIONING NEPHRONS
Do not think of CKD simply as:

“Creatinine has been high for a long time.”

The central disease process is:

A PROLONGED LOSS OF FUNCTIONAL

NEPHRONS THAT REDUCES THE
KIDNEY’S ABILITY TO FILTER,
REGULATE AND PRODUCE
HORMONES
A nephron is the functional unit of the kidney.

Each nephron contains:

 Glomerulus
  Proximal tubule
 Loop of Henle
 Distal tubule
 Collecting system

When nephrons are permanently damaged:

The remaining nephrons must perform more work.

Initially, this compensation maintains near-normal internal balance.

But excessive workload gradually damages the surviving nephrons.

Therefore CKD often progresses through a cycle:

NEPHRON LOSS
↓

SURVIVING NEPHRONS
HYPERFILTER
↓

INTRAGLOMERULAR PRESSURE
RISES
↓

PROTEIN LEAKAGE AND SCARRING

INCREASE
↓

MORE NEPHRONS ARE LOST

This is the fundamental progression pathway.
PART 2 — WHY CKD MAY BE SILENT
FOR YEARS
The kidneys have a large functional reserve.

A person can lose substantial nephron function while still having:

 Normal urine output

 No edema
 No nausea
 No obvious neurological symptoms

Why?

Remaining nephrons increase their filtration and excretion.

Therefore early CKD is often detected by:

 Albuminuria
 Reduced estimated GFR
 Incidental creatinine elevation
 Hypertension
 Abnormal ultrasound

By the time obvious uremic symptoms develop:

Kidney function is usually severely reduced.

PART 3 — CKD DEFINITION

The supplied Approach to Internal Medicine source defines CKD as:

Abnormal kidney function lasting more

than three months
which suggests an irreversible or persistent component.

Conceptually, CKD may be diagnosed by persistent:

 Reduced GFR
 Albuminuria or proteinuria
 Abnormal urine sediment
  Structural kidney abnormality
 Histological kidney damage
 Electrolyte abnormalities caused by tubular disease

The key word is:

CHRONICITY
The abnormality must persist or have clear evidence of long-standing disease.

PART 4 — CKD VERSUS AKI

Acute kidney injury
 Develops over hours to days
 Potentially reversible
 Creatinine changes rapidly
 Kidney size often normal
 Anemia and bone disease usually absent unless pre-existing

Chronic kidney disease

 Persists for more than three months
 Often irreversible
 Frequently associated with anemia
 May show small echogenic kidneys
 May show mineral and bone abnormalities
 Often has long-standing hypertension or proteinuria

The source identifies a previous creatinine abnormality lasting more than three months,
anemia and other chronic features as clues favouring CKD.

PART 5 — CLUES THAT RENAL

FAILURE IS CHRONIC
Look for:

 Previous elevated creatinine

 Long-standing hypertension
 Long-standing diabetes
 Persistent proteinuria
  Normocytic anemia
 Hyperphosphatemia
 Elevated PTH
 Renal bone disease
 Small echogenic kidneys
 Pruritus
 Peripheral neuropathy
 Chronic fatigue
 Sexual dysfunction

However:

Normal-sized or enlarged kidneys do not

exclude CKD.
Some chronic diseases may have large kidneys, including:

 Diabetic kidney disease

 Polycystic kidney disease
 Amyloidosis
 Infiltrative disorders

These examples are included only to prevent an important diagnostic mistake.

PART 6 — THE THREE QUESTIONS IN

EVERY CKD PATIENT
Ask:

1. What caused the CKD?

2. How severe is it?
3. What complications have developed?
Do not stop after saying:

“The eGFR is 35.”

You must identify:

  Cause
 GFR stage
 Albuminuria stage
 Rate of progression
 Cardiovascular risk
 Complications
 Need for nephrology or renal replacement planning

PART 7 — COMMON CAUSES

The most important chronic causes include:

 Diabetes mellitus
 Hypertension
 Chronic glomerular disease
 Chronic tubulointerstitial disease
 Polycystic kidney disease
 Reflux or obstructive nephropathy
 Systemic autoimmune disease
 Recurrent AKI
 Long-term nephrotoxin exposure

For SMLE scenarios, diabetes and hypertension are particularly common.

PART 8 — DIABETES AS A CAUSE OF

CKD
Chronic hyperglycemia damages renal microvasculature.

Initially:

Glucose-related hemodynamic changes

Afferent arteriolar dilation

Intraglomerular pressure rises.

↓
The glomerulus hyperfilters.

Over time:

 Glomerular basement membrane thickens

 Mesangial matrix expands
 Podocytes are injured
 Albumin leaks into urine
 Glomeruli scar

Therefore the progression is often:

HYPERFILTRATION
↓

ALBUMINURIA
↓

FALLING GFR
↓

ADVANCED CKD
The supplied source divides diabetic nephropathy into increasing albuminuria stages and
emphasizes glucose, blood pressure and lipid control, smoking cessation, RAAS blockade
and SGLT2 therapy in the indicated source-defined groups.

CLASSIC DIABETIC CKD SCENARIO

A patient with long-standing diabetes has:

 Hypertension
 Gradually increasing urine albumin
 Slowly falling eGFR
 No active urine sediment
 Diabetic retinopathy

Think:
Diabetic kidney disease.
The gradual course and albuminuria support chronic glomerular injury rather than an abrupt
AKI.

PART 9 — HYPERTENSION AS BOTH

CAUSE AND CONSEQUENCE
Hypertension damages small renal vessels.

Renal blood flow becomes abnormal.

Glomeruli become ischemic and scarred.

Nephrons are lost.

But CKD also causes hypertension through:

 Sodium retention
 Volume expansion
 RAAS activation
 Sympathetic activation

Therefore:

HYPERTENSION CAUSES CKD

and

CKD WORSENS HYPERTENSION

This creates another vicious cycle.
PART 10 — PROTEINURIA IS NOT
ONLY A MARKER
Proteinuria tells you that the glomerular barrier is damaged.

But filtered proteins also injure tubules.

Mechanism:

Albumin and other proteins enter tubular fluid.

Tubular cells reabsorb them.

Inflammatory and fibrotic pathways activate.

Interstitial scarring increases.

Therefore:

More proteinuria generally means faster

CKD progression.
The supplied source explicitly notes that proteinuria is not merely a surrogate marker but a
progression risk factor.

Extra Concept for Concept Building

WHY ACE INHIBITORS REDUCE
PROTEINURIA
Angiotensin II constricts the efferent arteriole.

This raises pressure inside the glomerulus.

ACE inhibition:
↓

Dilates the efferent arteriole.

Intraglomerular pressure decreases.

Less protein is forced across the filtration barrier.

Proteinuria falls.

Long-term glomerular stress and fibrosis decrease.

The source describes reduced intraglomerular pressure, proteinuria, hypertrophy and fibrosis
as the kidney-protective effects of ACE inhibition.

PART 11 — WHY CREATININE MAY

RISE AFTER ACE INHIBITOR
When efferent pressure is reduced:

GFR may initially fall slightly.

Creatinine may rise.

The supplied source states that a creatinine increase below approximately 30% after starting
an ACE inhibitor may be acceptable when the long-term renal benefit is important.

A large rise should prompt evaluation for:

 Bilateral renal artery stenosis

 Severe volume depletion
 NSAID use
 Excessive diuresis
 Advanced low-perfusion state
Also monitor:

Potassium
because RAAS blockade can cause hyperkalemia.

PART 12 — GFR STAGING

The supplied source stages CKD by GFR as follows:

G eGFR, mL/min/1.73
Concept
stage m²
Normal/high filtration but kidney-damage evidence
G1 ≥90
required
G2 60–89 Mild reduction; kidney-damage evidence required
G3a 45–59 Mild-to-moderate reduction
G3b 30–44 Moderate-to-severe reduction
G4 15–29 Severe reduction
G5 <15 Kidney failure

Important:

G1 or G2 alone does not establish CKD.

A patient with eGFR 85 needs evidence such as:

 Albuminuria
 Structural abnormality
 Abnormal sediment
 Histological disease

PART 13 — WHY G3 IS DIVIDED INTO

G3a AND G3b
Complication and progression risks rise significantly as GFR falls.

Compared with G3a, a patient in G3b is more likely to develop:

 Anemia
  Acidosis
 Mineral-bone abnormalities
 Hyperkalemia
 Cardiovascular disease
 Progression to kidney failure

Therefore G3b deserves closer monitoring and more active complication assessment.

PART 14 — ALBUMINURIA STAGING

The supplied source uses urinary albumin-to-creatinine ratio:

Albuminuria stage ACR Meaning

A1 <3 mg/mmol Normal to mildly increased
A2 3–30 mg/mmol Moderately increased
A3 >30 mg/mmol Severely increased

The same source associates higher albuminuria with stronger indications for renoprotective
therapy.

Albuminuria is important because it predicts:

 CKD progression
 Cardiovascular events
 Mortality

PART 15 — WHY USE ACR?

Urine concentration varies throughout the day.

A concentrated urine sample may show apparently high albumin concentration.

A dilute urine sample may show low concentration.

ACR compares albumin with urine creatinine.

This partially corrects for urine concentration.

Therefore:
Spot urine ACR is a practical test for
albuminuria.
A transient elevation can occur with:

 Fever
 Exercise
 Infection
 Severe hyperglycemia
 Acute hypertension

Therefore unexpected albuminuria may require confirmation.

PART 16 — CKD RISK IS A

COMBINATION
A patient with:

 G2
 A3 albuminuria

may have greater progression risk than a patient with:

 G3a
 A1 albuminuria

Therefore do not assess CKD from GFR alone.

Think:

CAUSE + GFR + ALBUMINURIA

Memory:

C-G-A

PART 17 — CLINICAL PRESENTATION

Early CKD
Often asymptomatic.

Possible clues:

 Hypertension
 Albuminuria
 Microscopic hematuria
 Nocturia
 Mild edema
 Incidental creatinine rise

Moderate CKD
 Fatigue
 Reduced exercise tolerance
 Anemia
 Hypertension
 Nocturia
 Edema
 Mild acidosis
 Mineral abnormalities

Advanced CKD
 Anorexia
 Nausea
 Vomiting
 Pruritus
 Sleep disturbance
 Muscle cramps
 Restless legs
 Cognitive impairment
 Neuropathy
 Sexual dysfunction
 Severe volume overload
 Uremic manifestations

The Approach source lists constitutional, neurological, gastrointestinal, hematologic,

musculoskeletal, dermatologic and sexual manifestations of advanced CKD.

PART 18 — WHY NOCTURIA MAY

APPEAR EARLY
Damaged kidneys lose concentrating ability.

During the day, the patient may not excrete the required solute and water efficiently.

At night:

Urine production continues.

The patient wakes repeatedly to urinate.

Therefore nocturia in CKD may reflect impaired concentration rather than simply excessive
total urine formation.

PART 19 — WHY EDEMA DEVELOPS

As GFR falls:

Sodium excretion becomes less efficient.

Sodium remains in the body.

Water follows sodium.

Extracellular volume expands.

Clinical manifestations:

 Ankle edema
 Weight gain
 Hypertension
 Raised JVP
 Pulmonary congestion
 Pleural effusion

Management depends on severity and includes:

  Sodium restriction
 Fluid management
 Diuretics
 Dialysis when refractory

The source recommends low-sodium intake and diuretics for CKD-related volume overload.

PART 20 — WHY HYPERKALEMIA

DEVELOPS
The kidneys normally excrete most dietary potassium.

As nephron function falls:

Potassium excretion becomes more difficult.

Hyperkalemia becomes more likely with:

 Low GFR
 Diabetes
 Type 4 RTA physiology
 ACE inhibitor
 ARB
 Mineralocorticoid antagonist
 NSAID
 High potassium intake
 Acidosis

Possible presentation:

 No symptoms
 Weakness
 Palpitations
 Peaked T waves
 Conduction abnormalities
 Cardiac arrest

Management follows the hyperkalemia algorithm already covered.

For chronic control, the supplied source includes dietary potassium reduction, diuretics
according to renal function, adjustment of RAAS therapy when necessary, and potassium
binders.
PART 21 — WHY METABOLIC
ACIDOSIS DEVELOPS
Healthy kidneys:

 Excrete hydrogen ions

 Generate ammonium
 Reclaim bicarbonate
 Generate new bicarbonate

As functioning nephron mass falls:

Total acid excretion falls.

Hydrogen ions accumulate.

Serum bicarbonate decreases.

Consequences include:

 Fatigue
 Tachypnea
 Muscle wasting
 Bone buffering and bone disease
 Hyperkalemia
 Faster CKD progression

The supplied source recommends considering sodium bicarbonate when CKD is associated
with low bicarbonate or acidemia.

PART 22 — CKD ANEMIA

CKD classically causes:

Normocytic, normochromic anemia

The main mechanism is:
Reduced erythropoietin production.
Normally, renal interstitial cells detect reduced oxygen delivery.

They release erythropoietin.

Bone marrow produces red blood cells.

In CKD:

Damaged kidneys produce less erythropoietin.

Bone marrow stimulation falls.

Hemoglobin decreases.

PART 23 — OTHER CONTRIBUTORS

TO CKD ANEMIA
Do not assume every anemia in CKD is caused only by erythropoietin deficiency.

Other contributors include:

 Iron deficiency
 Chronic inflammation
 Reduced red-cell lifespan
 Blood loss
 Dialysis-related blood loss
 Nutritional deficiency
 Occult gastrointestinal bleeding
 Secondary hyperparathyroidism

Therefore evaluate:

 CBC and indices

 Ferritin
 Transferrin saturation
  B12/folate when indicated
 Blood loss where suspected

The supplied source instructs that iron stores should be adequate before erythropoietin
therapy is started.

CKD ANEMIA SCENARIO

A patient with stage 4 CKD has:

 Fatigue
 Exertional dyspnea
 Pallor
 Hemoglobin 8.9 g/dL
 Normal MCV
 No hemolysis
 Low-normal reticulocyte response

Think:

CKD-associated hypoproliferative anemia.

But first:

Assess and correct iron deficiency.

PART 24 — TREATMENT OF CKD

ANEMIA
Management principles from the supplied source:

1. Confirm and treat iron deficiency.

2. Treat other reversible anemia causes.
3. Consider an erythropoiesis-stimulating agent in appropriate CKD-related anemia.
4. Avoid normalizing hemoglobin excessively.
5. Monitor blood pressure, iron status and hemoglobin response.

The Approach source gives epoetin alfa or darbepoetin as options and stresses adequate iron
stores before treatment.
Best treatment concept

Iron if iron-deficient; ESA when true CKD

erythropoietin deficiency remains clinically
significant.
Blood transfusion may be needed in selected severe or unstable cases, but repeated
transfusion can complicate future transplantation through sensitization.

PART 25 — CKD–MINERAL AND BONE

DISORDER
THE COMPLETE MECHANISM
This is one of the most important SMLE CKD mechanisms.

As GFR falls:

Phosphate excretion decreases.

Phosphate accumulates.

At the same time, damaged kidneys produce less active vitamin D:

1,25-dihydroxyvitamin D — calcitriol
Low calcitriol:

Intestinal calcium absorption decreases.

Phosphate retention also lowers free calcium.

↓
Serum calcium tends to fall.

The parathyroid glands respond:

PTH increases.

This is:

Secondary hyperparathyroidism.
The source gives the same chain:

↓ active vitamin D + ↑ phosphate → ↓

calcium → ↑ PTH → CKD-mineral bone
disease.

PART 26 — WHY PTH RISES

PTH attempts to restore serum calcium by:

 Increasing bone resorption

 Increasing renal calcium reabsorption
 Increasing phosphate excretion
 Stimulating active vitamin D formation

But in CKD:

 The kidney cannot excrete phosphate effectively.

 The kidney cannot adequately activate vitamin D.

Therefore the original stimulus persists.

PTH remains chronically elevated.

Bone turnover becomes abnormal.

PART 27 — RENAL OSTEODYSTROPHY
Renal osteodystrophy refers to the skeletal consequences of CKD-mineral bone disorder.

Possible patterns described by the supplied source include:

Osteitis fibrosa
High bone turnover due to secondary hyperparathyroidism.

Osteomalacia
Poor mineralization of bone.

Adynamic bone disease

Very low bone turnover, often from excessive suppression of PTH.

Mixed uremic bone disease

Combined abnormalities of turnover and mineralization.

PART 28 — CLINICAL PRESENTATION

OF CKD BONE DISEASE
 Bone pain
 Muscle weakness
 Fractures
 Skeletal deformity in severe long-standing disease
 Vascular and soft-tissue calcification
 Pruritus associated with phosphate imbalance
 Elevated PTH
 High phosphate
 Low or low-normal calcium
 Low active vitamin D

First Aid similarly associates CKD with hypocalcemia, high phosphate, high PTH and renal
osteodystrophy.
PART 29 — TREATMENT OF CKD-
MINERAL BONE DISORDER
The source-based framework includes:

 Dietary phosphate restriction

 Phosphate binders
 Correction of vitamin D deficiency
 Active vitamin D such as calcitriol in selected cases
 Monitoring calcium, phosphate and PTH
 Parathyroidectomy for severe refractory hyperparathyroidism

The Approach source specifically lists dietary phosphate restriction, phosphate binders,
calcitriol and parathyroidectomy as available strategies.

Important:

Excessive calcium or vitamin D treatment

can cause hypercalcemia, vascular
calcification or overly suppressed bone
turnover.
Therefore treatment is guided by trends rather than a single isolated PTH result.

PART 30 — SECONDARY VERSUS

TERTIARY HYPERPARATHYROIDISM
Secondary hyperparathyroidism
Low calcium/high phosphate/low calcitriol stimulate PTH.

Typical CKD pattern:

 PTH high
 Phosphate high
 Calcium low or normal

Tertiary hyperparathyroidism
After prolonged stimulation, the parathyroid glands become autonomous.

PTH secretion continues even when calcium is no longer low.

