Cystatin C: Research Priorities Targeted to Clinical Decision Making

Cystatin C and GFR Estimation 

In the first study, Stevens and colleagues from the Chronic Kidney Disease Epidemiology (CKD-EPI) collaboration developed 3 GFR estimating equations for cystatin C, using (1) cystatin C alone, (2) cystatin C with demographic coefficients, and (3) cystatin C with creatinine and demographic coefficients. To accomplish this, these investigators pooled patient level information of 3,418 individuals from 4 studies with direct measures of GFR. All subjects were known to have CKD, either by reduced GFR or by the presence of diabetic nephropathy; the mean age of the pooled cohorts was 52 years, and the mean measured GFR was 48 mL/min/1.73 m2 (0.8 mL/s/1.73 m2). In the 3 studies from the United States, GFR was measured by iothalamate clearance; in the French study that was used for external validation, GFR was measured by 51Cr-EDTA.

The first major finding was that an equation utilizing only cystatin C explained 82% of the variability in measured GFR (R2 = 0.82), roughly equivalent to the MDRD Study equation (83%) and superior to an equation using creatinine alone (74%). Combining creatinine, cystatin C, and demographic factors produced the equation with the best fit to measured GFR (87% of variability explained). The second major finding was that demographic characteristics had a significant influence on the association of cystatin C with GFR, though to a much smaller extent than for creatinine. Perhaps with excessive optimism, prior investigators (including this author) had declared cystatin C to be independent of influence from demographic factors; in this study, however, cystatin C levels were 9% lower in women, and 6% higher in blacks for a given GFR.11 Accordingly, the threshold for CKD (estimated GFR < 60 mL/min/1.73 m2 [1 mL/s1.73 m2]) in a 60-year-old would vary from a cystatin C value of 1.12 mg/L in a white woman, to 1.17 mg/L in a black woman, 1.21 mg/L in a white man, and 1.27 mg/L in a black man, an increase of 13% from the lowest to the highest. In contrast, for the 4-variable MDRD Study equation that is based on serum creatinine, these cutpoints would range from a creatinine value of 0.95 mg/dL (84 μmol/L) in a white woman to 1.46 mg/dL (129 μmol/L) in a black man, a relative difference of over 50%.

Cystatin C Levels in the United States 

In the second paper, Köttgen and colleagues report the population distributions of cystatin C in the United States, using sera from the Third National Health and Nutrition Examination Surveys (NHANES III), which was conducted from 1988 to 1994. The authors had several options for defining “normal” cystatin C levels in the US population: 1.23 mg/L, which corresponds to eGFRcys of 60 mL/min/1.73 m2 (1 mL/s/1.73 m2) by the CKD-EPI equation; 1.0 mg/L, the threshold proposed for “preclinical kidney disease” in the Cardiovascular Heath Study11; or an alternative cutpoint defined by the distribution within NHANES III. Based on precedent from other chemistry measures, the authors chose to define abnormal cystatin C levels by the 99th percentile of the cystatin C distribution among 20- to 40-year-olds without hypertension or diabetes. This level, 1.12 mg/L, results in an eGFR of 67, based on the CKD-EPI equation that uses only cystatin C.9

The most notable finding from the Köttgen study was the remarkable increase in the prevalence of abnormal cystatin C with higher age, from only 1% in the 20- to 40-year-old group to over 50% in persons over 80 years old within each demographic subgroup. Thus, by the 9th decade of life, “abnormal” cystatin C appears to become the rule rather than the exception. Other than demographic factors, the predictors of higher cystatin C levels included the expected risk factors for kidney disease—hypertension, current smoking, higher body mass index, elevated C-reactive protein and triglycerides, lower high-density liprotein (HDL) levels, and lower educational attainment. Another intriguing finding from this paper was that cystatin C levels varied by race among the healthy subgroup aged 20 to 40 years: levels were higher in whites than among blacks or Mexican Americans. At present it is unclear whether these differences are attributable to racial differences in kidney function in this age group or to ethnic differences in how cystatin C approximates GFR.

