Glomerular Disease — USMLE Step 1

Nephrotic & Nephritic Syndromes: Mechanisms, HSR Types, Pathology Imaging, and High-Yield Features
Images:
HSR Types: TYPE II — Ab-mediated cytotoxic TYPE III — Immune complex TYPE IV — Delayed / T-cell NON-IMMUNE
Nephrotic Syndrome
Podocyte injury → loss of GBM charge barrier → heavy proteinuria (>3.5 g/day), hypoalbuminemia, edema, hyperlipidemia, lipiduria, oval fat bodies
Feature Minimal Change (MCD) FSGS Membranous Nephropathy Amyloidosis Diabetic Nephropathy
Trigger Idiopathic; recent URI, NSAIDs, Hodgkin lymphoma HIV, heroin, obesity, sickle cell, APOL1 variants SLE, HBV/HCV, solid tumors, NSAIDs, anti-PLA2R autoAb Multiple myeloma (AL); chronic inflammatory disease (AA) Long-standing diabetes mellitus
Mechanism Cytokine-mediated podocyte damage → loss of charge barrier → selective albumin leak. No IC deposition. Podocyte injury & detachment → focal sclerosis. Primary (podocin/APOL1) or secondary (HIV, heroin, obesity, sickle cell). Subepithelial IC deposition (anti-PLA2R Ab) → complement activation → podocyte injury → GBM thickening. Misfolded protein (AL from myeloma, AA from chronic inflammation) deposits in mesangium & capillary walls. Hyperglycemia → glycosylation of GBM → mesangial expansion → Kimmelstiel-Wilson nodules. Hyperfiltration injury.
HSR Type TYPE IV
T-cell cytokine–mediated podocyte injury
NON-IMMUNE
Podocyte structural damage; adaptive in secondary
TYPE III
In-situ IC (anti-PLA2R) → subepithelial deposits
NON-IMMUNE
Protein misfolding / deposition
NON-IMMUNE
Non-enzymatic glycosylation of GBM
Age / Demographics Children #1 nephrotic in kids Adults #1 nephrotic in African Americans Adults European, Middle Eastern Adults Long-standing DM
Light Microscopy Normal
Focal, segmental sclerosis with hyalinosis
Diffuse capillary wall thickening
Amorphous eosinophilic deposits
Mesangial expansion, nodular sclerosis (Kimmelstiel-Wilson)
Immuno­fluorescence Negative
Negative or IgM/C1/C3 in sclerotic areas
Granular IgG and C3
Apple-green birefringence with Congo red
Linear IgG along GBM
Electron Microscopy Diffuse podocyte foot process effacement (only finding)
Foot process effacement + sclerosis
Subepithelial IC → "spike and dome"
Random fibrillar deposits (8–12 nm)
GBM thickening
ComplementNormalNormalNormalNormalNormal
Proteinuria Highly selectiveNon-selectiveNon-selectiveNon-selectiveNon-selective
Steroid Response ExcellentPoorVariableNoNo
Prognosis Very good→ ESRDVariableProgressiveProgressive
* All nephrotic syndromes have normal complement. MPGN (↓C3) has mixed nephritic/nephrotic features.
Nephritic Syndrome
Glomerular inflammation → GBM damage → RBC leakage → hematuria with dysmorphic RBCs & RBC casts, oliguria, azotemia, HTN, mild proteinuria (<3.5 g/day)
Feature PIGN IgA Nephropathy (Berger) RPGN Diffuse Prolif. GN (Lupus) Alport Syndrome MPGN
Trigger 2–4 wks post Group A Strep pharyngitis / impetigo. Adults: Staph URI or GI infection → hematuria within days (synpharyngitic) Autoimmune disease, infection, ANCA+ vasculitis SLE (autoimmune) Inherited (X-linked collagen IV defect) HBV, HCV, SLE, C3 nephritic factor
Mechanism IC vs strep Ag (M protein) → subepithelial deposits → complement activation (↓C3) → GBM damage Defective IgA1 glycosylation → mesangial IgA deposition → mesangial proliferation. I: Anti-GBM Ab (Goodpasture if +lungs)
II: IC (SLE, PIGN)
III: Pauci-immune / ANCA+ (GPA, MPA)
Anti-dsDNA + complement → subendothelial IC → severe inflammatory proliferation. Class IV. X-linked defect in type IV collagen (α5 chain) → abnormal GBM → progressive deterioration. I: subendothelial IC (HBV, HCV, SLE).
II: C3NeF stabilizes C3 convertase → intramembranous dense deposits.
HSR Type TYPE III
Circulating IC → subepithelial deposits
TYPE III
IgA IC → mesangial deposition
I: TYPE II anti-GBM
II: TYPE III IC
III: TYPE IV pauci-immune
TYPE III
Anti-dsDNA IC → subendothelial
NON-IMMUNE
Genetic collagen IV defect
TYPE III
I: IC. II: complement (C3NeF)
Onset Acute (2–4 wk latency)EpisodicRapid (weeks)VariableProgressiveSubacute
Age / Demographics Children & adults Young adults Any age Young women Children (X-linked boys) Children & young adults
Light Microscopy Enlarged, hypercellular glomeruli
Mesangial proliferation
Crescent formation (fibrin + macrophages)
"Wire-loop" capillaries
Normal early
"Tram-track" (GBM splitting)
Immuno­fluorescence Granular IgG, C3 "starry sky"
Granular IgA (mesangial)
I: Linear (anti-GBM)
II: Granular
III: Negative
IgG, IgA, IgM, C3 "full house"
Negative
Granular C3 ± IgG
Electron Microscopy Subepithelial humps
Mesangial deposits
Usually no deposits (III); depends on type
Subendothelial deposits
GBM thinning / splitting → "basket-weave"
I: subendothelial IC
II: intramembranous dense deposits
Complement ↓ C3NormalNormal↓ C3Normal↓ C3
Key Clinical Cola-colored urine, edema, HTN Hematuria within days of URI Rapid renal failure Systemic SLE signs Hearing loss, eye defects Mixed nephritic / nephrotic
Anti-GBM Ab NoNoYes (Type I / Goodpasture)NoNoNo
Treatment Supportive ± treat infection ACEi ± steroids Plasmapheresis + steroids (I); immunosuppression (II/III) Immunosuppression Supportive; transplant Treat underlying cause
Prognosis Kids: good. Adults: worseVariablePoor w/o TxVariableProgressiveOften progressive
* PIGN vs IgA: PIGN = 2–4 wk latency after strep; IgA = days (synpharyngitic). ↓C3 trio: PIGN, DPGN, MPGN.
* RPGN: I = anti-GBM / linear IF (Type II HSR), II = IC / granular IF (Type III HSR), III = pauci-immune / neg IF / ANCA+ (Type IV HSR).