Albuminuria

Albuminuria is excretion of albumin in urine above 30 mg in 24 hours, equivalent to an albumin:creatinine ratio above 3 mg/mmol (30 mg/g). It is the earliest and most sensitive marker of glomerular injury and endothelial dysfunction and the principal marker, with eGFR, used to stage chronic kidney disease.

Categories by albumin:creatinine ratio:

• A1 (normal to mildly increased): below 3 mg/mmol (30 mg/g)
• A2 (moderately increased, formerly microalbuminuria): 3 to 30 mg/mmol (30 to 300 mg/g)
• A3 (severely increased): above 30 mg/mmol (above 300 mg/g); above 220 mg/mmol (about 2000 mg/g) is nephrotic range

Albuminuria reflects increased glomerular permeability to albumin and reduced proximal reabsorption. It results from hyperfiltration and glomerular hypertension (diabetes, hypertension, obesity), inflammation, endothelial dysfunction and structural podocyte injury.

Its prognostic weight is independent of eGFR: each tenfold increase in albumin:creatinine ratio is associated with roughly two to three times the risk of end stage kidney disease and cardiovascular mortality.

Causes of transient albuminuria include fever, exercise within 24 hours, urinary tract infection, menstruation, acute heart failure, marked hyperglycaemia and uncontrolled hypertension.

• Asymptomatic in A1 and A2
• Frothy urine, oedema and hypoalbuminaemia in A3
• Co-existing diabetes (retinopathy, neuropathy), hypertension, obesity, metabolic syndrome, family history of kidney disease
• Associated cardiovascular disease: left ventricular hypertrophy, heart failure, peripheral arterial disease

Red flags: sudden rise in albuminuria, haematuria, short duration of diabetes with heavy albuminuria (suggests non-diabetic disease), absent retinopathy with heavy albuminuria in type 1 diabetes, falling eGFR, systemic symptoms.

• Preferred test: albumin:creatinine ratio on a first morning urine sample.
• Confirmation: two of three samples abnormal over 3 to 6 months. Exclude transient causes first.
• Dipstick albumin detects only above about 20 to 30 mg/L and is for screening.
• Annual screening is indicated in diabetes, hypertension, cardiovascular disease, family history of kidney disease and obesity; type 1 diabetes starts 5 years after diagnosis, type 2 at diagnosis.
• Complement with eGFR (creatinine and cystatin C where body mass is extreme), urinalysis for haematuria, lipid profile, HbA1c, fundoscopy.

Differentials:

• Diabetic kidney disease: A2 or A3 with retinopathy and long diabetes duration
• Hypertensive nephrosclerosis: modest albuminuria with long standing hypertension
• Glomerulonephritis: haematuria, red cell casts, low complement
• Obesity related and orthostatic albuminuria
• Pre-eclampsia in pregnancy

All patients with A2 or A3 albuminuria

• ACE inhibitor or angiotensin receptor blocker in diabetes with A2 or higher and in non-diabetic A3: ramipril 2.5 mg daily titrated to 10 mg daily; losartan 50 to 100 mg daily; irbesartan 150 to 300 mg daily. Target reduction in albumin:creatinine ratio of at least 30%.
• Check creatinine and potassium at 1 to 2 weeks after any change; accept creatinine rise up to 30%.
• Blood pressure below 130/80 mmHg when albumin:creatinine ratio is above 70 mg/mmol; below 140/90 mmHg otherwise.
• SGLT2 inhibitor: dapagliflozin 10 mg daily or empagliflozin 10 mg daily; reduces progression independent of diabetes.
• Atorvastatin 20 mg daily; increase to 80 mg in established cardiovascular disease.
• Smoking cessation, weight loss, sodium below 2 g daily, protein intake 0.8 g/kg daily.

Type 2 diabetes

• Finerenone 10 mg daily (20 mg when eGFR at least 60) if potassium is below 5.0 mmol/L and A2 or A3 persists despite maximum tolerated ACE inhibitor or angiotensin receptor blocker.
• GLP-1 receptor agonist: semaglutide 0.25 mg weekly for 4 weeks, then 0.5 mg, titrating to 1 mg weekly.
• Glycaemic control: HbA1c 48 to 58 mmol/mol.

Monitoring

• A2: albumin:creatinine ratio and eGFR every 6 to 12 months.
• A3: every 3 to 6 months.

Refer to nephrology for A3 persisting after treatment, albumin:creatinine ratio above 70 mg/mmol, a sustained fall in eGFR of 25% or more or 15 mL/min/1.73 m2 in 12 months, haematuria with albuminuria, or suspected non-diabetic disease.

Special groups

• Pregnancy: ACE inhibitors and angiotensin receptor blockers are contraindicated; protein:creatinine ratio above 30 mg/mmol with hypertension after 20 weeks indicates pre-eclampsia.
• Hyperkalaemia risk: potassium above 5.5 mmol/L requires dietary review, a potassium binder (sodium zirconium cyclosilicate 5 to 10 g daily) or dose reduction before stopping renoprotective therapy.