Another New Biomarker for Cardiovascular Disease

Abstract & Commentary

By Jonathan Abrams, MD, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque. Dr. Abrams serves on the speaker's bureau for Merck, Pfizer, and Parke-Davis.

Synopsis: Among elderly persons without chronic kidney disease, cystatin C is a prognostic biomarker of risk for death, cardiovascular disease, and chronic kidney disease.

Source: Shlipak MG, et al. Cystatin C and Prognosis for Cardiovascular and Kidney Outcomes in Elderly Persons without Chronic Kidney Disease. Ann Intern Med. 2006;145:237-246.

Many reports of biomarkers for evaluation of cardiovascular disease (CVD) risk have appeared over the past several years. High sensitivity CRP and brain natriuretic peptides (BNP) are the most familiar, contributing to the evaluation of patients with and without CVD. BNP and its inactive precursor, Nt-proBNP, are markers for ventricular muscle stretch and congestive heart failure. Cystatin C, a new biomarker candidate, is the focus of a report from the Cardiovascular Health Study (CHS), a community based longitudinal study of adults > 65 years old at baseline. This cohort is the back-ground for an extensive analysis of cystatin C as marker of prognosis for CV death, chronic kidney disease (CKD), and CVD. Cystatin C represents an alternative measurement of glomerular filtration rate (GFR), and may be a superior marker for prognosis of CKD than the standard MDRD (Modification of Diet in Renal Disease) estimate of GFR, (discussed in the same issue: Levy, et al. Ann Intern Med. 2006;145:237-246). The data from the CHS suggest that cystatin C provides a superior estimate of GFR, when compared to the MDRD formula, as it is independent of body muscle mass and unaffected by age or gender. Cystatin C is a member of a family of competitive inhibitors of lysosomal cysteine proteinases, and is involved in a variety of intracellular functions, including modulation of the immune system. Cystatin C levels (normal < 1.0 mg/L) have been found to be elevated in elderly patients with a GFR > 60, suggesting that this compound may better detect individuals at risk for subsequent CKD, death, or CVD than MDRD.

The CHS consists of 4 sites around the United States who enrolled relatively healthy patients > 65 years of age. The analysis consists of 4663 CHS participants followed for a median of 9.3 years, with serial measurements of creatinine and cystatin C. GFR was measured using the MDRD formula; CKD was diagnosed by an estimated GFR < 60 mL/min per 1.73 m2. The primary end point included new CKD, as well as various cardiovascular events (death, stroke, heart failure, and myocardial infarction). All subjects were evaluated for GFR (MDRD formula), mean cystatin C, and creatinine concentration. Patients were categorized into 3 baseline groups: CKD; no CKD but high cystatin C (> 1.0 mg/L); and no CKD and low cystatin C.

Results: Seventy-eight percent of the study cohort (4663 participants) had no CKD at entry; 22% of CKD subjects had low GFR, a high cystatin C concentration, and elevated creatinine. Patients without CKD had normal values for all 3 parameters. Serum creatinine was not associated with subsequent mortality, but elevated cystatin C was associated with increased mortality, with increased risk beginning at > 1.0 mg/L. Two-fold risk occurred when levels were at 1.3-1.4 mg/L. Thus, CVD risk was related to baseline cystatin C but not baseline creatinine. In individuals without CKD, elevated cystatin C was associated with increased adverse events, including CV death, heart failure, and stroke. Event rates for all-cause CVD death, non-cardiovascular death, heart failure, and stroke were lowest in individuals who had no CKD and low cystatin C levels at baseline. Baseline CKD predicted increased risk for adverse events. Individuals without CKD who had high elevated cystatin C "were 50% more likely to die, were nearly twice as likely to have a cardiovascular death, and were 30% more likely to have a non-cardiovascular death." Heart failure, stroke, and myocardial infarction rates were also substantially increased. Patients who had no CKD and high cystatin at base-line developed CKD far more often than those with low baseline cystatin (odds ratio 4- to 5-fold). Participants with high cystatin C who developed CKD during the study were at substantially higher risk for death and cardiovascular events, with increased risk ranging from 35% for stroke to 80% for CVD death and heart failure.

Finally, enrollees with elevated cystatin C at baseline and no CKD during the study also had a greater risk for death, heart failure, and myocardial infarction. Levy and colleagues summarize, "whereas serum creatinine levels had almost no statistically significant associations with the outcomes … cystatin C concentrations were strongly related with risk for death, heart failure, myocardial infarction, and stroke." Forty percent of the entire cohort had elevated cystatin C levels without CKD at baseline; the subjects had substantially increased risk for death, cardiovascular risk, and progression to CKD. Levy et al believe the data support that "a state of pre-clinical kidney disease … is prevalent among elderly persons." They make the analogy to pre-hypertension or pre-diabetes as being as potentially eligible for prophylactic treatment. Thus, elevated baseline cystatin C with preserved GFR was associated with increased risk for a variety of events. "Cystatin C concentrations seem primarily to reflect GFR, and do so better than serum creatinine." Cystatin C was felt to be a better predictor of subsequent kidney function than MDRD GFR. Overall, elevated cystatin C was clearly a marker for major adverse events.

Levy et al conclude, "We believe that elevated cystatin C concentrations represent preclinical kidney disease, which portends increased cardiovascular and renal risk." They call for further studies, particularly to define the role of micro-albuminuria vs cystatin C as a major risk factor for CVD and renal outcomes, asking "whether cystatin C … will have a useful clinical role."

Commentary

While this report focuses on individuals who were > 65 of age at entry into the study, and clearly defines cystatin C as a marker of subsequent adverse events, including death, one does not know if cystatin C would have a comparable predictive value in younger healthy individuals. In any case, it would appear that cystatin C is an excellent predictor of GFR, as opposed to serum creatinine. It is generally accepted, particularly in the elderly populations, that creatinine levels between one and 2 are very difficult to interpret, with respect to the degree of GFR abnormality. It may not yet be fully appreciated that CKD is now identified as an important marker for cardiovascular risk, and should be included in any risk stratification algorithm. The current study suggests that in a healthy, older population, an elevated cystatin C imparts considerable risk for the development of CKD and/or for major cardiovascular events. It would be of great interest to see whether these findings are reproducible, and to see if the use of cystatin C assays may amplify the risk profile for CVD and mortality, particularly in younger individuals. Whether routine measurements of cystatin C will become available remains to be seen, but this study, as well as other data in the literature, clearly indicates that renal function, as estimated by creatinine concentration, albuminuria, or cystatin C, is a major risk factor for vascular events, and is much more common than many of us would have believed.