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Cystatin: What Is Its Role
Cystatin: What Is Its Role
W H AT I S I T S R O L E
IN ESTIMATING GFR?
Introduction
HOW IS KIDNEY FUNCTION DETERMINED?
The rate at which glomeruli in the kidney filter impurities in the blood is the glomerular filtration rate (GFR). GFR is defined as the volume of plasma that can be completely cleared of a particular substance by the kidneys in a unit of time.2 There is no simple and practical way to measure GFR directly, so it is estimated. To estimate the GFR, an endogenous substance in the blood that is cleared by the kidney is used. This substance is currently serum creatinine, which is used to estimate GFR in equations that include age, race, and gender, so it can be adjusted to account for average differences in muscle mass among subgroups. The Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) Study equations are serum creatinine-based equations that are used to estimate GFR. GFR determinations by creatininebased equations are not precise, so other substances, such as cystatin C, are being explored to estimate GFR. Cystatin C, a non-glycosylated 13 kDa protein, has the potential to improve estimates of GFR, because it is thought to be less influenced by muscle mass or diet.
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Does cystatin C have the potential to make estimates of GFR more accurate? Are estimating equations that use both creatinine and cystatin C more accurate than those that use only one of these? What patient populations would most benefit from using cystatin C in GFRestimating equations? Will adjustments based on patient age, sex, race, or size be needed in cystatin C GFR-estimating equations?
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KEY POINT
This publication has been made possible through a grant from Siemens Healthcare Diagnostics Inc.
Accurate estimation of glomerular filtration rate (GFR) is essential for the diagnosis, staging, and management of chronic kidney disease (CKD).1 Combining serum creatinine with cystatin C in a GFR estimating equation may provide a more accurate measure of true GFR than creatinine-based methods in adult and pediatric patients with CKD. More studies are required to see if this is true in those without CKD.
www.kidney.org
TWO META-ANALYSES hAVE CONCLUDED ThAT SERUM CYSTATIN C IS SUpERIOR TO SERUM CREATININE AS A MARKER OF KIDNEY FUNCTION.3,4
However, recent findings suggest an equation that uses both serum creatinine and cystatin C with age, sex, and race would be better than equations that use only one of these serum markers. 5,6 In May 2009, Levey et al7 reported that the CKD-EPI creatinine equation was somewhat more precise than the MDRD Study equation, especially at higher GFRs. Using the new equation could decrease false-positive results, the team reported. The gold standard for determining GFR is to measure the clearance of an exogenous substance such as inulin. However, the measurement of
More information is needed, however, because the filtration properties of cystatin C are difficult to determine since it is not excreted in the urine. In addition, there are substantial differences among assays used to measure cystatin C. It is also important to note that serum creatinine is being standardized nationwide. This has not yet happened for cystatin C, although it is in progress. GFR is needed to determine the stage of CKD and is used to determine the appropriate clinical action plan.
1.2 mg/dL
1.2 mg/dL
1.2 mg/dL
66 mL/min/1.73 m2
46 mL/min/1.73 m2
Kidney function
Stage 3 CKD
KEY POINT
An equation that uses both serum creatinine and cystatin C with age, sex, and race may be better than equations that use only one of these serum markers.5
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USINg CYSTATIN C
CLINICAL CONSIDERATIONS WITh VARYINg DEgREES OF KIDNEY FUNCTION
Kidney Transplantation
CysCGFR after transplant has been used to detect allograft rejection and monitor drug nephrotoxicity, with reported diagnostic value.45 In kidney transplant patients, cystatin C was reported to be more sensitive than serum creatinine for detecting decreases in GFR and delayed graft function, offering an opportunity for timely intervention.46 Follow-up studies have found GFR was overestimated 30% when derived from plasma creatinine levels.47 Even though cystatin C underestimated GFR by 14%, it was still more sensitive in detecting kidney damage, with no false-negative results. Note also, though, that routine or rejectionnecessitated treatment with corticosteroids led to a significantly increased serum cystatin C concentration.48
RELATED TERMS
Albuminuria, proteinuria, hematuria Albuminuria, proteinuria, hematuria Chronic renal insufficiency, early renal insufficiency Chronic renal insufficiency, late renal insufficiency, pre-ESRD
