What is the diagnosis, differential diagnosis, and management of immune complex-mediated glomerulonephritis (GN)?

Immune Complex-Mediated Glomerulonephritis: Diagnosis, Differential Diagnosis, and Management

Diagnosis

The diagnosis of immune complex-mediated GN requires kidney biopsy with immunofluorescence microscopy showing positive immunoglobulin deposition (with or without complement), which directs the workup toward distinguishing between monoclonal deposition diseases, autoimmune diseases, and infection-associated diseases. 1

Essential Diagnostic Steps

• Kidney biopsy is mandatory and remains the gold standard for diagnosis, as it is the only method to identify IC-MPGN and distinguish it from complement-mediated diseases like C3 glomerulopathy 2, 3
• Immunofluorescence findings guide the diagnostic pathway: If positive for immunoglobulins (with or without complement), focus on distinguishing between monoclonal deposition diseases, autoimmune IC diseases, and infection-associated diseases 1
• Serum and urine studies must include: serum creatinine, urinalysis with quantification of proteinuria (24-hour or protein-to-creatinine ratio), complement levels (C3 and C4), protein electrophoresis with immunofixation, and free light chain analysis 4, 5
• Serologic testing should include: antinuclear antibody, anti-double stranded DNA, ANCA (anti-MPO and anti-PR3), hepatitis B and C serologies, cryoglobulin titers, and HIV testing 1, 5
• Screen for infections including viral (hepatitis C, hepatitis B, HIV), bacterial (endocarditis, infected shunts, visceral abscesses), and protozoal causes before initiating immunosuppression 1, 4
• Evaluate for autoimmune diseases including SLE, Sjögren's syndrome, rheumatoid arthritis, and mixed connective tissue disease 1
• Screen for monoclonal gammopathies with serum and urine electrophoresis, immunofixation, and free light chain analysis when monoclonal immunoglobulin deposits are found 4
• Patients ≥50 years with C3 glomerulopathy pattern should be evaluated for monoclonal proteins, as monoclonal gammopathies can initiate C3G without glomerular immunoglobulin deposition 1, 4
• Comprehensive complement analysis should be performed even in the absence of hypocomplementemia to assist with diagnosis 4

Histologic Patterns

• Membranoproliferative pattern shows mesangial and/or endocapillary hypercellularity with thickening of capillary walls caused by subendothelial deposits, with lobular accentuation and GBM double contours ("tram-tracking") 1, 5
• Document the percentage of globally sclerosed glomeruli and extent of tubulointerstitial fibrosis, as these determine chronicity and prognosis 1, 5

Critical Diagnostic Pitfall

• Proteolytic digestion on paraffin-embedded tissue may be necessary to detect monoclonal immunoglobulins masked during routine immunofluorescence investigation 1
• Complement dysregulation may occur in IC glomerular diseases, and conversely C3G may appear as ICGN, especially if triggered by infection—therefore exclude complement-mediated processes before diagnosing idiopathic ICGN 1

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Differential Diagnosis

In adults, idiopathic immune complex glomerulonephritis is rare, and all other diagnostic possibilities must be exhausted before making this diagnosis. 1

Infection-Related IC-GN

• Viral causes: Hepatitis C (including HCV-associated mixed cryoglobulinemia), hepatitis B, HIV 1
• Bacterial causes: Endocarditis, infected ventriculo-atrial shunt, visceral abscesses, leprosy, meningococcal meningitis 1
• Protozoal/other infections: Malaria, schistosomiasis, mycoplasma, leishmaniasis, filariasis, histoplasmosis 1

Autoimmune IC-GN

• Systemic lupus erythematosus (lupus nephritis) 1
• Sjögren's syndrome 1
• Rheumatoid arthritis 1
• Mixed connective tissue disease 1
• Lupus-like glomerulonephritis: Pattern with IgG, IgA, IgM, C3, and C1q deposition in patients who fail to meet ACR criteria for SLE 6

Monoclonal Immunoglobulin-Related GN

• Monoclonal gammopathy due to plasma cell or B cell disorders 1
• Fibrillary glomerulonephritis 1
• Waldenström macroglobulinemia with cryoglobulin-like deposits 1

Complement-Mediated Diseases (Must Exclude)

• C3 glomerulopathy (C3 GN or dense deposit disease) if immunofluorescence shows complement-dominant pattern 1
• C4 glomerulopathy 1

Other Considerations

• Thrombotic microangiopathy if immunofluorescence is negative 1
• Antiphospholipid antibody syndrome 1

