Proteinuria

Proteinuria is excretion of protein in urine in excess of the normal range: more than 150 mg in 24 hours, a urine protein:creatinine ratio above 15 mg/mmol (150 mg/g), or an albumin:creatinine ratio above 3 mg/mmol (30 mg/g). Nephrotic range proteinuria is above 3.5 g in 24 hours, or a protein:creatinine ratio above 300 mg/mmol (3000 mg/g).

Mechanisms:

• Glomerular: increased filtration of albumin and larger proteins through a damaged filtration barrier (loss of charge or size selectivity), for example in minimal change disease, membranous nephropathy, focal segmental glomerulosclerosis and diabetic nephropathy
• Tubular: failure of proximal reabsorption of low molecular weight proteins (beta-2 microglobulin, retinol binding protein) with total usually below 2 g daily; found in Fanconi syndrome, tubulointerstitial nephritis and heavy metal toxicity
• Overflow: excess filtered light chains (myeloma), myoglobin or haemoglobin that exceed reabsorptive capacity
• Post-renal: inflammation or tumour of the urinary tract adding protein

Functional proteinuria is transient and benign: fever, exercise, orthostatic proteinuria (adolescents; protein only when upright, less than 1 g daily), pregnancy and acute illness.

Persistent proteinuria is both a marker of kidney damage and an independent driver of progression and cardiovascular risk.

• Often asymptomatic and detected by dipstick or screening
• Frothy urine, oedema (periorbital, ankle, generalised), weight gain in nephrotic syndrome
• Features of the cause: haematuria and hypertension (nephritic), polyuria and bone pain (myeloma, tubular), arthralgia and rash (lupus), diabetic retinopathy
• Complications of heavy proteinuria: venous thromboembolism, infection, hyperlipidaemia

Red flags: nephrotic range, haematuria with proteinuria, rising creatinine, hypertension in a young patient, symptoms of myeloma or malignancy, loin pain with renal vein thrombosis, systemic features of autoimmune disease.

• Dipstick: 1+ is about 30 mg/dL; detects albumin and misses light chains and low molecular weight proteins. Confirm positives with a quantitative ratio on a first morning urine sample; repeat to confirm persistence over 3 months.
• Quantify: urine protein:creatinine ratio, urine albumin:creatinine ratio (albumin proportion above 70% implies glomerular origin). A 24-hour collection is rarely necessary.
• Orthostatic proteinuria: split collection (overnight supine and daytime upright); overnight protein below 50 mg in 8 hours confirms the benign form.
• Blood tests: creatinine, eGFR, albumin, lipids, HbA1c, complement C3 and C4, antinuclear antibody, anti-dsDNA, hepatitis B and C, HIV, syphilis, serum protein electrophoresis with free light chains, ANCA, anti-PLA2R antibody.
• Urine electrophoresis if dipstick negative but protein:creatinine ratio high (light chains).
• Ultrasound for size and echogenicity.
• Kidney biopsy for nephrotic syndrome in adults (except diabetes with typical features), protein:creatinine ratio above 100 mg/mmol with haematuria or unexplained, declining eGFR, or suspected systemic disease.

Differentials: transient and orthostatic proteinuria, urinary tract infection, haematuria contamination, overflow states, tubular disease.

All patients with persistent proteinuria

• Blood pressure target below 130/80 mmHg.
• ACE inhibitor or angiotensin receptor blocker at maximum tolerated dose: ramipril 2.5 mg daily titrated to 10 mg daily, or losartan 50 mg daily titrated to 100 mg. Check creatinine and potassium at 1 to 2 weeks; accept a creatinine rise of up to 30%; stop for potassium above 6.0 mmol/L.
• SGLT2 inhibitor: dapagliflozin 10 mg daily (eGFR at least 25 mL/min/1.73 m2) or empagliflozin 10 mg daily (eGFR at least 20). Hold on sick days.
• Sodium intake below 2 g daily; avoid NSAIDs.
• Statin: atorvastatin 20 mg daily.

Diabetes with albuminuria

• Add finerenone 10 mg daily (20 mg if eGFR at least 60) if potassium is below 5.0 mmol/L and eGFR at least 25.
• Semaglutide 1 mg subcutaneously once weekly reduces albuminuria and cardiovascular events in type 2 diabetes.
• Target HbA1c 48 to 58 mmol/mol, individualised.

Specialist management by histology

• Minimal change disease: prednisolone 1 mg/kg daily (maximum 80 mg) until remission, then taper over 12 to 16 weeks.
• Membranous nephropathy: supportive care for 6 months in low risk disease; rituximab 1 g on days 1 and 15 for persistent nephrotic syndrome.
• Focal segmental glomerulosclerosis: prednisolone 1 mg/kg daily (maximum 80 mg) for up to 16 weeks; calcineurin inhibitor for steroid resistance.
• Nephrotic complications: furosemide 40 to 120 mg daily for oedema, atorvastatin 20 mg daily for hyperlipidaemia, and prophylactic enoxaparin 40 mg daily when albumin is below 20 g/L in membranous disease.

Refer to nephrology for protein:creatinine ratio above 50 mg/mmol (albumin:creatinine ratio above 70 mg/mmol) unless due to known diabetes, for proteinuria with haematuria, for eGFR below 30, or for a fall in eGFR greater than 25% with category change.

Special groups. In pregnancy, protein:creatinine ratio above 30 mg/mmol after 20 weeks with hypertension signals pre-eclampsia; ACE inhibitors and angiotensin receptor blockers are contraindicated and should be stopped before conception or at confirmation of pregnancy.