Residency · Residency · Internal Medicine

Glomerulonephritis: Rapid Recognition and Initial Management

Overview

Glomerulonephritis encompasses a group of diseases characterized by inflammation and damage to the glomeruli. Presentation ranges from asymptomatic urinary abnormalities to rapidly progressive GN (RPGN) with renal failure developing over days to weeks. Early recognition and treatment of RPGN is critical because delays directly worsen renal outcomes. Classification based on clinical syndrome (nephritic versus nephrotic) and histologic pattern guides workup and treatment.

Clinical Syndromes

Nephritic Syndrome

Nephritic syndrome presents with an active urine sediment containing dysmorphic red blood cells and RBC casts (which are pathognomonic), along with hypertension, edema, oliguria, elevated creatinine, and modest proteinuria (usually below 3.5 g/day, though overlap exists).

Nephrotic Syndrome

Nephrotic syndrome is characterized by heavy proteinuria (above 3.5 g/day), hypoalbuminemia, peripheral edema (often severe, reaching anasarca), hyperlipidemia, lipiduria (oval fat bodies and Maltese crosses on urine microscopy), and a hypercoagulable state due to loss of antithrombin III.

Rapidly Progressive Glomerulonephritis (RPGN)

RPGN presents as nephritic syndrome with rapid loss of renal function (doubling of creatinine over days to weeks). Histologically, it is characterized by crescent formation on biopsy involving more than 50% of glomeruli. This constitutes a medical emergency because irreversible renal damage occurs without prompt treatment. | RPGN Type | IF Pattern | Serologic Marker | Associated Diseases |

Three immunofluorescence patterns define the differential: Type I (Anti-GBM) shows linear IgG staining and corresponds to Goodpasture syndrome; Type II (Immune complex) shows granular staining and corresponds to lupus nephritis, IgA nephropathy, and post-infectious GN; Type III (Pauci-immune) shows little or no staining and corresponds to ANCA-associated vasculitis (GPA, MPA, EGPA).

<image>Classification of rapidly progressive glomerulonephritis by immunofluorescence pattern showing linear (anti-GBM), granular (immune complex), and pauci-immune patterns with associated diseases</image>

Urgent Serologic Workup

ANCA testing differentiates c-ANCA/anti-PR3, which points to GPA (granulomatosis with polyangiitis), from p-ANCA/anti-MPO, which points to MPA (microscopic polyangiitis) or EGPA. Anti-GBM antibody identifies Goodpasture disease, which often presents with pulmonary-renal syndrome. ANA, anti-dsDNA, and complement (C3, C4) evaluate for lupus nephritis, where low complements are characteristic. PLA2R antibody identifies primary membranous nephropathy. ASO titer with low C3 suggests post-streptococcal GN. Serum IgA levels may be checked for IgA nephropathy, though they are often normal and diagnosis requires biopsy. Hepatitis B and C serologies are important because HBV is associated with membranous nephropathy and HCV with MPGN/cryoglobulinemia. HIV testing is relevant because HIV-associated nephropathy presents as collapsing FSGS. Serum and urine protein electrophoresis with free light chains rule out monoclonal gammopathy-related GN.

Complement Levels Guide Diagnosis

Low C3 with low C4 is seen in lupus nephritis, cryoglobulinemia, and endocarditis-associated GN. Low C3 with normal C4 occurs in post-infectious GN, C3 glomerulopathy, and atypical HUS. Normal complement levels are found in ANCA-associated vasculitis, anti-GBM disease, IgA nephropathy, and membranous nephropathy.

Renal Biopsy

Indications for biopsy include RPGN, unexplained AKI with active sediment, nephrotic syndrome in adults, and suspected systemic disease affecting the kidneys. Contraindications include uncontrolled hypertension, bleeding diathesis, solitary kidney (relative), and small echogenic kidneys indicating chronic damage. The biopsy includes light microscopy, immunofluorescence, and electron microscopy, with results guiding specific immunosuppressive therapy.