6089
3059
Severe GFR
1529
Kidney Failure
CLASSIFICATION BY TREATMENT
CYSTATIN C EqUATIONS
3. CKD-EPI cystatin equation not adjusted for age, sex, and race14: eGFR = 76.7 CysC1.19 4. CKD-EPI cystatin equation adjusted for age, sex, and race14: eGFR = 127.7 CysC1.17 age0.13 0.91 (if female) 1.06 (if African American) 5. CKD-EPI cystatin and creatinine equation adjusted for age, sex, and race15: eGFR = 177.6 SCr0.65 CysC0.57 age0.20 0.80 (if female) 1.11 (if African American)
Note: GFR is expressed as mL/min/1.73 m2; Age is expressed in years; weight is expressed in kilograms. Conversion factors for units: GFR in mL/min/1.73 m2 to mL/s/1.73 m2, 0.01667; SCr in mg/dL to mol/L, x 88.4; serum CysC in mg/L to nmol/L, 74.9. Abbreviations: CKD, chronic kidney disease; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; CysC, serum cystatin C; eGFR, estimated glomerular
filtration rate; MDRD, Modification of Diet in Renal Disease; SCr, serum creatinine
KEY POINT
There are many formulae that can be used to estimate GFR. Currently, the question of which is most precise and clinically valuable is being studied.
predicting equations according to bias, precision,and accuracy. Bias expresses the systematic deviation from the gold standard measure of GFR and is given by the difference between the true and estimated values of GFR (absolute bias). Clinically this is relevant at lower GFRs, as there is less concern about the difference between
Additional experience will be needed to determine the bias, precision, and accuracy of cystatin C-based GFR estimates.
100 and 130 mL/min/1.73 m2 than between 30 and 60 mL/min/1.73 m2. Precision expresses the variability (or dispersion) of predictions around the true GFR and corresponds to the standard deviation of the difference between the true and estimated GFR. This considers the reproducibility of the result. Accuracy combines precision and bias and is measured by the proportion of estimates falling within a certain percent of the true GFR (eg, 30% accuracy is the proportion of predicted GFR within 30% of the true GFR). Bias, precision, and accuracy, as defined by the National Kidney Foundation, are simple and reproducible criteria. It refers to how close the measurement is to a traceable or standard value.
USINg CYSTATIN C:
Diabetes and HIV
Diabetes: Cystatin C has been reported to be a reliable marker of GFR in patients with mild-tomoderate impairment of kidney function (stages 23 of CKD) in both type 1 and type 2 diabetes,24 although the studies reporting this are of varying quality.25-27 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. Hoek et al28 reported that not only was cystatin C a better indicator of GFR than creatinine in people with diabetes, it was the parameter which had the best correlation (r = 0.66) with changes in GFR over two years, making it a useful measure for follow-up of patients with diabetes. HIV: More research is needed, since cystatin C is increased with HIV , but creatinine-based estimates of GFR have not been tested rigorously in HIV-infected persons. This population is known to be influenced by malnutrition, wasting syndrome, and anabolic steroid treatment.29 Because of an increase of cystatin C levels with active HIV infection, an overestimation of kidney impairment may occur, particularly in treatment-naive patients.30
Cardiovascular Disease
Cystatin C has been reported to be a potent predictor of cardiovascular mortality beyond classical risk factors in patients with CAD and normal or mildly reduced kidney function.37 Serum cystatin C may have a stronger association with mortality and cardiovascular disease than serum creatinine in patients without CKD, as reported in a large study of older adults.38
Prediabetes
Diabetic nephropathy is likely to be more susceptible to intervention at early stages. Early kidney impairment indexed with cystatin C imparted a three-fold excess risk of progression to prediabetes in 1,455 subjects free of type 2 diabetes and known cardiovascular disease at baseline (19962001), who were re-examined in 20022004.36
USINg CYSTATIN C:
Pediatrics
Adolescents
Adjustment of GFR estimates for gender and height and other variables may be necessary (see the cKiD estimating formula below). In adolescents, serum cystatin
After age 1, serum cystatin C concentration is constant, but higher values are found in the newborn period. In full-term newborns, cystatin C progressively declines over the first week of life, and less significantly, over the first month.16 CysCGFR has been reported to be more accurate in children with cancer17 and in patients with spina bifida or spinal injury.18 After age 1, body mass exerts a minimal effect on CysCGFR estimation, but height and gender influence it.19 See an estimating equation below.
