Diabetic Nephrotic Syndrome

Diabetic nephrotic syndrome is nephrotic range proteinuria (above 3.5 g daily) with hypoalbuminaemia (under 30 g/L) and oedema in a patient with diabetic kidney disease.

It develops in about 5 to 10% of patients with diabetic kidney disease. It usually appears after 10 to 15 years of type 1 diabetes or 5 to 10 years of type 2 diabetes (which may already be present at diagnosis). It signals advanced glomerular injury with rapid progression. Median time from nephrotic syndrome to kidney failure is 3 to 5 years without treatment.

Diabetes is the leading cause of kidney failure worldwide, and diabetic kidney disease raises the risk of cardiovascular death three- to tenfold. Glomerular findings are mesangial expansion, nodular glomerulosclerosis (Kimmelstiel-Wilson nodules), thickened glomerular basement membrane and arteriolar hyalinosis.

Pathophysiology. Hyperglycaemia, intraglomerular hypertension and activation of the renin angiotensin system, inflammation and oxidative stress injure podocytes and the endothelium, driving albuminuria and fibrosis. Kidney size is often normal or increased even with advanced disease.

• Heavy proteinuria, oedema (often resistant to diuretics), hypertension, hyperlipidaemia.
• Almost always accompanied by retinopathy and often neuropathy (typical in type 1 diabetes); absent retinopathy suggests another diagnosis, particularly in type 1.
• Falling insulin requirements as kidney function declines (reduced insulin clearance) with a risk of hypoglycaemia.
• Anaemia and bone disease appear earlier in diabetes.
• Complications: heart failure, cardiovascular disease, infection, venous thrombosis, hyperkalaemia (from hyporeninaemic hypoaldosteronism with renin angiotensin blockade).

Red flags: suspect a non-diabetic cause (or renal artery stenosis) when

• Diabetes of under 5 years in type 1, or no retinopathy.
• Active urinary sediment (red cell casts, dysmorphic haematuria).
• Sudden onset of nephrotic syndrome or rapid fall in eGFR (above 5 mL/min/1.73 m² in a year), or fall in eGFR above 30% after starting an ACE inhibitor.
• Low complement, positive ANCA or anti-GBM, monoclonal band, or symptoms of systemic disease.
• Haematuria with loin pain, or small kidneys with heavy proteinuria.

• Urine albumin:creatinine ratio (above 300 mg/g, or above 30 mg/mmol), urine protein:creatinine ratio, serum albumin, lipid profile, creatinine and eGFR (creatinine and cystatin C), HbA1c, urine microscopy, blood pressure.
• Retinal examination and foot and neuropathy assessment.
• Complement, antinuclear antibodies, ANCA, hepatitis B and C, HIV, serum protein electrophoresis with free light chains when the picture is atypical.
• Kidney ultrasound (normal or enlarged kidneys); renal artery imaging if refractory hypertension or flash pulmonary oedema.
• Kidney biopsy when the diabetes is of short duration, retinopathy is absent, the sediment is active, onset is sudden, function falls rapidly or systemic disease is suspected.

Differential diagnosis

• Amyloid, light chain deposition disease (nodular glomerulosclerosis), membranous nephropathy, focal segmental glomerulosclerosis, minimal change disease, lupus nephritis, hypertensive nephrosclerosis, ischaemic nephropathy, heart failure.

