Residency · Residency · Nephrology

Glomerulonephritis - Overview and Classification

Introduction

Glomerulonephritis encompasses a heterogeneous group of immune-mediated diseases affecting the glomerulus, representing the third leading cause of end-stage renal disease worldwide. These disorders span a wide spectrum of clinical presentations and pathologic patterns, and precise diagnosis requires the integration of clinical features, serologic testing, and renal biopsy findings interpreted through light microscopy, immunofluorescence, and electron microscopy. Understanding the classification framework for glomerulonephritis is essential for directing the serologic workup, interpreting biopsy findings, and selecting appropriate therapy.

Glomerular Anatomy and Pathophysiology

Normal Glomerular Structure

The glomerulus is composed of four principal cell types, each with distinct structural and functional roles. Endothelial cells line the glomerular capillaries and are characterized by fenestrations measuring 70 to 100 nanometers in diameter, which allow passage of plasma but restrict formed blood elements. The endothelial glycocalyx, a negatively charged surface layer of glycoproteins and proteoglycans, provides a charge barrier that repels anionic plasma proteins. The glomerular basement membrane consists of a network of type IV collagen composed of alpha-3, alpha-4, and alpha-5 chains, along with laminin and proteoglycans, organized into three ultrastructural layers: the lamina rara interna adjacent to the endothelium, the central electron-dense lamina densa, and the lamina rara externa adjacent to the podocytes. Podocytes, or visceral epithelial cells, are terminally differentiated cells that extend interdigitating foot processes along the outer surface of the GBM, connected by slit diaphragms whose molecular components include nephrin, podocin, and CD2AP. Because podocytes cannot regenerate, their loss through injury or detachment inevitably leads to glomerulosclerosis. Mesangial cells are contractile and phagocytic cells embedded within the mesangial matrix that provides structural support to the capillary tuft. Parietal epithelial cells line Bowman's capsule and, when activated, contribute to crescent formation in rapidly progressive glomerulonephritis.

Filtration Barrier

The glomerular filtration barrier consists of three layers that work in concert to permit the filtration of water and small solutes while restricting the passage of macromolecules. Size selectivity is determined primarily by the GBM and slit diaphragm, with a molecular weight cutoff of approximately 60 to 70 kilodaltons. Albumin, at 69 kilodaltons, exists at the threshold of this size barrier. Charge selectivity is provided by anionic sites distributed throughout all three layers, including heparan sulfate proteoglycans in the GBM and podocalyxin on the podocyte surface, which repel negatively charged proteins such as albumin. Disruption of either the size or charge barrier results in proteinuria.

Mechanisms of Glomerular Injury

Glomerular injury occurs through several distinct pathogenic mechanisms. Antibody-mediated injury encompasses anti-GBM disease with antibodies directed against the alpha-3 chain of type IV collagen, immune complex deposition in subepithelial, subendothelial, or mesangial locations, and ANCA-mediated neutrophil activation and endothelial damage. Complement-mediated injury involves dysregulation of the alternative complement pathway, as seen in C3 glomerulopathy, or lectin pathway activation. Cell-mediated injury involves T lymphocytes, as in minimal change disease, and the formation of crescents from proliferating parietal epithelial cells and infiltrating macrophages. Metabolic and hemodynamic injury encompasses diabetic nephropathy, hypertensive nephrosclerosis, and hyperfiltration-mediated glomerular damage. Podocytopathy refers to primary podocyte injury, as in minimal change disease and focal segmental glomerulosclerosis.

<image>Detailed cross-sectional diagram of the glomerular filtration barrier showing three layers: fenestrated endothelium with glycocalyx on the capillary lumen side, the three-layered GBM (lamina rara interna, lamina densa, lamina rara externa) with type IV collagen network, and podocyte foot processes with slit diaphragm proteins (nephrin, podocin, CD2AP, TRPC6) on the urinary space side. Show the location of immune complex deposition sites: subendothelial (between endothelium and GBM), intramembranous (within GBM), subepithelial (between GBM and podocyte foot processes), and mesangial. Label the size and charge selectivity properties of each layer.</image>

Clinical Presentations

Nephrotic Syndrome

Nephrotic syndrome is defined by proteinuria exceeding 3.5 grams per day or a urine protein-to-creatinine ratio exceeding 3.5 g/g, accompanied by hypoalbuminemia below 3.0 g/dL, peripheral edema, hyperlipidemia from hepatic lipoprotein overproduction stimulated by hypoalbuminemia, and lipiduria characterized by oval fat bodies displaying a Maltese cross pattern under polarized light microscopy. A clinically important complication of the nephrotic syndrome is hypercoagulability, resulting from urinary loss of anticoagulant proteins including antithrombin III, protein C, and protein S, combined with increased hepatic synthesis of procoagulant factors. The primary glomerular causes include minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, diabetic nephropathy, and amyloidosis.