C is significantly affected by gender, age, race/ethnicity, uric acid, and blood urea nitrogen.21
Seniors
PATIENT CHARACTERISTICS AND CYSTATIN C RESEARCH
GFR declines with age and cystatin C may better reflect true kidney function in older people because muscle mass does not Serum cystatin C concentration varies in pregnancy, because it is not consistently produced. In preeclampsia, however, altered kidney function is more likely to be detected by CysCGFR than by creatinine-based formulas.20 influence it.22 After age 50, reference values of serum cystatin C concentration are higher. The prevalence of stage 3 CKD in an elderly population when GFR is estimated by the MDRD Study equation, is significantly higher than the prevalence obtained when CysC GFR equations are used.23
Obstetrics
References
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19. Sharma AP , Kathiravelu A, Nadarajah R, et al. Body mass does not have a clinically relevant effect on cystatin C eGFR in children. Nephrol Dial Transplant. 2008. E-pub ahead of print. 20. Stevens H, Wide-Swensson D, Grubb A. Serum cystatin C is a better marker for preeclampsia than serum creatinine or serum urate. Scand J Clin Lab Invest. 2001;61:575-80. 21. Groesbeck D, Kottgen A, Parekh R, et al. Age, gender, and race effects on cystatin C levels in US adolescents. Clin J Am Soc Nephrol. 2008;3:1777-1785. 22. ORiordan SE, Webb MC, Stowe HJ, Simpson DE, Kandarpa M, Coakley AJ, et al. Cystatin C improves the detection of mild renal dysfunction in older patients. Ann Clin Biochem. 2003;40:648-655. 23. Delanaye P , Cavalier E, Saint-Remy A, et al. Discrepancies between creatininebased and cystatin C-based equations in estimating prevalence of stage 3 chronic kidney disease in an elderly population. Scand J Clin Lab Invest. 2008;2:1-6. E-pub ahead of print. 24. Willems D, Wolff F, Mekhali F, Gillet C. Cystatin C for early detection of renal impairment in diabetes. Clin Biochem. 2009;42:108-110. 25. Grubb A, Nyman U, Bjrk J, et al. Simple cystatin Cbased prediction equations for glomerular filtration rate compared with the Modification of Diet in Renal Disease prediction equation for adults and the Schwartz and the CounahanBarratt prediction equations for children. Clin Chem. 2005;51:1420-1431. 26. Pucci L, Triscornia S, Lucchesi D, et al. Cystatin C and estimates of renal function: searching for a better measure of kidney function in diabetic patients. Clin Chem. 2007;53:480-488. 27. Mussap M, Dalla Vestra M, Fioretto P , et al. Cystatin C is a more sensitive marker than creatinine for the estimation of GFR in type 2 diabetic patients. Kidney Intl. 2002;61:1453-1461. 28. Hoek FJ, Kemperman FA, Krediet RT. A comparison between cystatin C, plasma creatinine and the Cockroft and Gault formula for the estimation of glomerular filtration rate. Nephrol Dial Transplant. 2003;18:2024-2031. 29. Winston JA. Estimating glomerular filtration rate in patients with HIV infection. Sem Nephrology. 2008;28:576-580. 30. Mauss S, Berger F, Kuschak D, et al. Cystatin C as a marker of renal function is affected by HIV replication leading to an underestimation of kidney function in HIV patients. Antivir Ther. 2008;13:1091-1095. 31. Fricker M, Wiesli P , Brndle M, et al. Impact of thyroid dysfunction on serum cystatin C. Kid Intern. 2003;63:1944-1947. 32. Orlando R, Mussap M, Plebani M, et al. Diagnostic value of plasma cystatin C as a glomerular filtration marker in decompensated liver cirrhosis. Clin Chemistry. 2002;48:850-858. 33. Samyn M, Cheeseman P , Bevis L, et al. Cystatin C, an easy and reliable marker for assessment of renal dysfunction in children with liver disease and after liver transplantation. Liver Transpl. 2005;11:344-349. 34. Biancofiore G, Pucci, L, Cerutti E, et al. Cystatin C as a marker of renal function immediately after liver transplantation. Liver Transpl. 2006;12:285-291.