Cornerstones (start together)

• Blood pressure below 130/80 mmHg.
• ACE inhibitor or angiotensin receptor blocker at maximum tolerated dose: ramipril 2.5 mg daily increased to 10 mg daily, or losartan 50 mg daily increased to 100 mg daily, or irbesartan 150 mg daily increased to 300 mg daily.
• Check creatinine and potassium at 1 to 2 weeks. Accept a rise up to 30%. Stop if potassium exceeds 6.0 mmol/L. Never combine an ACE inhibitor with an angiotensin receptor blocker.
• SGLT2 inhibitor: dapagliflozin 10 mg daily (eGFR at least 25) or empagliflozin 10 mg daily (eGFR at least 20). Expect an initial eGFR fall of up to 10 to 15%. Withhold during acute illness or before surgery (3 days) because of ketoacidosis risk. Genital mycotic infection and volume depletion are common.
• Finerenone 10 mg daily (20 mg if eGFR is at least 60) when eGFR is at least 25 and potassium is under 5.0 mmol/L. Check potassium at 4 weeks. Reduce or stop if potassium exceeds 5.5 mmol/L.
• GLP-1 receptor agonist for cardiovascular and renal protection: semaglutide 0.25 mg subcutaneously weekly for 4 weeks, then 0.5 mg, increasing to 1 mg weekly (maximum 2 mg weekly if tolerated); dulaglutide 0.75 mg weekly, increasing to 1.5 mg weekly. No dose change for kidney failure.
• Glycaemic target HbA1c 53 to 64 mmol/mol (7.0 to 8.0%), looser at advanced disease with hypoglycaemia risk.
• Metformin: stop if eGFR is under 30 mL/min/1.73 m². Halve the dose (maximum 1 g daily) when eGFR is 30 to 44 and avoid starting.
• Insulin: reduce doses by about 25% when eGFR falls under 30, with closer glucose monitoring.
• Avoid sulphonylureas except gliclazide with caution. DPP-4 inhibitors need renal dose adjustment (linagliptin 5 mg daily needs no adjustment).
• Lipids: atorvastatin 20 mg daily (up to 80 mg) or rosuvastatin 5 to 10 mg (maximum 10 mg when eGFR is under 30).
• Antiplatelet therapy for established cardiovascular disease: aspirin 75 mg daily.
• Sodium under 2 g daily; stop smoking; protein 0.8 g/kg daily; exercise and weight loss.

Oedema

• Furosemide 40 to 80 mg once or twice daily, increased to 120 mg twice daily, with metolazone 2.5 to 5 mg for resistance.
• Thiazolidinediones and non-dihydropyridine calcium channel blockers worsen oedema and should be avoided.

Thromboprophylaxis. Enoxaparin 40 mg daily (20 mg if eGFR is under 30) when albumin is under 20 g/L with other risk factors and bleeding risk is low.

Complications and screening

• Retinopathy screening yearly (laser or anti-VEGF treatment).
• Foot check at every visit.
• Cardiovascular risk management.
• Anaemia: epoetin alfa 50 to 100 units/kg three times weekly when haemoglobin is under 100 g/L, target 100 to 120 g/L.
• Bone and mineral disorder at usual thresholds.

Kidney failure. Plan early at eGFR under 20. Start dialysis at eGFR 5 to 10 with symptoms or complications. Peritoneal dialysis needs glucose load adjustment; haemodialysis hypotension and vascular access are harder. Pre-emptive transplantation is preferred. Consider simultaneous pancreas and kidney transplantation in selected type 1 diabetes.

Monitoring. Albumin:creatinine ratio, creatinine and potassium every 3 months; HbA1c every 3 months; lipids yearly; retinal screening yearly; blood pressure at every visit.

Referral and escalation. Nephrology when albumin:creatinine ratio is above 70 mg/mmol or eGFR is under 30, falls quickly, or the picture is atypical. Urgent referral for hyperkalaemia above 6.5 mmol/L or fluid overload.

Special groups

• Pregnancy: stop ACE inhibitors, angiotensin receptor blockers, SGLT2 inhibitors, finerenone and statins before conception. Use labetalol or nifedipine. Give aspirin 75 to 150 mg daily from 12 weeks. Control HbA1c under 48 mmol/mol (6.5%) before conception if safe.
• Older adults: avoid tight control and hypoglycaemia; stop sulphonylureas.
• Children and young adults: yearly urine albumin screening from age 12 or after 5 years of type 1 diabetes.