Cystatin C GFR

Cystatin C as a GFR Marker
A substantial body of evidence has developed over the past several years which supports the use of Cystatin C as an alternative and more sensitive endogenous marker for the estimation of GFR than serum creatinine and serum creatinine based GFR estimations.(5,6,9-12)

Cystatin C is a small 13 –kDa protein that is a member of the cysteine proteinase inhibitor family that is produced at a constant rate by all nucleated cells. Due to its small size it is freely filtered by the glomerulus, and is not secreted but is fully reabsorbed and broken down by the renal tubules. This means the primary determinate of blood Cystatin C levels is the rate at which it is filtered at the glomerulus making it an excellent GFR marker. A recent meta-analysis demonstrated that serum Cystatin C is a better marker for GFR than serum creatinine.

Unlike creatinine, Cystatin C serum levels are virtually unaffected by age (>1 yr), muscle mass, gender and race. A number of very simple formulas have been introduced which can be used to obtain an estimated GFR using Cystatin C. Multiple studies have found Cystatin C to be more sensitive to actual changes in GFR in the early stages of CKD than creatinine based GFR estimates. (A significant advantage of Cystatin C based formulas, unlike creatinine based equations, is that Cystatin C based estimated GFR formulas are not biased according to GFR(13-14) and there is no GFR blind area with Cystatin C.)

Cystatin C and the MDRD
The creatinine based MDRD underestimates GFR in healthy subjects and shows decreased accuracy in older patients (with decreased muscle mass) and patients with body mass indexes (BMI) <21 and >30. While MDRD and serum creatinine show good diagnostic accuracy in severe renal failure (GFR <15 mL/min per 1.73 m2) creatinine based measurements show a lack of sensitivity in stage 2 and stage 3 renal disease when early intervention may improve outcomes.11 Cystatin C based estimates of GFR have been reported to be a more sensitive maker of decline in GFR especially in the earliest stages of CKD.

Cystatin C for Early Detection of CKD in Diabetes
Multiple reports indicate that Cystatin C is a reliable marker of GFR in patients with mild to moderate impairment of kidney function (stages 2-3 of CKD).10 This high degree of sensitivity has been demonstrated in both Type 1 and Type 2 Diabetes.(13,14) In addition, several studies indicate that although clinical proteinuria was associated with both MDRD and Cystatin C estimates of GFR only Cystatin C was associated with microalbuminuria. This finding supports the enhanced sensitivity of Cystatin C based formulas for the early detection of kidney damage. Elevated serum Cystatin C levels have also recently been identified as a significant prognostic indicator for the development of cardiovascular disease in people with diabetes.

Cystatin C GFR as a Guide for Dose Adjustments of Medications
GFR is commonly determined in clinical practice to guide the dosage of potentially toxic drugs including digoxin, chemotherapy medications and aminoglycoside antibiotics. Serum creatinine often does not increase until the GFR has moderately decreased (about 40 ml/min/1.73 m2). This insensitivity to small to moderate decreases in GFR in the so called creatinine blind GFR area (40–70 ml/min/1.73 m2) may result in an unnecessarily high drug dose thus increasing the risk to the patient and the cost of possible resulting side effects. Some studies have advocated the preferential use of Cystatin C based GFR estimations for establishing the appropriate dose adjustment of drugs that are mainly eliminated by the kidneys.

Advantages of Cystatin C as a GFR Marker

Advantage

Comments

Virtually unaffected by non-renal factors

Muscle Mass Weight HeightAge (>1 year) – Cystatin C parallels age related decreases in GFR and may be used reliably with children GenderDietIntestinal bacterial overgrowth Less inter individual variation than creatinine

Primary determinate of Cystatin C levels are renal factors

Cystatin C is not secreted but is fully absorbed and broken down by tubular cell. Since there is no tubular secretion of Cystatin C, it is extremely sensitive to small changes in GFR in the earliest stages of CKD.

Sensitive to changes in the so-called creatinine blind GFR (40–70 ml/min/1.73 m2 )

Enables early detection and treatment of CKD.

