SAN FRANCISCO – Routine lab tests for estimating the average glomerular filtration rate (GFR) are too imprecise, according to Michael G. Shlipak, MD.

“If you study 100 patients, the average GFR based on creatinine is going to be pretty close to estimated GFR,” Dr. Shlipak said at the UCSF Annual Advances in Internal Medicine meeting. “But with individual patients, the average GFR is going to be plus or minus 30%, which is a lot. If the estimated GFR is 70 mL/min per 1.73 m², the real GFR could be between 50 and 90 mL/min per 1.73 m²; so that’s a wide range.”

An estimated GFR of less than 60 mL/min per 1.73 m² is concerning as far as potential kidney disease, but it’s not specific, said Dr. Shlipak, chief of general internal medicine at San Francisco VA Medical Center. The three equations used to estimate GFR include the Cockcroft-Gault equation, which is used by the Food and Drug Administration and most pharmacies; the Modification of Diet in Renal Disease (MDRD) study equation; and the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI), which is used by most laboratories.

“The main appeal of the Cockcroft-Gault equation is that you can almost do it in your head, so that’s a real positive,” said Dr. Shlipak, who is also scientific director of the Kidney Health Research Collaborative at the University of California, San Francisco, and professor of internal medicine, epidemiology, and biostatistics at UCSF Medical Center. “The main disadvantage is that it’s really a terrible equation. The Cockcroft-Gault equation is clearly inadequate, as it is standardized to creatinine clearance and very inaccurate, so it should no longer be used. The MDRD and the CKD-EPI are newer equations that are at least validated to real GFR and not creatinine clearance. In our system, the pharmacy uses the Cockcroft-Gault equation, and the lab gives us the MDRD GFR equation, so it’s quite confusing.”

Dr. Shlipak described using estimated GFR in clinical decision making as “better than using just creatinine, because it integrates demographic characteristics, which are determinants in part of the creatinine production, which is what determines how much creatinine is in the blood before it gets filtered. The equations make us think of GFR and kidney function instead of just the lab value.”

The downsides of using GFRs, he added, include the fact that they are mostly validated in younger patients with kidney disease, they rely on the assumption that demographic characteristics alone can define muscle mass, they were only developed in whites and blacks, and estimated GFR can be interpreted only as “suggested GFR.”

A blood test of kidney function known as cystatin C has been shown to be an alternative, better marker of creatinine, compared with GFR, and is supported by the Kidney Disease: Improving Global Outcomes CKD work group’s 2012 clinical practice guidelines for the evaluation and management of CKD. “Because cystatin C is not related to muscle mass, age, sex, and race, it has major advantages over creatinine,” Dr. Shlipak said. “It is a reliable, standardized, and automated measure that is available for clinical use.”

He and his associates conducted a meta-analysis comparing cystatin C and creatinine in determining prognosis for patients with baseline kidney disease. They included 16 studies involving 90,750 patients and compared associations of estimated GFR (eGFR) as measured with creatinine, cystatin C, and both creatinine and cystatin C with mortality risk; they also determined proportions reclassified by cystatin C in each subgroup of eGFR using creatinine and by the effect on risk associations (N Engl J Med. 2013 Sep 5; 369[10]:932-43).

In the general-population cohorts, the prevalence of an eGFR of less than 60 mL/min per 1.73 m² of body surface area was higher with the cystatin C–based eGFR than with the creatinine-based eGFR (13.7% vs. 9.7%). Across all eGFR categories, the reclassification of the eGFR to a higher value with the measurement of cystatin C, compared with creatinine, was associated with a reduced risk of all three study outcomes. Reclassification to a lower eGFR was associated with an increased risk.

“When we looked at the threshold for where risk begins, traditionally we’ve said it starts when the GFR declines below 60 mL/min per 1.73 m²,” Dr. Shlipak explained. “That’s exactly what we found with creatinine. But with cystatin C, the threshold of risk was at 88 mL/min per 1.73 m^2.

“So, from 88 mL/min per 1.73 m² downward, every incremental reduction in GFR is associated with higher mortality and cardiovascular risk,” he added. “So cystatin C opens this new window of between 60 and 90 mL/min per 1.73 m² to start measuring relative declines in kidney function. If you combine creatinine and cystatin C together in an equation, you get a similar estimate. Many advocate that the combined CKD-EPI creatinine-cystatin C equation is the best way to measure GFR.”

Dr. Shlipak reported that he is on the scientific advisory boards of TAI Diagnostics and Cricket Health.

dbrunk@frontlinemedcom.com

Obtaining cystatin-C levels useful in chronic kidney disease