STEPTRACKERRENAL | PATHOLOGY + IMMUNOLOGY + ENDOCRINE | HIGH-YIELD REVIEW

Nephrotic Syndrome II — MPGN, Diabetes, Amyloid & Lupus

Glomerular diseases that deposit something in the glomerulus — immune complexes, glycated matrix, amyloid fibrils — and the lupus classes.

FOCUS ON

Diabetic nephropathy: efferent arteriole hyalinosis → hyperfiltration → GBM thickening, mesangial expansion, Kimmelstiel-Wilson nodules; ACE inhibitors/ARBs and SGLT2 inhibitors protect. Amyloid: Congo red, apple-green birefringence. MPGN: tram-track GBM, low C3, HBV/HCV. Lupus: class IV (nephritic, wire loops) vs class V (nephrotic, membranous).

DISEASE

MECHANISM

FINDINGS

CLUE

MPGN (immune complex)

Subendothelial immune complexes → mesangial cells grow into the capillary wall and lay down new GBM

"Tram-track" double-contoured GBM; nephrotic or nephritic; ↓ C3

HBV, HCV (cryoglobulinemia), SLE, chronic infection

C3 glomerulopathy / dense deposit disease

C3 nephritic factor (autoantibody) stabilizes C3 convertase → persistent complement activation

Dense intramembranous deposits; persistently low C3

Partial lipodystrophy

Diabetic nephropathy — mechanism

Nonenzymatic glycation of GBM and arteriolar walls; efferent > afferent hyalinosis → ↑ glomerular pressure

Early hyperfiltration → microalbuminuria → overt proteinuria → CKD

Most common cause of ESRD

Diabetic nephropathy — pathology

Matrix accumulates

GBM thickening, diffuse mesangial expansion, nodular sclerosis (Kimmelstiel-Wilson), hyaline arteriolosclerosis

Pink PAS⁺ round mesangial nodules

Diabetic nephropathy — management

Lower intraglomerular pressure

ACE inhibitor / ARB (dilate efferent), SGLT2 inhibitor (restores tubuloglomerular feedback → afferent constriction), glycemic and BP control

Screen yearly for albuminuria

AL amyloidosis

Misfolded immunoglobulin light chains (plasma cell dyscrasia, myeloma)

Nephrotic syndrome, restrictive cardiomyopathy, macroglossia, neuropathy, periorbital purpura

Kidney is the organ most often involved

AA amyloidosis

Serum amyloid A from chronic inflammation

RA, IBD, TB, bronchiectasis, osteomyelitis, familial Mediterranean fever

Treat the inflammation

Amyloid — pathology

β-pleated sheet fibrils in mesangium and vessels

Amorphous pink deposits; Congo red → apple-green birefringence under polarized light

Kidneys often normal or enlarged

Lupus nephritis — class IV

Diffuse subendothelial immune complexes (> 50% of glomeruli)

Wire-loop capillaries; nephritic ± nephrotic; ↓ C3/C4; full-house IF

Most common and most severe class

Lupus nephritis — class V

Subepithelial immune complexes

Membranous pattern → nephrotic syndrome

Treat with immunosuppression

Picture it — deposits and thickening

MPGNSubendothelial deposits; new GBM below them gives the "tram-track" double contour; mesangial interposition.

Dense deposit diseaseA dense ribbon of C3 within the GBM itself.

Diabetic nephropathyThick GBM and a mesangial Kimmelstiel-Wilson nodule.

AmyloidosisFibrils in mesangium and capillary walls (apple-green with Congo red).

Lupus nephritis IVLarge subendothelial deposits — "wire loops".

Schematic diagrams, not to scale. Red = abnormal.

Mechanism — diabetic kidney injury

Hyperglycemia

→

Efferent hyalinosis+ ↑ Na⁺ reabsorption (SGLT2)

→

↑ Intraglomerular pressureHyperfiltration

→

Mesangial expansion, thick GBM

→

Albuminuria → CKD

ACE inhibitors dilate the efferent arteriole; SGLT2 inhibitors deliver more Na⁺ to the macula densa so the afferent constricts — both lower glomerular pressure.

Complement levels in glomerular disease

LOW C3

NORMAL C3

Post-streptococcal GN

IgA nephropathy / IgA vasculitis

MPGN, C3 glomerulopathy

Anti-GBM disease

Lupus nephritis (low C4 too)

Pauci-immune (ANCA) GN

Cryoglobulinemia (low C4)

Minimal change, FSGS, membranous

Endocarditis, shunt nephritis

Diabetic nephropathy, amyloid

How it's tested

COMMON CONFUSIONKimmelstiel-Wilson nodules (diabetes) and amyloid both expand the mesangium. Amyloid is Congo red ⁺ with apple-green birefringence; diabetic nodules are PAS ⁺ and Congo red negative.

THE TRAPPersistently low C3 more than 8 weeks after a "post-strep GN" means it wasn't post-strep — think MPGN or C3 glomerulopathy.

YOUR APPROACHUnderlying disease (DM, myeloma, chronic inflammation, HCV, SLE) → deposit location (subendothelial, subepithelial, mesangial) → complement → special stain.

If you see… think…

Long-standing diabetic, microalbuminuria → early diabetic nephropathy — start ACEi/ARB

Round PAS⁺ mesangial nodules → Kimmelstiel-Wilson (diabetic)

Arteriole hyalinosis affecting efferent more than afferent → diabetes

Tram-track GBM + HCV + low complement → MPGN with cryoglobulinemia

Low C3 + C3 nephritic factor + lipodystrophy → dense deposit disease

Myeloma with nephrotic syndrome and macroglossia → AL amyloidosis

RA for 20 years, now nephrotic → AA amyloidosis

Apple-green birefringence with Congo red → amyloid

SLE, hematuria, RBC casts, wire loops → lupus class IV (diffuse proliferative)

SLE with heavy proteinuria and subepithelial deposits → lupus class V