Diabetic nephropathy

1. Definition

• Progressive kidney disease from angiopathy of glomerular capillaries.
• Characterized by nephrotic syndrome + diffuse GN.
• Result of long-standing DM.

2. Three Lesions

1. Glomerular lesions
2. Renal vascular lesions (arteriolosclerosis)
3. Pyelonephritis (± papillary necrosis)

3. Glomerular Lesions — Three Alterations

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

Pathogenesis

• Non-enzymatic glycation of proteins → advanced glycation end-products (AGEs) → cross-link polypeptides → GBM thickening.
• ↑ Collagen IV + fibronectin synthesis → BM thickening.
• Hyperglycemia → hyperosmolar filtrate → overload of filtration capacity.
• Glomerular hyperfiltration (early) — ↓ efferent arteriole resistance via efferent arteriolar arteriolosclerosis → ↑ capillary pressure → mechanical injury.

Clinical

• Early: polyuria + ↑ GFR (hyperfiltration).
• Microalbuminuria (30–300 mg/day) — earliest detectable abnormality.
• Macroalbuminuria (> 300 mg/day) — overt nephropathy + HTN onset.
• Late: sclerosis → ↓ GFR > 75 % → renal failure (end-stage kidney).

4. Renal Vascular Lesions

• Renal atherosclerosis + arteriolosclerosis — part of macrovascular disease.
• Hyaline arteriolosclerosis affects BOTH afferent AND efferent arterioles.
  • Efferent involvement is characteristic of DM (rarely seen in non-diabetics).
  • Efferent arteriolar narrowing → ↑ intraglomerular pressure → hyperfiltration injury.

5. Pyelonephritis in Diabetics

• Acute/chronic interstitial inflammation; more severe in diabetics.
• Papillary necrosis — special pattern more prevalent in DM patients with acute pyelonephritis.

6. Stages of Diabetic Nephropathy

Stage	Feature	Albuminuria	GFR
1. Hyperfiltration	Early; ↑ GFR + polyuria	Normal	↑
2. Silent	GBM thickening, mesangial expansion	Normal	Normal
3. Incipient nephropathy	Earliest clinical sign	Microalbuminuria 30–300 mg/d	Normal/↓
4. Overt nephropathy	HTN appears; Kimmelstiel-Wilson nodules	Macroalbuminuria > 300 mg/d	↓↓
5. End-stage	Renal failure, dialysis	Massive	< 15

7. Epidemiology of Progression

• 80 % of T1DM patients develop overt nephropathy.
• 20–40 % of T2DM patients develop overt nephropathy.
• Macroalbuminuria typically accompanies onset of hypertension.
• Progression marked by drop in GFR > 75 %.

💡 High-yield: Diabetic nephropathy = 3 lesions (glomerular + vascular + pyelonephritis). Hallmark glomerular finding = Kimmelstiel-Wilson nodules + GBM thickening + diffuse mesangial sclerosis. Mechanism = AGEs + non-enzymatic glycation. Hyaline arteriolosclerosis affects BOTH afferent + efferent (efferent = DM-specific). Earliest sign = microalbuminuria (30–300 mg/day); macroalbuminuria + HTN = overt nephropathy. 80 % of T1DM, 20–40 % of T2DM progress. Papillary necrosis = DM-prone complication of acute pyelonephritis.