Nephritic Syndrome

Nephritic syndrome is characterized by hematuria with dysmorphic red blood cells and red blood cell casts, proteinuria that is usually in the subnephrotic range but can reach nephrotic levels, hypertension, oliguria, edema resulting from salt and water retention, and azotemia. The primary causes include IgA nephropathy, post-infectious glomerulonephritis, lupus nephritis, ANCA-associated vasculitis, and anti-GBM disease.

Rapidly Progressive Glomerulonephritis (RPGN)

Rapidly progressive glomerulonephritis is defined by the loss of more than 50 percent of renal function over days to weeks, with histologic evidence of crescentic glomerulonephritis affecting more than 50 percent of glomeruli on biopsy. The classification of RPGN is based on the immunofluorescence pattern: type I, or linear IF, corresponds to anti-GBM disease, accounting for 10 to 15 percent of cases, with linear IgG staining along the GBM; type II, or granular IF, corresponds to immune complex-mediated glomerulonephritis, accounting for 40 to 45 percent, including lupus nephritis, IgA nephropathy, post-infectious GN, and membranoproliferative GN; type III, or pauci-immune, corresponds to ANCA-associated vasculitis, accounting for 45 to 50 percent, with minimal or absent immune deposits.

Nephrotic-Nephritic Overlap

Some glomerular diseases present with features of both nephrotic and nephritic syndromes, combining heavy proteinuria with an active urine sediment. This overlap pattern is characteristic of membranoproliferative glomerulonephritis, lupus nephritis with combined class IV and V involvement, and fibrillary glomerulonephritis.

Serologic Evaluation

Complement Levels

Serum complement levels provide critical diagnostic information. Low C3 and C4 levels indicate classical complement pathway activation and narrow the differential to lupus nephritis, cryoglobulinemia, and endocarditis-associated glomerulonephritis. Low C3 with normal C4 indicates alternative pathway activation and suggests C3 glomerulopathy, post-infectious glomerulonephritis, atypical hemolytic uremic syndrome, or atheroembolic disease. Normal C3 and C4 levels are found in IgA nephropathy, ANCA-associated vasculitis, anti-GBM disease, FSGS, minimal change disease, and membranous nephropathy.

Autoantibodies

A targeted autoantibody panel guides the serologic evaluation. ANA, anti-dsDNA, and anti-Smith antibodies are markers of lupus nephritis. c-ANCA with anti-PR3 specificity is associated with granulomatosis with polyangiitis, while p-ANCA with anti-MPO specificity is associated with microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis. Anti-GBM antibodies identify Goodpasture disease. Anti-PLA2R and anti-THSD7A antibodies are highly specific for primary membranous nephropathy, with anti-PLA2R present in 70 to 80 percent of cases and carrying a specificity exceeding 99 percent. ASO titers, anti-DNase B, and streptozyme testing support the diagnosis of post-streptococcal glomerulonephritis. Cryoglobulins are associated with hepatitis C-related membranoproliferative GN and essential cryoglobulinemia.

Serum/Urine Protein Electrophoresis

Serum and urine protein electrophoresis with free light chain analysis should be performed in any adult over 40 with unexplained glomerulonephritis, as monoclonal gammopathy-associated renal diseases are frequently underdiagnosed. The differential includes AL amyloidosis, light chain deposition disease, fibrillary GN, proliferative GN with monoclonal immunoglobulin deposits, and immunotactoid GN.

<image>Diagnostic workup flowchart for glomerulonephritis. Start with clinical presentation: nephrotic syndrome (proteinuria >3.5 g/day, edema, hypoalbuminemia) versus nephritic syndrome (hematuria with RBC casts, hypertension, AKI) versus RPGN (rapid GFR decline). For each presentation, show the recommended serologic workup: complement levels (C3, C4), ANCA (PR3, MPO), anti-GBM, ANA/anti-dsDNA, anti-PLA2R, hepatitis B and C serologies, HIV, SPEP/UPEP/free light chains, cryoglobulins, and ASO titer. Show how complement levels narrow the differential: low C3/C4 (lupus, cryoglobulinemia), low C3 only (post-infectious GN, C3 glomerulopathy, MPGN), normal complement (IgA, ANCA, anti-GBM, MN). End with renal biopsy as the definitive diagnostic step, listing the three modalities: light microscopy, immunofluorescence, and electron microscopy.</image>

Renal Biopsy Interpretation

Light Microscopy Patterns

The light microscopy pattern provides the initial classification framework. Mesangial proliferative patterns are characteristic of IgA nephropathy and early lupus nephritis. Endocapillary proliferative patterns are seen in post-infectious GN and lupus nephritis. The membranoproliferative pattern, with thickened capillary walls and mesangial hypercellularity, is seen in immune complex-mediated MPGN, C3 glomerulopathy, and monoclonal gammopathy-associated disease. Crescentic patterns indicate RPGN from any cause. Membranous thickening of the GBM without proliferation characterizes membranous nephropathy. Nodular glomerulosclerosis is seen in diabetic nephropathy, amyloidosis, light chain deposition disease, and fibrillary GN. Segmental sclerosis characterizes FSGS.

