CHAPTER 32 NOTESLM

I. Systemic Lupus Erythematosus (SLE) and Lupus Nephritis (LN)

• Definition and Epidemiology: Lupus nephritis (LN) is a frequent and serious complication of
SLE. Approximately 60% of adults with SLE develop renal disease during their course. SLE
and LN are more common and associated with more severe renal involvement in African-
American, Asian, and Hispanic populations.
• Pathogenesis: Abnormalities in immune regulation lead to loss of self-tolerance and
production of autoantibodies and immune complexes. These circulating immune complexes
deposit in the glomeruli, activate complement, and incite an inflammatory response.
• Diagnosis (ACR Criteria): Renal involvement is defined clinically by persistent proteinuria
exceeding 500 mg/dL/day (or 3+ on dipstick) or the presence of cellular urinary casts.
• Serology: The presence of anti-dsDNA antibodies is a more specific marker for SLE, and
high-avidity, complement-fixing IgG anti-dsDNA antibodies correlate best with the presence of
renal disease. Levels of C4 and C3 often decline before a clinical flare.
• Pathology (ISN/RPS Classification):
◦ Class I (Minimal Mesangial LN): Normal by light microscopy (LM), but mesangial
immune deposits are detected by immunofluorescence (IF) and electron microscopy (EM),.
◦ Class II (Mesangial Proliferative LN): Purely mesangial hypercellularity with mesangial
immune deposits,. Patients typically have mild or minimal clinical renal findings.
◦ Class III (Focal LN): Involves less than 50% of total glomeruli sampled,.
◦ Class IV (Diffuse LN): Involves 50% or more of total glomeruli sampled,. Patients with
Class IV typically present with the most active clinical features (e.g., high anti-DNA, low
complement, active urinary sediment) and up to 50% have nephrotic syndrome.
◦ Class V (Membranous LN): Defined by regular subepithelial immune deposits,. Patients
typically present with nephrotic syndrome.
• IF Findings: The presence of IgG, IgM, IgA, C3, and C1q is known as "full house" staining
and is highly suggestive of LN.
• Treatment Principles: Class III and IV lesions require aggressive treatment using
combinations of corticosteroids and other immunosuppressive agents,. Mycophenolate mofetil
(MMF) or azathioprine are effective and safer than continued cyclophosphamide for long-term
maintenance therapy,.
II. ANCA-Associated Vasculitis (AAV)
• Classification: AAV comprises Granulomatosis with Polyangiitis (GPA), Microscopic
Polyangiitis (MPA), and Eosinophilic GPA (EGPA); these are pauci-immune small vessel
vasculitides.
• Pathology: The classic finding is focal segmental necrotizing and crescentic
glomerulonephritis. They are termed "pauci-immune" because of negative or only focal low-
intensity IF staining.
• ANCA Specificity:
◦ GPA: Often associated with C-ANCA (cytoplasmic pattern) directed against Proteinase 3
(PR3).
◦ MPA: Often associated with P-ANCA (perinuclear pattern) directed against
Myeloperoxidase (MPO),.
• Treatment: Induction therapy involves corticosteroids plus either cyclophosphamide or
rituximab, which are considered equally efficacious for severe disease,,. Plasma exchange is
recommended for patients with severe renal failure (serum creatinine >5.7 mg/dL) or severe
diffuse pulmonary hemorrhage,.
III. Anti-Glomerular Basement Membrane (Anti-GBM) Disease
• Pathogenesis: Caused by circulating autoantibodies directed against the α3 chain of type IV
collagen in the GBM,.
• Goodpasture Syndrome: The classic triad is (1) proliferative, crescentic GN; (2)
pulmonary hemorrhage; and (3) presence of anti-GBM antibodies.
• Pathology (IF): Diagnostic finding is intense and diffuse linear staining for IgG along the
GBMs. EM typically shows no immune-type electron-dense deposits.
• Treatment: Combination therapy with corticosteroids, cyclophosphamide, and
plasmapheresis is standard. Plasmapheresis removes the circulating anti-GBM antibodies.
