Nephrology

MKSAP 19 board
basics

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Glomerular Filtration Rate
At high levels of GFR, small changes in the serum creatinine may reflect large
changes in GFR. At low levels of GFR, large changes in the serum creatinine
reflect relatively smaller changes in GFR.

Serum cystatin C is an alternative marker of GFR less influenced than serum

creatinine by age, sex, muscle mass, and body weight; it is more sensitive than
serum creatinine in identifying milder decrements in kidney function.

Conditions that decrease kidney perfusion and urine flow, such as hypovolemia
or HF, are associated with increased resorption of urine urea nitrogen in the
proximal tubules, resulting in a disproportionate increase in the BUN-creatinine
ratio, typically to 20:1 or higher.

Don't Be Tricked
• A reduction or loss of muscle mass because of advanced age, liver
failure, or malnutrition may cause a disproportionately low serum
creatinine concentration, which results in overestimation of the GFR.
• When the MDRD study equation is used to estimate GFR, higher levels
of GFR are reported only as >60 mL/min/1.73 m2, but this does not
guarantee an absence of structural kidney disease.

Urinalysis
Proteinuria

Albumin is the only protein that is detected on dipstick urinalysis.

Protein detected by urine dipstick should always be quantified with either a 24-hour
urine collection or protein-creatinine or albumin-creatinine ratio on random urine
samples.

The albumin-creatinine ratio measures only albumin in the urine and is used to
evaluate diabetic kidney disease:

• 30 to 300 mg/g defines moderately increased albuminuria.

• >300 mg/g defines severely increased albuminuria.

A protein-creatinine ratio can be used to measure proteinuria (abnormal protein-

creatinine ratio defined as ≥150 mg/g).

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Proteinuria is a marker of renal parenchymal and glomerular disease and an
independent predictor of progressive kidney disease, cardiovascular disease, and
peripheral vascular disease.

Don't Be Tricked
• Dipstick urinalysis does not detect immunoglobulin light chains associated
with multiple myeloma.
• Because moderately increased albuminuria may go undetected by dipstick,
direct quantification using a random (spot) protein-creatinine ratio or albumin-
creatinine ratio is required when screening patients at high risk.
• Positional (orthostatic) proteinuria, a benign cause of isolated proteinuria, is
diagnosed by obtaining split daytime (standing) and nighttime (supine) urine
collections.

Hematuria

Hematuria is classified as glomerular and extraglomerular. Erythrocyte casts and

dysmorphic erythrocytes (acanthocytes, erythrocytes with “Mickey Mouse” ears) in
the urine indicate glomerular disease (see The Nephritic Syndrome
following). Coexisting proteinuria supports glomerular causes of hematuria, even in
the absence of casts.

Hematuria with preserved erythrocyte morphology in the urine and without

proteinuria or casts is consistent with extraglomerular bleeding (GU cancer, kidney
stones, trauma, infection, and medications) and requires additional diagnostic studies
to locate the extraglomerular source. The proper evaluation is directed by findings in
the history and physical examination.

Figure 1. Evaluation of Patients With Hematuria:

Algorithm summarizing the American College of Physicians recommendations for the
evaluation of patients with hematuria. AMH = asymptomatic microscopic hematuria;
UA = urinalysis.

Reprinted with permission from Nielsen M, Qaseem A; High Value Care Task Force
of the American College of Physicians. Hematuria as a marker of occult urinary tract
cancer: advice for high-value care from the American College of Physicians. Ann
Intern Med. 2016;164:488-97. PMID: 26810935. Copyright 2016, American College
of Physicians.

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Don't Be Tricked
• Evaluate hematuria even in patients taking antiplatelet drugs or anticoagulants.

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Leukocytes and Other Formed Elements

Leukocytes in the urine may be caused by glomerular or tubulointerstitial

inflammation, infection, or an allergic reaction.

Remember:

• Sterile pyuria (pyuria and a negative urine culture) suggests Mycobacterium

tuberculosis, interstitial cystitis, or interstitial nephritis.
• Eosinophiluria suggests AIN, postinfectious GN, atheroembolic disease of the
kidney, septic emboli, or small-vessel vasculitis.

Don't Be Tricked
• Absence of eosinophiluria does not rule out AIN, postinfectious GN,
atheroembolic disease of the kidney, septic emboli, or small-vessel vasculitis.

Patients with hemolysis and rhabdomyolysis test positive for blood on dipstick
urinalysis in the absence of erythrocytes on urine microscopy. Urine lipids and fat are
almost always associated with heavy proteinuria or the nephrotic syndrome. These
may appear as free lipid droplets, round or oval fat bodies, or fatty casts.

Casts are cylindrical aggregates of Tamm-Horsfall mucoproteins that trap the

intraluminal contents and appear in the urine.

Different types of casts are associated with specific disorders:

• Erythrocyte casts indicate glomerular disease.

• Leukocyte casts indicate inflammation or infection of the renal parenchyma.
• Muddy brown casts are associated with ATN.
• Broad casts are associated with CKD.

Imaging
The three main modalities of kidney imaging are ultrasonography, CT, and
MRI.

Ultrasonography is used to look for:

• nephrolithiasis
• kidney size and cortical thickness (increased echogenicity implies
parenchymal disease)
• renal cysts and tumors
• obstruction and hydronephrosis
• bladder size, postvoid residual, and the prostate in bladder outlet
obstruction

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CT is used to look for:

• nephrolithiasis (noncontrast abdominal helical CT)

• renal tumors and cysts (contrast abdominal CT)
• causes of unexplained nonglomerular hematuria (CT urography)

MRI is used:

• to characterize renal masses, cysts, and renal vein thrombosis

• to look for renal artery stenosis using MRA with gadolinium contrast

Kidney Biopsy
Kidney biopsy should be considered in patients with:

• glomerular hematuria
• severely increased albuminuria
• acute or chronic disease of unclear origin
• kidney transplant dysfunction

Common contraindications to kidney biopsy include bleeding diatheses, severe

anemia, UTI, hydronephrosis, uncontrolled hypertension, renal tumor, and
atrophic kidneys.

Hyponatremia
Diagnosis

The first step in assessing low serum sodium is to determine whether true
hyponatremia is present by measuring serum osmolality.

Isotonic hyponatremia is a laboratory artifact caused by severe hyperlipidemia or

hyperproteinemia. In isotonic hyponatremia, the measured osmolality is normal.

If true hyponatremia exists, classify it as hypertonic or hypotonic.

Hypertonic hyponatremia (osmolality >295 mOsm/kg H2O) is caused by the

presence of an osmotically active substance, such as:

• glucose (most common)

• BUN
• alcohols
• mannitol
• sorbitol
• glycine (bladder irrigation during urologic procedures)

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Hypotonic hyponatremia (osmolality <275 mOsm/kg H2O) is the most common
form of hyponatremia and is further classified based on the patient's volume status.

Study Table: Evaluating Hypotonic Hyponatremia

Volume Laboratory
Status Studies Differential Diagnosis
Hypovolemic Spot urine GI or kidney sodium losses, mineralocorticoid
(hypotension, sodium <20 insufficiency
tachycardia) mEq/L

BUN/creatinine
>20:1
Hypervolemic Spot urine HF, cirrhosis, kidney failure
(edema, sodium <20
ascites) mEq/L (HF and
cirrhosis in
absence of
diuretic
therapy)

Spot urine
sodium >20
mEq/L (acute
and chronic
kidney failure)
Isovolemic Spot urine SIADH, hypothyroidism, adrenal insufficiency
(normal sodium >20
volume) mEq/L

Urine
osmolality
usually >100
mOsm/kg H2O
Isovolemic Spot urine Compulsive water drinking
(normal sodium <20
volume) mEq/L

Urine
osmolality 50
to 100
mOsm/kg H2O

Causes of SIADH include malignancy (SCLC); intracranial pathology; and

pulmonary diseases, especially those that increase intrathoracic pressure and decrease
venous return to the heart. Many medications can cause SIADH, including

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thiazides, SSRIs, tricyclic antidepressants, opioids, phenothiazines, and
carbamazepine.

Don't Be Tricked
• Do not miss adrenal insufficiency as a cause of hypotonic hyponatremia.

Treatment

IV volume replacement with normal saline is indicated for hypovolemic hypotonic

hyponatremia resulting from volume depletion.

Acute symptomatic isovolemic hypotonic hyponatremia (urine osmolality >100

mOsm/kg H2O) should be treated with a 100-mL bolus of 3% saline to increase the
serum sodium by 2.0 to 3.0 mEq/L.

Chronic symptomatic isovolemic hypotonic hyponatremia (>48 hours or

unknown) should be treated to a target of 4 to 6 mEq/L in 24 hours.

If neurologic impairment is significant (seizures or coma), sodium can be acutely

increased 2.0-4.0 mEq/L using a bolus of 3% saline as long as the total increase
remains ≤10 mEq/L in 24 hours.

If the serum sodium concentration is overcorrected, administer desmopressin and IV

5% dextrose in water. Central pontine myelinolysis (osmotic demyelination
syndrome) may occur if hyponatremia is corrected too rapidly.

