Key Facts

Diabetic nephropathy is preventable and its progression can be significantly slowed. Annual screening, early ACEi/ARB initiation, SGLT2 inhibitors, and glycaemic/BP optimisation are the cornerstones of management.

Epidemiology

~30-40% of T1DM and ~20-30% of T2DM develop nephropathy. Accounts for ~25% of patients starting renal replacement therapy in UK. Peak incidence of ESRD in T1DM: 15-20 years after diagnosis.

Aetiology

Chronic hyperglycaemia → microvascular damage to glomerular capillaries. Risk factors: poor glycaemic control, hypertension, genetic susceptibility, smoking, dyslipidaemia.

Pathophysiology

Hyperglycaemia → AGEs, PKC activation, polyol pathway → mesangial expansion, GBM thickening, podocyte injury → glomerulosclerosis (Kimmelstiel-Wilson nodules — pathognomonic). Early: glomerular hyperfiltration (↑GFR) → microalbuminuria → progressive proteinuria → declining GFR → ESRD. Tubulointerstitial fibrosis also contributes to progression.

Stages

• Stage 1: hyperfiltration (GFR may be supranormal); no albuminuria
• Stage 2: normoalbuminuria; GBM thickening on biopsy
• Stage 3: microalbuminuria (ACR 3-30 mg/mmol); earliest clinical marker; reversible with treatment
• Stage 4: macroalbuminuria (ACR >30); GFR declining; usually accompanied by retinopathy
• Stage 5: ESRD (GFR <15); requiring renal replacement therapy

Clinical Features

• Usually asymptomatic until advanced (detected on screening)
• Peripheral oedema (nephrotic syndrome if heavy proteinuria)
• Hypertension (often precedes or accompanies albuminuria)
• Uraemic symptoms (advanced): fatigue, nausea, pruritis, confusion

Red Flags

• Absence of retinopathy with nephropathy in T1DM → consider non-diabetic kidney disease
• Rapid GFR decline → consider renal artery stenosis, RPGN, obstruction
• Active urinary sediment → glomerulonephritis (not typical of diabetic nephropathy)

Screening (Annual — NICE)

• Urine ACR: first morning void; confirm positive result on 2 of 3 samples
• eGFR: calculated from serum creatinine
• Staging: ACR + GFR → KDIGO CKD classification

Additional

• U&Es: creatinine, potassium, bicarbonate
• Serum albumin: if nephrotic range proteinuria
• Renal USS: if rapid decline, haematuria, obstruction suspected
• Renal biopsy: if atypical features (no retinopathy in T1DM, haematuria, rapid decline, short duration of DM)

Glycaemic Control

• HbA1c ≤48 mmol/mol (individualised; avoid hypoglycaemia in advanced CKD)
• Adjust medication doses for GFR (metformin: stop if eGFR <30; sulfonylureas: reduce/stop)

Blood Pressure (Target <130/80)

• ACEi/ARB first-line: ramipril 1.25-10mg OD or losartan 25-100mg OD; titrate to maximum tolerated; start when ACR ≥3 mg/mmol even if normotensive
• Monitor K⁺ and eGFR 1-2 weeks after starting/dose change (accept up to 25% eGFR fall; >30% → investigate)
• Do NOT combine ACEi + ARB (ONTARGET trial — no benefit, increased harm)

SGLT2 Inhibitors

• Dapagliflozin 10mg OD: DAPA-CKD trial — 39% reduction in renal composite; recommended for all T2DM with CKD and ACR ≥3 (NICE NG28); can initiate down to eGFR 20
• Empagliflozin, canagliflozin: also renoprotective

Finerenone

• Non-steroidal MRA: FIDELIO-DKN/FIGARO-DKN trials — additional renal and CV benefit on top of ACEi/ARB + SGLT2i; NICE TA877

Lipids

• Atorvastatin 20-80mg OD

Advanced CKD

• Dietitian: low-protein diet consideration
• Erythropoiesis-stimulating agents (ESAs) for renal anaemia
• Phosphate binders, vitamin D analogues for CKD-MBD
• Pre-dialysis planning: nephrology referral when eGFR <30
• Renal replacement: haemodialysis, peritoneal dialysis, transplant

Referral Criteria

• Nephrology: ACR >70 mg/mmol, eGFR <30, rapid decline (>5 mL/min/year), resistant HTN, suspected non-diabetic kidney disease

With modern management (ACEi/ARB + SGLT2i + glycaemic/BP control), progression to ESRD has significantly decreased. Microalbuminuria: ~30% progress to macroalbuminuria over 10 years; ~30% regress to normoalbuminuria with treatment. Macroalbuminuria: higher risk of progression to ESRD (~50% at 10 years without intervention). T1DM with ESRD: median survival on dialysis ~5 years. Cardiovascular disease remains the leading cause of death in diabetic nephropathy.

KDIGO CKD Classification (Simplified)

Key Renoprotection Trials