<image>Renal biopsy findings in common glomerulonephritides showing light microscopy, immunofluorescence, and electron microscopy patterns for ANCA vasculitis, lupus nephritis, and membranous nephropathy</image>

Specific Glomerular Diseases

ANCA-Associated Vasculitis (GPA and MPA)

ANCA-associated vasculitis is the most common cause of RPGN in adults, presenting with pauci-immune crescentic GN on biopsy. Induction therapy uses rituximab (which the RAVE trial demonstrated is non-inferior to cyclophosphamide) or IV cyclophosphamide with high-dose corticosteroids. Maintenance therapy employs rituximab (which MAINRITSAN showed is superior to azathioprine) or azathioprine. Plasma exchange, evaluated in the PEXIVAS trial, showed no mortality or ESRD benefit overall but may still be considered in severe pulmonary hemorrhage or with anti-GBM overlap.

Anti-GBM Disease (Goodpasture Syndrome)

Anti-GBM disease shows linear IgG on immunofluorescence and often presents with pulmonary-renal syndrome. Treatment combines plasma exchange (to remove circulating antibodies) with cyclophosphamide and corticosteroids. Prognosis depends on presentation: patients presenting with dialysis-dependent renal failure rarely recover function. Anti-GBM antibody levels guide the duration of plasmapheresis.

Lupus Nephritis

Class III/IV (proliferative) disease requires aggressive immunosuppression. Induction uses mycophenolate mofetil or IV cyclophosphamide plus corticosteroids. Add-on therapies include belimumab (BLISS-LN) or voclosporin (AURORA), both of which improve renal response. Maintenance therapy combines mycophenolate with hydroxychloroquine, which forms the backbone of all lupus therapy. Class V (membranous) may require immunosuppression if nephrotic-range proteinuria is present.

IgA Nephropathy

IgA nephropathy is the most common GN worldwide. It presents with episodic gross hematuria that is often synpharyngitic (occurring during a URI, not 2 weeks after) along with persistent microscopic hematuria and proteinuria. Management includes optimizing RAAS inhibition, SGLT2 inhibitors (supported by the DAPA-CKD subgroup), targeted-release budesonide (Nefecon/TARPEYO, supported by the NEFIGAN trial), and systemic immunosuppression for aggressive disease (the TESTING trial showed benefit with steroids but significant infectious toxicity).

Membranous Nephropathy

Membranous nephropathy is the most common cause of nephrotic syndrome in White adults. PLA2R antibody is positive in approximately 70% of primary cases. Management involves observation with antiproteinuric therapy (ACE inhibitor/ARB) for 6 months if renal function is stable, with rituximab for persistent nephrotic syndrome (the MENTOR trial demonstrated non-inferiority to cyclosporine with fewer relapses).

<image>Diagnostic workup algorithm for glomerulonephritis showing initial serologic tests, complement level patterns, and biopsy indications with pathway to specific diagnoses</image>

Supportive Management

Blood pressure control with ACE inhibitors or ARBs is preferred for their antiproteinuric effect. Edema is managed with loop diuretics and sodium restriction. Anticoagulation should be considered for nephrotic syndrome (especially membranous) when albumin falls below 2.5 g/dL. Statin therapy addresses nephrotic hyperlipidemia. Infection prophylaxis during immunosuppression includes PJP prophylaxis with TMP-SMX and HBV screening before rituximab.

Clinical Pearls

RBC casts on urine microscopy are pathognomonic for glomerulonephritis, and their presence should prompt urgent nephrology consultation. Empiric immunosuppression should not be delayed while awaiting biopsy results in suspected RPGN with rapidly declining GFR, because delays cause irreversible nephron loss. "Dual-positive" disease (ANCA plus anti-GBM) occurs in approximately 30% of anti-GBM cases and may carry a slightly better renal prognosis than isolated anti-GBM disease. Post-infectious GN in adults can mimic RPGN, and complement levels (low C3 with normal C4) along with timing after infection help distinguish the two. PLA2R antibody levels correlate with disease activity in membranous nephropathy and can be used for monitoring response to therapy. Hepatitis B screening must always precede rituximab due to the risk of HBV reactivation.

References

• KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276.
• Stone JH, et al. Rituximab vs. Cyclophosphamide for ANCA-Associated Vasculitis (RAVE). N Engl J Med. 2010;363:221-232.
• Walsh M, et al. Plasma Exchange and Glucocorticoids in Severe ANCA Vasculitis (PEXIVAS). N Engl J Med. 2020;382:622-631.
• Fervenza FC, et al. Rituximab vs. Cyclosporine in Membranous Nephropathy (MENTOR). N Engl J Med. 2019;381:36-46.
• Rovin BH, et al. Voclosporin in Lupus Nephritis (AURORA). Lancet. 2021;397:2070-2080.

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