Water restriction is used initially for asymptomatic or minimally symptomatic

outpatients with SIADH. Demeclocycline can also be used for outpatients who do not
respond to fluid restriction. The IV V1 and V2 receptor antagonist conivaptan and the
oral V2 receptor antagonist tolvaptan (vaptans) are approved for treatment of
euvolemic and hypervolemic hyponatremia. Oral tolvaptan should be reserved for the
management of a serum sodium concentration <120 mEq/L and persistent SIADH
that has failed water restriction. No data show that the vaptans are associated with
improved patient outcomes compared with conventional therapy.

Don't Be Tricked
• Vaptan agents should not be used to treat hypovolemic hyponatremia or acute
symptomatic hyponatremia.
• Unless documentation indicates that hyponatremia is acute, treat all cases of
hyponatremia as chronic.

Test Yourself

A 53-year-old man has a 3-week history of increasing weakness and anorexia.

On physical examination, his volume status is normal. Laboratory studies:

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serum creatinine, 0.8 mg/dL; serum sodium, 123 mEq/L; potassium, 3.4
mEq/L; and urine sodium, 110 mEq/L.

Answer: For diagnosis, choose SIADH. For management, select serum

osmolality measurement to confirm the presence of hypo-osmolality. If hypo-
osmolality is present, the patient likely has SIADH (most common), thyroid
disease, or adrenal insufficiency.

Hypernatremia
Diagnosis

Hypernatremia is defined as a serum sodium level >145 mEq/L. Severe

hypernatremia indicates a defective thirst mechanism, inadequate access to water
(older patients in nursing homes), a kidney concentrating defect (DI, most commonly
caused by lithium), and/or impaired pituitary secretion of ADH (e.g., sarcoidosis).
Most commonly, hypernatremia results from loss of hypotonic fluids (GI, kidney,
skin) with inadequate water replacement.

Treatment

Treatment is directed at free water replacement and correction of the underlying

problem leading to hypotonic fluid loss. The water deficit is calculated as [(Na+ −
140)/140] × TBW, where TBW = 0.5 × weight (kg) in women or 0.6 × weight (kg) in
men. Correct the water deficit over 48 to 72 hours.

In volume depletion, fluid resuscitation with normal saline should precede correction
of the water deficit with hypotonic fluids. Neurogenic (central) DI is treated with
intranasal or oral desmopressin.

Hyperkalemia
Diagnosis

The most common causes of hyperkalemia include:

• hyporeninemic hypoaldosteronism (type 4 [hyperkalemic

distal] RTA; commonly seen among patients with diabetes)
• acute and chronic kidney failure
• low urine flow states
• medications (ACE inhibitors, ARBs, potassium-sparing diuretics,
pentamidine, trimethoprim-sulfamethoxazole, and cyclosporine)
• potassium shifts (rhabdomyolysis, hemolysis, hyperosmolality, insulin
deficiency, β-adrenergic blockade, and metabolic acidosis)

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The earliest ECG changes of hyperkalemia are peaking of the T waves and shortening
of the QT interval. As hyperkalemia progresses, the PR interval is prolonged, a loss of
P waves occurs, and eventual widening of the QRS complexes is seen with a “sine-
wave” pattern that may precede asystole.

Pseudohyperkalemia is an in vitro phenomenon caused by the mechanical release of

potassium from cells during phlebotomy or specimen processing or in the setting of
marked leukocytosis and thrombocytosis. In patients with pseudohyperkalemia, the
plasma potassium concentration is normal.

Don't Be Tricked
• Significant hyperkalemia associated with a normal ECG suggests
pseudohyperkalemia.

Treatment

If hyperkalemia is associated with ECG changes or arrhythmias, begin IV calcium

gluconate to stabilize the myocardium. Use insulin and glucose or inhaled β-
adrenergic agonists to shift potassium inside the cells. Remove potassium from the
body with loop diuretics (particularly if the patient is volume overloaded), patiromer,
or sodium zirconium cyclosilicate, and institute dietary potassium restriction.

Hemodialysis is often needed to correct life-threatening hyperkalemia but is never the

“first step” because of the time delay in initiating dialysis.

Don't Be Tricked
• Absolute levels of potassium cannot reliably determine whether a life-
threatening condition exists. Only ECG can assess the effect of hyperkalemia
on the cardiac membrane.

Figure 2. Characteristics of Hyperkalemia:

ECG showing flattened P waves; prolonged PR interval; widened QRS; and tall,
peaked T waves characteristic of hyperkalemia.

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Hypokalemia
Diagnosis and Testing

The most common causes of hypokalemia are vomiting and diarrhea and use of
diuretics. A spot urine potassium-creatinine ratio <13 mEq/g identifies hypokalemia
secondary to lack of intake, transcellular shifts, or gastrointestinal losses.

Other causes include:

• primary aldosteronism (hypertension, urine [Cl–] >40 mEq/L, low plasma

renin activity, and elevated aldosterone level)
• Bartter syndrome (normal BP, hypokalemia, metabolic alkalosis, and elevated
renin and aldosterone levels)
• Gitelman syndrome (normal BP, hypokalemia, and hypomagnesemia)
• inhaled β2-agonists (may lead to hypokalemia in certain clinical settings)
• hypokalemic periodic paralysis

Hypokalemic periodic paralysis is a rare familial or acquired disorder characterized

by flaccid generalized weakness from a sudden intracellular potassium shift
precipitated by strenuous exercise or a high-carbohydrate meal. The acquired form
occurs with thyrotoxicosis and is found in men of Asian or Mexican descent. It is
resolved with treatment of hyperthyroidism.

Characteristic findings of hypokalemia include ileus, muscle cramps, rhabdomyolysis,

and hypomagnesemia. ECGs may show U waves and flat or inverted T waves.

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Treatment

For severe hypokalemia, IV potassium chloride is indicated. Total body potassium

deficits are typically large (200 mEq for each 1 mEq/L decrease in plasma
potassium). Hypomagnesemia and metabolic alkalosis should be corrected, if present.

Hypomagnesemia
Diagnosis and Testing

If hypomagnesemia is suspected, look for neuromuscular irritability, hypocalcemia,

and hypokalemia.

The most common causes of hypomagnesemia include:

• GI losses (diarrhea, steatorrhea, intestinal bypass, pancreatitis)

• kidney losses (loop and thiazide diuretics, alcohol induced)
• medications (cisplatin, aminoglycosides, amphotericin B, cyclosporine)
• hungry bone syndrome following parathyroidectomy

Usually the source of hypomagnesemia is obvious. If no cause is clinically apparent,

GI and kidney losses can be differentiated by measuring the 24-hour urine magnesium
excretion (elevated in kidney losses, low in GI losses). Hypomagnesemia is often
associated with hypokalemia because of urine potassium wasting. Hypomagnesemia
is also associated with hypocalcemia because of lower PTH secretion and end-organ
resistance to PTH.

Don't Be Tricked
• Correction of hypokalemia and hypocalcemia is difficult unless magnesium
depletion is also corrected.

Treatment

Administer oral slow-release magnesium (mild to moderate hypomagnesemia) or IV

magnesium sulfate to achieve a serum magnesium level >1 mg/dL.

Test Yourself

A 30-year-old woman with Crohn disease has an ileostomy. For the past week,
she has noted increased ostomy output, weakness, and paresthesias. Laboratory
studies show serum sodium, 129 mEq/L; potassium, 2.9 mEq/L; bicarbonate,
18 mEq/L; calcium, 5.5 mg/dL; and phosphorus, 1.3 mg/dL. After treatment
with isotonic saline plus potassium chloride and sodium bicarbonate, the
bicarbonate concentration is 22 mEq/L. However, the serum potassium level is
still 2.9 mEq/L, and the serum calcium level is 5.3 mg/dL.

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Answer: For diagnosis, choose hypomagnesemia. For management, measure
magnesium level and, if low, begin IV magnesium replacement.

Hypophosphatemia
Diagnosis

Phosphate is primarily excreted through the kidneys and is reabsorbed mainly in the
proximal tubule. The primary hormonal factors regulating phosphorus balance
are PTH (which decreases phosphorus reabsorption and promotes kidney phosphate
excretion) and calcitriol (which stimulates phosphate absorption in the gut).
Characteristic findings in severe hypophosphatemia are HF, muscle weakness,
rhabdomyolysis, hemolytic anemia, and metabolic encephalopathy.

Common causes include:

• refeeding after starvation

• insulin administration for severe hyperglycemia
• hungry bone syndrome following parathyroidectomy
• respiratory alkalosis
• chronic diarrhea
• chronic alcoholism
• hyperparathyroidism
• vitamin D deficiency

If the cause of hypophosphatemia is not evident from the history, a 24-hour urine
phosphate collection or calculation of the FEPO4 from a random urine sample can help
differentiate renal from extrarenal causes. The FEPO4 can be calculated as follows:

(Urine PO4 × Serum Creatinine × 100)/(Serum PO4 × Urine Creatinine)

Urine phosphate excretion >100 mg/d or an FEPO4 >5% indicates renal phosphate
wasting.

