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Cystatin C, Serum Creatinine, and Estimates of Kidney Function: Searching for Better Measures of Kidney Function and Cardiovascular Risk

Posted on: Tuesday, 12 April 2005, 03:00 CDT

Because kidney dysfunction is associated with adverse cardiovascular outcomes and death, clinicians are beginning to realize that accurately detecting even modest reductions in kidney function could help to identify patients who need extra attention.

Why is it important to identify early-stage kidney dysfunction accurately? Reduced kidney function is associated with increased incidence of cardiovascular morbidity and mortality in large cohorts of both selected and unselected patients (1, 2). This finding has led to the hypothesis that earlier recognition of kidney disease and successful intervention may improve outcomes of cardiovascular disease (CVD). No studies to date have determined the mechanism by which deteriorating kidney function worsens the prognosis of CVD. Moreover, no one knows whether strategies to delay the progression of chronic kidney disease actually improve the prognosis of CVD. The known associations of kidney dysfunction and inflammation and inflammation and CVD suggest that inflammation could be the link between kidney disease and CVD along with metabolic and hormonal abnormalities associated with chronic kidney disease (3).

Serum creatinine concentration is now recognized as an unreliable measure of kidney function because it is affected by age, weight, muscle mass, race, and various medications (4, 5). Several equations have been developed to improve the accuracy of serum creatinine level as a measure of glomerular filtration rate (GFR). The most widely used in adult populations are the Cockcroft-Gault (6) equation and the abbreviated Modification of Diet in Renal Disease equation (7). Even with these equations, measurement of GFR is difficult because the equations are less accurate at higher levels of kidney function and are affected by interlaboratory variation in measuring creatinine level.

Cystatin C concentration is a new and promising marker for kidney dysfunction in both native and transplanted kidneys (8-10). Cystatin C is a cysteine proteinase inhibitor produced by all nucleated cells at a constant rate, regardless of several pathologic conditions. Because of its low molecular weight, cystatin C is freely filtered at the glomerulus and is almost completely reabsorbed and catabolized, but not secreted, by tubular cells. Given these characteristics, cystatin C concentration may be superior to creatinine concentration both in chronic kidney disease and as a marker of acute kidney injury (11).

Cystatin C plays a role in many biological processes, such as degradation of cellular proteins and regulation of enzymes, and pathologic processes. It is present in all body fluids and is important in arterial wall remodeling and atherogenesis (12). It also predicts hyperhomocysteinemia, Alzheimer disease, leukoencephalopathy with progressive dementia, impairment of the blood-brain barrier, and degenerative diseases of the retina (13). However, because cystatin C is ubiquitous, it may have low specificity for kidney dysfunction. In 2 large studies of more than 8000 and 1200 patients, respectively, Knight and colleagues (14) and Wasen and colleagues (15) determined that many factors (such as age, male sex, weight, height, cigarette smoking, higher serum C- reactive protein levels, steroid therapy, and rheumatoid arthritis) were independently associated with higher serum cystatin C levels after adjustment for kidney function.

Studies have compared cystatin C concentration with serum creatinine level; creatinine-based estimates of GFR (by using the Cockcroft-Gault or Modification of Diet in Renal Disease equation) by using more direct measures of GFR, such as tracers (^sup 125^I- iothalamate and ^sup 51^Cr-EDTA); and inulin or iohexol clearances as a gold standard test. Studies have been conducted in various populations, including the elderly and diabetic populations (16- 20). Overall, when direct measures of GFR are used as the gold standard, cystatin C concentration modestly outperforms creatinine- based estimates of GFR, especially at higher values of GFR. Typically, they give similar results. Therefore, cystatin C concentration is an accurate measure of GFR, at least similar to, and possibly superior to, creatinine-based measures of GFR. Whether it is superior to creatinine-based measures as a predictor of heart disease is not settled.