Future Clinical and Research Directions 

Although cystatin C appears to be a very promising marker of GFR that could be an alternative or complement to creatinine, it has not been adopted into widespread use in the United States. This is appropriate because research has not yet addressed the fundamental question for any diagnostic test: Can cystatin C improve medical decision making and lead to more favorable patient outcomes? I believe that the foundation for such research has been developed by the papers in this issue of AJKD and by prior studies, and that it is now time to move forward by addressing the questions that are most meaningful to clinicians. While it remains interesting and valuable to evaluate the factors that bias cystatin C levels in their approximation of GFR, Stevens et al have found that this variability accounts for at most 18% of the cystatin C level in persons with CKD.

Among patients with known CKD, defined by reduced creatinine-based eGFR, cystatin C appears to offer only a moderate gain over creatinine for approximating GFR, at least in cross-sectional studies. Of note, the CKD patients who participated in the studies represented in CKD-EPI are younger and healthier than the average CKD patient; this population may be less generalizable to the wider CKD population, where older age and chronic disease may result in diminished muscle mass and therefore decreased creatinine generation. A critical next step in CKD patients will be to extend longitudinally the comparisons of cystatin C and creatinine with measured GFR to compare their value for monitoring changes in kidney function. In diabetics with early kidney disease, cystatin C tracked measured GFR far more effectively than creatinine12. Since CKD is associated with frailty and decreased health status,13 creatinine generation may decrease in parallel with GFR decline, effectively masking the actual loss of GFR, particularly in older adults. If cystatin C has an advantage over creatinine for tracking GFR over time, then subsequent studies could evaluate whether cystatin C assists decision making for referral to nephrologist care, for dosing medications with narrow therapeutic windows, and for the timing of dialysis initiation.

Among populations without established CKD, cystatin C has even more clinical potential, but there has been far less prior research on cystatin C’s approximation of GFR. Since large population-based studies of healthy adults in the United States have not measured GFR, an essential first step is to measure GFR in a representative adult cohort with diversity of age, sex, and race. Such a study would allow the development of an equation to link cystatin C to GFR in the general population, which may have important differences from the equation reported for CKD patients by Stevens et al. Moreover, cystatin C appears to have unique advantages over creatinine in elderly persons and in the setting of chronic diseases (heart failure, cirrhosis, AIDS, etc); these and similar populations should have the highest priority for studies of GFR measurement and for refining GFR estimates based on cystatin C, creatinine, or both. In some populations, we may find that neither marker represents GFR adequately for clinical decision making in situations where GFR must be known precisely.

Perhaps the most promising use of cystatin C will be as a marker of preclinical or early kidney disease among persons with creatinine-based eGFR in the “normal” range (eGFR ≥60mL/min/1.73 m2) but elevated cystatin C.11 Among persons older than 70 years in NHANES III, the prevalence of CKD (eGFRcreatinine < 60 mL/min/1.73m2) was approximately 25%,14 whereas the proportion with cystatin C level greater than 1.0 mg/L was about 50%.10 Therefore, one-fourth of the US population over 70 meets this definition of “preclinical kidney disease,” which portends elevated cardiovascular and kidney disease risk compared with the 50% of that age group with cystatin C level less than 1.0 mg/L.9 The critical question is whether aggressive risk factor targeting to this high-risk subgroup without CKD could reduce the risk for developing CKD and its attendant complications. A clinical trial that addresses this question would need to demonstrate positive results before a widespread cystatin C screening program could be endorsed as “evidence based.”

There are many important research questions to be addressed, as work with cystatin C moves forward with a focus on clinical decision-making. With appropriate study designs and research funds prioritization, this work may result in improved strategies for screening, monitoring, and treating kidney disease to reduce its impact on the health of our patients.