Treatment

In asymptomatic patients, administer oral phosphorus replacement as a sodium or

potassium salt. Parenteral therapy with either of these agents is indicated for
symptomatic patients or for those whose phosphorus level is <2 mg/dL.

Approach to Acid-Base Problem

Solving
Answer these four questions when solving acid-base problems:

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 1. What is the primary disturbance?
2. Is compensation appropriate?
3. What is the anion gap?
4. Does the change in the anion gap equal the change in the serum bicarbonate
concentration (a value called the delta-delta)?

When diagnosing a primary acid-base disorder, remember that:

• Acidemia is defined as a pH <7.37. Metabolic acidosis = [HCO3] <22 mEq/L.

Respiratory acidosis = arterial PCO2 >44 mm Hg.
• Alkalemia is defined as a pH >7.44. Metabolic alkalosis = [HCO3] >26
mEq/L. Respiratory alkalosis = arterial PCO2 <36 mm Hg.

Study Table: Compensatory Response to a Primary Acid-Base Disturbance

Expected
Condition CompensationInterpretation
Metabolic Acute: Δ Failure of the arterial PCO2 to decrease to expected
acidosis arterial PCO2 = value = complicating respiratory acidosis
(1.5)[HCO3–] +
8±2 Excessive decrease of the arterial PCO2 =
complicating respiratory alkalosis
Respiratory Acute: 1 Failure of the [HCO3–] to increase to the expected
acidosis mEq/L ↑ in value = complicating metabolic acidosis
[HCO3 ] for
–

each 10 mm Excessive increase in [HCO3–] = complicating

Hg ↑ in arterial metabolic alkalosis
PCO2

Chronic: 3.5
mEq/L ↑ in
[HCO3–] for
each 10 mm
Hg ↑ in arterial
PCO2
Metabolic 0.7 mm Hg ↑ This response is limited by hypoxemia
alkalosis in arterial
PCO2 for each 1
mEq/L ↑ in
[HCO3–]
Respiratory Acute: 2 Failure of the [HCO3–] to decrease to the expected
alkalosis mEq/L ↓ in value = complicating metabolic alkalosis
[HCO3–] for
each 10 mm Excessive decrease in [HCO3–] = complicating
Hg ↓ in arterial metabolic acidosis
PCO2

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Study Table: Compensatory Response to a Primary Acid-Base Disturbance

Expected
Condition CompensationInterpretation

Chronic: 4-5
mEq/L ↓ in
[HCO3–] for
each 10 mm
Hg ↓ in arterial
PCO2
Anion Gap

The anion gap = [Na+] − ([Cl–] + [HCO3–]). The normal anion gap is 8-10 ± 2 mEq/L.
Acidoses can be divided into normal anion gap acidosis and increased anion gap
acidosis.

Always calculate the anion gap, regardless of the metabolic disturbance.

• When the primary disturbance is a metabolic acidosis, the anion gap

differentiates increased anion gap from normal anion gap acidosis.
• A reduced anion gap (<4 mEq/L) suggests multiple myeloma or
hypoalbuminemia.

Increased Anion Gap Acidosis

Common causes of increased anion gap metabolic acidosis include:

• DKA
• CKD
• lactic acidosis (usually because of tissue hypoperfusion)
• aspirin toxicity
• alcoholic ketoacidosis
• methanol and ethylene glycol poisoning (also typically associated with an
osmolar gap)

Normal Anion Gap Acidosis

Common causes of normal anion gap metabolic acidosis include:

• GI HCO3– loss (diarrhea)

• kidney HCO3– loss (type 2 proximal RTA)
• reduced kidney H+ secretion (type 1 hypokalemic distal RTA, type 4
hyperkalemic distal RTA)
• Fanconi syndrome (phosphaturia, glucosuria, uricosuria, aminoaciduria)
• carbonic anhydrase inhibitor use (acetazolamide and topiramate)

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Urine Anion Gap

Increased acid excretion by the kidney is reflected as a marked increase in urine

ammonium. Because chloride is excreted into the urine in amounts equal to
ammonium, the amount of chloride in the urine reflects the amount of ammonium
present.

The ability to excrete acid in the form of ammonia is calculated with the UAG. The
UAG is defined as (urine [Na+] + urine [K+]) – urine [Cl–].

• During normal anion gap metabolic acidosis resulting from extrarenal

bicarbonate loss (diarrhea), the kidney will excrete increased urine ammonium
(and chloride), resulting in a negative UAG.
• During impaired urine acidification caused by type 1 hypokalemic distal RTA,
urine ammonium (and chloride) excretion is impaired, with the UAG being
positive.

Renal Tubular Acidosis

Normal anion gap metabolic acidosis is seen in all three types of RTA.

Study Table: Differential Diagnosis of Renal Tubular Acidosis

Metabolic
Diagnosis Findings Associated Findings
Type 1 Normal anion Nephrolithiasis and nephrocalcinosis,
hypokalemic distal gap metabolic autoimmune disorders (SLE, Sjögren
RTA acidosis, syndrome), amphotericin B use, urinary
hypokalemia, obstruction
positive
UAG, urine
pH >5.5 (only
in the setting
of systemic
acidosis),
serum [HCO3]
≅ 10 mEq/L
Type 2 proximal Normal anion Glycosuria, phosphaturia, hypouricemia,
RTA gap metabolic aminoaciduria (Fanconi syndrome); tubular
acidosis, proteinuria
normal or
negative
UAG,
hypokalemia,
urine pH
<5.5, serum

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Study Table: Differential Diagnosis of Renal Tubular Acidosis

Metabolic
Diagnosis Findings Associated Findings
[HCO3] ≅ 16-
18 mEq/L
Type 4 Normal anion Diabetes mellitus, urinary tract obstruction
hyperkalemic distal gap metabolic
RTA acidosis,
(hyporeninemic hyperkalemia,
hypoaldosteronism) positive
UAG, urine
pH <5.5
Treatment

In distal (type 1) RTA, administration of bicarbonate usually corrects the metabolic

acidosis. The potassium deficit should be corrected before correcting the acidemia.

In proximal (type 2) RTA, correction of acidemia with bicarbonate therapy is often

not possible. The addition of a thiazide diuretic may help by inducing volume
depletion, lowering the GFR, and thereby decreasing the filtered load of bicarbonate.
The addition of a potassium-sparing diuretic may limit the degree of kidney potassium
wasting.

In type 4 RTA, the primary goal of therapy is to correct the hyperkalemia, which will
treat the acid-base disturbance. These patients, often with early CKD and diabetes,
may develop severe hyperkalemia following treatment with ACE inhibitors or ARBs.

Test Yourself

A 31-year-old woman with IBD passes a kidney stone. Serum sodium is 142
mEq/L, potassium is 2.9 mEq/L, chloride is 112 mEq/L, and bicarbonate is 20
mEq/L. Urine pH is 6.5.

Answer: For diagnosis, choose type 1 hypokalemic distal RTA.

Delta-Delta

In increased anion gap acidosis, the expected ratio between the change in anion gap
(measured anion gap − normal anion gap) and the change in plasma [HCO3] (normal
HCO3 − measured HCO3) concentration (Δ anion gap/Δ [HCO3]) is 1 to 2.

• If (Δ anion gap/Δ [HCO3]) is <0.5-1, consider concurrent normal anion gap

acidosis.
• If (Δ anion gap/Δ [HCO3]) is >2, consider concurrent metabolic alkalosis.

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Metabolic alkalosis is often caused by upper GI loss of hydrogen chloride from
vomiting or by kidney loss of hydrogen chloride during diuretic therapy. Metabolic
alkalosis is maintained by extracellular fluid volume contraction, chloride depletion,
hypokalemia, or elevated aldosterone activity.

You must be able to answer questions like these:

• Problem 1: pH, 7.31; arterial PCO2, 10 mm Hg; sodium, 127 mEq/L; chloride,
99 mEq/L; bicarbonate, 5 mEq/L. Answer: Mixed increased anion gap and
normal anion gap metabolic acidosis and respiratory alkalosis (triple acid-base
disorder)
• Problem 2: pH, 7.20; arterial PCO2, 23 mm Hg; sodium, 134 mEq/L; chloride,
80 mEq/L; bicarbonate, 8 mEq/L. Answer: Mixed increased anion gap
metabolic acidosis and metabolic alkalosis (double acid-base disorder)

Alcohol Poisoning
Diagnosis

Determine the presence of an osmolal gap, which is the difference between measured
and calculated osmolality. The calculated plasma osmolality = (2 × serum [Na+]) +
[BUN]/2.8 + blood [glucose]/18; sodium concentration is measured as mEq/L, and
BUN and glucose concentration are measured as mg/dL.

The normal osmolal gap is 10 mOsm/kg H2O. If a larger gap exists, consider alcohol
poisoning as the source of unmeasured osmoles. Ethanol is the most common cause of
alcohol poisoning. Methanol, isopropyl alcohol, and ethylene glycol may also
increase the osmolal gap.

