Describe diabetic nephropathy with its pathogenesis, morphology and clinical stages.
Definition and Significance
Diabetic nephropathy is progressive kidney disease caused by damage to the glomerular capillaries from long-standing diabetes mellitus. It is the leading cause of end-stage renal disease worldwide.
- Develops in 30 to 40% of patients with type 1 and a smaller proportion with type 2 diabetes, but because type 2 is so much commoner it contributes most cases
- India has among the largest diabetic populations in the world, so this is a problem of national scale
Pathogenesis
Chronic hyperglycaemia → Non-enzymatic glycation of proteins → advanced glycation end products (AGEs) cross-link collagen and trap proteins in the basement membrane → The polyol pathway — aldose reductase converts glucose to sorbitol, causing osmotic and oxidative stress → Protein kinase C activation → TGF-beta, VEGF and matrix production → Glomerular hyperfiltration and intraglomerular hypertension — efferent arteriolar constriction raises capillary pressure → Thickened basement membrane and mesangial matrix expansion → Podocyte loss → albuminuria → progressive glomerulosclerosis
- Hyperfiltration is the key early event, and explains why ACE inhibitors and ARBs work so well — they dilate the efferent arteriole and lower intraglomerular pressure, protecting the kidney beyond their effect on systemic blood pressure
Morphology
| Lesion | Description |
|---|---|
| Diffuse glomerulosclerosis | The commonest and earliest — diffuse mesangial matrix expansion with basement membrane thickening |
| Nodular glomerulosclerosis | Kimmelstiel–WILSON lesion — rounded, laminated, PAS-positive hyaline nodules at the periphery of the glomerulus; virtually pathognomonic of diabetes |
| Hyaline arteriolosclerosis | Affects both afferent and efferent arterioles — involvement of the efferent arteriole is essentially specific to diabetes |
| Capsular drop and fibrin cap | Hyaline deposits in Bowman capsule and in capillary loops |
| Tubulointerstitial | Tubular atrophy, interstitial fibrosis; Armanni–Ebstein change |
| Papillary necrosis | Diabetics are particularly prone, especially with infection |
CLINICAL PEARL
Hyalinisation of the efferent arteriole is what distinguishes diabetes from hypertension. Hypertensive nephrosclerosis affects the afferent arteriole; diabetes affects both. That is not a trivial detail — efferent narrowing raises intraglomerular pressure and drives the hyperfiltration that causes the disease.
Clinical Stages
| Stage | Feature | Timing (type 1) |
|---|---|---|
| 1 — Hyperfiltration | Raised GFR; enlarged kidneys | At diagnosis |
| 2 — Silent | Structural change without albuminuria | 2–5 years |
| 3 — microalbuminuria | Albumin 30–300 mg a day; "incipient" nephropathy; the last reversible stage | 5–10 years |
| 4 — Overt proteinuria | Over 300 mg a day; dipstick positive; falling GFR and rising blood pressure; may reach nephrotic range | 10–20 years |
| 5 — End-stage renal disease | Dialysis or transplantation required | 20–30 years |
Applied Aspects
- Annual screening with the urine albumin:creatinine ratio from diagnosis in type 2 diabetes and from 5 years in type 1 — microalbuminuria is the earliest detectable and the last reversible stage
- ACE inhibitors or ARBs are given even if blood pressure is normal once albuminuria appears; the two classes are not combined, as that increases harm
- Tight glycaemic and blood pressure control markedly slows progression; SGLT2 inhibitors now have proven renal protective benefit independent of glucose lowering
- Diabetic retinopathy almost always accompanies nephropathy in type 1 — its absence should raise doubt about the diagnosis and prompt consideration of another renal disease
- Diabetics are prone to other renal problems too — urinary infection, papillary necrosis, neurogenic bladder, type 4 renal tubular acidosis, and contrast nephropathy
- Prevention through control of diabetes is far cheaper than dialysis, which matters greatly where renal replacement therapy is limited by cost and access
All questions in Renal & Genitourinary Pathology
- Q1Describe the mechanisms of glomerular injury. Differentiate the nephritic from the nephrotic syndrome and add a note on rapidly progressive glomerulonephritis. ★
- Q2Define nephrotic syndrome. Describe its pathophysiology, causes, morphology and complications. ★
- Q3Classify acute kidney injury. Describe acute tubular necrosis with its types, morphology and clinical course. ★
- Q4Describe acute and chronic pyelonephritis. Add a note on chronic kidney disease and its systemic consequences. ★
- Q5Classify renal tumours. Describe renal cell carcinoma and Wilms tumour. ★
- SN1Describe acute post-streptococcal glomerulonephritis with its pathogenesis and morphology. ★
- SN2Classify renal calculi. Describe their pathogenesis and complications. ★
- SN3Classify cystic diseases of the kidney. Describe adult polycystic kidney disease. ★
- SN4Differentiate benign prostatic hyperplasia from carcinoma of the prostate. ★
- SN5Describe carcinoma of the urinary bladder with its aetiology, morphology and clinical features. ★
- SN6Describe diabetic nephropathy with its pathogenesis, morphology and clinical stages. ★
- SN7Classify testicular tumours. Differentiate seminoma from non-seminomatous germ cell tumours.