Pam Harrison

June 05, 2014

AMSTERDAM — In patients with chronic kidney disease (CKD), declines in estimated glomerular filtration rate (eGFR) can be used as a predictor of progression to end-stage renal disease (ESRD) and mortality, according to results from a new meta-analysis.

Historically, the doubling of serum creatinine was used to define progression of CKD; however, in this analysis, smaller decreases in eGFR "strongly" and "consistently" identified a greater proportion of people at risk for ESRD and mortality.

"We now have evidence that the optimal level of eGFR decline is approximately 30% over 2 years. At this level, you have the best information about who is going to progress to end-stage renal disease," said Ron Gansevoort, MD, PhD, associate professor of nephrology at the University Medical Center of Groningen in the Netherlands, and colleagues.

"We adopted a doubling of the serum creatinine as an end point in renal trials because, at that time, we didn't even have an eGFR; there was only creatinine," Dr. Gansevoort told Medscape Medical News.

"But the doubling of serum creatinine turned out to be a 57% decrease in eGFR, which is a very strict and a very rare end point," he explained.

The study results were presented here at the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) 51st Congress, and were published online simultaneously in JAMA.

Association Between eGFR and ESRD

The meta-analysis involved approximately 1.7 million participants in the Chronic Kidney Disease Prognosis Consortium. It included cohorts of people from the general population, patients at high risk for cardiovascular events, and patients with CKD.

For all participants, repeated measures of serum creatinine and outcomes data were available. A total of 12,344 ESRD events and 223,944 deaths were identified.

The investigators examined the association between the decrease in eGFR over 1, 2, and 3 years and the risk for ESRD and mortality.

Greater decreases in eGFR over 2 years were associated with higher adjusted hazard ratios (HRs) for both ESRD and mortality.

For participants with a baseline eGFR below 60 mL/min per 1.73 m², the adjusted HR for ESRD was higher in those with a decrease in eGFR of 57% than in those with a decrease of 30% (32.0 vs 5.4).

Over 2 years, more patients had a decrease of at least 30% than of at least 57% (6.9% vs 0.79%).

The cumulative population-attributable risk over 2 years was higher when the 30% threshold was used than when the 57% threshold was used (44% vs 10%). Similarly, mortality risk was approximately 10-fold when the 30% threshold was used.

A Need For Change

The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have recognized that requiring a doubling in serum creatinine from baseline as a marker of CKD progression is a major hurdle for clinical trials in nephrology, Dr. Gansevoort told Medscape Medical News.

"The duration of clinical trials is normally 3 years," he explained, "but this end point is very rare. That might be one of the reasons why there are fewer randomized controlled trials in CKD than in other chronic diseases."

Both agencies agree that there is an urgent need to have a more readily attainable end point to define CKD progression, but they couldn't support such a change without the evidence to prove it.

"We set off with a couple of researchers to try to get sufficient evidence that lesser decreases in eGFR would be acceptable as an end point," Dr. Gansevoort said. "Based on the evidence that we had from all kinds of epidemiologic studies, analyses of randomized controlled trials, and computer modeling, we proposed a 30% decrease in eGFR to the FDA at a conference about a year ago. The evidence is now here."

Dr. Gansevoort is optimistic that industry will be more enthusiastic about doing trials in nephrology because it will cost less once the new end point for progression is officially adopted by the FDA and EMA. "I hope this is going to be an impetus for research in our field," he said.

There is a need to ensure that end points used in clinical trials for CKD progression reflect a reality that is meaningful to both patients and healthcare providers, said Adeera Levin, MD, professor of medicine, University of British Columbia in Vancouver, who is president-elect of the International Society of Nephrology.

The end point has to be such that carrying out studies will be feasible. "As noted by others, previous reliance on a doubling of serum creatinine or ESRD as end points, which are both rare events in shorter studies, have limited our ability to conduct some trials and even led to some trials not being conducted at all," Dr. Levin told Medscape Medical News.

With this demonstration that a 30% reduction in eGFR is a strong predictor of progression to ESRD and mortality, "we may be able to increase the number of trials we can conduct using therapeutic agents and strategies," she added.

Dr. Levin noted that, clinically, a 30% reduction in eGFR is already recognized as a causal pathway leading to ESRD. This analysis provides evidence for an end point that can be used in clinical trials moving forward.

ERA-EDTA president Raymond Vanholder, MD, PhD, professor of medicine at the University of Ghent in Belgium, agrees. These findings are "important" and "might increase the number of studies performed in nephrology," he said.

The CKD-PC Data Coordinating Center is funded in part by the US National Kidney Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Gansevoort, Dr. Levin, and Dr. Vanholder have disclosed no relevant financial relationships.

European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) 51st Congress: Abstract TO031. Presented June 3, 2014.

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