Typical pattern:

 PTH very high

 Phosphate high in CKD
 Calcium high

This distinction is included because it is directly necessary to understand a major CKD

complication.

PART 31 — CARDIOVASCULAR
COMPLICATIONS
Patients with CKD are at high risk of:

 Hypertension
 Left ventricular hypertrophy
 Heart failure
 Coronary disease
 Stroke
 Arrhythmia
 Sudden cardiac death
 Vascular calcification

Why?

 Volume overload
 Hypertension
 Anemia
 Chronic inflammation
 Dyslipidemia
 Mineral imbalance
 Endothelial dysfunction
 Diabetes

Therefore cardiovascular disease is a major source of morbidity and mortality in CKD.

PART 32 — UREMIA
Uremia is the clinical syndrome produced by retention of toxins and metabolic products in
advanced renal failure.

It is not defined by one particular urea concentration.

Affected systems include:

Constitutional
 Fatigue
 Weakness
 Weight loss

Gastrointestinal
 Anorexia
 Nausea
 Vomiting
 Metallic taste
 Gastritis

Neurological
 Poor concentration
 Sleep disturbance
 Peripheral neuropathy
 Asterixis
 Confusion
 Seizures

Dermatological
 Pruritus
 Sallow skin
 Uremic frost in extreme disease

Hematological
 Platelet dysfunction
 Easy bruising
 Bleeding

Reproductive
 Sexual dysfunction
 Infertility
 Menstrual disturbance
These manifestations are listed in the supplied Approach source.

PART 33 — UREMIC PERICARDITIS

Retained uremic toxins can inflame the pericardium.

Presentation:

 Pleuritic chest pain

 Pain relieved by sitting forward
 Pericardial rub
 Possible pericardial effusion

This is an important indication for:

Dialysis
because it reflects clinically significant uremia.

PART 34 — UREMIC PLATELET

DYSFUNCTION
Platelet count may be normal.

But platelet adhesion and aggregation are impaired.

Therefore the patient may develop:

 Epistaxis
 Gum bleeding
 Easy bruising
 GI bleeding
 Prolonged bleeding after procedures

Clinical lesson:

A normal platelet count does not exclude

uremic bleeding.
Dialysis helps remove uremic toxins and improve platelet function.
PART 35 — UREMIC
ENCEPHALOPATHY
Presentation may include:

 Reduced attention
 Confusion
 Drowsiness
 Asterixis
 Myoclonus
 Seizures
 Coma

This is not treated by waiting for creatinine to improve.

It is a major indication for:

Renal replacement therapy.

PART 36 — INVESTIGATIONS
The supplied source recommends assessment including:

 CBC
 Electrolytes
 Urea and creatinine
 Glucose and HbA1c
 Calcium
 Phosphate
 Magnesium
 PTH
 Albumin
 Lipid profile
 Urinalysis
 Urinary albumin/protein measurement

A structured CKD workup includes:

Kidney function
 Creatinine
  eGFR
 Trend over time

Urine damage markers

 Urine ACR
 Urinalysis
 Hematuria
 Proteinuria
 Casts when present

Complications
 Potassium
 Bicarbonate
 Hemoglobin
 Iron studies
 Calcium
 Phosphate
 PTH
 Albumin

Cause-directed studies
 HbA1c
 Autoimmune tests
 Hepatitis testing
 SPEP/UPEP/free light chains when appropriate
 Renal imaging

PART 37 — RENAL ULTRASOUND

Ultrasound assesses:

 Kidney size
 Cortical thickness
 Echogenicity
 Cysts
 Hydronephrosis
 Structural abnormalities

Typical chronic irreversible disease may show:

 Small kidneys
  Thin cortex
 Increased echogenicity

However, normal or enlarged kidneys may occur in some chronic diseases.

Therefore ultrasound helps establish:

 Chronicity
 Structural cause
 Obstruction

but does not determine every CKD cause.

PART 38 — WHEN KIDNEY BIOPSY IS

CONSIDERED
Biopsy may be useful when:

 Cause is unclear
 Proteinuria is substantial
 Active urine sediment is present
 Systemic disease is suspected
 GFR is declining unexpectedly
 Histology will change management

Biopsy is less useful when kidneys are severely small and scarred because:

 Diagnostic yield may be low

 Bleeding risk may be higher
 Damage may already be nonspecific and irreversible

PART 39 — ASSESSING RATE OF

PROGRESSION
A single eGFR gives severity at one moment.

Serial results tell you:

How fast the disease is progressing.

A stable eGFR of 35 for years is different from a fall from 60 to 35 over six months.
Rapid decline should prompt evaluation for:

 Superimposed AKI
 Poorly controlled hypertension
 Obstruction
 Nephrotoxic medication
 Active glomerular disease
 Severe hyperglycemia
 Renovascular disease
 Recurrent infection

PART 40 — GENERAL MANAGEMENT

GOALS
CKD treatment has four major goals:

1. Treat the underlying cause

2. Slow progression
3. Prevent and treat complications
4. Prepare for renal replacement therapy
when needed

PART 41 — SLOWING CKD

PROGRESSION
The supplied source emphasizes:

 Blood pressure control

 RAAS blockade in proteinuric disease
 Diabetes control
 Lipid control
 Avoidance of nephrotoxins
 Smoking cessation
 SGLT2 therapy in the source-defined diabetic albuminuric population
The key conceptual targets are:

Reduce glomerular pressure

 ACE inhibitor or ARB when indicated

Reduce protein leakage

 RAAS blockade
 Disease-specific treatment

Reduce metabolic injury

 Glycemic control

Reduce cardiovascular risk

 Blood-pressure and lipid management
 Smoking cessation

Prevent additional nephron loss

 Avoid nephrotoxins
 Prevent dehydration
 Treat obstruction and infection

PART 42 — ACE INHIBITOR OR ARB

Useful particularly when CKD is associated with:

 Albuminuria
 Proteinuria
 Diabetes
 Hypertension

Benefits:

 Lower systemic blood pressure

 Lower intraglomerular pressure
 Reduce albuminuria
 Slow fibrotic progression

Monitor after initiation or dose change:

  Creatinine
 Potassium
 Blood pressure

Avoid combining ACE inhibitor and ARB routinely because excessive RAAS blockade can
increase:

 AKI
 Hyperkalemia
 Hypotension

PART 43 — SGLT2 INHIBITOR

CONCEPT
Extra Concept for Concept Building
The supplied Approach source includes SGLT2 inhibitors in diabetic CKD with significant
albuminuria according to its stated thresholds.

Mechanistically:

SGLT2 inhibition increases sodium delivery to the macula densa.

Tubuloglomerular feedback is restored.

Afferent arteriolar tone increases.

Excess intraglomerular pressure decreases.

Hyperfiltration and albuminuria fall.

This is included because it directly explains a source-listed CKD treatment.

PART 44 — GLYCEMIC CONTROL

Persistent hyperglycemia worsens:

 Glomerular hyperfiltration
 Albuminuria
 Vascular injury
 Neuropathy
 Cardiovascular risk

But in advanced CKD:

 Insulin clearance decreases

 Some drugs accumulate
 Hypoglycemia risk rises

Therefore glucose treatment should be individualized and adjusted to renal function.

PART 45 — DIETARY PRINCIPLES

The exact diet depends on stage and complications.

Common principles include:

 Sodium restriction when hypertensive or edematous

 Potassium restriction when hyperkalemic
 Phosphate restriction when phosphate rises
 Avoidance of excessive protein intake
 Adequate nutrition
 Fluid restriction only when clinically needed

Do not impose every restriction automatically.

A patient without hyperkalemia does not necessarily require extreme potassium restriction.

A malnourished patient should not receive excessive protein restriction that worsens wasting.

PART 46 — AVOID NEPHROTOXINS

Important examples:

 NSAIDs
 Unnecessary iodinated contrast
 Unmonitored herbal preparations
 Nephrotoxic antibiotics
 Repeated dehydration
  Inappropriately dosed renally cleared medication

Patients should also be advised about “sick-day” situations in which dehydration may
increase AKI risk, with medication adjustment guided by their treating team.

PART 47 — MANAGING VOLUME

OVERLOAD
Mild/moderate
 Reduce sodium intake
 Loop diuretic
 Monitor weight
 Monitor blood pressure

Severe/refractory
 Intensify diuretic strategy when appropriate
 Oxygen/ventilatory support if pulmonary edema
 Dialysis if refractory

As GFR falls, loop diuretics are generally more useful than thiazide monotherapy for major
volume removal; the supplied source similarly distinguishes diuretic choices according to
renal function in its complication framework.

PART 48 — VACCINATION AND

INFECTION PREVENTION
Advanced CKD and dialysis are associated with impaired immune function.

Important preventive principles include:

 Appropriate routine vaccination

 Hepatitis B vaccination before dialysis when feasible
 Infection prevention for vascular or peritoneal access
 Early treatment of infection

This section is clinically related to CKD management but detailed vaccine schedules are not
provided in the supplied excerpts, so they are not expanded here.
PART 49 — WHEN TO REFER OR PLAN
EARLY
Early nephrology involvement is important when there is:

 G4 or G5 CKD
 Rapid progression
 Severe albuminuria
 Resistant hypertension
 Recurrent hyperkalemia
 Unexplained CKD
 Active urine sediment
 Significant anemia or bone disease
 Preparation for dialysis or transplantation

Why early planning?

Because creating permanent dialysis access and evaluating for transplantation take time.

PART 50 — KIDNEY FAILURE VERSUS

DIALYSIS REQUIREMENT
G5 means:

eGFR below 15 mL/min/1.73 m²

But G5 does not automatically mean immediate dialysis.

The supplied source notes that many patients do not start dialysis until a lower GFR range
and that there is no single strict GFR cutoff independent of symptoms and complications.

Therefore dialysis is started according to:

 Symptoms
 Complications
 Nutritional decline
 Refractory metabolic problems
 Volume control
 Overall clinical state
PART 51 — INDICATIONS FOR
DIALYSIS
Use:

AEIOU
A — Acidosis
Severe or refractory metabolic acidosis.

E — Electrolytes
Especially refractory or dangerous hyperkalemia.

I — Intoxications
Selected dialysable toxins.

O — Overload
Pulmonary edema or volume overload not controlled medically.

U — Uremia
 Encephalopathy
 Pericarditis
 Bleeding
 Severe nausea/vomiting
 Progressive malnutrition
 Other significant uremic symptoms

The source identifies uremic symptoms, acute indications and very advanced renal failure as
dialysis considerations.

PART 52 — HEMODIALYSIS
Hemodialysis moves blood through an extracorporeal filter.

Across a semipermeable membrane:

  Solutes diffuse
 Excess water is removed
 Potassium falls
 Acidosis improves
 Uremic toxins are reduced

Requires vascular access:

 Temporary dialysis catheter

 Tunneled catheter
 Arteriovenous fistula
 Arteriovenous graft

Best long-term vascular access

Arteriovenous fistula
when feasible, because it generally provides better long-term function and lower infection
risk than a catheter.

PART 53 — PERITONEAL DIALYSIS

Dialysate is placed inside the peritoneal cavity.

The peritoneal membrane acts as the dialysis membrane.

Solutes and water move between:

 Blood in peritoneal capillaries

 Dialysate

Advantages described in the supplied Approach source include greater patient autonomy and
preservation of residual renal function.

Major complication:

Peritonitis
Typical features:

 Abdominal pain
 Cloudy dialysate
 Increased dialysate white cells
The source identifies this triad and recommends intraperitoneal antimicrobial treatment
according to culture and local resistance.

PART 54 — KIDNEY
TRANSPLANTATION
For eligible patients with kidney failure:

Kidney transplantation is the best definitive

renal replacement option.
Why?

A functioning transplanted kidney can restore:

 Filtration
 Fluid regulation
 Endocrine function
 Better quality of life than long-term dialysis in suitable patients

However, it requires:

 Donor evaluation
 Immunosuppression
 Rejection monitoring
 Infection and malignancy surveillance

The supplied source lists dialysis, renal transplantation or palliation as options in advanced
G5 disease.

PART 55 — CONSERVATIVE KIDNEY

MANAGEMENT
Not every patient is an appropriate dialysis candidate.

For a frail patient with severe comorbidity, management may focus on:

 Symptom control
 Volume management
 Anemia treatment
  Pruritus control
 Nausea control
 Advance-care planning
 Palliative support

The supplied source includes palliation among options for advanced kidney failure.

PART 56 — COMPLICATIONS DURING

CKD
 Hypertension
 Volume overload
 Pulmonary edema
 Hyperkalemia
 Metabolic acidosis
 Anemia
 Secondary hyperparathyroidism
 Renal osteodystrophy
 Fractures
 Vascular calcification
 Uremic encephalopathy
 Uremic pericarditis
 Platelet dysfunction
 Malnutrition
 Infection
 Cardiovascular disease
 Sexual dysfunction

PART 57 — COMPLICATIONS AFTER

PROGRESSION TO KIDNEY FAILURE
 Dialysis dependence
 Access infection or thrombosis
 Dialysis hypotension
 Peritoneal dialysis peritonitis
 Cardiovascular death
 Severe frailty
 Recurrent hospitalization
 Transplant-related immunosuppression complications

The exact complication depends on the chosen renal-replacement strategy.

PART 58 — CLINICAL SCENARIOS
Scenario 1 — Early diabetic CKD
A patient with long-standing diabetes has:

 Normal serum creatinine

 eGFR 95
 Persistent ACR elevation

Diagnosis:

CKD can still be present despite normal

GFR because persistent albuminuria
represents kidney damage.
Management:

 Glycemic control
 Blood-pressure control
 RAAS blockade when indicated
 Source-supported renoprotective therapy
 Smoking and lipid management

Scenario 2 — Hypertensive CKD

A patient has:

 Long-standing poorly controlled hypertension

 Gradual creatinine rise
 Mild proteinuria
 Small echogenic kidneys

Diagnosis:

Chronic hypertensive kidney damage.

Management:

 Blood-pressure control
  Proteinuria reduction
 Cardiovascular-risk management
 Complication monitoring

Scenario 3 — CKD anemia

Stage 4 CKD patient:

 Fatigue
 Pallor
 Normocytic anemia
 Low reticulocyte response

Diagnosis:

Erythropoietin-deficiency anemia.
Next steps:

 Iron studies
 Exclude bleeding and nutritional deficiencies
 Replace iron if deficient
 Consider ESA when appropriate

Scenario 4 — CKD mineral-bone disease

Patient with advanced CKD has:

 Bone pain
 Phosphate high
 Calcium low-normal
 PTH high
 Active vitamin D low

Diagnosis:

Secondary hyperparathyroidism due to

CKD.
Mechanism:

Phosphate retention + low calcitriol

↓

Low calcium

PTH rises.

Treatment:

 Phosphate control
 Phosphate binder
 Vitamin D strategy
 PTH monitoring

Scenario 5 — Tertiary hyperparathyroidism

A long-term dialysis patient develops:

 Very high PTH

 High phosphate
 High calcium

Diagnosis:

Autonomous tertiary hyperparathyroidism.

Definitive treatment in severe refractory disease may include:

Parathyroidectomy.

Scenario 6 — Hyperkalemia
Patient with CKD taking an ACE inhibitor has:

 Potassium 6.6 mmol/L

 Peaked T waves

Immediate management:

 Cardiac stabilization
 Intracellular shifting
 Potassium removal
Do not delay emergency treatment to debate whether long-term RAAS therapy should
eventually be resumed.

Scenario 7 — Volume overload

Advanced CKD patient has:

 Orthopnea
 Raised JVP
 Crackles
 Severe edema
 Poor response to loop diuretic

Diagnosis:

Refractory CKD-related volume overload.

Definitive management:

Dialysis/ultrafiltration when medical

treatment fails.

Scenario 8 — Uremic pericarditis

Advanced CKD patient has:

 Pleuritic chest pain

 Pericardial rub
 Severe uremic symptoms

Best treatment:

Dialysis.

Scenario 9 — Uremic encephalopathy

Patient with advanced renal failure develops:
  Confusion
 Asterixis
 Drowsiness
 No alternative neurological explanation

Diagnosis:

Uremic encephalopathy.
Definitive treatment:

Dialysis.

Scenario 10 — G5 without symptoms

Patient has:

 eGFR 12
 No hyperkalemia
 No acidosis
 No pulmonary edema
 No uremic symptoms
 Stable nutrition

Do not start dialysis solely because eGFR is below 15.

Instead:

 Nephrology follow-up
 Transplant assessment
 Access planning
 Complication monitoring
 Start dialysis when clinical indications arise

PART 59 — BEST TEST / GOLD

STANDARD / DEFINITIVE
TREATMENT
Best screening tests for CKD in a high-risk patient
Serum creatinine/eGFR + urine ACR
Best evidence of chronicity

Abnormal kidney structure or function

persisting for more than three months
Best test for albuminuria

Spot urine albumin-to-creatinine ratio

Best imaging to assess size and chronic structural changes

Renal ultrasound
Gold standard when renal histology is required

Kidney biopsy
Best progression markers

Serial eGFR + albuminuria trend

Best treatment for proteinuric CKD

Cause-specific therapy plus

intraglomerular-pressure and proteinuria
reduction
Best treatment for CKD anemia

Correct iron deficiency, then consider ESA

for persistent appropriate CKD anemia
Best treatment for refractory uremic complications

Dialysis
Best definitive renal replacement treatment in a suitable
patient

Kidney transplantation

PART 60 — HIGH-YIELD
COMPARISON: AKI VERSUS CKD
Feature AKI CKD
Duration Hours to days >3 months
Previous creatinine Often normal Persistently abnormal
Anemia Usually absent initially Common
Mineral-bone disease Usually absent Common in advanced disease
Kidney size Often normal Often small/echogenic
Reversibility Frequently possible Usually partly irreversible
Urine output Variable Often preserved until late
Main goal Reverse acute insult Slow progression and manage complications

PART 61 — SMLE EXAM TRAPS

Trap 1
CKD means eGFR must be below 60.