IV. Henoch–Schönlein Purpura (HSP)/IgA Vasculitis
• Definition and Clinical Features: Systemic vasculitis involving skin (palpable purpura), GI
tract, joints, and kidney. Renal involvement is more frequent and severe in older children and
adults.
• Pathology (IF): IgA is the dominant or codominant immunoglobulin deposited in the
mesangium,.
• Prognosis and Treatment: Most cases are self-limited with a good long-term outcome,
especially in children. A poor renal prognosis is predicted by nephrotic syndrome or a high
percentage of crescents on biopsy. Corticosteroids treat systemic symptoms but have not clearly
been proven to ameliorate the renal lesions.
V. Amyloidosis
• General Features: Characterized by extracellular deposition of fibrils that bind Congo red,
yielding apple green birefringence under polarized light.
• AL Amyloidosis: Fibrils are derived from monoclonal immunoglobulin light chains,
predominantly the λ light chain subtype in renal disease,. Kidneys are the most common major
organ involved. Treatment aims to decrease light chain production, often using chemotherapy
agents or stem cell transplantation.
• AA Amyloidosis: Fibrils derived from Serum Amyloid A (SAA) protein, typically secondary
to chronic inflammatory diseases (e.g., rheumatoid arthritis, Familial Mediterranean Fever
(FMF)),. Treatment focuses on controlling the underlying inflammatory process.
• Pathology (EM): Reveals characteristic nonbranching 8- to 12-nm fibrils randomly
distributed in the mesangium and GBM.
VI. Hereditary Nephropathies
• Alport Syndrome: An inherited disorder of collagen α3α4α5(IV), leading to ESKD,
sensorineural deafness, and ocular abnormalities,. EM findings are characteristic: variable
thickening, thinning, basket weaving, and lamellation ("split and splintered" appearance) of
the GBM,.
• Fabry Disease (FD): X-linked inborn error due to α-galactosidase A deficiency. Leads to
glycosphingolipid accumulation, especially in vascular endothelium and podocytes,. Renal
biopsy shows podocyte enlargement with foamy cytoplasm on LM. EM shows characteristic
"myelin figures" or "zebra bodies" within the cytoplasm of podocytes,. Treatment includes
enzyme replacement therapy (ERT).
VII. Viral Infection-Associated Glomerulonephritis
• HIV-Associated Nephropathy (HIVAN): Highly associated with HIV-infected Black
patients. The characteristic LM pattern is Focal Segmental Glomerulosclerosis (FSGS) of the
"collapsing" type. EM reveals numerous tubuloreticular inclusions (TRIs) in glomerular and
vascular endothelial cells,. Treatment involves anti-retroviral therapy (cART) and sometimes
ACE inhibitors or corticosteroids,.
• Hepatitis C (HCV): Strongly associated with Mixed Cryoglobulinemia,. The predominant
glomerular lesion is Membranoproliferative Glomerulonephritis (MPGN),. Pathology often
includes intraluminal protein "thrombi" and organized deposits (annular–tubular structures) on
EM. Treatment has been revolutionized by oral direct-active antiviral (DAA) drugs,.
• Hepatitis B (HBV): Most associated with Membranous Nephropathy. Antiviral therapy is
generally advocated for patients with progressive renal dysfunction.

SLE
SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) & LUPUS NEPHRITIS (LN)
Lupus nephritis (LN) is recognized as a frequent and potentially serious complication of
systemic lupus erythematosus (SLE). Kidney disease, including complications of its therapy,
significantly influences both morbidity and mortality in SLE patients.
I. Epidemiology and Demographics
• Prevalence of Renal Involvement: Approximately 60% of adults with SLE will develop
clinical renal disease during the course of their illness. Between 25% and 50% of unselected
lupus patients show clinical renal disease at the time of onset.
• Race and Severity: SLE and LN are more common and associated with more severe renal
involvement in African-American, Asian, and Hispanic populations. Nearly half of all end-
stage renal disease (ESKD) patients with SLE in the United States are African-Americans.
• Gender and Age: Females generally outnumber males by about 10 to 1, although males with
SLE have the same incidence of renal disease as females. The peak onset of the disease is
between 15 and 45 years of age.
