Novel Marker of Kidney Function a Good Predictor of Mortality

July 3, 2007

BOSTON -- Testing for cystatin C appears to be as good as, if not better than, standard measures of kidney function to predict mortality risk in advanced chronic kidney disease, researchers found.

BOSTON, July 3 -- Testing for cysatin C appears to be as good as, if not better than, standard measures of kidney function to predict mortality risk in advanced chronic kidney disease, researchers found.

In a retrospective analysis of a clinical trial, blood levels of cystatin C were more strongly associated with all-cause mortality (hazard ratio 1.45) and cardiovascular disease-specific mortality (HR 1.64) than the gold-standard glomerular filtration rate (GFR) or creatinine concentration, according to a report in the July 3 issue of the Annals of Internal Medicine.

Although confidence intervals overlapped, the findings warrant further study of cystatin C for risk stratification, said researchers Mark J. Sarnak, M.D., of Tufts-New England Medical Center here, and colleagues.

Cystatin C may be a practical alternative to measured GFR, which is "too cumbersome for clinical practice," and serum creatinine, which may be less accurate for older patients and in the setting of mild kidney dysfunction, they wrote.

However, no studies had compared the three as predictors of outcomes in patients with chronic kidney disease.

So, the researchers analyzed these factors in the larger Modification of Diet in Renal Disease Study, a randomized controlled trial of dietary protein restriction and blood pressure control that was also used to develop an equation for estimating GFR from creatinine concentration.

Their analysis included 825 patients with stage 3 or 4 nondiabetic chronic kidney disease who had stored baseline serum samples available to be assayed for cystatin C levels.

Glomerular filtration rate had been measured at screening and baseline using iothalamate clearance. High serum creatinine concentration was one of the original inclusion criteria (1.2 to 7.0 mg/dL for women and 1.4 to 7.0 mg/dL for men).

Means were 2.2 mg/L for cystatin C, 2.4 mg/dL for creatinine concentration, and 33 mL/min per 1.73 m2 for GFR. Both cystatin C and creatinine were strongly associated with GFR (both P

However, creatinine concentration appeared to be the best predictor of kidney failure, which most patients (66%) reached during follow-up. The multivariate-adjusted findings were:

  • A 2.36-fold increase in risk with each standard deviation increase in cystatin C (HR 2.36, 95% CI 2.10 to 2.66).
  • A 2.41-fold increase in risk with each standard deviation decrease in GFR (HR 2.41, 95% CI 2.15 to 2.70).
  • A 2.81-fold increase in risk with each standard deviation increase in creatinine concentration (HR 2.81, 95% CI 2.48 to 3.18).

But, the apparent advantage of creatinine concentration in this measure may have been a function of treatment bias, Dr. Sarnak and colleagues noted.

"The slightly higher hazard ratio for serum creatinine for kidney failure may be attributed to the fact that decisions of when to initiate kidney replacement therapy were based on the serum creatinine concentration because neither iothalamate GFR nor cystatin C values were available to clinicians," they wrote.

One explanation for the advantage of cystatin C over glomerular filtration rate for mortality may be that "cystatin C provides prognostic information beyond its role as an index of kidney function and is a better overall measure of the spectrum of pathophysiologic abnormalities that accompany kidney disease," they added.

The investigators cautioned that participants in the study might not be a representative sample of all patients with chronic kidney disease not associated with diabetes.

The population was predominantly white with a low prevalence of cardiovascular disease and included few elderly patients. Also, entry criteria artificially truncated the range of kidney function.

"Although our analyses establish an association between cystatin C and outcomes, they do not provide information on the clinical predictive utility of this marker," the researchers said.

They also pointed out that as "the hazard ratios had relatively wide and overlapping CIs, the results suggest, but do not prove, that cystatic C is associated with a higher risk for mortality than other indices of kidney function."