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Management

Treatment for immune complex-mediated GN must be tailored to the underlying etiology: infection-associated diseases generally respond to controlling the infection, autoimmune diseases require immunosuppression, and monoclonal immunoglobulin-associated diseases require B or plasma cell clone-directed therapy. 1, 7

Treatment Algorithm Based on Etiology and Severity

For Infection-Related IC-GN

• Hepatitis C-associated ICGN with indolent disease: Treat with direct-acting antivirals (DAAs) alone without dose adjustment as first-line therapy 4
• HCV-associated ICGN with nephrotic syndrome but stable kidney function: Use DAAs prior to other treatments 4
• HCV-associated ICGN with rapidly progressive GN or cryoglobulinemic flare: Initiate combined therapy with DAAs plus immunosuppressive agents with or without plasma exchange 4, 8
• HCV-associated ICGN with persistent disease despite DAA therapy: Use rituximab as first-line immunosuppressive agent 4
• Non-HCV infection-related GN: Treat the underlying infection (bacterial endocarditis, cellulitis, etc.) as primary therapy 5

For Autoimmune IC-GN

• Lupus nephritis: Follow ISN/RPS classification-based treatment protocols with immunosuppression 1
• Other autoimmune diseases: Treat with immunosuppression targeting the underlying autoimmune process 1

For Monoclonal Immunoglobulin-Related GN

• Focus on controlling the B cell or plasma cell clone responsible for monoclonal immunoglobulin production 1
• Treat underlying hematologic disorder (e.g., Waldenström macroglobulinemia) 5

For Idiopathic IC-GN (After Excluding All Secondary Causes)

The approach to idiopathic ICGN is nuanced and tailored to disease severity, with restraint in aggressive treatment for patients with chronic disease. 1

Indolent Disease

• Provide supportive therapy with RAS inhibition alone for patients with non-nephrotic proteinuria and stable kidney function 4
• Monitor closely every 3-4 months with renal function, proteinuria, and urine microscopy 5

Moderate Disease (Nephrotic Syndrome with Stable Function)

• Consider oral cyclophosphamide or mycophenolate mofetil (MMF) plus low-dose alternate-day or daily corticosteroids for less than 6 months 5
• Mycophenolic acid can be considered as a cost-effective substitute for MMF in healthcare systems where coverage differs 4

Severe Disease (Rapidly Progressive GN or Crescentic GN)

• Non-HCV related cases with severe presentation: Use cyclophosphamide and corticosteroids plus plasmapheresis 4
• For rapidly progressive disease: Consider combination of two pulses of intravenous cyclophosphamide with rituximab 8

Pediatric Patients

• Alternate-day prednisone (40 mg/m²) for 6 to 12 months as first-line treatment for children with MPGN pattern and nephrotic syndrome and/or impaired renal function 5

Contraindications to Immunosuppression

Do not treat with immunosuppression in the following scenarios: 5

• Normal eGFR with non-nephrotic-range proteinuria
• Advanced CKD with severe tubulointerstitial fibrosis
• Small kidney size
• Chronic inactive disease on biopsy

Supportive Care (All Patients)

• Blood pressure control: Use ACE inhibitors or ARBs at maximum tolerated doses as first-line therapy, targeting systolic BP <120 mmHg 8
• Edema management: Sodium restriction and diuretics as first-line agents 8
• Anticoagulation consideration: Patients with nephrotic syndrome have 29% incidence of renal vein thrombosis and 17-28% incidence of pulmonary embolism due to loss of anticoagulant proteins 5

Monitoring and Follow-Up

• Regular assessment of proteinuria and surveillance for ≥40% decline in GFR from baseline over 2-3 years as surrogate outcomes for kidney failure 8
• Safety monitoring for immunosuppression: Screen for latent infections, monitor therapeutic drug levels, review vaccination status, and consider fertility preservation 8

Critical Management Pitfalls to Avoid

• Failing to distinguish primary from secondary MPGN leads to inappropriate treatment 5
• Not recognizing MPGN pattern without immune deposits (which would be complement-mediated, not IC-mediated) 5
• Treating patients with advanced chronic disease with immunosuppression is contraindicated 5
• Delaying treatment while awaiting biopsy in patients with clinical presentation compatible with rapidly progressive GN and positive serologies 8
• Limited access to plasmapheresis should be factored into urgency of diagnostic workup 4

Prognosis

• Patients with nephrotic-range proteinuria >3.8 g/day have a 35% risk of end-stage renal disease within 2 years 5
• The extent of glomerulosclerosis, tubular atrophy, and interstitial fibrosis on biopsy determines chronicity and long-term prognosis 1, 9