Study Table: Presentation and Treatment of Alcohol Poisoning

Common Major Anion Osmolar

Alcohol Sources Findings Gap Gap Treatment
Ethanol Alcoholic CNS depression Possible Yes Supportive care (0.9%
beverages saline IV, glucose,
Flank pain, thiamine)
hematuria,
oliguria
Isopropyl Rubbing CNS depression No Yes Supportive care (similar
alcohol alcohol to ethanol)
↑ Ketones
Methanol Windshield CNS depression Yes Yes Fomepizole
wiper fluid
Vision loss Dialysis (if severe)
De-icing
solutions Folic acid

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Study Table: Presentation and Treatment of Alcohol Poisoning

Common Major Anion Osmolar

Alcohol Sources Findings Gap Gap Treatment
Ethylene Antifreeze CNS depression Yes Yes Fomepizole
glycol
De-icing Acute kidney Dialysis (if severe)
solutions injury

Calcium
oxalate crystals
in the urine
Figure 3. Calcium Oxalate Crystals:
Characteristic envelope-shaped calcium oxalate dihydrate crystals, which may be seen
in late ethylene glycol intoxication.

Hypertension
Diagnosis

Before labeling a person as having hypertension, use an average BP based on two or

more readings obtained on two or more occasions. Out-of-office ABPM and HBPM
are recommended to confirm the diagnosis of hypertension and for titration of BP-
lowering medication.

White coat hypertension. In adults with an untreated SBP >130 but <160 mm Hg
or DBP >80 but <100 mm Hg, it is reasonable to evaluate for the presence of white
coat hypertension using either daytime ABPM or HBPM before diagnosis of
hypertension.

Masked hypertension. Masked hypertension is defined as elevated BP detected by

ABPM or HBPM but with a normal office BP measurement. In adults with elevated
office BP (120-129/<80 mm Hg) but not meeting the criteria for hypertension,
evaluating for masked hypertension with daytime ABPM or HBPM is reasonable.

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Target BP for older adult patients. The ACC/AHA target SBP for
noninstitutionalized, ambulatory, community-dwelling patients aged ≥65 years is
<130 mm Hg. The ACP guideline recommends a target SBP <150 mm Hg in patients
aged ≥60 years.

Target BP for patients with selected comorbidities. The ACC/AHA recommends a

target BP <130/80 mm Hg for all patients with comorbidities, including all forms
of ASCVD, HF, CKD, and diabetes. The ADA recommends a target BP <140/80 mm
Hg for patients with diabetes; a target BP <130/80 mm Hg may be considered if 10-
year ASCVD risk is ≥15%. ACP guidelines indicate a target SBP <140 mm Hg may
be reasonable in some patients aged ≥60 years at high cardiovascular risk or with a
history of stroke or TIA based on individualized assessment.

Secondary hypertension. Most patients with established hypertension have primary

hypertension. Consider secondary hypertension in patients who have atypical clinical
features (early onset, absent family history, hypokalemia, evidence of kidney disease)
or have resistant hypertension (not at target goal despite the use of three
antihypertensive agents, including a diuretic).

Study Table: Selected Secondary Causes of Hypertension

Condition Notes
Drug induced NSAIDs, amphetamines/cocaine, sympathomimetics, oral
contraceptives, glucocorticoids
CKD Elevated BUN, serum creatinine, and potassium
Renovascular Onset of hypertension at young age, especially in women
disease (fibromuscular); atherosclerotic disease often associated
(atherosclerotic and with cigarette smoking, flash pulmonary
fibromuscular) edema, CAD, flank bruits, advanced retinopathy, increased
creatinine (usually with bilateral renovascular disease), and
increased creatinine after treatment with an ACE inhibitor
or ARB
Primary Muscle cramping, nocturia, thirst; physical examination
hyperaldosteronism normal; hypokalemia (50%) and elevated plasma
aldosterone–plasma renin activity ratio
Cushing syndrome Weight gain, menstrual irregularity, hirsutism; truncal
obesity, abdominal striae; hypokalemia, metabolic
alkalosis
Pheochromocytoma Sweating, pounding headache; pallor; tachycardia;
hypertension may be episodic with intervals of
normal BP; increased urine or plasma catecholamines or
metanephrine

Don't Be Tricked
• Do not use plasma renin activity to risk stratify patients with hypertension or
to predict response to specific drugs.
20
Test Yourself

A 35-year-old woman is evaluated for persistent fatigue and resistant

hypertension. Serum potassium level is 3.3 mEq/L.

Answer: For diagnosis, choose primary aldosteronism. For management, select

measurement of plasma aldosterone–plasma renin activity ratio.

Testing

Collect data on cardiovascular risk factors and possible underlying secondary causes.
Initial evaluation includes:

• laboratory testing for kidney function, fasting blood glucose, fasting lipid
panel, serum potassium, and serum calcium
• ECG
• urinalysis and albumin-creatinine ratio

Treatment
Study Table: ACC/AHA Classification and Treatment of Blood Pressure

Office-
Based
Readings
BP Category (mm Hg) Treatment BP Target (mm Hg)
Normal SBP NA NA
<120 and
DBP <80
Elevated BP SBP 120- Nonpharmacologic SBP <120 and DBP <80
129 and therapy (NPT)
DBP <80
Hypertension, SBP 130- NPT if 10-year <130/80
stage 1 139 or ASCVD risk
DBP 80- <10%
89
NPT + first-line
drugs if
clinical CV disease
or 10-year
ASCVD risk
≥10%
Hypertension, SBP Two first-line <130/80
stage 2 ≥140 or drugs of different
DBP ≥90 classes, preferably
with once-daily
dosing, if BP

21
Study Table: ACC/AHA Classification and Treatment of Blood Pressure

Office-
Based
Readings
BP Category (mm Hg) Treatment BP Target (mm Hg)
20/10 mm Hg
above target

First-line antihypertensive agents are those shown to reduce clinical events.

For hypertension in the non-Black population (see below), older adults, and patients
with diabetes without albuminuria:

• thiazide diuretic
• CCB
• ACE inhibitor or ARB

For patients with diabetes and albuminuria:

• ACE inhibitor or ARB

For patients with stage G3 kidney disease or higher or proteinuric kidney disease
(urine albumin-creatine ratio ≥300 mg/g):

• ACE inhibitor or ARB

For stage 1 hypertension in the Black population (see below) without CKD or HF and
with or without diabetes (but no albuminuria):

• thiazide diuretic
• CCB

For patients with stage 2 hypertension:

• combination of two first-line antihypertensive drugs of different classes

(except ACE inhibitors and ARBs)

Explanation of race: Current guidelines recommend that initial antihypertensive

therapy should include a thiazide diuretic or a CCB in Black persons; however,
physicians are increasingly aware of the limitations in making management decisions
based on skin color and that labeling patients as Black or not Black may be overly
simplistic and inappropriate. Without more precise variables to explain differences in
response to therapy among patients, many experts and guidelines continue to use race-
based terminology, although guidelines addressing race-based recommendations are
evolving.

Don't Be Tricked
22
 • Thiazide diuretics are not effective in patients with kidney disease (GFR <30
mL/min/1.73 m2); select a loop diuretic.

Renovascular Hypertension

Testing

Routine testing for renovascular disease in older patients with ASCVD is not
recommended.

In young women with resistant hypertension and a high clinical suspicion for
fibromuscular dysplasia, renal artery imaging may be considered:

• renal duplex Doppler ultrasonography

• MRA or CTA (most accurate, but avoid in severe CKD)

Treatment

Renal artery angioplasty is no better than medical therapy in patients with

atherosclerotic renovascular disease and stable kidney function. Therapy is directed at
controlling ASCVD risk factors.

In young persons with fibromuscular dysplasia, angioplasty may improve BP and cure
hypertension.

Hypertensive Urgency

The treatment of hypertensive urgency (BP >180/120 mm Hg in the absence of

symptoms or progressive target-organ damage) differs if the patient has previously
treated hypertension or untreated hypertension.

Systolic BP should be lowered no more than 25% within the first hour, then to
<160/100 mm Hg within the next 2 to 6 hours, then cautiously to target during the
following 24 to 48 hours.

In patients with preexisting treated hypertension:

• slowly restart the medication(s) in nonadherent patients.

• in adherent patients, either increase the dose of the medication(s) or add an
additional agent.

In patients with previously untreated hypertension:

• consider oral furosemide or small doses of clonidine or captopril and observe

for several hours for a BP drop of 20 to 30 mm Hg (not to normal BP).
• begin a long-acting agent; discharge home with follow-up in 2 to 3 days.

23
Hypertensive Emergency
Hospitalize a patient with hypertensive emergency (BP ≥180/120 mm Hg and
symptoms or evidence of end-organ damage).

For a compelling condition (such as aortic dissection, severe preeclampsia or

eclampsia, or pheochromocytoma crisis), SBP should be reduced to <140 mm
Hg during the first hour and to <120 mm Hg in aortic dissection.

