Cystatin C

Cystatin C is a 13 kDa cysteine protease inhibitor made at a constant rate by all nucleated cells. It is freely filtered by the glomerulus, then reabsorbed and fully broken down in the proximal tubule, with no tubular secretion. Serum concentration therefore rises as GFR falls and is largely independent of muscle mass, diet and sex. It is measured by particle enhanced immunoturbidimetry or nephelometry, calibrated to the international reference material.

It is used to estimate GFR when creatinine is unreliable, and as a confirmatory test for chronic kidney disease. The combined creatinine and cystatin C equation is more accurate than either marker alone, and is the preferred estimate when precision matters. Higher cystatin C also predicts cardiovascular events and death independently of GFR.

Indications.

• Confirmation of chronic kidney disease when creatinine based eGFR is 45 to 59 mL/min/1.73 m² with no other marker of kidney damage.
• Extremes of muscle mass or diet: sarcopenia, frailty, amputation, paraplegia, cirrhosis, malnutrition, bodybuilding, creatine use and vegetarian diet.
• Dosing of drugs with a narrow therapeutic range or toxicity when eGFR is borderline, including chemotherapy and some antibiotics.
• Kidney donor assessment.
• Cardiovascular and mortality risk stratification in selected patients.

Specimen. Serum or lithium heparin plasma. Fasting is not needed. The sample is stable for days at 2 to 8 °C and for longer when frozen.

Reference values. About 0.6 to 1.0 mg/L in younger adults, with an upper limit of about 1.2 mg/L in those over 60 years. Neonates have higher values (about 1.3 to 2.0 mg/L) that fall to adult values by about 1 year. Local ranges take precedence, and assays calibrated to the international reference material are needed for use in equations.

Equations. Race free equations estimate GFR from cystatin C alone, or from creatinine and cystatin C together. Results are expressed in mL/min/1.73 m², with the same chronic kidney disease categories as creatinine based eGFR. The combined equation is more accurate than the creatinine only equation, and should be used when creatinine may be misleading.

Confirmatory use. If the creatinine based eGFR is 45 to 59 mL/min/1.73 m² and the combined or cystatin C eGFR is 60 or over with no other marker of kidney damage, chronic kidney disease is not confirmed. If the cystatin C-based value is under 60, chronic kidney disease is confirmed.

Discordance between markers. A difference of more than 30% between the creatinine based and cystatin C-based eGFR should prompt a search for a cause.

• Cystatin C eGFR lower than creatinine eGFR: low muscle mass (the creatinine value overestimates true GFR), obesity, smoking, inflammation, high dose corticosteroids, hyperthyroidism, diabetes, and sometimes malignancy.
• Cystatin C eGFR higher than creatinine eGFR: high muscle mass, creatine supplements, high meat intake, hypothyroidism, and drugs that block tubular creatinine secretion (trimethoprim, cimetidine, dolutegravir).

Factors that raise cystatin C independent of GFR. Obesity, smoking, raised C-reactive protein and inflammation, hyperthyroidism, high dose corticosteroids, older age, male sex, diabetes, hypertension, some cancers, and ciclosporin.

Factors that lower cystatin C independent of GFR. Hypothyroidism, and possibly some immunosuppressive drugs.

Clinical use in cirrhosis. Cystatin C overestimates GFR less than creatinine does, and is more accurate for hepatorenal assessment, although values are still affected by inflammation.

Acute kidney injury. Cystatin C can rise earlier than creatinine, by about 12 to 24 hours, but it is not validated for diagnosing or staging acute kidney injury, and the value is not at steady state.

Findings needing immediate action. A markedly reduced cystatin C-based eGFR that disagrees with a near normal creatinine value should prompt immediate review of renally cleared and nephrotoxic drugs, and of contrast exposure.

Pitfalls.

• Assays and calibrators are not interchangeable, and results from a non-calibrated assay should not enter an equation.
• Not valid in acute kidney injury or any unsteady state.
• Thyroid disease, corticosteroids, inflammation and obesity alter levels independent of GFR.
• Availability and cost limit use, and it is not suitable for repeated routine monitoring in most patients.
• Pregnancy: levels rise in the third trimester and more in pre-eclampsia, so GFR is overestimated in low values and underestimated in high.
• Equations are not validated in kidney transplant recipients on high dose immunosuppression, in HIV with advanced disease, or on dialysis.

Special groups.

• Children: age specific ranges apply, and paediatric equations using cystatin C, creatinine and height are used. Values fall to adult levels by about 1 year.
• Neonates and preterm infants: higher values, and levels reflect gestation.
• Older adults and frail patients: cystatin C estimates are less affected by loss of muscle mass.
• Kidney donors: measured GFR is the reference, and cystatin C improves the estimate when measurement is not available.

Follow up tests. Creatinine and eGFR, urine albumin-to-creatinine ratio, urinalysis, measured GFR (iohexol or isotope clearance), C-reactive protein, thyroid function tests, renal tract ultrasound, repeat testing at 3 months to confirm chronic kidney disease.