Urine Protein-to-Creatinine Ratio

The urine protein-to-creatinine ratio (PCR) measures total urinary protein relative to creatinine in a spot sample, and correlates well with 24-hour protein excretion, so it has largely replaced the timed collection. Total protein includes albumin, Tamm-Horsfall protein, immunoglobulins, low molecular weight tubular proteins and light chains. It is measured by turbidimetric (benzethonium chloride) or dye binding (pyrogallol red) methods, which differ in their sensitivity to albumin, globulins and light chains.

It quantifies proteinuria of any origin and is the preferred test for suspected nephrotic syndrome, glomerulonephritis, tubular disease, paraprotein related kidney disease and pre-eclampsia. It adds to the albumin-to-creatinine ratio when non-albumin protein is suspected.

Indications. Positive dipstick protein, nephrotic syndrome, suspected glomerulonephritis, monitoring of response to immunosuppression, chronic kidney disease without diabetes, pre-eclampsia, suspected myeloma kidney, tubulointerstitial disease, drug nephrotoxicity (tenofovir, lithium, ifosfamide, cisplatin), kidney transplant follow up, and unexplained oedema.

Specimen. First morning urine is preferred, to avoid orthostatic and exercise effects. Random samples are acceptable. Use a clean container without preservative.

Reference values. Adults: PCR under 15 mg/mmol (about 150 mg/g), equivalent to under 150 mg of protein in 24 hours.

Units and conversion. Multiply mg/mmol by 8.84 to give mg/g. A PCR of 100 mg/mmol is about 0.9 g in 24 hours, since daily creatinine excretion is roughly 9 to 11 mmol.

Categories.

• Under 15 mg/mmol: normal.
• 15 to 50 mg/mmol (about 150 to 500 mg/g): mildly to moderately increased.
• Over 50 mg/mmol (over 500 mg/g): corresponds to an albumin-to-creatinine ratio over 30 mg/mmol (category A3).
• Over 300 to 350 mg/mmol (over 3 to 3.5 g/g): nephrotic range.

Nephrotic syndrome. Proteinuria over 3.5 g in 24 hours (PCR over about 350 mg/mmol), serum albumin under 30 g/L, oedema and hyperlipidaemia. In children, a PCR over 200 mg/mmol (2 g/g) with serum albumin under 25 g/L defines it.

Glomerular proteinuria. Albumin makes up most of the protein (ACR to PCR ratio over about 0.4). Causes: minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, diabetic kidney disease, lupus nephritis, amyloidosis, post-infectious glomerulonephritis, and secondary glomerular disease from HIV, hepatitis B and C, malaria (Plasmodium malariae), schistosomiasis, sickle cell disease and drugs (non-steroidal anti-inflammatory drugs, gold, penicillamine). Values are usually over 100 mg/mmol in nephrotic states.

Tubular proteinuria. Low molecular weight proteins (beta-2 microglobulin, retinol binding protein, lysozyme) predominate, with little albumin (ACR to PCR ratio under about 0.4). PCR is usually under 100 to 200 mg/mmol. Causes: Fanconi syndrome (tenofovir, ifosfamide, cisplatin, lithium, heavy metals such as cadmium and lead), tubulointerstitial nephritis (non-steroidal anti-inflammatory drugs, proton pump inhibitors, antibiotics, sarcoidosis), reflux nephropathy, sickle cell disease, Dent disease and other inherited tubulopathies.

Overflow proteinuria. Excess filtered low molecular weight protein from myeloma (light chains), rhabdomyolysis (myoglobin), intravascular haemolysis (haemoglobin) and monocytic leukaemia (lysozyme). Albumin is low and the PCR is disproportionately high. Dye binding methods can underdetect light chains, and urine electrophoresis is needed.

Transient or functional proteinuria. Fever, exercise, urinary tract infection, heart failure, seizures and orthostatic proteinuria, which is present in the daytime but absent in the first morning urine, and affects adolescents.

Pregnancy. A PCR of 30 mg/mmol or more (0.3 g/g) at 20 weeks or later, together with hypertension, indicates significant proteinuria and supports a diagnosis of pre-eclampsia. The level does not predict severity of pre-eclampsia.

Critical findings needing immediate action.

• Nephrotic range PCR with oedema, hypoalbuminaemia, or evidence of thrombosis, particularly renal vein thrombosis.
• Proteinuria with haematuria, red cell casts and a rising creatinine (rapidly progressive glomerulonephritis).
• High PCR with a low ACR, hypercalcaemia, anaemia and acute kidney injury (suspected myeloma cast nephropathy).
• Haemoglobinuria or myoglobinuria with acute kidney injury.
• Pre-eclampsia with severe hypertension, headache, visual disturbance or abnormal liver enzymes.

Interferences and pitfalls.

• Muscle mass changes urinary creatinine, so low muscle mass raises the ratio and high muscle mass lowers it. Non-steady states such as acute kidney injury invalidate the ratio.
• Macroscopic haematuria, menstrual blood, semen, vaginal discharge and pus give false results.
• Contrast media, penicillins and some drugs can precipitate protein or interfere with turbidimetric assays within 24 to 48 hours of administration.
• The correlation with 24-hour protein is weaker at values over 3 g, and a timed collection may be needed in clinical doubt.
• Methods differ in sensitivity to albumin, globulins and light chains, so values are not interchangeable between laboratories.
• Dipstick protein detects mainly albumin and misses light chains.
• Individual day-to-day variation is large, and a single result should be confirmed.

Special groups.

• Children: age specific ranges apply. The upper limit is about 0.5 g/g under 2 years and about 0.2 g/g over 2 years, and nephrotic syndrome in children is defined by a PCR over 200 mg/mmol with serum albumin under 25 g/L.
• Pregnancy: use the 30 mg/mmol threshold, and compare with a 24-hour collection when unsure.
• Older adults: low creatinine excretion raises the ratio.
• Transplant recipients: persistent proteinuria suggests rejection, recurrence or drug toxicity.

Follow up tests. Urine albumin-to-creatinine ratio, urinalysis with microscopy for dysmorphic red cells and casts, serum albumin and lipid profile, eGFR and cystatin C, serum protein electrophoresis with immunofixation, serum free light chains, urine protein electrophoresis, complement C3 and C4, antinuclear antibodies, anti-dsDNA, ANCA, anti-GBM antibody, anti-PLA2R antibody, hepatitis B and C and HIV serology, malaria testing, renal tract ultrasound, 24-hour urine collection, kidney biopsy.