Immunofluorescence Patterns

The immunofluorescence pattern is the single most important piece of the renal biopsy for classification. Linear IgG staining along the GBM is pathognomonic for anti-GBM disease. The "full house" pattern, with positive staining for IgG, IgM, IgA, C3, and C1q, is virtually diagnostic of lupus nephritis. Dominant or co-dominant IgA staining identifies IgA nephropathy. Granular IgG and C3 in a subepithelial pattern is characteristic of membranous nephropathy. C3-dominant staining without significant immunoglobulin defines C3 glomerulopathy. Pauci-immune staining, with scant or absent immune deposits, is the hallmark of ANCA-associated vasculitis. Monoclonal light chain restriction on IF identifies monoclonal immunoglobulin deposition diseases.

Electron Microscopy Findings

Electron microscopy provides ultrastructural detail that refines the diagnosis. Subepithelial deposits appearing as "humps" are characteristic of post-infectious GN and membranous nephropathy. Subendothelial deposits are typical of lupus nephritis class III and IV and MPGN. Mesangial deposits are found in IgA nephropathy and lupus class I and II. Intramembranous dense deposits define dense deposit disease within the C3 glomerulopathy spectrum. Diffuse podocyte foot process effacement is the ultrastructural hallmark of podocytopathies, with greater than 80 percent effacement in MCD and variable, often segmental effacement in FSGS. Fibrillary deposits measuring approximately 20 nanometers characterize fibrillary GN, while randomly arranged fibrils of 8 to 12 nanometers are found in amyloidosis. Organized microtubular deposits of 30 to 50 nanometers define immunotactoid GN.

MPGN Classification (Updated)

Immune Complex-Mediated MPGN

The updated classification of membranoproliferative glomerulonephritis has replaced the older type I, II, and III scheme with a pathogenesis-based approach. Immune complex-mediated MPGN is characterized by classical complement pathway activation with IgG or IgM, C3, and C1q on immunofluorescence. The underlying causes include hepatitis C with cryoglobulinemia, hepatitis B, autoimmune diseases such as SLE, and monoclonal gammopathies. Treatment is directed at the underlying cause rather than the MPGN pattern itself.

Complement-Mediated (C3 Glomerulopathy)

C3 glomerulopathy is defined by C3-dominant staining on immunofluorescence without significant immunoglobulin deposition, indicating alternative complement pathway dysregulation. C3 glomerulonephritis presents with mesangial and subendothelial C3 deposits and is associated with C3 nephritic factor, an autoantibody that stabilizes the C3 convertase, and with mutations in complement regulatory proteins factor H and factor I. Dense deposit disease is characterized by intramembranous electron-dense "sausage-shaped" deposits on electron microscopy, with C3 nephritic factor detectable in approximately 80 percent of cases. Treatment remains challenging and includes mycophenolate, corticosteroids, and emerging complement-directed therapies such as eculizumab and the factor B inhibitor iptacopan.

Key Clinical Pearls

• The IF pattern is the single most important piece of the renal biopsy for classification: linear (anti-GBM), granular (immune complex), pauci-immune (ANCA), C3-dominant (complement-mediated)
• "Full house" IF (IgG, IgM, IgA, C3, C1q) is virtually diagnostic of lupus nephritis
• Anti-PLA2R antibody has transformed the approach to membranous nephropathy: a positive anti-PLA2R in a patient with nephrotic syndrome may obviate renal biopsy in some clinical scenarios
• MPGN is not a diagnosis but a pattern; the updated classification (immune complex-mediated vs complement-mediated) guides treatment toward the underlying cause
• Always send SPEP/UPEP/free light chains in any adult >40 with unexplained GN; monoclonal gammopathy-associated renal disease is underdiagnosed

References

1. Sethi S, Fervenza FC. Membranoproliferative Glomerulonephritis — A New Look at an Old Entity. N Engl J Med. 2012;366(12):1119-1131.
2. Couser WG. Primary Membranous Nephropathy. Clin J Am Soc Nephrol. 2017;12(6):983-997.
3. Jennette JC, Nachman PH. ANCA Glomerulonephritis and Vasculitis. Clin J Am Soc Nephrol. 2017;12(10):1680-1691.
4. Sethi S, Haas M, Markowitz GS, et al. Mayo Clinic/Renal Pathology Society Consensus Report on Pathologic Classification, Diagnosis, and Reporting of GN. J Am Soc Nephrol. 2016;27(5):1278-1287.
5. Beck LH Jr, Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361(1):11-21.

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