Incorrect.

Persistent albuminuria or structural kidney damage can establish CKD with eGFR above 60.

Trap 2
A normal urine output excludes advanced CKD.
Incorrect.

Patients may continue producing urine despite poor filtration.

Trap 3
Creatinine alone accurately reflects severity in every patient.

Incorrect.

Creatinine depends on muscle mass and should be interpreted with eGFR and baseline trend.

Trap 4
Proteinuria is only a marker.

Incorrect.

Filtered protein promotes tubular inflammation and fibrosis.

Trap 5
ACE inhibitors damage all CKD kidneys.

Incorrect.

They can reduce intraglomerular pressure and slow proteinuric CKD progression, although
creatinine and potassium must be monitored.

Trap 6
Any creatinine rise after ACE inhibitor means it must be permanently stopped.

Incorrect.

A small expected rise may be acceptable; a large rise requires evaluation for perfusion
problems or renal artery stenosis.
Trap 7
CKD anemia should immediately be treated with erythropoietin.

Incorrect.

First assess and correct iron deficiency and other causes.

Trap 8
CKD hypocalcemia is caused only by dietary calcium deficiency.

Incorrect.

Major mechanisms are:

 Phosphate retention
 Reduced active vitamin D
 Secondary hyperparathyroidism

Trap 9
PTH elevation in CKD is primary hyperparathyroidism.

Incorrect.

It is usually secondary to phosphate retention, hypocalcemia and low calcitriol.

Trap 10
All stage G5 patients require immediate dialysis.

Incorrect.

Dialysis is based on symptoms and complications, not eGFR alone.

Trap 11
Dialysis is started when creatinine reaches a particular number.
Incorrect.

Use clinical indications such as:

AEIOU.

Trap 12
Diuretics reverse nephron loss.

Incorrect.

They control volume but do not restore lost nephron mass.

Trap 13
High total-body fluid means renal perfusion is adequate.

Incorrect.

Heart failure and cirrhosis may cause edema with low effective renal perfusion.

Trap 14
Kidney transplantation merely filters waste like dialysis.

Incorrect.

A functioning graft also restores many endocrine and homeostatic renal functions.

PART 62 — MEMORY MAPS

CKD DIAGNOSIS: 3–CGA
3

Abnormality for more than 3 months

C

Cause

GFR stage

Albuminuria stage

CKD PROGRESSION: PRESSURE–

PROTEIN–SCAR
High glomerular pressure

Protein leakage

Tubular inflammation

Fibrosis and nephron loss

MAJOR CKD COMPLICATIONS: A-

BONE-FLUID-K
A — Anemia and acidosis

BONE — Phosphate, vitamin D, PTH

FLUID — Edema and hypertension

K — Hyperkalemia
CKD BONE CHAIN
LOW GFR
↓

PHOSPHATE HIGH


CALCITRIOL LOW
↓

CALCIUM LOW
↓

PTH HIGH
↓

RENAL BONE DISEASE

CKD ANEMIA CHAIN

DAMAGED KIDNEY
↓

EPO LOW
↓

MARROW STIMULATION LOW

↓
NORMOCYTIC ANEMIA

RENAL REPLACEMENT: D-T-C

D — Dialysis

T — Transplant

C — Conservative care

DIALYSIS: AEIOU
A — Acidosis

E — Electrolytes

I — Intoxications

O — Overload

U — Uremia

PART 63 — FINAL MASTER

FLOWCHART
Persistent kidney abnormality
↓

Confirm duration greater than 3 months

↓

Identify the cause

  Diabetes
 Hypertension
 Glomerular disease
 Tubulointerstitial disease
 Structural/obstructive disease
 Genetic disease

Classify severity
 GFR stage
 Albuminuria stage

Assess progression
 Serial eGFR
 Serial ACR
 Blood-pressure control
 New AKI or nephrotoxins

Look for complications

 Volume overload
 Hyperkalemia
 Acidosis
 Anemia
 Calcium/phosphate/PTH disorder
 Uremia
 Cardiovascular disease

Slow progression
 Treat cause
 Control blood pressure
 Reduce proteinuria
 Control diabetes
 Avoid nephrotoxins
 Stop smoking
 Address cardiovascular risk
↓

Treat complications
 Diuretics for overload
 Potassium management
 Bicarbonate when indicated
 Iron ± ESA for anemia
 Phosphate and vitamin D/PTH management

Prepare for kidney failure

 Nephrology
 Access planning
 Transplant evaluation
 Conservative-care discussion

Start dialysis when clinically indicated

AEIOU—not creatinine alone.

FINAL MASTER CONCEPT

Chronic kidney disease is not simply a persistently high creatinine.

It is:

PROGRESSIVE LOSS OF
FUNCTIONING NEPHRONS
The surviving nephrons initially compensate through hyperfiltration.

But excessive intraglomerular pressure causes:

 Protein leakage
 Glomerular scarring
 Tubular inflammation
  Further nephron loss

Therefore CKD progresses through:

NEPHRON LOSS
↓

HYPERFILTRATION
↓

PROTEINURIA
↓

FIBROSIS
↓

MORE NEPHRON LOSS

As filtration declines, the kidney progressively fails in four major roles:

1. EXCRETION
 Urea
 Potassium
 Acid
 Phosphate

2. FLUID REGULATION
 Sodium retention
 Edema
 Hypertension
 Pulmonary edema

3. ENDOCRINE FUNCTION
 Erythropoietin falls → anemia
 Calcitriol falls → hypocalcemia and secondary hyperparathyroidism
4. TOXIN CLEARANCE
 Uremic neurological, gastrointestinal, hematological and cardiac manifestations

The SMLE approach is:

Confirm chronicity
↓

Find the cause

↓

Stage GFR and albuminuria

↓

Slow progression
↓

Detect and treat complications

↓

Prepare for dialysis or transplantation

before an emergency develops
The most important final distinction is:

Dialysis supports a failing kidney.

Transplantation replaces kidney function
more completely.
And dialysis is started because of:
ACIDOSIS, ELECTROLYTES,
INTOXICATION, OVERLOAD OR
UREMIA
—not simply because the creatinine looks frightening.

MEDICINE → NEPHROLOGY
TOPIC 5: PRIMARY HYPERTENSION
SMLE 2026 — Mastery Level 2
Complete Conceptual, Interlinked and Scenario-Based Notes

The next adult Nephrology topic after Chronic Kidney Disease in the SMLE 2026 blueprint
is:

PRIMARY HYPERTENSION —
MASTERY LEVEL 2
The blueprint places Primary Hypertension before Secondary Hypertension. Therefore, this
chapter focuses only on primary/essential hypertension, its diagnosis, pathophysiology,
clinical presentation, organ damage, investigations and management. Secondary causes will
be covered separately in the next TOS topic.

SOURCE FRAMEWORK
Reference-book-based
Approach to Internal Medicine

Used for:

 Correct blood-pressure measurement

 Office, automated-office, home and ambulatory monitoring
 Confirmation of hypertension
 Initial assessment
 Cardiovascular risk assessment
 Investigation for target-organ damage
  Lifestyle treatment
 Drug-selection principles
 Long-term follow-up
 Recognition of urgency and emergency

The source distinguishes automated office measurement, conventional office measurement,

24-hour ambulatory monitoring and validated home monitoring, and recommends confirming
persistent hypertension rather than relying blindly on one routine reading when there is no
hypertensive crisis.

Clinical algorithm source

First Aid Clinical Algorithms for the USMLE Step 2 CK 2024

Used especially for:

 Essential hypertension scenario

 Confirmation with ambulatory blood-pressure monitoring
 Lifestyle interventions
 First-line antihypertensive classes
 Comorbidity-directed drug selection
 Target-organ complications
 Hypertensive urgency versus emergency
 Emergency blood-pressure reduction strategy

First Aid’s essential-hypertension algorithm uses sustained hypertension confirmed outside

the office, recommends lifestyle modification and lists thiazides, calcium-channel blockers,
ACE inhibitors and ARBs as major initial drug classes.

IMPORTANT SOURCE NOTE

The supplied First Aid source defines hypertension as:

Systolic BP ≥130 mmHg and/or diastolic BP

≥80 mmHg.
Different international guidelines may use somewhat different diagnostic and treatment
thresholds. Because you asked that these notes remain grounded in your provided books, the
numerical framework below follows the supplied sources. In an actual clinical setting, always
use the guideline adopted by the local institution or examining body.
PART 1 — THE MASTER CONCEPT
WHAT IS BLOOD PRESSURE?
Blood pressure is the force exerted by circulating blood against arterial walls.

It is determined mainly by:

Blood Pressure=Cardiac Output×Systemic Vascular Resistance\text{Blood Pressure} =

\text{Cardiac Output} \times \text{Systemic Vascular
Resistance}Blood Pressure=Cardiac Output×Systemic Vascular Resistance

Therefore blood pressure rises when:

 The heart pumps more blood

 Blood vessels become more constricted
 Blood volume increases
 Or several of these occur together

This is the starting point for understanding hypertension.

PART 2 — WHAT IS CARDIAC

OUTPUT?
Cardiac output means the amount of blood pumped by the heart per minute.

Cardiac Output=Heart Rate×Stroke Volume\text{Cardiac Output} = \text{Heart Rate} \times

\text{Stroke Volume}Cardiac Output=Heart Rate×Stroke Volume

Cardiac output rises when:

 Heart rate increases

 Contractility increases
 Circulating volume increases
 Venous return increases

Therefore excess sodium and water retention can raise blood pressure by increasing:

Circulating volume → stroke volume →

cardiac output
PART 3 — WHAT IS SYSTEMIC
VASCULAR RESISTANCE?
Systemic vascular resistance is the opposition that arteries and arterioles provide to blood
flow.

When arterioles constrict:

Their radius decreases.

Resistance rises sharply.

Blood pressure increases.

Important regulators include:

 Sympathetic nervous system

 Angiotensin II
 Endothelin
 Nitric oxide
 Local vascular autoregulation

Therefore hypertension may be driven by:

More volume
and/or

More vascular constriction

PART 4 — SYSTOLIC AND DIASTOLIC

PRESSURE
Systolic blood pressure
The peak arterial pressure during ventricular contraction.

It is influenced by:

 Stroke volume
 Aortic stiffness
 Rate of blood ejection
 Large-artery compliance

Diastolic blood pressure

The lowest arterial pressure during ventricular relaxation.

It is influenced mainly by:

 Arteriolar resistance
 Heart rate
 Arterial recoil

Pulse pressure
Pulse Pressure=SBP−DBP\text{Pulse Pressure} = \text{SBP}-
\text{DBP}Pulse Pressure=SBP−DBP

A wide pulse pressure is common in older patients with stiff large arteries.

PART 5 — WHAT IS PRIMARY

HYPERTENSION?
Primary hypertension, also called essential hypertension, means:

Persistently elevated blood pressure without

one single identifiable secondary disease
causing it.
This does not mean:

“There is no cause.”

It means:
The disease develops from multiple
interacting genetic, environmental, renal,
neural and vascular factors rather than one
removable lesion.
Primary hypertension is therefore a:

MULTIFACTORIAL DISORDER

PART 6 — PRIMARY VERSUS

SECONDARY HYPERTENSION
Primary hypertension
 Develops gradually
 Usually appears in adulthood
 Often associated with obesity, family history, dietary sodium, inactivity and aging
 No single curable cause is identified
 Represents most chronic hypertension encountered clinically

Secondary hypertension
 Produced by a specific identifiable disorder or substance
 May be abrupt, severe, resistant or unusual for age
 Examples belong to the next SMLE TOS topic and will not be explained here

The essential distinction is:

Primary = multifactorial chronic regulation

failure
Secondary = one identifiable underlying
cause
PART 7 — WHY PRIMARY
HYPERTENSION DEVELOPS
Primary hypertension usually develops through several connected mechanisms:

1. Renal sodium retention

2. Increased sympathetic activity
3. RAAS activation
4. Endothelial dysfunction
5. Vascular remodeling and stiffness
6. Metabolic and environmental influences
7. Genetic susceptibility
These mechanisms reinforce each other.

PART 8 — THE KIDNEY’S CENTRAL

ROLE
The kidneys determine long-term blood pressure by controlling total-body sodium and water.

If the kidneys retain more sodium:

Water follows sodium.

Extracellular volume expands.

↓
Venous return increases.

Stroke volume and cardiac output increase.

Blood pressure rises.

Initially, the body might excrete the excess sodium once pressure rises.

But in hypertension, the pressure required to excrete a normal sodium load may become
abnormally high.

This is called a shift in:

Pressure natriuresis

Extra Concept for Concept Building

PRESSURE NATRIURESIS
A normal kidney responds to increased blood pressure by excreting more sodium.

More arterial pressure

More sodium delivered and excreted

Water follows

Blood volume falls

Pressure returns toward normal.

In primary hypertension, this relationship may shift.

The kidney may need a higher pressure before it excretes enough sodium.

Therefore the body “accepts” a higher blood pressure to maintain sodium balance.

This helps explain why sodium intake affects some patients more strongly than others.

PART 9 — SALT SENSITIVITY

Some patients experience a larger blood-pressure rise after high sodium intake.

This is called:

Salt-sensitive hypertension
More likely in:

 Older adults
 CKD
 Diabetes
 Obesity
 Certain genetic backgrounds
 Patients with low-renin physiology

Mechanism:

Inability to excrete sodium efficiently

Volume expansion

Blood pressure rises.

This is why sodium restriction is clinically useful even though not every hypertensive patient
responds equally.

PART 10 — SYMPATHETIC NERVOUS

SYSTEM
Increased sympathetic activity causes:
  Faster heart rate
 Increased contractility
 Arteriolar constriction
 Renin release
 Renal sodium retention

Therefore:

Sympathetic activation

Cardiac output rises

and

Systemic vascular resistance rises

Blood pressure rises.

Obesity, stress, sleep disturbance and insulin resistance may contribute to sympathetic
overactivity.

PART 11 — RAAS
Reduced renal perfusion, sympathetic stimulation or low sodium delivery to the macula densa
stimulates renin.

Renin converts angiotensinogen toward angiotensin I.

ACE converts angiotensin I into angiotensin II.

Angiotensin II causes:

 Arteriolar vasoconstriction
 Aldosterone release
 Increased sodium reabsorption
 Increased thirst
 ADH stimulation
 Vascular and cardiac remodeling

Aldosterone causes:
  Sodium retention
 Water retention
 Potassium excretion

Therefore excessive RAAS activity raises pressure through:

VASOCONSTRICTION + VOLUME
RETENTION

PART 12 — ENDOTHELIAL
DYSFUNCTION
The vascular endothelium normally produces vasodilators such as nitric oxide.

When endothelial function is impaired:

 Nitric oxide effect falls

 Vasoconstrictor influence rises
 Inflammation increases
 Arterial stiffness develops

Therefore the arteries remain more constricted and less adaptable.

Hypertension then causes further endothelial injury.

This creates a cycle:

HIGH PRESSURE
↓

ENDOTHELIAL DAMAGE
↓

LESS VASODILATION
↓

MORE VASCULAR RESISTANCE

↓

HIGHER PRESSURE

PART 13 — VASCULAR REMODELING

Persistent pressure causes arteriolar walls to thicken.

Smooth muscle hypertrophies.

The lumen becomes relatively narrower.

Resistance rises.

Large arteries also become stiff.

A stiff aorta cannot expand normally during systole.

Systolic pressure rises.

This is why older adults commonly develop:

Isolated systolic hypertension

where systolic pressure is elevated but diastolic pressure is normal or relatively low.

PART 14 — OBESITY AND

HYPERTENSION
Obesity raises blood pressure through several mechanisms:

 Increased sympathetic activity

 Insulin resistance
 RAAS activation
 Sodium retention
 Increased circulating volume
 Sleep apnea association
  Vascular inflammation

More body tissue also requires more blood flow.

Cardiac output increases.

Therefore obesity is not merely associated with hypertension; it actively promotes its
physiology.

PART 15 — GENETIC SUSCEPTIBILITY

Primary hypertension often runs in families.

No single gene usually explains common essential hypertension.

Instead, multiple genetic variants may influence:

 Renal sodium transport

 Sympathetic activity
 RAAS sensitivity
 Vascular tone
 Endothelial function

These genetic factors interact with environmental exposures.

Therefore:

Genes load the tendency; environment

influences its expression.

PART 16 — RISK FACTORS

Important contributors include:

 Family history
 Aging
 Obesity
 High sodium intake
 Physical inactivity
 Excess alcohol
  Smoking-related vascular risk
 Diabetes
 Dyslipidemia
 Chronic psychosocial stress
 Poor sleep
 CKD

Not every risk factor directly causes hypertension through the same pathway, but together
they increase blood-pressure burden and cardiovascular risk.

PART 17 — WHY HYPERTENSION IS

CALLED A SILENT DISEASE
Most patients with chronic primary hypertension have:

No specific symptoms.
A patient may feel completely well while progressive damage occurs in:

 Heart
 Brain
 Kidneys
 Retina
 Arteries

Therefore diagnosis depends on:

Measuring blood pressure correctly

not waiting for symptoms.

PART 18 — CAN HYPERTENSION

CAUSE HEADACHE?
Mild or moderate chronic hypertension does not reliably cause headache.

Headache is more concerning when pressure is:

 Very high
 Rising abruptly
  Associated with encephalopathy
 Associated with retinal damage
 Associated with intracranial pathology

Therefore:

Headache alone does not diagnose

hypertension.
And:

Absence of headache does not exclude

severe chronic hypertension.

PART 19 — POSSIBLE PRESENTATIONS

Primary hypertension may be found:

1. Incidentally
During routine examination.

2. Through target-organ disease

 Stroke
 Heart failure
 CKD
 Retinopathy
 Coronary disease

3. During hypertensive crisis

Very high pressure with or without acute organ injury.

4. Through nonspecific symptoms

 Headache
 Dizziness
 Blurred vision
 Palpitations
But these symptoms are not specific enough to establish the diagnosis.

