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Mechanistic Deep Dive
Glomerular Filtration Barrier
- Three layers:
- Endothelium (fenestrated)
- GBM (negatively charged, restricts anions)
- Podocyte foot processes + slit diaphragm (nephrin, podocin)
- Loss â proteinuria
Nephrotic vs Nephritic Histology
- Nephrotic: podocyte effacement, GBM thickening
- Nephritic: hypercellularity (mesangial, endocapillary), crescents (in RPGN)
Immune Complex Deposition
- Subepithelial (MN, PSGN â âhumpsâ)
- Subendothelial (MPGN, lupus, hep C)
- Mesangial (IgA, lupus, post-infectious)
Recent Trials & Updates
Anti-PLA2R Antibody (2009 Discovery)
- PLA2R = phospholipase A2 receptor
- 70-80% of primary MN
- Useful for diagnosis + monitoring
- Treatment response correlates with antibody decline
Anti-THSD7A + Anti-NELL-1
- Less common MN antibodies
- Sometimes associated with malignancy (NELL-1)
Rituximab for Membranous Nephropathy (MENTOR 2019, GEMRITUX 2017)
- Effective for primary MN
- Now first-line for most
Sparsentan (DUPLEX FSGS, PROTECT IgA)
- ETA + AT1R dual antagonist
- â Proteinuria
Iptacopan + Other Complement Inhibitors
- C3G + IgA + lupus
- APPLAUSE-IgAN
Belimumab for Lupus Nephritis (BLISS-LN 2020)
- BAFF inhibitor
- Class III/IV + V
- Reduce IS
Voclosporin for Lupus Nephritis (AURORA 2020)
- New CNI
- More potent than tacrolimus
- â Proteinuria
High-Yield Specialist Points
Adult vs Pediatric GN
- Children: PSGN, IgA vasculitis, MCD
- Adults: MN, FSGS, IgA, lupus
- Biopsy approach differs
Light Microscopy Patterns
- Diffuse vs focal
- Global vs segmental
- Membranous vs proliferative
- Crescents
- Sclerosis
- Necrotizing
Immunofluorescence Patterns
- Granular (immune complex)
- Linear (anti-GBM)
- Mesangial IgA (IgA nephropathy)
- C3-only (C3G, PSGN)
- Pauci-immune (vasculitis ANCA)
- Full house (lupus)
- Dominant IgG (MN)
- Dominant IgM (MCD)
- Dominant IgA (IgA, IgA vasculitis)
- Light chain restricted (deposition disease, amyloid)
Electron Microscopy Patterns
- Podocyte effacement (MCD, FSGS, MN)
- GBM thickening + spikes (MN)
- Mesangial expansion + deposits (IgA)
- Subendothelial deposits (MPGN, lupus)
- Subepithelial deposits (MN, PSGN humps)
- Dense deposits (DDD/C3G)
- Fibrillary deposits (amyloid, fibrillary GN)
- Tubuloreticular inclusions (lupus, HIV)
Cryoglobulinemia
- Type I: monoclonal (myeloma, Waldenström)
- Type II + III: mixed (Hep C, lupus, sjögren)
- Symptoms: purpura, neuropathy, renal disease
- Cold-induced precipitation
- Treatment: address underlying; rituximab for severe
Monoclonal Gammopathy of Renal Significance (MGRS)
- Light chain deposition disease
- Amyloidosis (AL)
- Cryoglobulinemia
- Type I MPGN with monoclonal Ig
- Treatment: hematologic therapy
Anti-Phospholipid Syndrome + Renal
- Thrombotic microangiopathy
- Renal vein thrombosis
- Treatment: AC + IS
Hereditary GN
- Alport syndrome (X-linked, COL4A5 mutation)
- Thin basement membrane disease (familial benign hematuria)
- Fabry disease (LM âvacuolatedâ tubular cells)
- Genetic testing
Pregnancy in GN
- â Proteinuria + AKI risks
- Preeclampsia differentiation challenging
- Multidisciplinary
- Some IS safe (azathioprine, low-dose steroids)
- Avoid: MMF, cyclophosphamide
Glomerular Disease in Cancer
- Paraneoplastic GN
- MN with solid tumors (colon, lung, breast, prostate)
- MCD with Hodgkin lymphoma
- Amyloid AL with myeloma
- MPGN with monoclonal Ig
Drug-Induced GN
- Penicillamine: MN
- NSAIDs: MCD
- Hydralazine: lupus-like + ANCA-associated
- Lithium: FSGS, MCD
- Pamidronate: collapsing GN, FSGS
- Anti-VEGF (bevacizumab): TMA
COVID-19 + Glomerular Disease
- Collapsing GN (FSGS variant)
- Especially APOL1 risk genotype
- Black population at risk
- Treatment: supportive + IS variable
Pearls
- Nephrotic: > 3.5 g/24h + hypoalbuminemia + edema
- Nephritic: hematuria + RBC casts + HTN + AKI
- RPGN: rapid decline + crescents
- Anti-PLA2R: primary MN (70-80%)
- C3 low: PSGN, lupus, MPGN, C3G, cryoglobulin
- Biopsy with LM + IF + EM is gold standard
- Anticoagulation in nephrotic if albumin < 2.0-2.5
- Vaccinations: pneumococcal essential