II. Pathogenesis
• Loss of Self-Tolerance: Abnormalities of immune regulation lead to a loss of self-tolerance,
autoimmune responses, and the production of various autoantibodies and immune complexes.
• Immune Complex Deposition: Autoantibodies combine with self-antigens to produce
circulating immune complexes that deposit in the glomeruli, activate complement, and incite an
inflammatory response. This is considered the human prototype of classic experimental chronic
immune complex–induced glomerulonephritis.
• Key Molecular Players:
◦ In proliferative LN, deposited complexes often consist of nuclear antigens (like DNA) and
high-affinity complement-fixing immunoglobulin G (IgG) antibodies.
◦ Activation of the complement cascade leads to complement-mediated damage and
subsequent inflammation.
◦ Neutrophil extracellular traps (NETs), if not degraded properly in lupus patients, are a source
of autoantigen presentation.
◦ Some lupus patients may present with focal segmental necrotizing glomerular lesions
without significant immune complex deposition, resembling a "pauci-immune"
glomerulonephritis; these cases may be associated with antineutrophil cytoplasmic antibodies
(ANCAs).
III. Diagnosis and Serologic Findings
• ACR Renal Criterion: Renal involvement is clinically defined by persistent proteinuria
exceeding 500 mg/dL/day (or 3+ on the dipstick) or the presence of cellular urinary casts.
• Antinuclear Antibodies (ANA): Highly sensitive for SLE (found in >90% of untreated
patients) but not specific, and the titer does not correlate well with renal involvement severity.
• Anti-dsDNA Antibodies: More specific for SLE and found in almost three-fourths of
untreated active patients. High-avidity, complement-fixing IgG anti-dsDNA antibodies
correlate best with the presence of renal disease.
• Complement Levels: Levels of C4 and C3 often decline before a clinical flare of SLE or
LN,. Normalization of depressed serum complement levels is frequently associated with
improved renal outcomes.
• Other Serology: Anti-Sm antibodies are highly specific for SLE but found in only about 25%
of patients.
IV. Pathology (ISN/RPS Classification)
The International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification
(2003, with minor revisions in 2018) classifies LN by combining light microscopic (LM),
immunofluorescence (IF), and electron microscopic (EM) findings,.
ISN/RPS Description/LM Findings Clinical Correlation
Class
Class I Minimal Mesangial LN: Normal by LM; Little evidence of clinical renal
mesangial immune deposits detectable only disease.
by IF and EM.
Class II Mesangial Proliferative LN: Purely Mild or minimal clinical renal
mesangial hypercellularity ( >3 cells per findings; proteinuria usually <1
mesangial area) with mesangial immune g/day.
deposits.
Class III Focal LN: Affects less than 50% of total Hypertension and active urinary
glomeruli sampled,. Features include sediment are common. Proteinuria
segmental proliferation, cellular crescents, >1 g/day; 25% to 33% present
and fibrinoid necrosis. with nephrotic syndrome.
Class IV Diffuse LN: Affects 50% or more of total Typically presents with the most
glomeruli sampled,. Active features include active clinical features (high anti-
"wire loop" deposits (subendothelial DNA, low complement, active
immune complexes visible by LM), hyaline sediment). Up to 50% have
thrombi, and crescents,. nephrotic syndrome.
Class V Membranous LN: Defined by regular Typically presents with
subepithelial immune deposits. Causes proteinuria, edema, and nephrotic
glomerular capillary wall thickening and syndrome.
"spike" formation. May coexist with
proliferative classes (V + III or V + IV).
Class VI Advanced Sclerosing LN: >90% of Usually end-stage disease; anti-
glomeruli are globally sclerosed with no DNA and complement levels often
residual activity. normalize at this stage.
• Immunofluorescence (IF): A pattern known as "full house" staining—the presence of IgG,
IgM, IgA, C3, and C1q—is highly suggestive of LN.
• Electron Microscopy (EM): Reveals electron-dense and granular deposits. Tubuloreticular
inclusions (TRIs), 24-nm branching tubular structures within endothelial cell endoplasmic
reticulum, are commonly observed in SLE biopsies.
