Triple-Marker Approach for Kidney Disease Risk Assessment

Megan Brooks

April 11, 2011

April 11, 2011 (Vancouver, British Columbia) — Adding cystatin C to creatinine and the urine albumin-to-creatinine ratio (ACR) increases the ability to gauge the risk for end-stage renal disease (ESRD) and death from any cause in patients with chronic kidney disease (CKD), according to a prospective study.

The study was published online today in the Journal of the American Medical Association to coincide with its presentation at the annual meeting of the World Congress of Nephrology.

"I think our study is very relevant to clinical practice," study presenter and first author Carmen A. Peralta, MD, MAS, from the nephrology division at the San Francisco Veterans Affairs Medical Center in California, told Medscape Medical News.

The findings are timely because the guidelines for the evaluation and staging of CKD are currently being revised, "with the explicit objective of developing staging systems that accurately reflect prognosis for CKD complications," she and her colleagues note in their paper.

"We hope that our study will encourage consideration by the guideline leadership of cystatin C for confirmation of CKD," Dr. Peralta told Medscape Medical News. However, "with respect to screening for occult CKD, more research is needed to understand how, or if, a triple-marker approach has a role in targeted public health strategies for CKD screening," she emphasized.

Adding Cystatin C Improves Risk Forecast

Currently, CKD is defined as a creatinine-based estimated glomerular filtration rate (eGFR) below 60 mL/min per 1.73 m2 or a urine ACR of 30 mg/g or higher. However, serum creatinine levels are affected by muscle mass, age, and race, and eGFRs are less reliable for assessing renal function when GFR is greater than 60 mL/min, the study team notes.

Research has shown that serum cystatin C, an alternative biomarker of kidney function, is a better predictor of death and cardiovascular events than creatinine, and is less affected by muscle mass, age, and race.

Dr. Peralta's team found that adding cystatin C to creatinine and urine ACR can improve risk stratification over creatinine and ACR alone.

Their finding stems from data from 26,643 American adults enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Subjects were categorized into 8 groups, defined by creatinine-based and cystatin C–based eGFR (below 60 mL/min and 60 mL/min or higher) and ACR (below 30 mg/g and 30 mg/g or higher). The incidence of ESRD and all-cause mortality were the primary outcomes.

Of the subjects, 40% were black, 54% were women, 21% had diabetes, and 59% had hypertension. Over a median of 4.6 years, 177 subjects developed ESRD and 1940 died.

Altogether, 2904 subjects (11%) were classified as having CKD on the basis of creatinine assessments. Among these individuals, CKD was defined in 701 (24%) by creatinine alone, in 148 (5%) by creatinine and ACR, in 1172 (40%) by creatinine and cystatin C, and in 883 (30%) by all biomarkers.

The researchers report that the adjusted risk for death was more than 3-fold higher in patients with CKD defined by creatinine-based and cystatin-based eGFR than in those with CKD defined by creatinine-based eGFR alone; it was nearly 6-fold higher in patients with CKD defined by all 3 markers.

Hazard Ratio by Biomarker

Biomarker Hazard Ratio (95% CI)
Creatinine alone Reference
Creatinine + ACR 3.3 (2.0 to 5.6)
Creatinine + cystatin C 3.2 (2.2 to 4.7)
All 3 biomarkers 5.6 (3.9 to 8.2)

The risk for kidney failure was highest in those with CKD defined by all 3 markers. The risk for incident ESRD was 34.1 per 1000 person-years (95% confidence interval [CI], 28.7 to 40.5), compared with 0.33 per 1000 person-years (95% CI 0.05 to 2.3) for those with CKD defined by creatinine alone.

The authors of a related commentary note that relying on creatinine-based eGFR alone failed to identify 3863 patients (16%) in whom CKD had been identified by cystatin-based eGFR or ACR; 415 of these patients met both criteria (1.7% of the entire cohort). In these 415 patients, the risks for death and kidney failure were 6-fold and 20-fold higher, respectively, than in patients with CKD identified only by creatinine alone.


These findings "reinforce the limitations" of eGFR for creatinine alone for risk prediction of CKD, Marcello Tonelli, MD, SM, FRCPC, and Braden Manns, MD, MSc, FRCPC, from the Alberta Kidney Disease Network, in Canada, write in their commentary.

Regardless of whether creatinine-based eGFR was normal or abnormal, "the presence of either abnormal ACR or abnormal cystatin C–based eGFR was associated with increased risk," they point out.

Dr. Peralta's team noted that, when they added cystatin C to creatinine and ACR, the net reclassification improvement for death was 13.3%; for ESRD, it was 6.4%.

Nearly Ready for Prime Time

These results, the study team writes, suggest that this triple-marker approach "more accurately" discriminates prognosis for death and CKD progression than creatinine and ACR alone.

But Dr. Tonelli and Dr. Manns argue that it would be "premature" to introduce this triple-marker approach in routine clinical practice. Several "knowledge gaps should be addressed" before this happens, they conclude.

"Our findings need to confirmed in other populations, especially the very elderly, the very young, and other ethnic groups," Dr. Peralta added.

The study was funded by the National Institute of Neurological Disorders and Stroke and the Department of Health and Human Services. Dr. Peralta has disclosed no relevant financial relationships. Three coauthors report receiving research support and/or serving as a consultant to Amgen Corporation. Dr. Tonelli and Dr. Manns have disclosed no relevant financial relationships.

JAMA. Published online April 11, 2011. Full text, Commentary


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