35. Schck O, Gottfriedova H, Maly J, et al. Glomerular filtration rate assessment in individuals after orthotopic liver transplantation based on serum cystatin C levels. Liver Transpl. 2002;8:594-599. 36. Donahue RP . Elevated cystatin C concentration is associated with progression to prediabetes: the Western New York Study. Diabetes Care. 2007;30:1724-1729. 37. Keller T, Martina Messow C, Lubos E, et al. Cystatin C and cardiovascular mortality in patients with coronary artery disease and normal or mildly reduced kidney function: results from the AtheroGene study. Eur Heart J. 2009;30:314-320. 38. Shilpak M, Katz R, Sarnak M, et al. Cystatin C and prognosis for cardiovascular and kidney outcomes in elderly persons with chronic kidney disease. Ann Intern Med. 2006;145:237-246. 39. Ix JH, Shlipak MG, Chertow GM, Whooley MA. Association of cystatin C with mortality, cardiovascular events, and incident heart failure among persons with coronary heart disease. Circulation. 2007;115:173-179. 40. Chew JSC, Saleem M, Florkowski CM, et al. Cystatin Ca paradigm of evidence based laboratory medicine. Clin Biochem Rev. 2008;29:47-62. 41. Stevens LA, Levey AS. Chronic kidney disease in the elderlyhow to assess risk. N Engl J Med. 2005;352:2122-2124. 42. Jerums G, Premaratne E, Panagiotopoulos S, et al. New and old markers of progression of diabetic nephropathy. Diabetes Res Clin Pract. 2008;82(suppl 1):S30-S37. 43. Yang YS, Peng CH, Lin CK, et al. Use of serum cystatin C to detect early decline of glomerular function in type 2 diabetes. A new approach for evaluating renal function and its practical application. J Pharmacol Sciences. 2007;46:801-806. 44. Rosolowsky ET, Niewczas MA, Ficociello LH, et al. Between hyperfiltration and impairment: demystifying early renal functional changes in diabetic nephropathy. Diabetes Res Clin Pract. 2008;82(suppl 1):S46-S53. 45. Pge U, Gerhardt T, Stoffel-Wagner B, et al. Cystatin C-based calculation of glomerular filtration rate in kidney transplant recipients. Kidney Intl. 2006;70:204-210. 46. Le Bricon T, Thervet E, Benlakeha M, et al. Changes in plasma cystatin C after renal transplantation and acute rejection in adults. Clin Chem.1999;45:2243-2249. 47. Le Bricon T, Thervet E, Froissart M, et al. Plasma cystatin C is superior to 24-h creatinine clearance and plasma creatinine for estimation of glomerular filtration rate 3 months after kidney transplantation. Clin Chem. 2000;46:1206-1207. 48. Pge U, Gerhardt T, Bkenkamp A, et al. Time course of low molecular weight proteins in the early kidney transplantation period influence of corticosteroids. Nephrol Dial Transplant. 2004;19:2858-2863. 49. Haase-Fielitz A, Bellomo R, Devarajan P , et al. Novel and conventional serum biomarkers predicting acute kidney injury in adult cardiac surgerya prospective cohort study. Crit Care Med. 2009. E-pub ahead of print. 50. Herget-Rosenthal S, Marggraf G, Hsing J, et al. Early detection of acute renal failure by serum cystatin C. Kidney Intl. 2004;66:1115-1122. 51. Levey AS, Eckardt KU, Tsukamoto Y , et al. Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Intl. 2005;67:2089-2100.
17. Grnroos MH, Jahnukainen T, Irjala K, et al. Comparison of glomerular function tests in children with cancer. Pediatr Nephrol. 2008;23:797-803. 18. Roos JF, Doust J, Tett SE, Kirkpatrick CM. Diagnostic accuracy of cystatin C compared to serum creatinine for the estimation of renal dysfunction in adults and children: meta-analysis. Clinical Biochem. 2007;40:383-391.
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