• Activity and Chronicity Scoring: Renal biopsies should be given an activity score (0-24,
measuring reversible lesions like inflammation and necrosis) and a chronicity score (0-12,
measuring irreversible lesions like sclerosis and fibrosis),. These scores help track the efficacy of
therapy.
V. Treatment of Lupus Nephritis
The goal is to achieve remission while minimizing adverse reactions. Severe lesions (Class III
and IV) require aggressive treatment,.
Treatment Phase Recommended Key Findings
Regimens/Agents
Induction Corticosteroids (oral or IV Both MMF and CYC regimens are
(Severe LN) pulse) combined with: supported by KDIGO and ACR
Cyclophosphamide (CYC) guidelines as first-line therapy. MMF was
(oral or IV pulses),, OR superior in achieving remissions in high-
Mycophenolate Mofetil risk populations in some studies, and
(MMF) (2–3 g/day oral),. generally has a better side-effect profile
(fewer severe infections, leukopenia,
amenorrhea) than prolonged CYC,.
Induction Treatment is individualized, MMF and IV CYC yielded virtually
(Membranous reflecting conflicting data,. identical rates of remission for Class V
LN, Class V) Options include MMF, LN in trials. Patients with superimposed
cyclosporine, tacrolimus, or proliferative lesions (V + III or V + IV)
CYC pulses,. are treated as proliferative disease.
Maintenance MMF or Azathioprine,. Both MMF and Azathioprine
maintenance were superior to continued
cyclophosphamide. MMF proved
superior to azathioprine in preventing
time to treatment failure in one large trial
(ALMS).
VI. Prognosis and Special Considerations
• Prognostic Indicators: A poor prognosis is predicted by severe renal dysfunction (elevated
serum creatinine or decreased GFR), heavy proteinuria/nephrotic syndrome, and black race,.
Renal flares during the disease course are also associated with poor outcomes.
• Drug-Induced Lupus: Often associated with procainamide and hydralazine. Renal
involvement is relatively uncommon. It is primarily diagnosed by the presence of antihistone
autoantibodies in the absence of anti-DNA antibodies.
• Pregnancy: SLE flares may increase during or shortly after pregnancy. Patients with renal
disease face a high risk of fetal loss (20–40%). Cyclophosphamide is contraindicated due to
teratogenicity.
• End-Stage Kidney Disease (ESKD) and Transplantation: SLE disease activity frequently
diminishes once patients progress to ESKD and dialysis. Allograft survival rates are comparable
to non-lupus patients. Recurrence of LN in the transplanted kidney is low (typically <4% in
most series).
ANTIPHOSPHOLIPID SYNDROME (APS)
The Antiphospholipid Syndrome (APS) may involve glomerular disease, small and large vessel
renal issues, and coagulation problems in patients on dialysis or those who have received renal
transplants.
I. Definition and Diagnosis
• Defining Antibodies (APL Antibodies): APS patients possess autoantibodies directed against
plasma proteins bound to phospholipids. These include:
◦ IgG and/or IgM anticardiolipin antibodies.
◦ Antibodies to β2-glycoprotein I (IgG or IgM isotype).
◦ Lupus anticoagulant activity.
• Serologic Documentation: The presence of APL antibodies must be confirmed on two or
more occasions at least 12 weeks apart and within 5 years of the clinical manifestations.
• Clinical Criteria: In addition to having one of these antibodies, patients must have
experienced one or more episodes of venous, arterial, or small vessel thrombosis, or fetal
morbidity.
• Laboratory Findings: Thrombocytopenia and prolonged partial thromboplastin time are
common laboratory findings. The presence of APL antibodies often causes a false-positive
Venereal Disease Research Laboratory (VDRL) test result.
• Epidemiology:
◦ Primary APS (PAPS): Occurs in approximately 30% to 55% of patients with APL
antibodies who have no associated autoimmune disease.
◦ Secondary APS: APL antibodies are found in 25% to 75% of SLE patients. Patients
initially thought to have idiopathic APS may evolve into SLE-associated APS over time.