Without a compelling condition, SBP should be reduced by no more than 25%

within the first hour; then, if stable, reduce to 160/100 mm Hg within the next 2
to 6 hours; finally, cautiously reduce to normal during the following 24 to 48
hours. See Neurology for treatment of hypertension associated with ischemic
stroke and intracerebral hemorrhage.

For patients without a compelling indication, treatment consists of short-acting

IV drugs administered in the ICU (e.g., nitroglycerin, nitroprusside, labetalol,
nicardipine).

Study Table: IV Antihypertensive Drugs for Treatment of Hypertensive

Emergencies in Patients With a Compelling Comorbidity
ComorbidityPreferred Drugs
Acute aortic Esmolol, labetalol
dissection
Acute Nitroglycerin, nitroprusside
pulmonary
edema β-Blockers contraindicated
ACS Esmolol, nitroglycerin
AKI Nicardipine
Eclampsia or Hydralazine, labetalol, nicardipine
preeclampsia
ACE inhibitors, ARBs, renin inhibitors, nitroprusside
contraindicated.

Don't Be Tricked

• Do not select sublingual nifedipine for either hypertensive urgency or

emergency.

Hypertension in Pregnancy

24
Diagnosis

Chronic hypertension in pregnancy. Hypertension before the 20th week of

gestation is most consistent with previously undiagnosed chronic hypertension.

Gestational hypertension is hypertension that develops after 20 weeks of pregnancy

without preexisting hypertension, proteinuria, or other end-organ damage. Gestational
hypertension is a risk factor for preeclampsia and the development of chronic
hypertension.

Preeclampsia is new-onset hypertension after 20 weeks of pregnancy with

proteinuria. Eclampsia is the presence of generalized, tonic-clonic seizures in a
woman with preeclampsia.

Treatment

Treatment of hypertension less than 160/110 mm Hg during pregnancy is

controversial, and benefits of treatment have not been demonstrated.

Drugs that may be used during pregnancy:

• methyldopa
• labetalol
• calcium channel blockers (e.g., long-acting nifedipine)

Antihypertensive medications absolutely contraindicated during pregnancy:

• ACE inhibitors
• ARBs
• renin inhibitors

Diuretics may induce oligohydramnios if initiated during pregnancy.

Preeclampsia. Definitive treatment is delivery, including induction of labor in

women at or near term. In the event of a hypertensive crisis, maternal BP stabilization
should occur before delivery, even in urgent circumstances.

Don't Be Tricked
• Treatment of gestational hypertension does not prevent the occurrence of
preeclampsia or chronic hypertensio

Glomerular Diseases
Glomerular disease should be suspected when proteinuria and/or hematuria are seen
on urinalysis.

25
The most common distinction is usually made between the nephrotic syndromes and
the nephritic syndromes, also referred to as GN. Some conditions may present with
either or both patterns, and some may progress from one pattern to the other.

The Nephrotic Syndrome

Diagnosis

The nephrotic syndrome is characterized by:

• urine protein excretion >3500 mg/24 h or a urine protein-creatinine ratio

>3500 mg/g
• hypoalbuminemia, edema, and hyperlipidemia may be present

The nephrotic syndrome may be primary or secondary to systemic diseases such as

diabetes, infection, or autoimmune diseases.

Study Table: Common Causes of the Nephrotic Syndrome

Clinical
Condition Associations Diagnosis Treatment
Focal segmental “Collapsing” variety Biopsy Glucocorticoids or
glomerulosclerosis associated with HIV calcineurin inhibitors

Associated with
morbid obesity
Membranous Positive antibody Biopsy 30% spontaneously
nephropathy against remit in 12-24 mo. Treat
phospholipase A2 with RAS blockade,
receptor statins, and diuretics

Secondary causes If persistent:

include infection glucocorticoids and
(hepatitis B and C, cyclophosphamide,
malaria, calcineurin inhibitors, or
syphilis), SLE, drugs rituximab
(NSAIDs), cancer
(solid tumors, Treat concurrent
lymphoma) conditions in secondary
membranous
High propensity for nephropathy
thrombosis,
especially renal vein
thrombosis
Minimal change Most common cause Biopsy Initial treatment consists
glomerulopathy of primary nephrotic of glucocorticoids

26
Study Table: Common Causes of the Nephrotic Syndrome

Clinical
Condition Associations Diagnosis Treatment
syndrome in
children

10% of nephrotic
syndrome in adults
Diabetic kidney Most common Clinical Excellent BP and
disease secondary cause of diagnosis glucose control
the nephrotic (diabetes of
syndrome and the long duration, ACE inhibitors or ARBs
most common albuminuria,
overall cause in and evidence
adults of other
microvascular
and/or
macrovascular
disease)

Don't Be Tricked
• Nephrotic range proteinuria in a patient with diabetes but without
microvascular (e.g., retinopathy) or macrovascular (e.g., CAD) disease is not
caused by diabetes. Kidney biopsy is required for definitive diagnosis.

Treatment

Treatment of the consequences of the nephrotic syndrome should occur

simultaneously with treatment of the specific cause (if nephrotic syndrome is
secondary to an underlying condition):

• statins for elevated lipid levels

• anticoagulation for thrombotic complications (because of urinary loss of
antithrombins)
• low-salt diet and loop diuretics for edema

Figure 4. Fat Droplet:

Typical “Maltese cross” appearance of a fat droplet under polarized light microscopy
commonly found in the nephrotic syndrome.

27
The Nephritic Syndrome

Diagnosis

The nephritic syndrome (glomerulonephritis) is associated with glomerular

inflammation resulting in hematuria, proteinuria, and leukocytes in the urine
sediment. The hallmark is the presence of dysmorphic erythrocytes and erythrocyte
casts. Proteinuria is variable. Systemic findings may include edema, hypertension, and
kidney failure.

Figure 5. Glomerulonephritis:
Erythrocyte casts consistent with glomerulonephritis.

Figure 6. Dysmorphic Erythrocytes:

Erythrocytes with abnormal morphology seen in glomerulonephritis, including those
with “Mickey Mouse ears.”

28
Don't Be Tricked
• The absence of erythrocyte casts does not rule out glomerulonephritis.

Study Table: Categorization of Glomerulonephritis Based on Immunofluorescence

Microscopy Findings

Immunofluorescence Staining Pattern

Pauci-
Granular immune Linear
Lupus nephritis ANCA- Anti-GBM antibody disease
associated
Infection-related GN
GN

IgA nephropathy

MPGN

Cryoglobulinemic
GN
Study Table: Categorization of Glomerulonephritis Based on Serum Complement
Levels

Low Serum C3
and/or C4 LevelsNormal Serum C3 and C4 Levels
Lupus nephritis IgA nephropathy
Infection-related ANCA-associated GN
GN
MPGN Anti-GBM antibody disease
Cryoglobulinemic
GN

29
Rapidly progressive GN is a clinical syndrome characterized by evidence of GN with
progression to kidney failure within weeks. Findings include oliguria, rising serum
creatinine levels, macroscopic or microscopic hematuria, erythrocyte casts, and
proteinuria. It may be associated with any cause of GN or may be idiopathic. Rapidly
progressive GN is particularly common with anti-GBM antibody disease (in younger
patients) and pauci-immune small-vessel vasculitis (in older patients). Serologic
testing (e.g., ANCA, anti-GBM antibodies, antinuclear antibodies) aids in the
diagnosis. Diagnosis is made by kidney biopsy.

Anti–Glomerular Basement Membrane Antibody Disease

Anti-GBM disease is an autoimmune disorder caused by antibodies directed against

type IV collagen. If pulmonary capillaries are involved, it causes pulmonary
hemorrhage (Goodpasture syndrome). Anti-GBM disease presents as RPGN with lung
involvement in >50% of patients.

Findings include normal complement levels and elevated levels of anti-GBM

antibodies. Kidney biopsy shows proliferative GN with linear deposition of
immunoglobulin.

Treatment is cyclophosphamide and glucocorticoids, combined with plasmapheresis.

ANCA-Associated Glomerulonephritis

Kidney manifestations range from only hematuria to RPGN. Systemic symptoms may
include arthritis, leukocytoclastic vasculitis (palpable purpura), and pulmonary
disease (pulmonary infiltrate to pulmonary hemorrhage).

More than 80% of patients with MPA or granulomatosis with polyangiitis are ANCA
positive; granulomatosis with polyangiitis is associated with (PR3)-ANCA, and MPA
is associated with (MPO)-ANCA.

Complement levels are normal. Kidney biopsy shows absent or minimal staining with
immunoglobulin.

Induction therapy consists of glucocorticoids and cyclophosphamide (or rituximab)

with plasmapheresis if alveolar damage is evident.

IgA Nephropathy

IgA nephropathy most commonly presents as asymptomatic microscopic hematuria

(with or without proteinuria) or episodic gross hematuria coincident with
a URI (synpharyngitic nephritis). IgA nephropathy may also present as an acute GN
or RPGN, with variable degrees of AKI, hypertension, edema, proteinuria, and
hematuria.

