Systemic diseases associated glomerular damage

1. Diabetic Glomerulosclerosis

Three glomerular alterations

1. GBM thickening
2. Diffuse glomerulosclerosis — sclerotic hyalinic precipitate (↑ mesangial matrix)
3. Nodular glomerulosclerosis — Kimmelstiel-Wilson lesion (segmental nodular sclerosis)

Pathogenesis

• Non-enzymatic glycation of proteins → advanced glycation end-products (AGEs) → cross-link polypeptides → GBM thickening.
• ↑ Synthesis of collagen IV + fibronectin → BM thickening.
• Hyperglycemia → hyperosmolar filtrate → overload of filtration capacity.

Clinical

• Early: polyuria with hyperfiltration (↑ GFR).
• Late: massive proteinuria (often non-nephrotic initially) → sclerosis → renal failure.

2. Renal Amyloidosis

Overview

• Amyloid = aggregates of insoluble misfolded proteins in tissue ECM.
• Kidney = most common AND most serious organ affected.
• Major sub-types in kidney:
  • AL (primary, light chains in multiple myeloma)
  • AA (secondary, chronic inflammation — RA, TB, chronic infections)

Morphology

• Amyloid in mesangial matrix + subendothelial layer → progressive obliteration of glomerulus.
• Renal vessels + interstitium also affected.
• Apple-green birefringence with Congo red under polarized light.

Clinical

• Severe proteinuria → nephrotic syndrome.
• Important: exclude amyloidosis before starting corticosteroids — steroids can worsen disease!

3. ANCA-Associated Vasculitides (Polyarteritis Nodosa, GPA/Wegener)

Polyarteritis nodosa (PAN)

• Granular IC deposits; not typically ANCA+.
• Necrotizing vasculitis of medium arteries; spares the lung.
• Often associated with HBV.

Granulomatosis with polyangiitis (Wegener)

• Necrotizing vasculitis with classic triad:
  1. Acute necrotizing granulomas of upper + lower respiratory tract
  2. Necrotizing vasculitis of small + medium vessels
  3. Renal disease: focal/segmental necrotizing GN → crescentic
• Pathogenesis: cell-mediated hypersensitivity; c-ANCA (PR3-ANCA) positive.

Renal lesion spectrum

• Early: focal/segmental necrotizing GN → hematuria, oliguria, ↓ GFR.
• Advanced: diffuse necrosis + fibrin deposition + crescentic GN (RPGN type III).

4. Lupus Nephritis (SLE)

Overview

• Multisystem autoimmune dz; kidney involvement is the most important clinical feature of SLE.
• DNA / anti-DNA IC deposition → inflammatory response → proliferation ± necrosis.

WHO/ISN Six Classes

Class	Name	Features
I	Minimal mesangial	No kidney involvement; minimal LM/EM/IF changes
II	Mesangial proliferative	Mesangial IC deposits; mild Sx (transient proteinuria)
III	Focal proliferative	< 50 % of glomeruli, segmental; mild hematuria + proteinuria
IV	Diffuse proliferative	Most common + most severe; entire glomerulus; subendothelial IC + wire-loop; hematuria, proteinuria, HTN, renal insufficiency
V	Membranous	GBM thickening (“wire loop”), subepithelial deposits (spike-and-dome); severe nephrotic syndrome
VI	Advanced sclerosing	> 90 % glomerular sclerosis; end-stage kidney, anuria

Key SLE-specific features

• “Wire-loop” lesion = subendothelial IC deposits (Class IV/V).
• IF: “full house” pattern — IgG, IgA, IgM, C3, C1q all positive.
• Serology: ↑ ANA, ↑ anti-dsDNA, ↑ anti-Sm; ↓ C3, ↓ C4 (active disease).

💡 High-yield: Diabetic nephropathy: GBM thickening, diffuse sclerosis, Kimmelstiel-Wilson nodules; hyperfiltration → proteinuria → renal failure. Renal amyloidosis: most common organ; Congo red → apple-green birefringence; nephrotic syndrome. GPA (Wegener): c-ANCA, upper + lower respiratory granulomas + segmental necrotizing GN. Lupus nephritis: 6 ISN/WHO classes; Class IV (diffuse proliferative) = most severe, “wire-loop”, “full-house” IF; Class V = membranous + nephrotic.