Urine Albumin-to-Creatinine Ratio

The urine albumin-to-creatinine ratio (ACR) measures urinary albumin concentration relative to creatinine in a spot sample, which corrects for urine dilution and avoids a 24-hour collection. Albumin is normally almost completely retained by the glomerular filter and reabsorbed by the proximal tubule, so a persistent increase indicates glomerular injury or endothelial dysfunction. It is measured by immunoturbidimetry or nephelometry, and creatinine by the Jaffe or enzymatic method.

It is the most sensitive routine test for early kidney damage, and it adds to eGFR in staging chronic kidney disease, predicting progression and estimating cardiovascular risk. It is the preferred test for screening and monitoring in diabetes, hypertension and chronic kidney disease. Moderately increased albuminuria is common in diabetes and hypertension and is often the first sign of kidney disease.

Indications.

• Annual testing in type 2 diabetes from diagnosis, and in type 1 diabetes from 5 years after diagnosis or from puberty.
• Hypertension, chronic kidney disease, cardiovascular disease, obesity, family history of kidney failure, systemic lupus erythematosus, HIV, kidney transplantation, and nephrotoxic drug therapy.
• Monitoring of response to ACE inhibitors, angiotensin receptor blockers and SGLT2 inhibitors.

Specimen. First morning void is preferred, since it avoids the effect of posture and exercise. A random sample is acceptable for screening, with a positive result confirmed on an early morning sample. Use a clean container without preservative. Samples are stable for about 7 days at 4 °C, and freezing at minus 20 °C can lower albumin results.

Units and conversion. Results are reported in mg/mmol or mg/g. Multiply mg/mmol by 8.84 to give mg/g, so 3 mg/mmol is about 30 mg/g and 30 mg/mmol is about 300 mg/g. An ACR of 30 mg/g is roughly equal to 30 mg of albumin excreted in 24 hours.

Categories.

Some services use sex specific upper limits for A1 (about 2.5 mg/mmol in men and 3.5 mg/mmol in women), since men have higher creatinine excretion. An ACR over about 2200 mg/g (over 220 mg/mmol) corresponds to nephrotic range albuminuria.

Confirmation. Two of 3 samples collected over 3 to 6 months must be abnormal before albuminuria is considered persistent.

Risk staging. ACR category and eGFR together define the risk of progression and cardiovascular events. For the same eGFR, risk increases with each rise in albuminuria category.

Persistently raised. Diabetic kidney disease, hypertensive kidney disease, glomerulonephritis (IgA nephropathy, membranous nephropathy, focal segmental glomerulosclerosis, minimal change disease), lupus nephritis, amyloidosis, obesity related glomerulopathy, pre-eclampsia, HIV nephropathy, and sickle cell nephropathy.

Transient increase (causes of false or temporary positives). Exercise in the previous 24 hours, urinary tract infection, fever or acute illness, marked hyperglycaemia, uncontrolled hypertension, heart failure, menstrual blood contamination, high protein meal, and orthostatic albuminuria in adolescents (present in the day but absent in the first morning void).

Effect of treatment. ACE inhibitors, angiotensin receptor blockers, SGLT2 inhibitors, finerenone and tight blood pressure and glucose control lower ACR, and a fall of 30% or more is associated with slower progression.

Albumin versus total protein. The ACR is the preferred test for glomerular disease, particularly in diabetes. It does not detect light chains (Bence Jones protein) or most tubular proteins, so these cases need a protein-to-creatinine ratio, protein electrophoresis and free light chains.

Relation to haematuria. Albuminuria with dysmorphic red cells or red cell casts indicates glomerular disease and needs early nephrology review.

Critical findings needing immediate action.

• ACR over 300 mg/g (over 30 mg/mmol) with a rising creatinine or haematuria suggests rapidly progressive glomerulonephritis.
• Nephrotic range ACR with oedema, low serum albumin or a thrombotic event.
• A fall in eGFR of more than 5 mL/min/1.73 m² in a year, or of 25% or more over a stage, with albuminuria.
• In pregnancy, a raised ACR with hypertension suggests pre-eclampsia.

Interferences and pitfalls.

• Muscle mass and diet alter urinary creatinine. Low muscle mass (older age, cachexia) overestimates the ratio, and high muscle mass underestimates it.
• Non-steady state and acute kidney injury make the ratio unreliable.
• Very dilute or very concentrated urine, blood contamination, vaginal discharge, semen, pus and macroscopic haematuria give false results.
• Albumin degrades on prolonged storage or freezing, and can fall, giving a falsely low result.
• Immunoassays can underestimate albumin that has been fragmented (immunochemically unreactive albumin), so total protein is needed when ACR seems out of keeping with the clinical picture.
• Assay differences exist between laboratories, and results are not interchangeable.
• Individual variation is large, with a coefficient of variation of about 20 to 40% between days.

Special groups.

• Children: the same categories apply from childhood. Testing in type 1 diabetes starts at puberty or 5 years after diagnosis, and a first morning sample excludes orthostatic albuminuria.
• Pregnancy: the ratio is less accurate than the protein-to-creatinine ratio for pre-eclampsia, and an ACR over about 8 mg/mmol (about 70 mg/g) suggests significant proteinuria.
• Older adults: higher variability and reduced creatinine excretion.
• Kidney transplant recipients: ACR is part of routine surveillance.

Follow up tests. Repeat early morning ACR, urine protein-to-creatinine ratio, urinalysis with microscopy, eGFR and cystatin C, HbA1c, lipid profile, blood pressure monitoring, serum protein electrophoresis and free light chains, antinuclear antibodies, complement, ANCA, anti-GBM antibody, hepatitis B and C and HIV serology, renal tract ultrasound, kidney biopsy.