30
Kidney biopsy shows glomerular IgA deposits on immunofluorescence. Complement
levels are normal.

Most patients have a benign course without treatment; patients with proteinuria and
risk factors for progression may benefit from ACE inhibitors or ARBs.

IgA Vasculitis (Henoch-Schönlein Purpura)

IgA vasculitis may present with the classic tetrad of rash, arthralgia, abdominal pain,
and kidney disease. Kidney involvement is similar to IgA nephropathy, and other
organ involvement may occur.

Diagnosis is confirmed either by finding an IgA-dominant leukocytoclastic vasculitis

or by kidney biopsy, which shows lesions similar to IgA nephropathy. Complement
levels are normal.

Treatment of kidney disease includes glucocorticoids and, in cases of associated

RPGN, cyclophosphamide.

Lupus Nephritis

Patients typically have extrarenal symptoms of SLE at the time of diagnosis of LN.

ANA and anti–double-stranded antibodies are positive, and C3 and C4 complement

levels are depressed.

Classification and recommended treatment of LN is made after kidney biopsy:

• Class I and II (minimal or proliferative mesangial) lesions require no specific

therapy other than RAS blockade.
• Class III and IV (focal and diffuse glomerular lesions) induction therapy
consists of high-dose glucocorticoids and either IV cyclophosphamide or
mycophenolate mofetil (less toxic).
• Class V (membranous) LN has a course similar to idiopathic membranous
nephropathy, and induction therapy consists of glucocorticoids and IV
cyclophosphamide, cyclosporine or tacrolimus, or mycophenolate mofetil (less
toxic).

Infection-Related Glomerulonephritis

Staphylococcal infection is as common as or more common than streptococcal

infection as a cause of infection-related GN. The clinical manifestations of
poststreptococcal GN typically occur after a latent period of 1 to 6 weeks (check
antistreptolysin O, anti-DNase titers) but may occur at the time of infection with other
infectious agents. The presentation of infection-related GN ranges from asymptomatic
microscopic hematuria to RPGN.

31
Diagnosis is clinical in nephritic patients who have an ongoing or preceding infection.
Complement levels are low.

Treatment focuses on the underlying infection.

Membranoproliferative Glomerulonephritis

MPGN manifests in children or young adults as proteinuria or the nephrotic

syndrome. Two forms exist: an immune-complex form mediated by antigen-antibody
interactions triggering the classic complement pathway and a complement-mediated
form caused by a hyperactive alternative complement pathway. It is associated with
immune complex disease (SLE), infections (HCV), and monoclonal gammopathy.

Complement levels are low. Diagnosis and distinction of the two types are made by
kidney biopsy and immunofluorescence microscopy.

Treatment of MPGN includes immunosuppression and treatment of any underlying

cause.

Kidney Manifestations of Deposition

Diseases
Various kidney diseases are associated with deposition of immunoglobulin (Ig)
and non-Ig proteins. Monoclonal Ig deposits are most commonly caused by:

• myeloma
• Waldenström macroglobulinemia
• chronic lymphocytic leukemia

Disease may also be caused by clonal expansion of Ig-secreting cells that do

not meet the strict definition of these disorders but may cause kidney disease,
which has been termed monoclonal gammopathy of renal significance.

The most common pathologic findings associated with monoclonal Ig

deposition include proliferative glomerulonephritis, AL amyloidosis, and type
1 cryoglobulinemia.

Polyclonal Ig deposits are associated with mixed cryoglobulinemias.

Kidney manifestations of monoclonal gammopathies may include proteinuria

(sometimes nephrotic range), tubular dysfunction, hypertension, and kidney
failure.

Management is focused on treatment of the underlying monoclonal disorder.

32
Study Table: Selected Deposition Diseases
Condition Pathology Clinical Syndrome
Amyloidosis Deposits that stain Proteinuria or nephrotic syndrome
apple green with
Congo red
Monoclonal Congo red–negative Proteinuria or nephrotic syndrome
immunoglobulin light or heavy chain
deposition deposits
disease
Multiple Serum free light Acute kidney injury
myeloma chains are extremely
elevated (usually >50 Acute or CKD associated with
mg/dL) Fanconi syndrome

Accumulation of light
chains in the renal
tubule (cast
nephropathy)

Light chains absorb

and crystallize in
proximal tubular cells
Cryoglobulinemia Vasculitic syndrome Most often associated with type II
with GN with cryoglobulins (HCV infection)
membranoproliferative
features Nephritic syndrome, RPGN

Low C4 (sometimes C3)

Monoclonal Most often caused by The presence of MGUS with kidney
gammopathy of monoclonal antibody abnormalities, including proteinuria,
renal significance deposition in the nephrotic syndrome, Fanconi
kidney syndrome, GN

Autosomal Dominant Polycystic

Kidney Disease
Diagnosis

The hallmark of ADPKD is large kidneys with multiple kidney cysts resulting from
genetic mutations in PKD1 and PKD2. More than 90% of PKD is as an autosomal
dominant trait.

Kidney ultrasonography is used to diagnose ADPKD. In patients with a family history

of ADPKD, the number of cysts needed for diagnosis increases with age.

33
Don't Be Tricked
• Direct mutational analysis of the PKD1 and PKD2 genes is reserved for
equivocal cases following imaging.

Hypertension is a common presentation. More than 50% of patients develop recurrent

flank or back pain from kidney stones, cyst rupture or hemorrhage, or infection.

A ruptured intracranial cerebral aneurysm is the most serious extrarenal complication

of ADPKD and occurs most commonly in patients with a family history of
hemorrhagic stroke or intracranial cerebral aneurysm.

Treatment

ADPKD has no specific treatments.

• Treat hypertension with an ACE inhibitor or an ARB.

• Treat cyst infection or pyelonephritis with fluoroquinolones or trimethoprim-
sulfamethoxazole.
• Tolvaptan has been approved to reduce the rate of increase in kidney size and
loss of GFR, but poor tolerance, hepatotoxicity, and expense limit its use.

Patients with a history of ADPKD, particularly those with a family history of

intracranial aneurysm, should be offered screening for aneurysm by CTA or MRA.

Don't Be Tricked
• Up to 25% of patients with newly diagnosed ADPKD may have a negative
family history owing to mild disease in an affected parent, spontaneous
germline mutation, or earlier death from other causes.

Inherited Collagen Type IV–Related

Nephropathies
Two relevant inherited collagen type IV–related nephropathies:

• hereditary nephritis
• thin GBM disease

Hereditary nephritis (Alport syndrome) is a glomerular disease associated

with sensorineural hearing loss and characteristic ocular findings such as
lenticonus. Proteinuria, hypertension, and CKD usually develop over time.
End-stage kidney disease occurs between the late teenage years and the fourth
decade of life. Management is supportive, including blood pressure control
with RAS blockade.

34
Thin GBM disease (benign familial hematuria) manifests as microscopic or
macroscopic hematuria without significant proteinuria and a family history of
similar phenotype, usually first appearing in childhood. Long-term prognosis is
excellent.

Acute Kidney Injury

Diagnosis and Testing

AKI is defined as an abrupt elevation in the serum creatinine concentration or a

decrease in urine output. The cause may be secondary to prerenal causes, intrinsic
kidney disease, or postrenal obstruction of urine outflow. Prerenal and postrenal
causes must be distinguished from intrinsic renal parenchymal disease because they
are often rapidly reversible.

AKI is also divided into oliguric (≤400 mL/24 h) and nonoliguric (>400 mL/24 h)
forms. The lower the urine output, the worse the prognosis.

Study Table: Diagnostic Findings in AKI

Urine
BUN- OsmolalityUrine
Creatinine(mOsm/kg Sodium Urinalysis and
ConditionRatio H2O) (mEq/L)FENa Microscopy
Prerenal >20:1 >500 <20 <1% Specific gravity >1.020;
normal or hyaline casts
ATN 10:1 ~300 >40 >2% a
Specific gravity ~1.010;
muddy brown casts and
tubular epithelial cells
AIN Variable Variable Variable Variable Mild proteinuria;
leukocytes; erythrocytes;
leukocyte casts; ±
eosinophiluria
Acute GN Variable Variable Variable Variable Proteinuria; dysmorphic
erythrocytes; erythrocyte
casts
Postrenal >20:1 Variable Variable Variable Variable, bland
• FE may be low in contrast nephropathy and pigment nephropathy.
a
Na

FENa may be >2% in prerenal patients who are taking diuretics. In the setting of
diuretics, the FEUrea, calculated as (UUrea × PCr)/(UCr × PUrea) × 100, is more accurate in
detecting volume-depleted states and prerenal AKI. FEUrea <35% is consistent with a
prerenal cause of AKI.

Knowing a few basic epidemiologic facts can help identify the cause of AKI:

35
 • Prerenal AKI is the most common form of AKI in the outpatient setting.
• A prolonged prerenal state may lead to ATN.
• The most common cause of hospital-acquired AKI is ATN.
• Hospital-acquired ATN is most commonly caused by toxins, such as
antibiotics (i.e., gentamicin).
• Obstruction of the upper tract (ureters or renal pelvis) must be bilateral to
cause AKI.