Indirect measures of GFR can do several things, such as measure GFR and give prognostic information. In this issue, Sarnak and colleagues (21) show that cystatin C concentration gives superior prognostic information, which makes it a potentially important innovation. They describe the association of 3 measures of kidney dysfunction (cystatin C concentration, serum creatinine level, and GFR estimated by using the abbreviated Modification of Diet in Renal Disease formula) with incident heart failure. In this well- conducted analysis of the Cardiovascular Health Study's 1992-1993 cohort of more than 4000 patients who were followed for a median of 9 years, Sarnak and colleagues (21) demonstrate that as cystatin C levels increase, the risk for heart failure increases. This relationship could be due to the increasing prevalence of risk factors for heart failure in patients with kidney dysfunction. To avoid mistakenly attributing differences in incident heart failure to cystatin C or creatinine levels, they used multivariate modeling techniques to adjust for the increased prevalence of those risk factors as kidney function worsens. They evaluated the 3 methods for estimating GFR to see how well they predicted incident heart failure. Cystatin C levels predicted incident heart failure, and the other 2 methods did not predict heart failure. Sarnak and colleagues appropriately concluded that cystatin C concentration is an independent risk factor for heart failure in older U.S. adults. This finding is consistent with other recent studies of the association of cystatin C concentration and CVD risk (22, 23).

Sarnak and colleagues go further. They state that because cystatin C concentration predicts heart failure better than serum creatinine level or creatinine-based GFR estimations, it may be a better measure of kidney function. This conclusion may be correct, but it goes beyond their evidence. The authors did not perform a gold standard method for measuring GFR and therefore could not confirm the accuracy of cystatin C and serum creatinine concentrations and the GFR equations in their study sample. Cystatin C concentration may biologically be a measure of CVD risk, but it may not reflect kidney function in this cohort. Indeed, Sarnak and colleagues acknowledge that they "cannot rule out the possibility that cystatin C is a marker of another pathologic process that is unrelated to kidney function" (21). Moreover, the study does not elucidate the mechanism by which cystatin C concentration predicts heart failure. Without a gold standard measurement for kidney function in this cohort, we cannot conclude that cystatin C concentration is a superior marker of kidney function simply because it is the best predictor of heart failure.

Another measure of a test is its sensitivity to change in the function it measures. However, some of the literature discuss the sensitivity of cystatin C concentration for detecting changes within an individual (13). Whether cystatin C levels will reflect changes in kidney function in large cohorts remains to be seen. We need longitudinal studies that measure cystatin C concentration and directly measure GFR in patients with progressive kidney disease, as Sarnak and colleagues acknowledge.

Sarnak and colleagues' study draws attention to the importance of better markers of early-stage kidney dysfunction in predicting incident heart failure. Cystatin C concentration may be a strong candidate to fill this role, but we need answers to several lingering questions. Since cystatin C concentration and the creatimne-bascd methods give similar results in measuring GFR, why is cystatin C concentration superior to creatinine level as a predictor of heart failure? We need to further explore the associations among cystatin C concentration, CVD, and kidney disease to learn which relationship, if any, is causative. We do not understand why chronic kidney disease increases the risk for developing heart failure. Perhaps the excellent prediction of heart failure by cystatin C concentration, together with increased understanding of the role of cystatin C in biological processes, will provide a clue to the factors that influence both the development of heart failure and chronic kidney disease.

Sarnak and colleagues underscore what we know (the association between chronic kidney disease and CVD), what we need to know (the mechanisms by which chronic kidney disease affects CVD), and what we can do with what we currently know (improve the accuracy of chronic kidney disease measurement and use cystatin C concentration as a novel prognostic indicator for heart failure). We must now test different diagnostic strategies for identifying progressive chronic kidney disease at an early stage. We must measure the effect of interventions for early-stage renal dysfunction on the incidence of heart failure. If we pursue these investigations, we may eventually remove kidney disease from the list of "identified but not clearly modifiable" risk factors for CVD.

R\eferences

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2005 American College of Physicians

Adeera Levin, MD

University of British Columbia

St. Paul's Hospital

Vancouver, British Columbia

V6Z 1W8 Canada

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Adeera Levin, MD, Division of Nephrology, University of British Columbia, St. Paul's Hospital, 1081 Burrard Street, Providence Wing, Room 6010A, Vancouver, British Columbia, V6Z 1W8 Canada; e-mail, alevin@providencehealth.bc.ca.

Ann intern Med. 2005;142:586-588.

Copyright American College of Physicians Apr 5, 2005

Source: Annals of Internal Medicine

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