PART 20 — WHY ONE BP READING IS

NOT ENOUGH
Blood pressure changes throughout the day.

It is affected by:

 Anxiety
 Pain
 Caffeine
 Exercise
 Smoking
 Talking
 Full bladder
 Cold temperature
 Incorrect cuff size
 Recent medication
 Acute illness

Therefore one elevated office reading may represent:

 True sustained hypertension

 White-coat hypertension
 Temporary stress response
 Measurement error

The Approach source recommends multiple measurements and distinguishes office, home
and ambulatory techniques.

PART 21 — CORRECT BLOOD-

PRESSURE MEASUREMENT
For a useful reading:

 Patient should rest quietly for at least several minutes

 Back should be supported
 Feet should be flat and uncrossed
 Arm should be supported at heart level
 Correct cuff size should be used
 Patient should not talk
  Recent caffeine, smoking and exercise should be considered
 Multiple readings should be obtained
 Both arms should be checked initially

A cuff that is too small can falsely elevate the reading.

A cuff that is too large may underestimate it.

PART 22 — WHY ARM POSITION

MATTERS
If the arm is below heart level:

Hydrostatic pressure adds to the reading.

BP may appear falsely high.

If the arm is above heart level:

BP may appear falsely low.

Therefore the arm should be supported near:

Heart level.

PART 23 — OFFICE BP
MEASUREMENT
The Approach source distinguishes:

Automated office blood pressure

An automated device takes multiple readings, often while the patient is alone.
This may reduce the white-coat response.

Conventional office blood pressure

The patient and clinician are present together during the reading.

Office measurement is useful for screening but may need confirmation outside the clinic.

PART 24 — AMBULATORY BLOOD-

PRESSURE MONITORING
ABPM records blood pressure repeatedly for approximately 24 hours during:

 Daytime activity
 Sleep
 Early morning

The Approach source describes measurements every approximately 20–30 minutes through
day and night.

ABPM helps identify:

 Sustained hypertension
 White-coat hypertension
 Masked hypertension
 Nighttime hypertension
 Abnormal nocturnal patterns

First Aid’s essential-hypertension scenario confirms sustained hypertension using at least 24

hours of ambulatory monitoring.

PART 25 — HOME BLOOD-PRESSURE

MONITORING
Home monitoring uses a validated device.

It helps:

 Confirm persistent hypertension

 Monitor treatment response
 Detect white-coat effect
  Improve patient involvement
 Assess adherence

Correct technique remains necessary.

A single home reading should not be overinterpreted; trends are more useful.

PART 26 — WHITE-COAT
HYPERTENSION
Blood pressure is high in the clinic but normal outside it.

Mechanism:

Anxiety or clinical-environment response.

Why it matters:

 It can lead to overdiagnosis

 It can lead to unnecessary medication
 It may still indicate some increased long-term risk compared with consistently normal
pressure

Best confirmation:

ABPM or structured home monitoring

PART 27 — MASKED HYPERTENSION

Office blood pressure is normal but home or ambulatory readings are elevated.

Possible reasons:

 Work stress
 Smoking
 Alcohol
 Sleep disturbance
 Physical activity patterns
 Medication timing

This is dangerous because the patient may appear normal in clinic while sustained organ
exposure continues.
Again:

ABPM or home monitoring reveals it.

PART 28 — NOCTURNAL BLOOD

PRESSURE
Normally blood pressure falls during sleep.

This is called:

Nocturnal dipping.
Failure to dip may be associated with:

 Higher cardiovascular risk

 CKD
 Diabetes
 Sleep apnea
 Autonomic dysfunction

ABPM is particularly useful because routine clinic readings cannot evaluate nighttime
pressure.

PART 29 — DIAGNOSIS
Based on the supplied First Aid framework:

Hypertension is defined as SBP ≥130 mmHg

and/or DBP ≥80 mmHg.
However, diagnosis generally requires:

 Repeated proper measurements

 Confirmation on separate occasions
 Or confirmation with ABPM/home BP
 Unless the patient has a hypertensive emergency or a clearly severe persistent
presentation
PART 30 — CLINICAL SCENARIO:
CONFIRMING PRIMARY
HYPERTENSION
A 54-year-old patient has office BP:

 148/92 mmHg
 Repeat 146/90 mmHg

He has no symptoms or acute organ damage.

Correct next principle:

Do not diagnose from one casual reading

alone.
Use:

 Repeated standardized office measurements

or
 Home monitoring
or
 Ambulatory monitoring

If sustained elevation is confirmed:

Diagnose hypertension.

Then assess:

 Cardiovascular risk
 Target-organ damage
 Possible secondary clues
 Need for lifestyle and medication

PART 31 — INITIAL HISTORY

The history should determine:
Is this truly primary hypertension?
Ask about:

 Duration of elevated BP
 Previous readings
 Family history
 Diet and sodium
 Weight gain
 Physical activity
 Alcohol
 Smoking
 Sleep
 Medication adherence
 OTC medications and substances
 Symptoms of organ damage

Secondary-hypertension symptoms are screened for, but their detailed interpretation belongs
to the next TOS topic.

PART 32 — TARGET-ORGAN
SYMPTOMS
Brain
 Transient neurological deficit
 Stroke symptoms
 Severe confusion
 Seizures

Heart
 Chest pain
 Dyspnea
 Orthopnea
 Reduced exercise tolerance
 Palpitations

Kidney
 Reduced renal function
 Proteinuria
 Hematuria
  Edema

Eye
 Blurred vision
 Visual loss

Peripheral arteries
 Claudication
 Cold limbs
 Vascular disease

PART 33 — PHYSICAL EXAMINATION

Assess:

 Blood pressure in both arms

 Pulse
 Weight and BMI
 Waist circumference
 Signs of heart failure
 Cardiac murmurs
 Peripheral pulses
 Abdominal bruits
 Neurological status
 Fundoscopy
 Edema
 Features suggesting endocrine or vascular disease

Primary hypertension often has no specific physical sign except elevated BP.

PART 34 — WHY CHECK BOTH ARMS?

A small difference may occur normally.

A marked persistent difference may suggest:

 Subclavian arterial disease

 Aortic pathology
 Other vascular abnormality
For future monitoring, use the arm with the consistently higher reading unless a clinical
reason suggests otherwise.

PART 35 — BASELINE
INVESTIGATIONS
The purpose is not to “prove” primary hypertension through one blood test.

The purpose is to:

1. Assess cardiovascular risk

2. Detect target-organ injury
3. Identify important comorbidities
4. Look for clues to secondary hypertension
5. Establish safety before treatment

Common baseline studies include:

 Serum creatinine/eGFR
 Sodium
 Potassium
 Glucose or HbA1c
 Lipid profile
 Urinalysis
 Urine albumin-to-creatinine ratio
 CBC where appropriate
 ECG

Additional tests depend on clinical context.

PART 36 — WHY CHECK CREATININE

AND URINE ALBUMIN?
Hypertension damages renal vessels and glomeruli.

Possible consequences:

 Reduced GFR
 Albuminuria
 CKD

Kidney disease also affects drug choice and potassium risk.

Therefore creatinine and albuminuria help determine:

 Existing target-organ injury

 Cardiovascular risk
 Need for RAAS blockade
 Safe drug selection

PART 37 — WHY CHECK POTASSIUM?

Potassium can reveal:

 Baseline electrolyte abnormality

 Safety before ACE inhibitor/ARB
 Possible mineralocorticoid-related disease if unexpectedly low
 CKD-related hyperkalemia risk

Detailed interpretation of low potassium as a clue to secondary hypertension belongs to the

next topic.

PART 38 — WHY CHECK GLUCOSE

AND LIPIDS?
Hypertension commonly coexists with:

 Diabetes
 Insulin resistance
 Dyslipidemia
 Obesity

Cardiovascular risk is determined by the total risk burden, not BP alone.

A patient with hypertension plus diabetes and high LDL is at much greater risk than a patient
with the same BP but no other risk factors.

PART 39 — ECG
ECG may show:

 Left ventricular hypertrophy

 Ischemia
  Prior myocardial infarction
 Arrhythmia

However, echocardiography is more sensitive for left ventricular structure when clinically
indicated.

Routine echocardiography is not required for every uncomplicated patient.

PART 40 — FUNDOSCOPY
Chronic hypertension can produce:

 Arteriolar narrowing
 Arteriovenous nicking
 Cotton-wool spots
 Hemorrhages
 Exudates
 Papilledema in severe acute disease

First Aid’s hypertensive-emergency scenario includes arteriolar narrowing, AV nicking and

cotton-wool spots as evidence of hypertensive retinal injury.

PART 41 — TARGET-ORGAN DAMAGE

WHY HYPERTENSION IS DANGEROUS
The main complications involve:

H-B-K-E-A
H — Heart

B — Brain

K — Kidneys

E — Eyes

A — Arteries
First Aid lists LV hypertrophy, stroke, heart failure, ischemic heart disease, CKD and
retinopathy among the major complications.

PART 42 — HEART DAMAGE

Persistent high arterial resistance means the left ventricle must generate greater pressure to
eject blood.

Cardiac muscle thickens.

Left ventricular hypertrophy develops.

Initially this is compensatory.

But a thick ventricle becomes:

 Stiff
 Less compliant
 More oxygen-demanding
 More prone to ischemia
 More prone to arrhythmia

Therefore hypertension can cause:

 Diastolic dysfunction
 HFpEF
 Later systolic dysfunction
 Ischemic heart disease
 Atrial fibrillation
 Sudden cardiac events

PART 43 — WHY LVH CAUSES

DIASTOLIC DYSFUNCTION
A thickened ventricle does not relax easily.

During diastole:
↓

Filling pressure rises.

Pressure transmits to the left atrium and pulmonary veins.

The patient develops:

 Exertional dyspnea
 Orthopnea
 Pulmonary congestion

This is a major pathway from chronic hypertension to:

HFpEF

PART 44 — CORONARY DISEASE

Hypertension damages endothelium.

Atherosclerosis accelerates.

At the same time, LVH increases myocardial oxygen demand.

Therefore:

 Coronary supply becomes impaired

 Oxygen demand rises

This increases risk of:

 Angina
 Myocardial infarction
 Ischemic cardiomyopathy

PART 45 — BRAIN DAMAGE

Hypertension damages small and large cerebral vessels.

Consequences include:

 Ischemic stroke
 Intracerebral hemorrhage
 Lacunar infarction
 Vascular cognitive impairment
 Hypertensive encephalopathy

Chronic hypertension also shifts cerebral autoregulation to tolerate higher pressure.

This is why excessively rapid BP lowering in severe chronic hypertension can reduce
cerebral perfusion.

PART 46 — KIDNEY DAMAGE

High systemic pressure reaches renal microvasculature.

Arterioles thicken and narrow.

Glomeruli become ischemic.

Nephrons are lost.

Proteinuria and CKD develop.

Then CKD causes:

 More sodium retention

 More volume expansion
 More RAAS activation

Hypertension worsens.

Therefore:
HTN → CKD → WORSE HTN

PART 47 — EYE DAMAGE

Retinal vessels are directly visible and reflect systemic microvascular injury.

Chronic changes include:

 Arteriolar narrowing
 AV nicking

More severe damage includes:

 Hemorrhages
 Exudates
 Cotton-wool spots

Papilledema suggests severe acute pressure-related injury and requires urgent evaluation.

PART 48 — LARGE-ARTERY DAMAGE

Hypertension accelerates:

 Atherosclerosis
 Peripheral arterial disease
 Aortic aneurysm
 Aortic dissection

It also contributes to arterial stiffness, which further increases systolic pressure.

Again, a vicious cycle forms.

PART 49 — TREATMENT GOALS

Treatment has two purposes:

1. Lower blood pressure safely

2. Reduce future cardiovascular and renal
events
The purpose is not merely to produce a normal number during one clinic visit.

Long-term treatment aims to prevent:

 Stroke
 Myocardial infarction
 Heart failure
 CKD
 Retinopathy
 Premature death

PART 50 — LIFESTYLE TREATMENT

Lifestyle therapy is essential for all patients, whether medication is used or not.

First Aid specifically lists:

 DASH diet
 Weight loss
 Aerobic physical activity
 Reduced alcohol consumption

as effective non-pharmacological measures.

PART 51 — DASH DIET

DASH emphasizes:

 Fruits
 Vegetables
 Whole grains
 Low-fat dairy
 Legumes
 Nuts
 Reduced saturated fat
 Reduced processed food
 Lower sodium intake

Its effect comes from:

  Lower sodium exposure
 Higher potassium and mineral content when clinically safe
 Better weight control
 Improved vascular function

Important:

Patients with advanced CKD or hyperkalemia may require individualized potassium advice
rather than unrestricted high-potassium foods.

First Aid reports an approximate systolic BP reduction of 11 mmHg with DASH-style dietary
intervention.

PART 52 — SODIUM REDUCTION

High sodium intake promotes:

 Water retention
 Increased circulating volume
 Vascular stiffness
 Blunted response to antihypertensive therapy

Reducing processed foods is often more effective than merely removing the salt shaker
because much dietary sodium is hidden in:

 Packaged foods
 Fast food
 Sauces
 Pickles
 Processed meats
 Snack foods

PART 53 — WEIGHT LOSS

Weight loss lowers blood pressure by reducing:

 Sympathetic activation
 Insulin resistance
 RAAS activity
 Sodium retention
 Sleep-apnea burden

First Aid reports an approximate reduction of around 5 mmHg with weight loss in its scenario
framework.
The exact benefit varies according to the amount lost and the individual patient.

PART 54 — PHYSICAL ACTIVITY

Regular aerobic exercise improves:

 Endothelial function
 Vascular compliance
 Weight control
 Insulin sensitivity
 Resting sympathetic tone

First Aid reports an approximate BP reduction of 5–8 mmHg with aerobic activity.

Exercise advice should be individualized in patients with:

 Severe uncontrolled hypertension

 Active ischemia
 Decompensated heart failure
 Major mobility limitation

PART 55 — ALCOHOL
Excess alcohol may raise blood pressure through:

 Sympathetic activation
 Poor sleep
 Weight gain
 Medication nonadherence
 Direct vascular effects

First Aid reports an approximate 4 mmHg reduction with decreased alcohol consumption.

PART 56 — SMOKING
Smoking may not be the sole cause of sustained hypertension, but it sharply raises:

 Acute sympathetic tone

 Endothelial injury
 Atherosclerotic risk
 Stroke risk
  Coronary risk

Therefore smoking cessation is essential for total cardiovascular-risk reduction.

PART 57 — WHEN MEDICATION IS

NEEDED
Medication is considered according to:

 Confirmed BP level
 Cardiovascular risk
 Diabetes
 CKD
 Established cardiovascular disease
 Target-organ damage
 Response to lifestyle treatment

Patients with substantially elevated pressure often need medication from the beginning rather
than lifestyle therapy alone.

First Aid notes that very elevated BP often requires two or more agents.

PART 58 — MAJOR FIRST-LINE DRUG

CLASSES
The supplied First Aid source lists:

1. Thiazide diuretic
2. Calcium-channel blocker
3. ACE inhibitor
4. ARB
Drug selection depends on:

 Comorbidities
  Kidney function
 Potassium
 Age
 Adverse-effect profile
 Pregnancy potential
 Volume status
 Ethnic and population response patterns
 Local guideline

PART 59 — THIAZIDE DIURETICS

Examples include:

 Hydrochlorothiazide
 Chlorthalidone
 Indapamide

Mechanism
Block sodium-chloride reabsorption in the distal convoluted tubule.

Sodium and water excretion increase initially.

Plasma volume falls.

Long-term vascular resistance also falls.

Benefits
 Effective in salt-sensitive hypertension
 Useful in older adults
 Helpful in isolated systolic hypertension
 Can combine well with ACE inhibitor, ARB or CCB

Adverse effects
 Hyponatremia
 Hypokalemia
 Metabolic alkalosis
 Hyperuricemia
 Hyperglycemia
  Volume depletion

Clinical scenario:

An older woman starts a thiazide and later develops confusion with sodium 118 mmol/L.

Think:

Thiazide-induced hyponatremia
which was covered under sodium disorders.

PART 60 — ACE INHIBITORS

Examples:

 Lisinopril
 Enalapril
 Ramipril

Mechanism
Reduce angiotensin II and aldosterone.

Vasoconstriction falls.

Sodium retention falls.

Blood pressure decreases.

They also dilate the efferent renal arteriole.

Intraglomerular pressure falls.

Proteinuria may decrease.

Particularly useful in
 Proteinuric CKD
 Diabetes with albuminuria
 HFrEF
 Post-MI ventricular dysfunction

First Aid specifically favours ACE inhibitor or ARB in CKD with proteinuria and diabetes,
and includes them in HFrEF-directed treatment.

Adverse effects
 Cough
 Hyperkalemia
 Creatinine rise
 Angioedema
 Hypotension

Avoid or use with major caution in

 Pregnancy
 Previous ACE-inhibitor angioedema
 Severe hyperkalemia
 Bilateral renal artery stenosis
 Acute severe volume depletion

PART 61 — WHY ACE INHIBITORS

CAUSE COUGH
ACE also breaks down bradykinin.

ACE inhibition:

Bradykinin accumulates.

Dry cough may develop.

Bradykinin accumulation also contributes to:

Angioedema
which can be life-threatening if the airway is involved.

PART 62 — ARBs
Examples:

 Losartan
 Valsartan
 Candesartan

ARBs block angiotensin-II receptors.

Effects:

 Reduce vasoconstriction
 Reduce aldosterone
 Reduce proteinuria
 Lower blood pressure

They are often used when an ACE inhibitor causes cough.

They still can cause:

 Hyperkalemia
 Creatinine rise
 Hypotension

They should not routinely be combined with an ACE inhibitor because combined RAAS
blockade increases renal and potassium complications.

PART 63 — CALCIUM-CHANNEL
BLOCKERS
For primary hypertension, the commonly used agents are usually dihydropyridines such as:

 Amlodipine
 Nifedipine extended release

Mechanism
Block L-type calcium channels in vascular smooth muscle.