Figure 7. Muddy Brown Granular Casts:

Muddy brown granular casts consistent with kidney injury secondary to tubular
necrosis.

Study Table: Differential Diagnosis of AKI

When you see

this… Think of… And select…
Minimal ATN FENa and/or spot urine sodium
proteinuria, no
hematuria or
pyuria; presence
of muddy brown
casts
Erythrocytes, GN As appropriate:
erythrocyte casts,
or dysmorphic Titers for ANA, anti-
erythrocytes dsDNA antibodies, and
antistreptolysin O antibodies;
C3, C4, and CH50; hepatitis and
HIV testing and
cryoglobulins; p-ANCA/c-
ANCA and anti-
GBM antibodies
Pyuria Pyelonephritis Urine culture

AIN Review of medication list

Eosinophilia, AIN Review of medication list
eosinophiluria,
and rash Cholesterol emboli

36
Study Table: Differential Diagnosis of AKI

When you see

this… Think of… And select…

Investigation for previous

vascular procedure
(angiography)
Livedo reticularis Cholesterol emboli Investigation for previous
(violaceous vascular procedure
reticular rash) Vasculitis (angiography)

Consider cryoglobulinemia
Hypercalcemia Multiple myeloma Serum and urine protein
and anemia electrophoresis, quantitative
immunoglobulins
Nephrotic Diabetes mellitus Plasma glucose
syndrome
Renal vein thrombosis Renal vein Doppler study
Obstruction on BPH Residual bladder volume,
kidney ultrasound noncontrast CT or MRI
Nephrolithiasis

Obstructing malignant mass

Retroperitoneal fibrosis
Complete anuria Renal cortical necrosis Kidney ultrasonography
Large kidneys on Amyloidosis, diabetes SPEP, blood glucose, HIV
ultrasound (early), HIV nephropathy testing
Kidney failure Phosphate-containing bowel Supportive care (fluids, stop
following prep (acute calcium ACE inhibitors, ARBs,
colonoscopy phosphate crystal deposition NSAIDs)
in the kidneys)
Recent abdominal Abdominal compartment Intravesicular pressure >20
surgery, syndrome mm Hg
hemorrhage, or
acute pancreatitis
Peripheral blood Thrombotic microangiopathy As
smear (HUS/TTP, DIC, scleroderma indicated, CBC, coagulation
schistocytes, renal crisis) parameters
thrombocytopenia
Urine dipstick Hemolysis, rhabdomyolysis Serum CK, serum haptoglobin,
positive for reticulocyte count, peripheral
blood, no blood smear
erythrocytes on
urinalysis

37
Study Table: Differential Diagnosis of AKI

When you see

this… Think of… And select…
AKI associated Tumor lysis syndrome Uric acid, phosphorus,
with acute potassium (all elevated)
leukemia or
lymphoma or its
treatment
Worsening Cardiorenal syndrome Diuretics, ACE inhibitors or
kidney function ARBs, vasodilators, and
in the setting of inotropes for improved cardiac
diuretic- function
resistant HF
Worsening Hepatorenal syndrome IV albumin and intravascular
kidney function volume repletion. Liver
in setting of transplantation (see
cirrhosis and Gastroenterology and
ascites Hepatology, Cirrhosis)
Test Yourself

A 65-year-old man develops eosinophilia, AKI, and a net-like rash on his lower
extremities following a cardiac catheterization.

Answer: For diagnosis, choose atheroembolic disease with cholesterol emboli

to the skin and kidney.

A 35-year-old woman with necrotizing pancreatitis and tense ascites develops

AKI.

Answer: For diagnosis, choose abdominal compartment syndrome; for

management, choose measurement of intravesicular pressure.

Treatment

Begin IV 0.9% saline for patients with volume depletion. Stop potential nephrotoxic
drugs and look particularly for aminoglycoside
antibiotics, ACE inhibitors, ARBs, loop diuretics, SGLT2 inhibitors (volume
depletion), cyclosporine, and NSAIDs.

Select dialysis for:

• refractory hyperkalemia, acidemia, or volume overload

• signs or symptoms of uremia (altered mentation, asterixis, pericardial friction
rub, vomiting)
• certain drug intoxications

38
For urinary obstruction, choose a catheter to relieve bladder outlet obstruction. If the
obstruction is above the bladder, select retrograde or antegrade nephrostomies.

Don't Be Tricked
• Do not withhold dialysis until BUN, creatinine, or both reach “threshold”
values.

Study Table: AKI Treatment Protocol

Indication Treatment
Severe acidemia (pH <7.20) IV bicarbonate or hemodialysis
Severe hypertension Vasodilators, β-blockers, calcium channel
blockers
Rapidly Immunosuppression
progressive GN, granulomatosis
with polyangiitis, and severe
IgA nephropathy
Scleroderma renal crisis ACE inhibitor, regardless of serum creatinine
level and even if administering hemodialysis
Hydronephrosis on ultrasound Depending on cause, bladder catheter or
nephrostomy tube
Abdominal compartment Surgical decompression
syndrome

Don't Be Tricked
• Do not select loop diuretics (without evidence of volume overload), dopamine,
or mannitol to treat AKI.

Contrast-Associated Nephropathy

Prevention

In patients at high risk requiring imaging with contrast, avoid volume depletion and
NSAIDs. Patients at high risk include those with recent AKI and those
with eGFR <30 mL/min/1.73 m2. Prophylaxis with IV 0.9% saline is indicated for
eGFR less <30 mL/min/1.73 m2 or AKI.

Diagnosis

CAN is defined by an increase in serum creatinine within 24 to 48 hours following

contrast exposure. AKI tends to be nonoliguric, with an FENa <1%. The urinary
sediment may be bland or show classic ATN findings.

Don't Be Tricked

39
 • Contrast-induced nephropathy is not prevented by dialysis immediately after
contrast media administration.
• Do not use oral or intravenous acetylcysteine or IV bicarbonate to prevent
AKI secondary to radiocontrast.

Nephrolithiasis
Diagnosis

Kidney stones are predominantly composed of calcium but may be formed by other
substrates, such as uric acid, struvite, and cystine.

The classic symptoms of nephrolithiasis are acute flank pain with radiation to the
groin and hematuria. Urinalysis usually reveals blood, and the urine sediment has
nondysmorphic erythrocytes. Ultrasonography (indicated during pregnancy) or
noncontrast CT is the preferred imaging choice.

Don't Be Tricked
• The absence of erythrocytes on urinalysis does not rule out nephrolithiasis.

Treatment

Treatment varies according to the specific findings. Kidney stones <5 mm in diameter
typically pass spontaneously. Stones >10 mm often require invasive measures.
Patients with 6- to 10-mm stones may be treated with tamsulosin, nifedipine,
silodosin, and tadalafil to enhance stone expulsion, but efficacy is controversial.
Because few adverse effects are attributed to these medications, they are often
recommended.

Urgent urologic consultation is indicated for patients with:

• pyelonephritis or urosepsis
• AKI
• large stones requiring surgical removal
• bilateral obstruction
• obstruction of a solitary kidney

Urologic referral is also indicated for ambulatory patients without an immediate

indication for stone removal who do not pass stones with conservative management or
who have stones >10 mm in diameter.

40
Study Table: Kidney Stone Risk Factors and Therapy

Stone
Type Risk Factors Therapy
Calcium Clinical: Increase fluids
oxalate hyperparathyroidism;
fat malabsorption; Decrease sodium intake
excess vitamin D or
C Maintain adequate dietary calcium

Biochemical: Thiazide diuretics

hypercalciuria;
hyperoxaluria;
hypocitraturia
Calcium Clinical: distal renal Increase fluids
phosphate tubular acidosis;
hyperparathyroidism; Decrease sodium intake
carbonic anhydrase
inhibitors Maintain adequate dietary calcium

Biochemical: Thiazide diuretics

elevated urine pH;
hypercalciuria; Treat hyperparathyroidism
hypocitraturia
Uric acid Clinical: metabolic Increase fluids
syndrome; gout;
diarrheal illnesses; Potassium citrate or bicarbonate
metabolic acidosis
Acetazolamide
Biochemical: Low
urine pH; Allopurinol
hyperuricosuria
Struvite Clinical: chronic Treat infection
urinary tract
infections with urea- Urologic intervention
splitting organism

Biochemical:
elevated urine pH
Cystine Clinical: strong Increase fluids
family history;
young age at onset Potassium citrate or bicarbonate

Biochemical: Acetazolamide
elevated urine
cysteine; low urine
pH
41
Don't Be Tricked
• Asymptomatic nonobstructing kidney stones found on imaging studies do not
require urgent stone removal.
• Do not select a low-calcium diet for patients with kidney stones. Calcium
restriction does not prevent stones and may actually increase stone formation
and contribute to bone demineralization.

Test Yourself

A 35-year-old woman is evaluated for nephrolithiasis. She has a long history of

Crohn disease and has had several operations to remove portions of her ileum
and colon.

