Key Facts

Diabetic nephropathy (diabetic kidney disease) is a clinical diagnosis based on persistent albuminuria and/or declining eGFR in a patient with diabetes, in the absence of alternative causes.

Epidemiology

• Most common cause of ESRD globally and in the UK
• Affects 30-40% of T1DM and 20-30% of T2DM patients
• Incidence increasing due to rising T2DM prevalence
• More common in South Asian and Afro-Caribbean populations
• Peak incidence: 15-25 years after diabetes diagnosis

Aetiology

• Chronic hyperglycaemia is the primary driver
• Risk factors: poor glycaemic control, hypertension, genetic susceptibility, smoking, obesity, dyslipidaemia
• Family history of diabetic nephropathy confers 3-4 fold increased risk

Pathophysiology

• Hyperglycaemia → advanced glycation end-products (AGEs), activation of protein kinase C, polyol pathway
• Early: glomerular hyperfiltration (increased GFR) and glomerular hypertension
• Mesangial matrix expansion and glomerular basement membrane thickening
• Kimmelstiel-Wilson nodules (nodular glomerulosclerosis): pathognomonic histological finding
• Progressive glomerulosclerosis → proteinuria → declining GFR
• Tubulointerstitial fibrosis contributes to progressive disease

Early Disease

• Asymptomatic – detected on screening
• Microalbuminuria (ACR 3-30 mg/mmol)
• Normal or elevated GFR (hyperfiltration phase)

Established Disease

• Macroalbuminuria (ACR >30 mg/mmol) with proteinuria
• Declining eGFR (typically 5-10 mL/min/year without treatment)
• Hypertension (present in >80%)
• Peripheral oedema and nephrotic syndrome
• Often co-exists with diabetic retinopathy (>90% of T1DM with nephropathy have retinopathy)

Advanced Disease

• Uraemic symptoms: fatigue, nausea, pruritus
• Fluid overload: pulmonary oedema, anasarca
• Accelerated cardiovascular disease

Red Flags

• Absence of diabetic retinopathy → consider alternative diagnosis
• Rapid decline in eGFR (>5 mL/min/year) → consider superimposed pathology
• Active urine sediment (red cell casts) → consider glomerulonephritis
• Short duration of diabetes (<5 years T1DM) with nephropathy → consider other causes

Bedside

• Urinalysis: dipstick for protein, blood
• Blood pressure: target <130/80
• Fundoscopy: assess for diabetic retinopathy (absent retinopathy questions diagnosis)
• Foot examination: peripheral neuropathy, peripheral vascular disease

Bloods

• eGFR: to stage CKD
• Urine ACR: early morning sample preferred; repeat × 2 if elevated to confirm
• HbA1c: glycaemic control
• Lipid profile: cardiovascular risk
• Calcium, phosphate, PTH: if eGFR <30
• FBC: anaemia (may occur earlier in diabetic nephropathy than other CKD causes)

Imaging

• Renal ultrasound: kidneys may be normal or large in early disease (unlike other CKD causes)
• MR angiography: if renovascular disease suspected

Special Tests

• Renal biopsy: NOT routine; indicated if atypical features (haematuria, rapid decline, short diabetes duration, no retinopathy)
• Retinal screening: essential (presence of retinopathy supports diagnosis)

Non-pharmacological

• Glycaemic control: dietary modification, structured education (DAFNE for T1DM, DESMOND for T2DM)
• Smoking cessation: critical for slowing progression
• Sodium restriction: <6g/day
• Weight management: aim for BMI 18.5-25
• Exercise: 150 minutes/week moderate intensity

Pharmacological

Blood pressure and renoprotection:

• ACE inhibitor (ramipril up to 10mg OD) or ARB (losartan up to 100mg OD): first-line for all patients with ACR ≥3 mg/mmol
• Target BP: <130/80 mmHg (NICE NG28/NG136)
• Add CCB (amlodipine) or thiazide as second-line

SGLT2 inhibitors:

• Dapagliflozin 10mg OD or empagliflozin 10mg OD: add to ACEi/ARB if ACR ≥22.6 mg/mmol
• CREDENCE trial: canagliflozin reduced composite renal endpoint by 30%
• DAPA-CKD trial: dapagliflozin reduced composite renal endpoint by 39%

Finerenone (non-steroidal MRA):

• Finerenone 10-20mg OD: for T2DM with CKD despite ACEi/ARB (FIDELIO-DKD trial – 18% reduction in kidney failure)
• Monitor potassium closely

Glycaemic control:

• HbA1c target: 48-58 mmol/mol (adjust based on CKD stage)
• Metformin: reduce dose if eGFR 30-45; stop if <30
• SGLT2 inhibitors: continue for renoprotection down to eGFR 15 even if glycaemic effect diminishes
• GLP-1 receptor agonists (semaglutide, liraglutide): cardiovascular and renal benefits
• Insulin: may be required as renal function declines (reduced clearance → hypoglycaemia risk)

Referral Criteria

• eGFR <30 or rapidly declining eGFR → nephrology
• Nephrotic-range proteinuria (ACR >220 mg/mmol)
• Atypical features suggesting non-diabetic kidney disease → renal biopsy consideration
• Planning for renal replacement therapy (eGFR <20)

• Without treatment: ~50% progress to ESRD within 10 years of macroalbuminuria
• ACEi/ARBs reduce progression to ESRD by 30-40%
• SGLT2 inhibitors provide additional 30-40% risk reduction on top of RAAS blockade
• 5-year survival on dialysis for diabetic patients: approximately 30-40% (vs 50-60% for non-diabetic)
• Cardiovascular mortality is the leading cause of death, not ESRD progression
• Early detection and treatment of microalbuminuria can reverse to normoalbuminuria in 30-50% of patients

Stages of Diabetic Nephropathy (Mogensen Classification – T1DM)

Landmark Trials