Glomerular Syndromes Classification and Management
Introduction to Glomerular Syndromes
- The primary types of glomerular syndromes include IgA nephropathy, membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, infection-related glomerulonephritis, ANCA-associated vasculitis, lupus nephritis, anti-GBM antibody glomerulonephritis, and complement-mediated glomerular diseases, as classified by the Kidney International guidelines 1, 2
Classification of Glomerular Syndromes
- IgA Nephropathy (IgAN) and IgA Vasculitis (IgAV) are characterized by mesangial IgA deposits, often presenting with hematuria and variable proteinuria, according to the Kidney International guidelines 1
- Membranous Nephropathy is an autoimmune disease with antibodies targeting podocyte antigens, typically presenting with nephrotic syndrome, as described in the Kidney International guidelines 1, 3
- Minimal Change Disease (MCD) is characterized by normal-appearing glomeruli on light microscopy but podocyte foot process effacement on electron microscopy, commonly causing nephrotic syndrome, as reported in the Kidney International guidelines 1, 4
- Focal Segmental Glomerulosclerosis (FSGS) features segmental sclerosis affecting some but not all glomeruli, can be primary (mediated by circulating factors) or secondary, according to the Kidney International guidelines 1, 4
- Membranoproliferative Glomerulonephritis (MPGN) is now reclassified as "Immunoglobulin- and complement-mediated glomerular diseases with an MPGN pattern of injury", as stated in the Kidney International guidelines 1, 3
- C3 Glomerulopathy is characterized by dominant C3 deposits with minimal or no immunoglobulin deposits, including dense deposit disease and C3 GN, as described in the Journal of the American Society of Nephrology guidelines 5
- Lupus Nephritis is glomerular involvement in systemic lupus erythematosus, classified according to ISN/RPS criteria, as reported in the Kidney International and Journal of the American Society of Nephrology guidelines 1, 6
- Infection-Related Glomerulonephritis is associated with bacterial, viral, or parasitic infections, as described in the Kidney International and Journal of the American Society of Nephrology guidelines 1, 6
- ANCA-Associated Vasculitis includes microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis, as reported in the Kidney International and Journal of the American Society of Nephrology guidelines 1, 5
- Anti-GBM Antibody GN (Goodpasture's Syndrome) is characterized by linear IgG deposits along the glomerular basement membrane, often with pulmonary involvement, as described in the Kidney International guidelines 1
Diagnostic Approach
- Kidney Biopsy is essential for definitive diagnosis, providing information on pattern of injury, immunofluorescence findings, and electron microscopy findings, as stated in the Journal of the American Society of Nephrology guidelines 5, 7
- Serological Testing includes anti-GBM antibodies, ANCA, anti-nuclear antibodies, complement levels, and specific autoantibodies, as reported in the Kidney International guidelines 1
Prognostic Considerations
- The presence of crescents, severe interstitial fibrosis and tubular atrophy, and high-grade proteinuria are associated with worse outcomes across most glomerular diseases, as described in the Kidney International and Journal of the American Society of Nephrology guidelines 1, 6
Treatment Principles
- Treatment approaches vary by specific glomerular disease but often include supportive care, disease-specific immunosuppressive therapy, and management of complications, as reported in the Kidney International guidelines 1
- Treatment decisions should be guided by disease severity, risk of progression, and patient-specific factors, as stated in the Kidney International guidelines 1, 4
Pathogenesis‑Based Classification of Glomerulonephritis
Overview
Glomerulonephritis (GN) should be grouped into five major pathogenic categories—immune‑complex GN, pauci‑immune GN, anti‑glomerular basement membrane (anti‑GBM) GN, monoclonal immunoglobulin (Ig) GN, and C3 glomerulopathy—based on the underlying mechanism rather than solely on histologic pattern. 8
The Mayo Clinic/Renal Pathology Society consensus states that a pattern‑based diagnosis alone is insufficient; every GN case must be classified according to its pathogenic mechanism. 9
Immune‑Complex Glomerulonephritis
Granular immunoglobulin deposits on immunofluorescence identify immune‑complex GN and reflect activation of the classical complement pathway. 8
Lupus nephritis is classified by the ISN/RPS system (Classes I–VI); Classes III and IV require aggressive immunosuppression. 10
Secondary immune‑complex membranoproliferative GN can arise from infectious agents (e.g., hepatitis B/C), autoimmune diseases (e.g., systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis, mixed cryoglobulinemia), and neoplastic conditions (e.g., chronic lymphocytic leukemia, lymphoma, solid tumors, monoclonal gammopathy of undetermined significance). 11
Pauci‑Immune Glomerulonephritis
Approximately 80–90 % of pauci‑immune GN patients are serologically ANCA‑positive (myeloperoxidase‑ANCA or proteinase 3‑ANCA). 8
Diagnosis must specify both the clinicopathologic phenotype (microscopic polyangiitis, granulomatosis with polyangiitis, or eosinophilic granulomatosis with polyangiitis) and the ANCA specificity (MPO‑ANCA or PR3‑ANCA). 8
The remaining 10–20 % of pauci‑immune GN cases are ANCA‑negative. 8
Anti‑GBM Glomerulonephritis
Anti‑GBM GN is defined by linear IgG (often with C3) deposits on immunofluorescence and the presence of circulating anti‑GBM antibodies. 8
About one‑quarter of anti‑GBM GN patients have concurrent ANCA positivity, representing a “double‑positive” disease phenotype. 8
Monoclonal Immunoglobulin Glomerulonephritis
Organized monoclonal deposits include:
Non‑organized monoclonal deposits comprise:
C3 Glomerulopathy
Dominant C3 deposition with minimal or absent immunoglobulin on immunofluorescence indicates dysregulation of the alternative complement pathway. 13
Two subtypes are recognized: dense deposit disease (formerly MPGN type II) and C3 glomerulonephritis (C3GN) lacking dense deposits. 13
Recommended work‑up includes genetic screening for mutations in complement genes (C3, factor H/I/B, CD46, CFHR1‑5) and assessment for acquired factors such as C3 nephritic factor and anti‑factor H antibodies. 11