Arteriolar relaxation occurs.

Systemic vascular resistance falls.

Adverse effects
 Ankle edema
 Headache
 Flushing
 Palpitations
 Gingival enlargement

The edema is caused mainly by increased precapillary arteriolar dilation, not necessarily by
total-body fluid overload.

PART 64 — WHY CCB-RELATED

EDEMA MAY NOT RESPOND FULLY TO
DIURETICS
Dihydropyridine CCBs dilate arterioles more than veins.

Pressure rises inside capillaries.

Fluid moves into interstitial tissue.

This is a distribution problem rather than simple sodium retention.

Therefore merely increasing a diuretic may not completely solve it.

Dose adjustment or combination with a RAAS blocker may help in suitable patients.
PART 65 — BETA-BLOCKERS
Beta-blockers are not listed by First Aid as one of the universal initial classes for
uncomplicated essential hypertension, but they are important when a compelling indication
exists.

Useful in:

 HFrEF with an evidence-based agent

 Post-MI disease
 Angina
 Certain tachyarrhythmias

Mechanism:

 Reduce heart rate

 Reduce contractility
 Reduce renin release

Adverse effects:

 Bradycardia
 Fatigue
 Sexual dysfunction
 Bronchospasm with nonselective drugs
 Masking of hypoglycemia symptoms

Do not stop chronic beta-blocker therapy abruptly because rebound sympathetic activity may
cause:

 Tachycardia
 Angina
 Severe hypertension

PART 66 — WHY MANY PATIENTS

NEED COMBINATION THERAPY
Blood pressure is controlled by several pathways.

One drug may block only one pathway.

The body then activates compensatory mechanisms.

For example:
A vasodilator lowers resistance.

The body may increase sympathetic tone or retain sodium.

Adding a second drug with a complementary mechanism improves control.

Common logical combinations include:

 ACE inhibitor/ARB + CCB

 ACE inhibitor/ARB + thiazide
 CCB + thiazide

Avoid:

ACE inhibitor + ARB routinely

because the combination increases:

 Hyperkalemia
 AKI
 Hypotension

without sufficient routine benefit.

PART 67 — STARTING ONE VERSUS

TWO DRUGS
A patient with mildly elevated BP and low overall risk may begin with:

 Lifestyle intervention
 One medication where indicated

A patient with markedly elevated confirmed BP often requires:

Two agents from complementary classes.

First Aid notes that BP above approximately 160/80 in its framework will often require at
least two drugs.
PART 68 — COMORBIDITY-DIRECTED
SELECTION
Proteinuric CKD
Prefer:

ACE inhibitor or ARB

because of proteinuria reduction.

Diabetes
The supplied First Aid source favours ACE inhibitor or ARB, particularly where kidney
protection is relevant.

HFrEF
Use disease-modifying heart-failure therapy, including appropriate RAAS blockade and
evidence-based beta-blockade.

Coronary disease
Beta-blocker and/or RAAS blockade may be selected according to the cardiac context.

Older patient with isolated systolic hypertension

A thiazide-type drug or dihydropyridine CCB is commonly effective.

PART 69 — BLOOD-PRESSURE
TARGET
Targets vary among guidelines and patient groups.

The supplied source provides a diagnostic threshold but the excerpt available does not
establish one universal treatment target for every patient.

Therefore the safe source-grounded principle is:

Treat to the target recommended by the
applicable guideline, individualized for
cardiovascular risk, age, frailty, CKD,
diabetes and treatment tolerance.
Avoid:

 Persistent uncontrolled pressure

 Symptomatic hypotension
 Excessive falls in perfusion pressure

PART 70 — FOLLOW-UP
After starting or changing treatment, reassess:

 BP
 Adherence
 Adverse effects
 Orthostatic symptoms
 Electrolytes
 Creatinine where relevant
 Home readings
 Lifestyle progress

After ACE inhibitor, ARB or diuretic:

Check renal function and electrolytes.

PART 71 — APPARENT TREATMENT

FAILURE
Before labelling hypertension as resistant, check:

 Incorrect measurement
 White-coat effect
 Poor adherence
 Inadequate drug doses
 Inappropriate combination
  High sodium intake
 NSAID use
 Alcohol
 Interfering medications
 Secondary hypertension

Detailed resistant and secondary hypertension evaluation belongs to the next TOS topic.

PART 72 — ORTHOSTATIC
HYPOTENSION DURING TREATMENT
An older patient may have acceptable seated BP but dizziness on standing.

Measure:

 Supine BP
 Standing BP

Possible contributors:

 Excess diuresis
 Autonomic dysfunction
 Dehydration
 Multiple medications

Treatment should reduce cardiovascular risk without causing:

 Falls
 Syncope
 Renal hypoperfusion

PART 73 — HYPERTENSIVE CRISIS

Hypertensive crisis refers to severely elevated blood pressure.

The crucial distinction is not the number alone.

Ask:

Is there acute target-organ damage?

No acute damage

Hypertensive urgency / severe

asymptomatic hypertension
Acute damage present

Hypertensive emergency
First Aid defines hypertensive emergency as severe BP elevation, generally at least 180
systolic and/or 120 diastolic, with acute end-organ damage; urgency has severe elevation
without acute damage.

PART 74 — HYPERTENSIVE URGENCY

The patient has severely elevated BP but no acute progressive target-organ injury.

They may be:

 Asymptomatic
 Mildly headachey
 Anxious
 Nonadherent to medication

But there is no evidence of:

 Encephalopathy
 Acute pulmonary edema
 Acute coronary syndrome
 Aortic dissection
 Acute kidney injury
 Retinal emergency
 Stroke-related acute injury

Management:

Do not rapidly normalize BP with

aggressive IV treatment.
Instead:
  Confirm correct measurement
 Assess for organ damage
 Restart or adjust oral medication
 Address adherence
 Arrange close follow-up
 Lower BP gradually

First Aid states that hypertensive urgency requires chronic oral management rather than
immediate rapid reduction.

PART 75 — WHY RAPID LOWERING IS

DANGEROUS IN URGENCY
In chronic hypertension, organs adapt to higher perfusion pressure.

If BP falls abruptly:

Cerebral, coronary and renal perfusion may fall.

Possible consequences:

 Ischemic stroke
 Myocardial ischemia
 AKI
 Syncope

Therefore:

Severe number without acute injury does

not justify uncontrolled rapid reduction.

PART 76 — HYPERTENSIVE
EMERGENCY
Hypertensive emergency means:
Severe hypertension plus acute target-
organ damage.
Possible manifestations:

 Hypertensive encephalopathy
 Intracranial hemorrhage
 Acute ischemic neurological syndrome
 Acute pulmonary edema
 Acute coronary syndrome
 Aortic dissection
 Acute kidney injury
 Severe retinopathy
 Microangiopathic hemolysis

This patient requires:

 Hospital admission
 IV medication
 Continuous monitoring
 Cause-specific management

PART 77 — HYPERTENSIVE
ENCEPHALOPATHY
Severe pressure overwhelms cerebral autoregulation.

Cerebral vessels dilate abnormally.

Endothelial leakage occurs.

Vasogenic brain edema develops.

Presentation:

 Severe headache
 Nausea/vomiting
 Confusion
  Visual disturbance
 Seizures
 Reduced consciousness

The neurological dysfunction is diffuse rather than a single fixed focal deficit.

Treatment:

Controlled IV BP reduction.

PART 78 — EMERGENCY BP-

REDUCTION PRINCIPLE
First Aid recommends:

 Reduce BP by approximately 10–20% in the first hour

 Then reduce by another approximately 5–15% over the next 24 hours

for most hypertensive emergencies.

The reason for controlled rather than immediate normalization is to preserve organ perfusion.

Important exceptions require disease-specific strategies, particularly:

 Aortic dissection
 Certain stroke situations

PART 79 — IV DRUGS IN
HYPERTENSIVE EMERGENCY
First Aid lists:

 Labetalol
 Esmolol
 Nicardipine
 Clevidipine
 Nitroprusside
 Nitroglycerin

The best drug depends on the organ emergency.

Examples:

Acute pulmonary edema

A vasodilator such as nitroglycerin may be useful, together with disease-specific heart-failure
treatment.

Aortic dissection
Rapid heart-rate and impulse control using an IV beta-blocker is central before or alongside
vasodilation.

Neurological emergency
Nicardipine or labetalol is frequently selected according to the specific neurological condition
and target.

PART 80 — WHY NITROPRUSSIDE

REQUIRES CAUTION
Nitroprusside is a powerful arterial and venous vasodilator.

It can lower BP rapidly.

However, prolonged or high-dose use may cause toxic metabolite accumulation, especially in
renal or hepatic dysfunction.

Therefore it requires:

 Intensive monitoring
 Careful selection
 Limited duration where possible

PART 81 — HYPERTENSIVE
EMERGENCY SCENARIO
A patient with poorly controlled hypertension presents with:

 BP 220/120 mmHg
 Severe headache
  Blurred vision
 Cotton-wool spots
 Acute creatinine rise

This is not just “very high BP.”

There is:

Acute retinal and renal target-organ injury.

Diagnosis:

Hypertensive emergency.
Management:

 Hospital admission
 IV titratable antihypertensive
 Controlled initial reduction
 Frequent neurological, renal and cardiac monitoring

PART 82 — SEVERE ASYMPTOMATIC

SCENARIO
A patient stopped medications for one week.

BP is:

 190/112 mmHg

They have:

 No chest pain
 No dyspnea
 Normal neurological examination
 No AKI
 No acute retinal injury

Diagnosis:

Severe hypertension without acute target-

organ damage.
Management:

 Restart or adjust oral drugs

 Assess adherence
 Avoid aggressive rapid IV lowering
 Arrange close follow-up

PART 83 — LONG-TERM
COMPLICATIONS
Primary hypertension can cause:

Heart
 LVH
 HFpEF
 HFrEF
 Coronary disease
 Arrhythmias

Brain
 Ischemic stroke
 Hemorrhagic stroke
 Cognitive decline

Kidney
 Albuminuria
 CKD
 Kidney failure

Eye
 Retinopathy
 Visual impairment

Vascular system
 Peripheral arterial disease
 Aortic aneurysm
 Aortic dissection
First Aid includes LVH, stroke, heart failure, ischemic heart disease, CKD and retinopathy
among major complications.

PART 84 — COMPLICATIONS OF
TREATMENT
Thiazide
 Hyponatremia
 Hypokalemia
 Hyperuricemia
 Dehydration

ACE inhibitor
 Cough
 Hyperkalemia
 Creatinine rise
 Angioedema

ARB
 Hyperkalemia
 Creatinine rise
 Hypotension

CCB
 Ankle edema
 Headache
 Flushing

Beta-blocker
 Bradycardia
 Fatigue
 Bronchospasm with nonselective agents
 Rebound effects if stopped abruptly

Treatment should therefore be monitored rather than prescribed and forgotten.

PART 85 — PRIMARY-HYPERTENSION
SCENARIOS
Scenario 1 — Incidental sustained hypertension
A 48-year-old man has repeated clinic BP around 148/92 mmHg.

ABPM confirms sustained elevation.

No symptoms or acute organ damage.

Diagnosis:

Primary hypertension after excluding

major secondary clues.
Management:

 Cardiovascular risk assessment

 Lifestyle modification
 Medication according to BP severity and risk
 Follow-up with home readings

Scenario 2 — Obesity and salt-sensitive hypertension

A patient has:

 Obesity
 High processed-food intake
 Sedentary lifestyle
 Gradual BP elevation

Mechanisms:

 Sympathetic activation
 Sodium retention
 RAAS activity
 Insulin resistance
 Increased volume

Management:

 Weight loss
  Sodium reduction
 Physical activity
 Appropriate medication

Scenario 3 — Older patient with isolated systolic

hypertension
BP:

 168/72 mmHg

Mechanism:

Large arteries are stiff.

They cannot expand during systole.

Systolic pressure rises.

Likely useful drug categories:

 Thiazide-type diuretic
 Dihydropyridine CCB

while monitoring for orthostatic symptoms.

Scenario 4 — Diabetes with albuminuria

A patient with diabetes has:

 Hypertension
 Elevated urine ACR
 Stable potassium

Preferred class:

ACE inhibitor or ARB

because it lowers BP and intraglomerular pressure.
Monitor:

 Potassium
 Creatinine

First Aid supports ACE inhibitor/ARB use in diabetes and proteinuric CKD.

Scenario 5 — ACE-inhibitor cough

Patient starts lisinopril.

Develops persistent dry cough.

Likely mechanism:

Bradykinin accumulation.
Reasonable alternative:

ARB
provided there is no contraindication.

Scenario 6 — Amlodipine edema

BP improves after amlodipine, but ankle swelling appears.

No raised JVP or pulmonary crackles.

Mechanism:

Precapillary arteriolar dilation

Increased capillary hydrostatic pressure

Peripheral edema.

This is not necessarily heart failure.

Scenario 7 — Thiazide complication
Older woman starts thiazide.

Later:

 Confusion
 Sodium 120 mmol/L
 Potassium low

Diagnosis:

Thiazide-associated electrolyte disturbance.

Management:

 Stop drug
 Assess severity
 Correct sodium and potassium safely

Scenario 8 — Hypertensive urgency

BP:

 192/110 mmHg

Patient feels well.

No organ injury.

Management:

Oral adjustment and gradual control—not

rapid IV normalization.

Scenario 9 — Hypertensive emergency

BP:
  225/125 mmHg

Patient has:

 Confusion
 Retinal hemorrhages
 AKI

Management:

IV titratable therapy with controlled

reduction and hospital monitoring.

Scenario 10 — Apparent resistant hypertension

Patient remains hypertensive despite several prescriptions.

Before adding many more drugs, check:

 Accurate measurement
 Adherence
 Sodium intake
 NSAID use
 Home BP
 Secondary causes

The detailed secondary-cause evaluation belongs to the next chapter.

PART 86 — BEST TEST / GOLD

STANDARD / DEFINITIVE
MANAGEMENT
Best way to diagnose hypertension

Repeated properly obtained BP

measurements with out-of-office
confirmation when appropriate.
Best method to detect white-coat or masked hypertension

24-hour ambulatory BP monitoring.

Best practical long-term monitoring method

Validated home BP monitoring.

Best initial evaluation

Cardiovascular-risk assessment + target-

organ assessment + baseline
renal/metabolic tests.
Best treatment for all patients

Lifestyle intervention.
Major first-line drug classes

Thiazide, ACE inhibitor, ARB or calcium-

channel blocker.
Best drug class for proteinuric CKD

ACE inhibitor or ARB.

Best treatment for hypertensive emergency

IV titratable antihypertensive with

controlled BP reduction and treatment of
the specific organ injury.
Best treatment for hypertensive urgency
Oral chronic therapy adjustment and
gradual reduction.
Definitive treatment of primary hypertension
There is usually no single curative procedure.

The definitive long-term strategy is:

Sustained lifestyle modification +

individualized lifelong pharmacological
control + cardiovascular-risk reduction.

PART 87 — HIGH-YIELD COMPARISON

Hypertensive
Feature Primary hypertension Hypertensive urgency
emergency
Chronic sustained BP Severe BP, no acute organ Severe BP with acute
Basic problem
elevation damage organ damage
Neurological, cardiac,
None or mild nonspecific
Symptoms Usually none renal or visual
symptoms
symptoms
Repeat BP and assess Immediate clinical
Confirmation Repeat/ABPM/HBPM
damage diagnosis
Usually oral
Treatment Hospital/ICU-level
Outpatient outpatient/observed
setting monitoring
management
Drug route Oral Oral IV titratable
Speed of
Gradual Gradual Controlled but prompt
lowering
Overtreatment causing Ongoing acute organ
Main danger Long-term organ injury
hypoperfusion destruction

PART 88 — SMLE EXAM TRAPS

Trap 1
Primary hypertension has no pathophysiological cause.

Incorrect.

It has multiple interacting causes, but no single specific secondary lesion.

Trap 2
One elevated clinic BP confirms hypertension.

Incorrect unless there is a crisis or a clearly severe persistent situation.

Repeat and confirm properly.

Trap 3
A patient without headache cannot have hypertension.

Incorrect.

Most chronic hypertension is asymptomatic.

Trap 4
Headache proves hypertension caused the symptoms.

Incorrect.

Headache is nonspecific.

Trap 5
Normal office BP excludes hypertension.

Incorrect.

Masked hypertension may be present.

Trap 6
High office BP always means sustained hypertension.

Incorrect.

White-coat hypertension may be present.

Trap 7
Every severely high BP requires IV medication.

Incorrect.

IV treatment is for hypertensive emergency with acute organ damage.

Trap 8
Hypertensive urgency should be normalized immediately.

Incorrect.

Rapid reduction may cause organ ischemia.

Trap 9
ACE inhibitors are contraindicated in all CKD.

Incorrect.

They are often kidney-protective in proteinuric CKD, with creatinine and potassium
monitoring.

Trap 10
ACE inhibitor and ARB should be combined for stronger renal protection.

Incorrect.
Routine combination increases AKI and hyperkalemia.

Trap 11
Amlodipine edema proves heart failure.

Incorrect.

It commonly results from altered capillary hydrostatic pressure.

Trap 12
Thiazides only cause potassium loss.

Incorrect.

They may also cause profound hyponatremia, hyperuricemia and volume depletion.

Trap 13
Beta-blockers are always first-line for uncomplicated hypertension.

Not according to the supplied First Aid framework.

They are especially useful when a compelling cardiac indication exists.

Trap 14
BP treatment is successful once the office number improves.

Incomplete.