Demonstrates higher diagnostic accuracy than MDRD, or C-G equations in patients with diabetes

Enables early detection and treatment of CKD in both Type 1 and Type 2 diabetes.

Can be used to detect and monitor kidney disease in patients with Hepatic Disease

Creatinine based GFR measurements are not reliable and are not recommend in hepatic disease. Cystatin C is reliable in Cirrhotic patients.

Has been advocated as the preferred endogenous marker for dosing medication eliminated by the kidneys

May detect mild to moderate decreases in GFR that are not evident with serum creatinine based measurements, thus avoiding unnecessarily high drug doses which may pose an increased risk to the patient and the associated cost of possible resulting side effects.

There is evidence to suggest that Cystatin C is a useful indicator of the association of mild kidney dysfunction with other diseases

This includes the increased risk of cardiovascular events, peripheral arterial disease, heart failure, and death.

Correlates to the appearance of microalbumin

Recent studies suggest that very early renal failure may be the first clinical indication of the progressive kidney damage associated with diabetes.

CONTRAINDICATIONS

Thyroid Function
Levels of Cystatin C are sensitive to changes in thyroid function and should not be used without knowledge of the patients thyroid status.17

Corticosteroids
It has been reported that Cystatin C serum concentrations are not affected by standardized high-dose corticosteroid therapy but may be increased in patients with impaired renal function receiving corticosteroids.14

Reference:

  1. Serum Cystatin C Predicts Progression of Subclinical Coronary Atherosclerosis in Individuals With Type 1 Diabetes DIABETES, VOL 56, NOVEMBER 2007
  2. United States Renal Data Systems. (www.usrds.org)
  3. National Kidney Disease Education Program. (www.nkdep.nih.gov)
  4. National Kidney Foundation Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification Ann Intern Med. 2003;139:137-147
  5. How to estimate GFR-serum creatinine, serum cystatin C or equations? Clinical Biochemistry 40 (2007) 153–161
  6. Cystatin C: An Improved Estimator of Glomerular Filtration Clinical Chemistry 48: 699-707, 2002
  7. Recommendations for Improving Serum Creatinine Measurement: A Report from the Laboratory Working Group of the National Kidney Disease Education Program, Clin. Chem., Jan 2006; 52: 5 – 18
  8. Cystatin C as a marker of GFR- History, indications and future research Clinical Biochemistry 38(2005) 1-8
  9. Serum cystatin C as an endogenous marker of renal function in patients with mild to moderate impairment of kidney function, Nephrology Dialysis Transplant (2006) 21: 1855–1862
  10. Simple Cystatin C–Based Prediction Equations for Glomerular Filtration Rate Compared with the Modification of Diet in Renal Disease Prediction Equation for Adults and the Schwartz and the Counahan–Barratt Prediction Equations for Children Clin. Chem., Aug 2005; 51: 1420 - 1431
  11. Improved GFR estimation by combined creatinine and cystatin C measurements. Kidney International advance online publication, 26 September 2007; doi:10.1038/sj.ki.5002566
  12. Use of serum Cystatin C to detect early decline of glomerular filtration rate in Type 2 diabetes A new approach for evaluating renal function and its practical application, Journal of Pharmacological Sciences May 2007 1-5 (proof)
  13. Cystatin C and Estimates of Renal Function: Searching for a Better Measure of Kidney Function in Diabetic Patients Clin. Chem., 2007; 53: 480 - 488
  14. Effect of Corticosteroid Therapy on Serum Cystatin C and ß2-Microglobulin Concentrations Clin. Chem., 2002; 48:1123-1126
  15. Diagnostic accuracy of cystatin C compared to serum creatinine for the estimation of real dysfunction in adults and children meta analysis, Clinical Biochemistry 40 (2007) 383-391
  16. 16) New Predictive equations improve monitoring of kidney function in patients with diabetes Diabetes Care., 2007; 30:1988-1994
  17. Serum Cystatin C is sensitive to small changes in thyroid function Clinica Chimica Acta, Volume 338, Number 1, December 2003 , pp. 87-90(4)