◦ Risk Correlation: The presence of specific β2-glycoprotein I antibodies has been
correlated with an increased risk of thrombotic events. High titers of IgG APL antibodies in
SLE usually correlate well with the risk of thrombosis.
II. Pathogenesis
• Mechanism: APL antibodies exert procoagulant effects at multiple sites in the clotting
cascade, including those involving prothrombin, protein C or S, annexin V, and coagulation
factors VII and XII. They also impair fibrinolysis.
• Result: These actions lead to endothelial damage and intravascular coagulation.
• "Second Hit" Hypothesis: Despite the presence of APL antibodies, a "second hit" may be
necessary to induce thrombotic events. Examples include pregnancy, SLE, nephrotic syndrome,
contraceptive use, or hyperlipidemia.
III. APL Nephropathy and Renal Manifestations
Renal involvement (APL nephropathy) occurs in up to 25% of patients with primary APS and
is characterized by thrombosis of blood vessels.
• Clinical Renal Features:
◦ The most frequent clinical renal findings include proteinuria (at times in the nephrotic
range), active urinary sediment, hypertension, and progressive renal dysfunction.
◦ Patients may present with acute deterioration in renal function.
◦ Major renal arterial involvement can lead to renal infarction.
◦ Renal vein thrombosis may occur, which can be silent or present with sudden flank pain.
• Pathology (Light Microscopy and Vessels):
◦ Renal lesions involve thrombosis of blood vessels ranging from glomerular capillaries to
the main renal artery and vein.
 ◦ Lesions involving arteries and arterioles often show both a thrombotic component and a
reactive/proliferative component with intimal mucoid thickening, subendothelial fibrosis, and
medial hyperplasia.
◦ Glomerular lesions include glomerular capillary thrombosis with associated
mesangiolysis, mesangial interposition, and duplication of glomerular basement membranes
(GBMs), resembling other forms of thrombotic microangiopathy (e.g., HUS and TTP).
◦ In some APS patients, renal biopsies with thrombotic microangiopathy may be misclassified
as Focal Segmental Glomerulosclerosis (FSGS), membranous nephropathy, or
Membranoproliferative Glomerulonephritis (MPGN).
◦ Other reported glomerular patterns in APS include membranous nephropathy, minimal
change/focal sclerosis, mesangial proliferative glomerulonephritis, and pauci-immune Rapidly
Progressive Glomerulonephritis (RPGN).
• Prognosis: The presence of APL antibodies in SLE patients is strongly correlated with a
greater incidence of thrombotic events and progression to chronic kidney disease (CKD).
IV. Treatment
The optimal treatment for APS remains to be fully defined.
• Asymptomatic Patients: Most APL-positive patients who do not experience thrombotic
complications require no special treatment. Some investigators recommend low-dose aspirin
and hydroxychloroquine for prophylaxis in asymptomatic patients.
• Clinical Thrombotic Events: Requires chronic anticoagulation with warfarin following
initial heparin administration. In one retrospective study, treatment with higher-dose warfarin
(International Normalized Ratio [INR] >3) was found to be more effective than lower doses
(INR <3) or aspirin alone in preventing recurrent thrombosis.
• Immunosuppression: The role of immunosuppression is uncertain in treating APS.
• Specific Scenarios:
◦ Severe Complications (Catastrophic APS): Plasmapheresis with corticosteroids and other
immunosuppressives may be used for catastrophic APS or in cases where anticoagulation is
contraindicated due to bleeding.
◦ Pregnancy: Heparin and low-dose aspirin have proven successful; prednisone therapy has
not.
V. APS in Dialysis and Transplantation
• Dialysis: APL antibodies are highly prevalent in hemodialysis patients (10% to 30%),
irrespective of age or gender. Elevated IgG anticardiolipin titers have been linked to a
significantly shorter time to arteriovenous (AV) graft failure.
• Transplantation: SLE patients with APL antibodies who receive renal transplants have had
problems related to APS (venous thromboses, pulmonary emboli) in 20% to 60% of cases. In
non-SLE transplant recipients, APL antibodies are associated with a threefold to fourfold
increased risk of arterial and venous thromboses. Anticoagulation therapy has been successful
in preventing recurrent thromboses and graft loss in these patients