Success also requires:

 Home control
 Adherence
 Tolerance
 Reduced organ risk
 Monitoring of kidney function and electrolytes
PART 89 — MEMORY MAPS
BLOOD PRESSURE
P = PUMP × PIPES
Pump

Cardiac output

Pipes

Systemic vascular resistance

PRIMARY HYPERTENSION
MECHANISMS
S-R-V-M
S — Sodium retention and sympathetic activity

R — RAAS

V — Vascular dysfunction/remodeling

M — Metabolic, lifestyle and genetic modifiers

TARGET ORGANS
H-B-K-E-A
H — Heart

B — Brain
K — Kidney

E — Eye

A — Arteries

CONFIRMATION
O-H-A
O — Office measurement

H — Home BP

A — Ambulatory BP

FIRST-LINE DRUGS
T-A-C
T — Thiazide

A — ACE inhibitor/ARB

C — Calcium-channel blocker

HYPERTENSIVE CRISIS
DAMAGE DECIDES
No acute damage

Urgency → oral and gradual

Acute damage
Emergency → IV and monitored

PART 90 — FINAL MASTER

FLOWCHART
Elevated office blood pressure
↓

Is there acute target-organ damage?

Look for:

 Encephalopathy
 Stroke-related emergency
 Acute pulmonary edema
 Acute coronary syndrome
 Aortic dissection
 AKI
 Severe retinal injury

Yes

Hypertensive emergency
 Admit
 IV titratable therapy
 Reduce pressure in a controlled manner
 Treat the organ-specific emergency

No
↓

Repeat measurement correctly

 Proper cuff
 Rest
 Arm at heart level
 Multiple readings
↓

Is severe BP still present?

If severe but no organ damage:

Hypertensive urgency/severe asymptomatic

hypertension
 Oral therapy
 Address adherence
 Gradual control
 Close follow-up

If not severely elevated:

Confirm sustained hypertension

 Repeat office readings
 Home BP
 ABPM

Assess
 Cardiovascular risk
 Diabetes
 CKD
 Albuminuria
 Lipids
 ECG
 Target-organ damage
 Secondary clues

Start lifestyle treatment

 DASH pattern
 Sodium reduction
 Weight loss
  Exercise
 Reduce excess alcohol
 Stop smoking

Add medication according to severity and

risk
 Thiazide
 ACE inhibitor
 ARB
 CCB

Choose according to comorbidity.

Monitor
 Home BP
 Adherence
 Creatinine
 Potassium
 Sodium
 Adverse effects
 Orthostatic symptoms

If uncontrolled
 Confirm true resistance
 Optimize combination
 Search for interfering factors
 Evaluate secondary hypertension

FINAL MASTER CONCEPT

Primary hypertension is not simply:

“The blood-pressure number is high.”

It is a chronic failure of blood-pressure regulation involving:

KIDNEY SODIUM HANDLING



SYMPATHETIC ACTIVITY


RAAS


VASCULAR RESISTANCE


ARTERIAL STIFFNESS


GENETIC AND ENVIRONMENTAL

FACTORS
The kidneys may retain sodium.

Volume rises.

The sympathetic and RAAS systems constrict vessels.

Resistance rises.

Persistent pressure then remodels the heart and arteries.

Hypertension becomes increasingly self-sustaining.

The diagnostic sequence is:

MEASURE CORRECTLY
↓

CONFIRM OUTSIDE THE OFFICE

WHEN NEEDED
↓

ASSESS RISK AND ORGAN DAMAGE

↓

BEGIN LIFESTYLE THERAPY

↓

SELECT DRUGS ACCORDING TO

COMORBIDITY
↓

MONITOR RESPONSE AND

COMPLICATIONS
The most important SMLE emergency distinction is:

SEVERE BP WITHOUT ACUTE ORGAN

DAMAGE
= gradual oral management

versus
SEVERE BP WITH ACUTE ORGAN
DAMAGE
= hypertensive emergency requiring controlled IV treatment

And the main long-term purpose of treatment is not simply to improve a clinic reading.

It is to prevent:

STROKE
HEART FAILURE
MYOCARDIAL INFARCTION
CKD
RETINOPATHY
PREMATURE DEATH
MEDICINE → NEPHROLOGY
TOPIC 6: SECONDARY
HYPERTENSION
SMLE 2026 — Mastery Level 1
Complete Conceptual, Interlinked and Scenario-Based Notes

The final listed adult Nephrology topic in the supplied SMLE 2026 blueprint is:

SECONDARY HYPERTENSION —
MASTERY LEVEL 1
The blueprint places Secondary Hypertension after Primary Hypertension.
Mastery level 1 does not mean the topic should be memorized as a superficial list. For the
SMLE, you must be able to recognize the clinical clue, select the appropriate screening
investigation, understand the mechanism, and identify the cause-specific treatment.

SOURCE FRAMEWORK
Reference-book-based
Approach to Internal Medicine

Used for:

 Classification of secondary hypertension

 Clinical clues suggesting an underlying cause
 Drug and substance causes
 Primary aldosteronism screening
 Pheochromocytoma screening
 Cortisol and thyroid investigations
 Renovascular hypertension investigations
 Obstructive sleep-apnea assessment
 Physical-examination clues

The source classifies secondary causes into renal, endocrine, drug-related, anatomic,
neurogenic and other causes. It specifically lists renal parenchymal disease, renal vascular
disease, primary aldosteronism, Cushing syndrome, pheochromocytoma, thyroid disease,
drugs, coarctation and obstructive sleep apnea.

Clinical algorithm source

First Aid Clinical Algorithms for the USMLE Step 2 CK 2024

Used especially for:

 Resistant-hypertension pathway
 Hypokalemia and aldosterone-to-renin ratio
 Episodic hypertension with catecholamine symptoms
 Cushingoid clinical clues
 Renal artery stenosis
 Sleep-study pathway
 Cause-specific definitive treatments

The First Aid hypertension algorithm directs resistant hypertension toward evaluation with
electrolytes, aldosterone, renin and cortisol, and then uses characteristic clinical clues to
investigate renal artery stenosis, primary hyperaldosteronism, pheochromocytoma, Cushing
syndrome and obstructive sleep apnea.
PART 1 — THE MASTER CONCEPT
WHAT IS SECONDARY
HYPERTENSION?
Secondary hypertension means:

HIGH BLOOD PRESSURE CAUSED BY

A SPECIFIC IDENTIFIABLE DISEASE,
DRUG OR PHYSIOLOGICAL
ABNORMALITY
Unlike primary hypertension, where many factors interact without one single removable
cause, secondary hypertension has a defined driver.

Examples:

 A narrowed renal artery

 Excess aldosterone
 Excess catecholamines
 Excess cortisol
 Sleep apnea
 A medication that retains sodium
 A congenital narrowing of the aorta

The key clinical importance is:

FINDING AND TREATING THE CAUSE

MAY GREATLY IMPROVE OR EVEN
CURE THE HYPERTENSION.
PART 2 — WHY YOU SHOULD NOT
SCREEN EVERY PATIENT FOR
EVERYTHING
Most adults with hypertension have primary hypertension.

Testing every hypertensive patient for:

 Pheochromocytoma
 Cushing syndrome
 Renal artery stenosis
 Aldosteronism
 Rare genetic disorders

would cause:

 False-positive results
 Unnecessary imaging
 Unnecessary procedures
 Confusion
 Increased cost

Therefore the correct approach is:

SCREEN ONLY WHEN THE HISTORY,

EXAMINATION OR LABORATORY
PATTERN CREATES CLINICAL
SUSPICION.
The Approach source repeatedly frames secondary investigations as guided by specific
clinical features.

PART 3 — WHEN SHOULD YOU

SUSPECT SECONDARY
HYPERTENSION?
The diagnosis should enter your mind when hypertension behaves unusually.
Use the mnemonic:

YOUNG–SUDDEN–SEVERE–
RESISTANT–STRANGE
Young
Hypertension develops at an unusually young age, particularly without obesity or family
history.

Sudden
Abrupt onset or abrupt worsening of previously stable hypertension.

Severe
Very high blood pressure or repeated hypertensive crises.

Resistant
Blood pressure remains uncontrolled despite appropriate multidrug therapy.

Strange
There are unusual clinical clues such as:

 Hypokalemia
 Episodic palpitations and sweating
 Renal bruit
 Snoring and daytime sleepiness
 Cushingoid appearance
 Arm–leg pressure difference
 Sudden creatinine rise after ACE inhibitor
 Drug or stimulant exposure

PART 4 — RESISTANT HYPERTENSION

The supplied Approach source defines resistant hypertension as:

 Uncontrolled hypertension despite three antihypertensive agents from different

classes, including a diuretic
or
  Hypertension requiring four or more agents regardless of whether it is controlled.

However, before declaring true resistant hypertension, exclude:

PSEUDORESISTANCE
Possible causes:

 Incorrect BP technique
 White-coat effect
 Poor adherence
 Inadequate drug doses
 Inappropriate drug combination
 Excess dietary sodium
 NSAID use
 Alcohol excess
 Secondary hypertension

Therefore the sequence is:

CONFIRM TRUE HIGH BP

↓

CONFIRM ADHERENCE
↓

OPTIMIZE THERAPY
↓

THEN SEARCH FOR SECONDARY

CAUSES

PART 5 — THE MASTER

CLASSIFICATION
Use:
R-E-D-A-O
R — Renal

E — Endocrine

D — Drugs and substances

A — Anatomic

O — Obstructive sleep apnea and other causes

SECTION A — RENAL CAUSES

PART 6 — WHY KIDNEY DISEASE
CAUSES HYPERTENSION
The kidneys regulate long-term blood pressure through:

 Sodium excretion
 Water balance
 Renin release
 RAAS activity
 Sympathetic signaling

Kidney disease can raise blood pressure by two major pathways:

1. SODIUM AND WATER RETENTION

Damaged kidneys cannot excrete sodium efficiently.

Extracellular volume expands.

Cardiac output rises.

Blood pressure rises.

2. EXCESS RENIN RELEASE
Reduced renal perfusion is interpreted as low circulating pressure.

Renin is released.

Angiotensin II and aldosterone rise.

Vasoconstriction and sodium retention develop.

The kidney may therefore cause hypertension even when systemic blood pressure is already
high.

PART 7 — RENAL PARENCHYMAL

DISEASE
The supplied source lists:

 Chronic renal failure

 Polycystic kidney disease

as renal parenchymal causes of secondary hypertension.

Other chronic renal parenchymal disorders may produce the same physiology, but this
chapter focuses on the source-listed framework.

PART 8 — CLINICAL PRESENTATION

OF RENAL PARENCHYMAL
HYPERTENSION
Possible clues:

 Elevated creatinine
 Reduced eGFR
  Proteinuria
 Hematuria
 Abnormal urine sediment
 Edema
 Nocturia
 Family history of cystic kidney disease
 Palpable abdominal masses in advanced polycystic disease
 Known CKD

Scenario:

A patient has:

 BP 170/100 mmHg
 Creatinine elevated
 Urine ACR markedly increased
 Bilateral small echogenic kidneys

The hypertension is likely secondary to:

Chronic renal parenchymal disease.

PART 9 — INVESTIGATIONS FOR

RENAL PARENCHYMAL DISEASE
Initial tests:

 Creatinine and eGFR

 Sodium and potassium
 Urinalysis
 Urine albumin-to-creatinine ratio
 Renal ultrasound

The Approach source includes electrolytes, urea, creatinine, urinalysis and urine
microalbumin in the basic hypertension evaluation.

Additional tests depend on the suspected renal disease.

PART 10 — MANAGEMENT OF RENAL

PARENCHYMAL HYPERTENSION
Management has two components:

1. TREAT THE KIDNEY DISEASE

Examples:

 Control diabetes
 Treat glomerular inflammation when present
 Relieve chronic obstruction
 Manage polycystic kidney disease
 Avoid nephrotoxins

2. CONTROL BLOOD PRESSURE

Especially important because hypertension accelerates nephron loss.

Proteinuric CKD generally benefits from:

ACE inhibitor or ARB

when not contraindicated, with monitoring of:

 Creatinine
 Potassium

Definitive management in advanced kidney failure may include:

 Dialysis
 Kidney transplantation

PART 11 — RENOVASCULAR
HYPERTENSION
Renovascular hypertension results from reduced blood flow through one or both renal
arteries.

Main causes listed in the source:

 Atherosclerosis
 Fibromuscular dysplasia
 Vasculitis
 Scleroderma-related vascular disease
The major SMLE causes are:

ATHEROSCLEROTIC RENAL ARTERY

STENOSIS
and

FIBROMUSCULAR DYSPLASIA

PART 12 — RENAL ARTERY STENOSIS

MECHANISM
Renal artery narrows.

Pressure reaching the affected kidney falls.

The kidney interprets this as systemic hypotension.

Renin rises.

Angiotensin II causes vasoconstriction.

Aldosterone causes sodium and water retention.

Systemic blood pressure rises.

But the affected kidney still receives reduced perfusion because the narrowing remains.

Therefore:
THE KIDNEY CREATES SYSTEMIC
HYPERTENSION TO DEFEND ITS OWN
PERFUSION.

PART 13 — UNILATERAL VERSUS

BILATERAL DISEASE
Unilateral stenosis
The affected kidney releases renin.

The opposite normal kidney sees the high systemic pressure and can excrete some sodium.

Hypertension is mainly renin-driven.

Bilateral stenosis
Both kidneys experience low perfusion.

Both retain sodium and depend heavily on angiotensin-II-mediated efferent constriction to

maintain filtration.

This creates increased risk of:

 Volume overload
 Flash pulmonary edema
 AKI after ACE inhibitor or ARB

PART 14 — ATHEROSCLEROTIC
RENAL ARTERY STENOSIS
Usually occurs in:

 Older patients
 Smokers
 Diabetes
 Coronary artery disease
 Peripheral arterial disease
  Diffuse atherosclerosis

Clinical clues:

 Abrupt or worsening hypertension after age 55

 Abdominal bruit
 Resistant hypertension
 Recurrent flash pulmonary edema
 Worsening kidney function
 Significant creatinine rise after ACE inhibitor or ARB

The Approach source specifically recommends renovascular evaluation when at least two
such features are present, including sudden hypertension at age over 55, bruit, resistant
hypertension, a creatinine rise of at least 30% after ACE inhibitor/ARB, atherosclerotic
disease or recurrent flash pulmonary edema.

PART 15 — FIBROMUSCULAR
DYSPLASIA
Fibromuscular dysplasia is a non-atherosclerotic, non-inflammatory arterial disorder.

Classically:

 Younger woman
 Severe or early hypertension
 No typical atherosclerotic risk factors
 Renal bruit may be present

The arterial wall develops alternating narrowing and dilation.

Classic angiographic description:

“STRING OF BEADS”
Why?

Alternating stenotic and dilated segments create a beaded appearance.

PART 16 — FLASH PULMONARY

EDEMA
Bilateral renal artery stenosis can produce recurrent sudden pulmonary edema.

Mechanism:

Renal hypoperfusion

RAAS activation

Sodium and water retention

Rapid volume expansion and hypertension

Left ventricular filling pressure rises

Pulmonary edema develops

Clinical scenario:

An older patient repeatedly presents with:

 Sudden severe dyspnea

 Marked hypertension
 Pulmonary edema
 Relatively preserved ventricular systolic function

Think:

Bilateral renal artery stenosis.

PART 17 — WHY ACE INHIBITORS CAN

CAUSE AKI
In severe bilateral renal artery stenosis:

The kidneys depend on angiotensin II to constrict the efferent arteriole.

↓

This maintains glomerular pressure despite low inflow.

ACE inhibitor or ARB is given.

Efferent arteriole dilates.

Glomerular pressure collapses.

GFR falls.

Creatinine rises.

A rise of at least approximately 30% after ACE inhibitor/ARB is one of the source-listed
clues for renovascular disease.

PART 18 — INVESTIGATIONS FOR

RENAL ARTERY STENOSIS
The supplied Approach source lists:

 Renal Doppler ultrasound

 CT angiography
 MR angiography
 Renal angiography

Initial non-invasive test

Renal artery Doppler ultrasound

Advantages:

 No radiation
 No iodinated contrast
 Evaluates flow
Limitations:

 Operator dependent
 Difficult in obesity or bowel gas

CT angiography
Provides detailed vascular anatomy.

Limitations:

 Iodinated contrast
 Radiation

MR angiography
Useful alternative in selected patients.

Limitations:

 Contrast and device considerations

 May overestimate stenosis

Gold standard anatomical test

Renal angiography
It is invasive, so it is usually reserved for cases where:

 Non-invasive tests are unclear

 Intervention is being considered

PART 19 — MANAGEMENT OF RENAL

ARTERY STENOSIS
Atherosclerotic disease
Most patients require aggressive medical management:

 Blood-pressure control
 Lipid management
 Smoking cessation
 Diabetes management
  Antiplatelet therapy when otherwise indicated
 Monitoring kidney function

ACE inhibitor or ARB may be used cautiously in selected unilateral disease but requires
creatinine and potassium monitoring.

Revascularization
Consider in selected patients with:

 Recurrent flash pulmonary edema

 Progressive renal dysfunction from critical disease
 Refractory hypertension
 Hemodynamically significant stenosis with compelling clinical features

Fibromuscular dysplasia

Percutaneous angioplasty
is often the preferred definitive intervention when clinically significant.

SECTION B — PRIMARY
ALDOSTERONISM
PART 20 — NORMAL ALDOSTERONE
PHYSIOLOGY
Aldosterone is produced by the adrenal zona glomerulosa.

It acts mainly in the distal nephron.

Its effects:

 Sodium reabsorption increases

 Water follows sodium
 Potassium excretion increases
 Hydrogen-ion excretion increases

Therefore excessive aldosterone causes:

HYPERTENSION
 

HYPOKALEMIA


METABOLIC ALKALOSIS

PART 21 — WHAT IS PRIMARY

ALDOSTERONISM?
Primary aldosteronism means:

THE ADRENAL GLAND PRODUCES

ALDOSTERONE AUTONOMOUSLY,
INDEPENDENTLY OF RENIN.
Aldosterone rises.

Sodium and water are retained.

Blood pressure rises.

The expanded circulation suppresses renin.