Answer: For diagnosis, select calcium oxalate stones secondary to increased

oxalate absorption in the GI tract and subsequent hyperoxaluria.

Chronic Kidney Disease

Screening

Screening patients at risk for CKD, including those with diabetes, hypertension, and a
family history of kidney disease, is generally recommended.

Diagnosis

Diagnosis requires an eGFR <60 mL/min/1.73 m2 confirmed at least 3 months after

initial assessment, or persistent proteinuria or albuminuria regardless of eGFR.
Kidney biopsy is used to determine the cause of CKD when a glomerular or
tubulointerstitial disease is likely and when specific therapy is available to delay or
prevent further kidney injury. Kidney biopsy is not routinely performed in the
presence of shrunken kidneys (<9 cm), which generally indicate chronic irreversible
disease.

Differential diagnosis of CKD:

• Diabetic kidney disease: Look for early moderately increased albuminuria

(spot albumin-creatinine ratio, 30-300 mg/g), followed by overt proteinuria,
declining GFR, and a bland urine sediment. The presence of retinopathy
strongly suggests coexisting diabetic kidney disease.
• Glomerular disease: Look for glomerular hematuria, proteinuria, and
hypertension, often with other systemic manifestations (LN and
postinfectious GN). If nephrotic syndrome is present, look for focal segmental
glomerulosclerosis, membranous nephropathy, and minimal change disease.
• Tubulointerstitial disease: Look for proteinuria, glycosuria, concentrating
defect, sterile pyuria, and leukocyte casts, as well as papillary necrosis on
ultrasound. Consider analgesic nephropathy (medication use, papillary
42
 necrosis), infection (TB, legionnaires disease, leptospirosis), allergic drug
reaction (eosinophilia, eosinophiluria), autoimmune disorder
(SLE, sarcoidosis, Sjögren syndrome), and lead nephropathy (occupational
exposure).
• Vascular disease: Look for hematuria, proteinuria, and associated systemic
illness. Vasculitis often presents with RPGN and palpable purpura
(leukocytoclastic vasculitis).
• After transplantation: CKD in the kidney transplant recipient may be caused
by chronic allograft nephropathy, drug toxicity (cyclosporine), polyomavirus
BK infection, or recurrence of disease.
• Structural disease (polycystic kidney disease): Look for hypertension,
hematuria, palpable kidneys (advanced disease), and family history of CKD.

Don't Be Tricked
• If the kidneys are markedly scarred and small (<9 cm), do not select
aggressive diagnostic or therapeutic measures.

Complications

Many patients with CKD are asymptomatic. When CKD progresses to ESKD, uremic
symptoms, such as fatigue, nausea, loss of appetite, insomnia, irritability, difficulty
concentrating, confusion, or pruritus, may occur. Uremia may also induce pleuritis
and pericarditis. Cardiovascular disease is the leading cause of death in patients with
CKD. Chronic anemia, metabolic acidosis, and bone disease are also common
complications.

Renal osteodystrophy refers to alteration of bone morphology in patients as a result of

CKD.

Acquired cystic kidney disease is common among patients with severe CKD and
ESKD. These cysts are at increased risk for transformation into renal cell carcinoma.
A high index of suspicion is warranted for patients with new gross hematuria,
unexplained flank pain, or persistently elevated hemoglobin levels. For cysts that are
highly suspicious for malignancy, partial nephrectomy is indicated for less severe
stages of CKD. For patients with advanced CKD or ESKD, radical nephrectomy is
preferred.

Study Table: Renal Osteodystrophy

Condition Mechanism Characteristics

Osteitis Secondary Subperiosteal resorption of bone, most
fibrosa hyperparathyroidism prominently at the phalanges
cystica
Adynamic Suppressed levels of Increased risk for fractures; made worse
bone disease PTH because of with bisphosphonate therapy
chronic illness or
overly aggressive
43
Study Table: Renal Osteodystrophy

Condition Mechanism Characteristics

treatment with
vitamin D analogues
Osteomalacia Vitamin D Bone pain, fractures
deficiency
Treatment

Avoid exposure to kidney toxins (contrast agents, NSAIDs). Avoid gadolinium-

enhanced MRI because of the risk for nephrogenic systemic fibrosis (greatest risk in
patients receiving dialysis). Begin restriction of sodium, potassium, and phosphorus.
Avoid significant protein restriction. Drug and alkali therapy is based on specific
findings.

In patients with CKD stages 3a to 5 not receiving dialysis:

• Lower elevated phosphorus levels toward the normal range but not into the
normal range with diet modification and phosphate binders (sevelamer,
lanthanum).
• Restrict or do not use calcium-based phosphate binders (calcium carbonate,
calcium acetate).
• Avoid hypercalcemia; mild and asymptomatic hypocalcemia can be tolerated.
• Avoid routine use of calcitriol and vitamin D analogues to lower PTH levels.

In patients receiving dialysis, calcimimetics, calcitriol, or vitamin D analogues, or

their combination, should be used to lower PTH levels.

Study Table: Drug Therapy for CKD

If you see
this… Select…
Hypertension BP target <130/80 mm Hg

ACE inhibitor or ARB for patients with stage G3 CKD or

higher or for those with stage G1 or G2 CKD with albuminuria
(albumin-creatinine ratio ≥300 mg/g)

Use a loop diuretic rather than a thiazide for GFR <30

mL/min/1.73 m2
Hyperlipidemia Statin therapy in all patients ≥50 years with non–dialysis-
dependent CKD and in adults aged 18-49 years with non–
dialysis-dependent CKD and any one of the
following: CAD, diabetes, previous ischemic stroke, or a >10%
cardiovascular risk

Do not treat patients receiving dialysis with statins (no benefit)

44
Study Table: Drug Therapy for CKD

If you see
this… Select…
Anemia Erythropoietin to maintain hemoglobin levels of 10-11 g/dL
and iron to maintain iron stores (always check iron levels
before starting erythropoietin and maintain transferrin
saturation levels >30% and serum ferritin levels >500 ng/mL)
Metabolic Start alkali therapy when [HCO3] is <22 mEq/L and maintain in
acidosis normal range
Figure 8. Nephrogenic Systemic Fibrosis:
This patient with CKD developed nephrogenic systemic fibrosis after an MRI with
gadolinium injection. The skin demonstrates erythema, edema, and a peau d’orange
appearance.

Don't Be Tricked
• The anemia of CKD is a diagnosis of exclusion.
• Do not use ACE inhibitors in combination with ARBs or renin inhibitors to
treat CKD patients with proteinuria.
• Do not use magnesium-containing antacids in patients with ESKD.

Test Yourself

A 55-year-old woman with chronic lower back pain, polyuria, and nocturia is
found to have CKD. Urinalysis shows no protein or erythrocytes, 5 to 10
leukocytes/hpf, and no casts. Urine culture shows no growth. Kidney
ultrasound shows only papillary necrosis.

Answer: For diagnosis, choose tubulointerstitial disease secondary to analgesic

abuse.

Kidney Replacement Therapy

Remember these points regarding kidney replacement therapy:

45
 • Clinical outcomes are equivalent for patients receiving peritoneal dialysis
compared with hemodialysis.
• Peritoneal dialysis catheters are placed approximately 1 month before therapy
is initiated.
• Patients who opt for hemodialysis should be referred for arteriovenous fistula
placement 2 months or more before their eGFR drops below 15 mL/min/1.73
m2 to allow sufficient time for arteriovenous fistula maturation.
• Kidney transplantation is associated with superior quality of life and improved
survival and is less expensive than long-term dialysis.
• All patients with ESKD are considered candidates for kidney transplantation
unless they have systemic malignancy, chronic infection, severe
cardiovascular disease, or neuropsychiatric disorders.
• Transplantation is particularly beneficial in young patients.
• Suitable candidates for kidney transplantation should be referred for
evaluation when their eGFR is 15 to 29 mL/min/1.73 m2.

Patients with kidney transplants must receive immunosuppressive medications to

prevent their immune system from rejecting the kidney allograft.

Study Table: Common Adverse Effects of Immunosuppressants

Class Medication Common Side Effects

Calcineurin Cyclosporine Hypertension, decreased GFR, dyslipidemia,
inhibitor hirsutism
Tacrolimus Diabetes, decreased GFR, hypertension
Antimetabolite Mycophenolate Leukopenia, anemia
Azathioprine Leukopenia
mTOR Sirolimus; Proteinuria, dyslipidemia, diabetes, anemia,
inhibitor everolimus leukopenia
Glucocorticoid Prednisone Osteopenia, hypertension, edema, diabetes
receptor
agonist

Immunosuppression increases the risk for infections and cancers.

• The most common malignancy in kidney transplant recipients is

cutaneous SCC.
• Kaposi sarcoma is much more common in kidney transplant recipients; reduce
the immunosuppression and switch to sirolimus-based immunosuppression.
• Posttransplant lymphoproliferative disease is associated with EBV infection;
reduce immunosuppression and administration of rituximab in patients with
CD20+ tumors.

46