Therefore the key biochemical pattern is:

ALDOSTERONE HIGH
RENIN LOW
This differs from secondary hyperaldosteronism, where both renin and aldosterone are
elevated because the RAAS system is appropriately activated.
PART 22 — CAUSES
The major causes are:

 Unilateral aldosterone-producing adrenal adenoma

 Bilateral adrenal hyperplasia

The First Aid endocrine algorithm distinguishes adrenal adenoma from bilateral hyperplasia
and links treatment to adrenalectomy versus aldosterone antagonism.

PART 23 — WHY THERE IS USUALLY

NO MAJOR EDEMA
Aldosterone initially retains sodium and water.

But chronic volume expansion triggers:

 Natriuretic peptides
 Increased pressure natriuresis
 Reduced proximal sodium reabsorption

This is called:

ALDOSTERONE ESCAPE
Therefore patients develop hypertension without persistent generalized edema.

First Aid specifically notes mild hypernatremia and metabolic alkalosis but no edema because
of aldosterone escape.

PART 24 — CLINICAL PRESENTATION

Many patients do not have dramatic symptoms.

Possible clues:

 Resistant hypertension
 Spontaneous hypokalemia
 Diuretic-induced severe hypokalemia
 Muscle weakness
 Muscle cramps
  Polyuria
 Polydipsia
 Metabolic alkalosis
 Adrenal incidentaloma with hypertension

The Approach source recommends screening when there is spontaneous potassium below 3.5
mmol/L, diuretic-induced potassium below 3.0 mmol/L, resistant hypertension or an adrenal
incidentaloma with hypertension.

Important:

NORMAL POTASSIUM DOES NOT

EXCLUDE PRIMARY
ALDOSTERONISM.
Mild disease may only become apparent after a thiazide causes disproportionate
hypokalemia.

PART 25 — WHY HYPOKALEMIA

CAUSES POLYURIA
Low potassium impairs the renal concentrating mechanism.

The kidney cannot respond normally to ADH.

More dilute urine is produced.

Polyuria and polydipsia develop.

This resembles partial nephrogenic diabetes insipidus physiology.

PART 26 — SCREENING TEST

Plasma aldosterone concentration to
plasma renin ratio
The typical pattern:

 Aldosterone inappropriately elevated

 Renin suppressed
 Aldosterone-to-renin ratio elevated

Both Approach and First Aid identify the aldosterone-to-renin ratio as the screening test.

PART 27 — INTERPRETING THE

RATIO
A high ratio is meaningful only if aldosterone itself is sufficiently elevated.

A falsely high ratio can occur if:

 Renin is extremely suppressed

 Aldosterone is not actually elevated
 Medication interferes
 Potassium is low

Hypokalemia should be corrected because severe potassium deficiency can suppress

aldosterone and distort testing.

Medication effects should be considered during specialist-directed testing.

PART 28 — CONFIRMATORY TESTING

If screening is positive, autonomous aldosterone secretion is confirmed using a suppression
test.

The First Aid endocrine algorithm specifically shows:

Aldosterone not suppressed with salt

loading.
Concept:
A normal adrenal gland should reduce aldosterone when sodium and volume are abundant.

In primary aldosteronism:

Aldosterone remains inappropriately high despite sodium loading.

PART 29 — LOCALIZATION
After biochemical confirmation:

Adrenal CT
is used to look for:

 Adrenal adenoma
 Bilateral adrenal enlargement
 Suspicious adrenal mass

However, an adrenal nodule may be incidental, especially in older adults.

Therefore imaging alone may not reliably prove which adrenal gland is overproducing
aldosterone.

PART 30 — GOLD STANDARD FOR

LATERALIZATION
Adrenal vein sampling
It compares aldosterone secretion from both adrenal veins.

Purpose:

 Unilateral secretion → surgical disease

 Bilateral secretion → medical treatment

The Approach source specifically identifies adrenal vein sampling for primary
hyperaldosteronism.
PART 31 — TREATMENT
Unilateral aldosterone-producing adenoma

Definitive treatment: laparoscopic

adrenalectomy
Before surgery:

 Control BP
 Correct potassium
 Mineralocorticoid-receptor antagonist may be used

Bilateral adrenal hyperplasia

Best treatment: mineralocorticoid-receptor

antagonist
Examples:

 Spironolactone
 Eplerenone

First Aid lists aldosterone antagonists/potassium-sparing therapy and adrenalectomy

according to the cause.

PART 32 — SPIRONOLACTONE
ADVERSE EFFECTS
Spironolactone blocks:

 Mineralocorticoid receptor
 Androgen-related pathways to some degree

Possible adverse effects:

 Hyperkalemia
 Gynecomastia
 Reduced libido
 Menstrual irregularity
  Renal-function deterioration in susceptible patients

Eplerenone has fewer antiandrogen effects but still carries hyperkalemia risk.

PRIMARY ALDOSTERONISM
SCENARIO
A 48-year-old has:

 Resistant hypertension
 Potassium 2.9 mmol/L
 Bicarbonate 32 mmol/L
 No edema

Interpretation:

Hypertension

Hypokalemia

Metabolic alkalosis

Think:

Primary aldosteronism.
First test:

Aldosterone-to-renin ratio.
If confirmed:

 Adrenal CT
 Adrenal vein sampling when surgery is contemplated

Definitive treatment:

 Unilateral adenoma → adrenalectomy

  Bilateral hyperplasia → spironolactone/eplerenone

SECTION C —
PHEOCHROMOCYTOMA
PART 33 — WHAT IS
PHEOCHROMOCYTOMA?
Pheochromocytoma is a catecholamine-producing tumor arising from adrenal medullary
chromaffin cells.

Catecholamines include:

 Norepinephrine
 Epinephrine

These stimulate alpha- and beta-adrenergic receptors.

PART 34 — HOW CATECHOLAMINES

RAISE BLOOD PRESSURE
Alpha-1 stimulation
Arteriolar vasoconstriction

Systemic vascular resistance rises

Blood pressure rises.

Beta-1 stimulation
 Heart rate increases
 Contractility increases
 Renin release increases
↓

Cardiac output rises.

Therefore catecholamine excess raises blood pressure through:

VASOCONSTRICTION +
TACHYCARDIA + INCREASED
CARDIAC OUTPUT

PART 35 — CLASSIC PRESENTATION

Use:

5 Ps
Pressure

Paroxysmal or severe hypertension

Pain

Headache

Perspiration

Diaphoresis

Palpitations

Tachycardia

Pallor/Panic

Adrenergic appearance

First Aid’s hypertension pathway highlights episodic hypertension, palpitations, headache

and tremor.
PART 36 — WHY HYPERTENSION MAY
BE EPISODIC
Catecholamine release may occur in bursts.

Vascular resistance and heart rate suddenly rise.

The patient experiences an attack.

Between attacks, blood pressure may:

 Remain high
 Return toward normal
 Occasionally become low because of depleted circulating volume or receptor effects

Therefore a normal reading between attacks does not exclude the diagnosis.

PART 37 — TRIGGERS
Episodes may be triggered by:

 Surgery
 Anesthesia
 Tumor manipulation
 Exercise
 Stress
 Certain medications
 Micturition in bladder paraganglioma
 Valsalva maneuver
 Beta-blocker exposure without prior alpha blockade

The Approach source mentions hypertension triggered by beta-blockers, MAO inhibitors,

micturition or Valsalva as important clinical clues.

PART 38 — ASSOCIATED GENETIC

SYNDROMES
The source identifies associations with:

 MEN2A
 MEN2B
 Von Hippel–Lindau syndrome
 Neurofibromatosis

These associations are high-yield because a young patient with:

 Pheochromocytoma
 Family history
 Bilateral tumor
 Other endocrine tumors

may require genetic evaluation.

PART 39 — COMPLICATIONS
During catecholamine surges:

 Hypertensive emergency
 Arrhythmia
 Myocardial ischemia
 Stress cardiomyopathy
 Heart failure
 Pulmonary edema
 Stroke
 Aortic catastrophe
 Hyperglycemia
 Sudden death

The tumor may therefore present as a cardiovascular emergency rather than a classic
outpatient triad.

PART 40 — BEST SCREENING TEST

The Approach source recommends:

 Plasma fractionated metanephrines

or
 24-hour urinary metanephrines

Why metanephrines?
Catecholamines may be released episodically.

But the tumor continuously metabolizes catecholamines into metanephrines.

Therefore metanephrines provide a more stable biochemical signal.

PART 41 — WHY NOT IMAGE FIRST?

An incidental adrenal mass is common.

Imaging before biochemical confirmation may identify an unrelated benign adrenal nodule.

Therefore the logical sequence is:

BIOCHEMICAL CONFIRMATION
↓

ANATOMICAL LOCALIZATION
Exceptions may occur in emergency or unusual clinical settings, but this is the exam
approach.

PART 42 — LOCALIZATION
After biochemical confirmation:

 CT or MRI of the adrenal glands/abdomen

 Functional imaging such as MIBG in selected cases

The Approach source lists MIBG scanning for pheochromocytoma.

PART 43 — DEFINITIVE TREATMENT

Surgical removal of the tumor
But surgery without preparation is dangerous.
Tumor manipulation can release massive catecholamine amounts.

Therefore preoperative preparation is essential.

PART 44 — ALPHA BEFORE BETA

This is one of the most important SMLE
rules.
First:

Alpha blockade
Examples in the supplied First Aid algorithm include doxazosin.

Then, after adequate alpha blockade and volume preparation:

Beta blockade may be added for persistent

tachycardia.
Why must alpha come first?

If beta receptors are blocked first:

Beta-mediated vasodilation and cardiac effects are removed.

Alpha vasoconstriction remains unopposed.

Severe hypertensive crisis may occur.

Memory:

“ALPHA OPENS THE ARTERIES

BEFORE BETA SLOWS THE HEART.”
PART 45 — VOLUME PREPARATION
Chronic catecholamine vasoconstriction often produces a contracted plasma volume.

After alpha blockade:

Vessels dilate.

Hypotension can occur if volume is not restored.

Therefore preoperative preparation often includes:

 Liberal salt intake when appropriate

 Fluid repletion
 Monitoring for orthostatic hypotension

PHEOCHROMOCYTOMA SCENARIO
A 36-year-old has episodic:

 Severe headache
 Sweating
 Palpitations
 Tremor
 BP 220/120 during attacks

Best initial investigation:

Plasma fractionated metanephrines or 24-

hour urinary metanephrines.
After biochemical confirmation:

 CT/MRI for localization

Before surgery:
Alpha blockade first.
Then:

 Beta blocker if required

Definitive treatment:

Surgical excision.

SECTION D — CUSHING SYNDROME

PART 46 — HOW CORTISOL CAUSES
HYPERTENSION
Cortisol raises blood pressure through several mechanisms:

 Increases vascular responsiveness to catecholamines

 Promotes sodium retention at high concentrations
 Increases angiotensinogen
 Contributes to insulin resistance and obesity

At very high levels, cortisol can activate mineralocorticoid receptors because the protective
enzyme system becomes overwhelmed.

Therefore cortisol excess produces:

VASCULAR SENSITIVITY + SODIUM

RETENTION + METABOLIC DISEASE

PART 47 — CLINICAL CLUES

Do not screen every obese hypertensive patient for Cushing syndrome.

Look for more specific features:

 Wide purple abdominal striae

 Easy bruising
  Proximal muscle weakness
 Facial rounding
 Dorsocervical fat pad
 Thin limbs with central fat accumulation
 New diabetes
 Osteoporosis
 Recurrent infections
 Menstrual irregularity
 Mood disturbance

The supplied sources highlight abdominal striae, Cushingoid appearance and proximal
myopathy.

PART 48 — WHY PROXIMAL MUSCLE

WEAKNESS OCCURS
Cortisol increases protein breakdown.

Muscle proteins are catabolized.

Large proximal muscles weaken.

The patient may struggle to:

 Rise from a chair

 Climb stairs
 Lift arms overhead

This is more suggestive of cortisol excess than simple obesity.

PART 49 — SCREENING TESTS

The Approach source lists:

 24-hour urine cortisol

 1-mg dexamethasone suppression test
 Late-night salivary cortisol

First Aid’s hypertension algorithm gives the same three screening approaches.
PART 50 — DEXAMETHASONE
SUPPRESSION CONCEPT
Dexamethasone is a glucocorticoid.

In a normal person:

Dexamethasone

Suppresses pituitary ACTH

Cortisol falls.

In Cushing syndrome:

Cortisol fails to suppress appropriately.

The First Aid endocrine algorithm explicitly shows failure of low-dose dexamethasone
suppression as evidence of hypercortisolism.

PART 51 — AFTER CONFIRMING

HYPERCORTISOLISM
Measure ACTH.

ACTH low
Think:

Adrenal cortisol production.

ACTH high or inappropriately normal
Think:
  Pituitary ACTH adenoma
 Ectopic ACTH secretion

Further testing localizes the source.

This level of distinction is included because it directly determines definitive treatment.

PART 52 — MANAGEMENT
Treat the source of cortisol excess.
Examples:

 Pituitary adenoma → pituitary surgery

 Adrenal cortisol-producing tumor → adrenal surgery
 Ectopic ACTH source → treat the underlying tumor
 Exogenous steroid use → gradual medically supervised reduction when possible

Associated problems must also be treated:

 Hypertension
 Diabetes
 Hypokalemia
 Infection
 Osteoporosis
 Thrombotic risk

CUSHING SCENARIO
A patient has:

 Resistant hypertension
 Diabetes
 Wide purple striae
 Easy bruising
 Proximal muscle weakness

Best screening choices:

 1-mg overnight dexamethasone suppression

 Late-night salivary cortisol
 24-hour urinary free cortisol
Definitive treatment:

Removal or treatment of the cortisol-

producing source.

SECTION E — OBSTRUCTIVE SLEEP

APNEA
PART 53 — WHAT IS OSA?
Obstructive sleep apnea involves repeated upper-airway collapse during sleep.

Airflow stops or falls.

Oxygen falls.

Carbon dioxide rises.

The brain briefly arouses the patient.

Airway tone returns.

This cycle may repeat many times per night.

PART 54 — HOW OSA CAUSES

HYPERTENSION
Each apnea causes:

 Hypoxemia
 Sympathetic surge
  Catecholamine release
 Vasoconstriction
 Heart-rate rise

Repeated episodes produce sustained sympathetic activation even during daytime.

OSA also promotes:

 RAAS activation
 Oxidative stress
 Endothelial dysfunction
 Loss of normal nocturnal BP dipping

Therefore OSA commonly causes:

RESISTANT OR NIGHTTIME
HYPERTENSION.

PART 55 — CLINICAL CLUES

 Loud snoring
 Witnessed apneas
 Gasping or choking during sleep
 Daytime sleepiness
 Morning headache
 Poor concentration
 Large neck circumference
 Obesity
 Resistant hypertension
 Atrial fibrillation

The Approach source highlights narrowed oropharynx and increased neck circumference on
examination.

PART 56 — BEST DIAGNOSTIC TEST

Sleep study
First Aid’s hypertension algorithm directs snoring and resistant hypertension toward sleep
testing.
The study measures:

 Airflow
 Respiratory effort
 Oxygen saturation
 Sleep stages
 Apnea–hypopnea frequency

PART 57 — TREATMENT
Continuous positive airway pressure —
CPAP
CPAP splints the upper airway open.

Apneas decrease.

Hypoxemia and sympathetic surges decrease.

Sleep quality and daytime symptoms improve.

First Aid identifies CPAP as the treatment pathway.

Also important:

 Weight reduction
 Avoid excess sedatives/alcohol
 Positional measures in selected patients
 Treat nasal obstruction when relevant
 Continue antihypertensive therapy as needed

Definitive cure is not guaranteed by CPAP, but treating OSA may improve blood-pressure
control and reduce cardiometabolic burden.

OSA SCENARIO
An obese patient has:

 Loud snoring
 Witnessed apneas
 Daytime somnolence
 Morning headaches
 Hypertension despite three medications

Most likely secondary cause:

Obstructive sleep apnea.

Best test:

Sleep study.
Best specific treatment:

CPAP plus weight management.

SECTION F — THYROID DISEASE

PART 58 — HYPERTHYROIDISM
Thyroid hormone increases:

 Heart rate
 Contractility
 Cardiac output

It also lowers systemic vascular resistance.

Therefore the typical blood-pressure pattern is:

SYSTOLIC PRESSURE HIGH

DIASTOLIC PRESSURE LOW OR
NORMAL
WIDE PULSE PRESSURE
Clues:

 Weight loss
 Tremor
 Heat intolerance
 Palpitations
 Hyperreflexia
 Goiter
 Atrial fibrillation

The Approach source includes TSH and free T4 in endocrine evaluation and notes goiter as a
physical clue.

Treatment:

Treat the hyperthyroidism.

Beta-blockers may control adrenergic symptoms while definitive thyroid treatment is
arranged.

PART 59 — HYPOTHYROIDISM
Hypothyroidism reduces cardiac output but increases systemic vascular resistance.

Therefore it may cause:

DIASTOLIC HYPERTENSION
Possible clues:

 Fatigue
 Weight gain
 Cold intolerance
 Dry skin
 Bradycardia
 Delayed reflexes
 Constipation

Investigation:

 TSH
 Free T4
Definitive treatment:

Thyroid-hormone replacement when

appropriate.

SECTION G — DRUG- AND

SUBSTANCE-INDUCED
HYPERTENSION
PART 60 — WHY MEDICATION
HISTORY IS ESSENTIAL
A patient may undergo expensive endocrine testing while the actual cause is:

 Ibuprofen
 Steroids
 Oral contraceptive
 Decongestant
 Stimulant
 Cocaine
 Cyclosporine
 Excess licorice

Therefore always ask about:

PRESCRIPTION + OVER-THE-
COUNTER + HERBAL +
RECREATIONAL SUBSTANCES
The supplied Approach source lists NSAIDs, corticosteroids, anabolic steroids, estrogen-
containing contraceptives, cocaine, amphetamines, antidepressants, erythropoietin,
calcineurin inhibitors, midodrine, alcohol excess and licorice root.

PART 61 — NSAIDs
NSAIDs inhibit renal prostaglandins.

Renal blood flow may fall.

Sodium and water retention increase.

Blood pressure rises.

They may also reduce the effect of:

 Diuretics
 ACE inhibitors
 ARBs

Clinical clue:

A previously controlled hypertensive patient develops:

 Edema
 Rising BP
 Rising creatinine

after frequent NSAID use.

Best treatment:

Stop or minimize the NSAID when

clinically possible.

PART 62 — GLUCOCORTICOIDS
Steroids raise BP through:

 Sodium retention
 Increased vascular sensitivity
 Weight gain
 Metabolic effects

Clinical clues:
  Long-term steroid therapy
 Cushingoid features
 New diabetes
 Worsening hypertension

Treatment:

 Use the lowest necessary dose

 Gradually taper only under medical supervision when appropriate
 Treat persistent BP elevation

Do not abruptly stop chronic steroids because adrenal suppression may be present.

PART 63 — ORAL CONTRACEPTIVES

Estrogen-containing contraceptives can increase hepatic angiotensinogen.

RAAS activity increases.

Blood pressure may rise.

Management:

 Reassess the contraceptive

 Consider an alternative method
 Monitor BP

PART 64 — SYMPATHOMIMETICS AND

STIMULANTS
Examples:

 Amphetamines
 Cocaine
 Some decongestants

Mechanism:

 Catecholamine release
  Vasoconstriction
 Tachycardia

Complications:

 Hypertensive emergency
 MI
 Stroke
 Aortic dissection
 Arrhythmia

Definitive management:

Stop the causative substance and treat

acute toxicity appropriately.

PART 65 — CALCINEURIN INHIBITORS

Cyclosporine and tacrolimus can cause:

 Renal vasoconstriction
 Sodium retention
 Nephrotoxicity
 Hypertension

Management:

 Monitor kidney function

 Review drug level
 Adjust immunosuppression with specialist input
 Treat BP

PART 66 — LICORICE
Natural licorice can inhibit the enzyme that normally protects mineralocorticoid receptors
from cortisol.

Cortisol activates mineralocorticoid receptors.

↓
Sodium retention increases.

Potassium falls.

Hypertension and metabolic alkalosis develop.

Biochemical pattern:

 Renin low
 Aldosterone low

This resembles mineralocorticoid excess but is not primary aldosteronism.

Best treatment:

Stop licorice exposure.

SECTION H — COARCTATION OF THE

AORTA
PART 67 — MECHANISM
Coarctation is congenital narrowing of the aorta, usually near the ductal region.

Pressure proximal to the narrowing rises.

Upper-body hypertension develops.

Pressure distal to the narrowing falls.

Lower-extremity perfusion decreases.

Renal hypoperfusion may also activate RAAS.

PART 68 — CLINICAL CLUES
 Hypertension in a young person
 Upper-body BP greater than lower-body BP
 Weak or delayed femoral pulses
 Radiofemoral delay
 Leg fatigue or claudication
 Continuous or systolic murmur over the back
 Better-developed upper body
 Rib notching on imaging in chronic disease

The Approach source highlights upper-body development, a continuous murmur,

radiofemoral delay and weak femoral pulses.

PART 69 — BEST INITIAL EXAM STEP

Measure blood pressure in both arms and
at least one leg.
A significant arm–leg pressure difference plus delayed femoral pulses strongly suggests
coarctation.

Imaging options:

 Echocardiography
 CT angiography
 MR angiography

Definitive treatment:

Surgical repair or catheter-based

intervention
depending on anatomy and age.

COARCTATION SCENARIO
A 19-year-old has:
  Arm BP 170/90
 Leg BP 120/70
 Weak femoral pulses
 Systolic murmur over the back

Diagnosis:

Coarctation of the aorta.

Definitive treatment:

Anatomical correction.

SECTION I — LESS COMMON

SOURCE-LISTED CAUSES
These are included because they are explicitly listed in the supplied source, but kept focused
at the recognition level appropriate to Mastery Level 1.

PART 70 — ACROMEGALY
Growth hormone excess causes:

 Sodium retention
 Insulin resistance
 Vascular remodeling
 Sleep apnea

Clinical clues:

 Enlarged hands and feet

 Coarse facial features
 Low-pitched voice
 Prognathism
 Headache
 Sweating

The source suggests IGF-1 testing when clinically suspected.

Best screening test:

IGF-1
Definitive treatment usually targets the pituitary source.

PART 71 — HYPERPARATHYROIDISM
Hyperparathyroidism and hypercalcemia may be associated with hypertension through:

 Vascular smooth-muscle effects

 Renal effects
 Volume and neurohormonal mechanisms

Clues:

 Hypercalcemia
 Kidney stones
 Bone symptoms
 Elevated PTH

Tests listed by the source:

 Calcium
 Albumin
 PTH

Treatment:

Treat the hyperparathyroid disorder.

PART 72 — NEUROGENIC
HYPERTENSION
The source lists:

 Baroreceptor malfunction
 Posterior fossa or lateral medullary lesions
 Raised intracranial pressure producing the Cushing triad

Cushing triad
  Hypertension
 Bradycardia
 Abnormal or depressed respiration

This suggests dangerous raised intracranial pressure.

It is not Cushing syndrome.

Important distinction:

CUSHING TRIAD = RAISED ICP

CUSHING SYNDROME = CORTISOL
EXCESS

PART 73 — RENIN–ALDOSTERONE
PATTERN TABLE
Disorder Renin Aldosterone Typical clue
Primary aldosteronism Low High HTN, hypokalemia, alkalosis
Bruit, creatinine rise after
Renal artery stenosis High High
ACEi
Volume loss, medication
Diuretic use High High
history
Licorice/apparent mineralocorticoid
Low Low HTN, hypokalemia, licorice
effect
Early severe HTN,
Liddle-type physiology Low Low
hypokalemia
Renal parenchymal disease Variable Variable Creatinine, proteinuria

This table is a conceptual synthesis of the source-listed renal, adrenal and pseudo-adrenal
categories.

PART 74 — COMPLETE DIAGNOSTIC

APPROACH
Step 1: Confirm true hypertension
 Correct technique
 Repeat readings
 Home or ambulatory confirmation when appropriate

Step 2: Exclude pseudoresistance

 Adherence
 White-coat effect
 Dose adequacy
 High sodium
 NSAIDs or stimulants

Step 3: Look for clinical clues

Hypokalemia
Think primary aldosteronism.

Episodic headache, sweating, palpitations

Think pheochromocytoma.

Cushingoid features
Think cortisol excess.

Bruit, flash pulmonary edema, ACEi creatinine rise

Think renal artery stenosis.

Snoring and daytime sleepiness

Think OSA.

Abnormal creatinine/proteinuria
Think renal parenchymal disease.
Arm–leg pressure difference
Think coarctation.

Step 4: Order targeted tests

 Aldosterone/renin ratio
 Plasma or urine metanephrines
 Cortisol screening
 TSH/free T4
 Renal Doppler/CTA/MRA
 Sleep study
 Renal function and urine studies
 Limb BP/imaging for coarctation

Step 5: Confirm and localize the cause

↓

Step 6: Treat the underlying cause

and continue BP control to prevent organ damage.

PART 75 — HIGH-YIELD SCENARIOS

Scenario 1 — Primary aldosteronism
 Resistant hypertension
 Potassium 2.8
 Bicarbonate 33
 No edema

Best screening test:

Aldosterone-to-renin ratio.
Definitive management:
  Unilateral adenoma → adrenalectomy
 Bilateral hyperplasia → mineralocorticoid antagonist

Scenario 2 — Renal artery stenosis

Older smoker with:

 Resistant hypertension
 Abdominal bruit
 Recurrent flash pulmonary edema
 Creatinine rises 35% after ACE inhibitor

Most likely diagnosis:

Bilateral renal artery stenosis.

Best non-invasive imaging:

Renal Doppler or CT/MR angiography.

Gold-standard anatomy:

Renal angiography.

Scenario 3 — Fibromuscular dysplasia

Young woman with:

 Severe hypertension
 Renal bruit
 No atherosclerotic risk factors
 “String-of-beads” renal artery appearance

Diagnosis:

Fibromuscular dysplasia.
Definitive treatment when significant:

Percutaneous angioplasty.
Scenario 4 — Pheochromocytoma
Patient has episodic:

 Headache
 Sweating
 Palpitations
 Severe hypertension

Best screening test:

Plasma fractionated metanephrines or 24-

hour urinary metanephrines.
Preoperative sequence:

Alpha blockade before beta blockade.

Definitive treatment:

Tumor excision.

Scenario 5 — Cushing syndrome

Patient has:

 Hypertension
 Diabetes
 Wide purple striae
 Easy bruising
 Proximal weakness

Screen with:

 Low-dose dexamethasone suppression

 Late-night salivary cortisol
 24-hour urinary cortisol

Definitive treatment:
Treat the cortisol source.

Scenario 6 — OSA
Obese patient has:

 Loud snoring
 Witnessed apnea
 Morning headache
 Daytime somnolence
 Resistant hypertension

Best test:

Sleep study.
Best specific treatment:

CPAP.

Scenario 7 — Drug-induced hypertension

Patient’s BP becomes uncontrolled after frequent ibuprofen use.

Also develops:

 Edema
 Creatinine rise

Cause:

NSAID-mediated sodium retention and

renal hemodynamic impairment.
Best treatment:

Stop the NSAID if possible.

Scenario 8 — Coarctation
Young adult:

 Upper-limb hypertension
 Weak femoral pulses
 Radiofemoral delay
 Lower leg BP

Diagnosis:

Coarctation of aorta.
Definitive treatment:

Surgical or catheter correction.

PART 76 — BEST TEST / GOLD

STANDARD / DEFINITIVE TREATMENT
SUMMARY
Primary aldosteronism
 Screening: aldosterone-to-renin ratio
 Confirmation: aldosterone suppression testing
 Localization: adrenal CT
 Gold-standard lateralization: adrenal vein sampling
 Unilateral definitive treatment: adrenalectomy
 Bilateral best treatment: spironolactone/eplerenone

Pheochromocytoma
 Best biochemical screening: plasma fractionated or urinary metanephrines
 Localization: CT/MRI
 Functional imaging when needed: MIBG
 Preoperative treatment: alpha blockade first
 Definitive treatment: surgical excision

Renal artery stenosis

 Initial non-invasive imaging: Doppler ultrasound/CTA/MRA
  Gold-standard anatomy: renal angiography
 FMD definitive treatment: angioplasty
 Atherosclerotic disease: primarily medical treatment, selective revascularization

OSA
 Best diagnostic test: sleep study
 Best specific treatment: CPAP
 Additional disease-modifying treatment: weight reduction

Cushing syndrome
 Screening: low-dose dexamethasone suppression, late-night salivary cortisol or 24-
hour urinary cortisol
 Definitive treatment: treat/remove cortisol-producing source

Coarctation
 Bedside clue: arm–leg BP difference and radiofemoral delay
 Imaging: echo/CTA/MRA
 Definitive treatment: anatomical repair

PART 77 — SMLE EXAM TRAPS

Trap 1
Every hypertensive patient needs a complete endocrine workup.

Incorrect.

Testing should be guided by clinical clues.

Trap 2
Resistant hypertension means secondary hypertension is definitely present.

Incorrect.

First exclude pseudoresistance and nonadherence.

Trap 3
Normal potassium excludes primary aldosteronism.

Incorrect.

Many patients are normokalemic.

Trap 4
A high aldosterone-to-renin ratio alone proves primary aldosteronism.

Incomplete.

Aldosterone should be elevated and confirmatory testing is generally required.

Trap 5
Adrenal CT alone distinguishes unilateral from bilateral aldosterone secretion.

Incorrect.

Adrenal vein sampling is the best lateralization test when surgery is planned.

Trap 6
Beta blocker should be given first in pheochromocytoma.

Dangerously incorrect.

Alpha blockade must come first.

Trap 7
Catecholamines are the best screening measurement for pheochromocytoma because they
cause the symptoms.

Metanephrines are generally better because their production is more continuous.

Trap 8
An adrenal mass should be biopsied immediately.

Incorrect.

A functioning pheochromocytoma must be excluded before invasive manipulation, and

adrenal biopsy often does not distinguish adenoma from carcinoma.

Trap 9
ACE inhibitor-associated creatinine rise always means ordinary drug toxicity.

A marked rise may indicate bilateral renal artery stenosis or severe hypoperfusion.

Trap 10
Renal artery stenosis always requires stenting.

Incorrect.

Many atherosclerotic cases are managed medically.

Trap 11
OSA causes hypertension only during sleep.

Incorrect.

Repeated nocturnal sympathetic activation can produce sustained daytime hypertension.

Trap 12
Every obese hypertensive patient with a round face has Cushing syndrome.

Incorrect.
Look for specific features such as:

 Purple striae
 Proximal weakness
 Easy bruising
 Osteoporosis

Trap 13
Hypertension plus hypokalemia always means primary aldosteronism.

Other possibilities include:

 Diuretics
 Renovascular disease
 Licorice
 Rare mineralocorticoid disorders

Use renin and aldosterone patterns.

Trap 14
Cushing triad and Cushing syndrome are the same.

Incorrect.

 Cushing triad → raised intracranial pressure

 Cushing syndrome → cortisol excess

PART 78 — MEMORY MAPS

WHEN TO SUSPECT
Y-S-S-R-S
Young

Sudden
Severe

Resistant

Strange laboratory or physical clue

SECONDARY CAUSES
RENAL–HORMONE–DRUG–PIPE–
SLEEP
Renal

Kidney disease or renal artery stenosis

Hormone

Aldosterone, catecholamines, cortisol, thyroid

Drug

NSAIDs, steroids, stimulants, OCPs

Pipe

Coarctation of aorta

Sleep

OSA

HYPOKALEMIC HYPERTENSION
A-R-L
A — Aldosterone excess

R — Renovascular renin excess

L — Licorice/mineralocorticoid-like effect

PHEOCHROMOCYTOMA
5 Ps
Pressure

Pain

Perspiration

Palpitations

Pallor/Panic

PHEOCHROMOCYTOMA TREATMENT
A BEFORE B
Alpha before beta

RENAL ARTERY STENOSIS

BRUIT–ACE RISE–FLASH
 Abdominal bruit
 Creatinine rise after ACEi/ARB
 Flash pulmonary edema

PRIMARY ALDOSTERONISM
HIGH A, LOW R
  Aldosterone high
 Renin low
 Potassium may be low
 Bicarbonate may be high

OSA
SNORE–STOP–SLEEPY–PRESSURE
 Snoring
 Breathing stops
 Daytime sleepiness
 Hypertension

PART 79 — FINAL MASTER

FLOWCHART
Confirmed hypertension
↓

Is it unusually young, sudden, severe or

resistant?
No
Primary hypertension more likely.

Yes
↓

Exclude pseudoresistance
 Technique
 White-coat effect
 Adherence
  Sodium
 NSAIDs/drugs

Look for the clue

Creatinine/proteinuria
Renal parenchymal disease

Abdominal bruit, ACEi creatinine rise, flash edema

Renal artery stenosis

Hypokalemia and alkalosis

Primary aldosteronism

Episodic headache, sweating and palpitations

Pheochromocytoma

Striae, bruising, proximal weakness

Cushing syndrome

Snoring, apnea, daytime sleepiness

OSA

Thyroid symptoms
TSH/free T4

Upper-limb hypertension with weak femoral pulses

Coarctation

New drug or substance exposure

Drug-induced hypertension

↓
Select the targeted test
 ACR/creatinine/ultrasound
 Doppler/CTA/MRA
 Aldosterone-to-renin ratio
 Plasma/urine metanephrines
 Cortisol screening
 Sleep study
 Thyroid function
 Limb pressures and aortic imaging

Confirm and localize

↓

Treat the cause

 Adrenalectomy
 Mineralocorticoid antagonist
 Alpha blockade then tumor surgery
 Treat cortisol source
 CPAP
 Stop causative drug
 Angioplasty in appropriate FMD
 Repair coarctation
 Treat renal disease

Continue blood-pressure control and

monitor organ damage

FINAL MASTER CONCEPT

Secondary hypertension should not be memorized as a random list.

Every cause raises pressure through one of four main physiological pathways:

1. VOLUME RETENTION
Examples:

 Renal parenchymal disease

 Aldosterone excess
 Steroids
 NSAIDs

2. RAAS ACTIVATION
Examples:

 Renal artery stenosis

 Renal hypoperfusion

3. EXCESS VASOCONSTRICTION OR
CARDIAC STIMULATION
Examples:

 Pheochromocytoma
 Stimulants
 Hyperthyroidism
 OSA-related sympathetic activation

4. FIXED ANATOMICAL
OBSTRUCTION
Example:

 Coarctation of the aorta

The correct SMLE approach is:

DO NOT TEST RANDOMLY.

Instead:

NOTICE THE CLUE

↓
CHOOSE THE TARGETED SCREENING
TEST
↓

CONFIRM THE DISORDER

↓

LOCALIZE IT WHEN NECESSARY

↓

TREAT THE UNDERLYING CAUSE

The highest-yield pairings are:

 Hypokalemia → aldosterone/renin ratio

 Episodic headache, sweating and palpitations → metanephrines
 Striae and proximal weakness → cortisol testing
 Snoring and daytime sleepiness → sleep study
 Bruit, flash pulmonary edema or ACEi creatinine rise → renal vascular imaging
 Arm hypertension with weak femoral pulses → coarctation imaging

And the most important treatment rule is:

PHEOCHROMOCYTOMA: ALPHA
BLOCKADE BEFORE BETA
BLOCKADE.
This completes the listed adult Nephrology TOS sequence:

1. Hyperkalemia and hypokalemia

2. Hyponatremia and hypernatremia
3. Acute kidney injury
4. Chronic kidney disease
5. Primary hypertension
6. Secondary hypertension