LAS VEGAS – A landmark study has provided physicians with an improved definition of clinically significant progression of chronic kidney disease for use as a major endpoint in clinical trials as well as in daily medical practice.
Specifically, it’s now clear from the study conducted by the global CKD Prognosis Consortium that a 30% decline in estimated glomerular filtration rate (eGFR) over the course of 2 years portends a 5- to 6-fold increased risk of developing end-stage renal disease (ESRD) during the next 2-3 years, Dr. Josef Coresh reported at a meeting sponsored by the National Kidney Foundation.
Dr. Josef Coresh
The magnitude of increased risk of ESRD in patients with a 30% 2-year decline in eGFR was similar regardless of their baseline stage of CKD. That is, patients with a low baseline eGFR of less than 60 mL/min per 1.73 m2 had an adjusted 5.4-fold increased risk if they had a 30% drop in eGFR, compared with those whose eGFR remained unchanged over a 2-year period, while those with a 30% eGFR drop starting from a higher baseline of 60 mL/min per 1.73 m2 or more had a 6-fold increased risk, said Dr. Coresh, professor of epidemiology and director of the George W. Comstock Center for Public Health Research and Prevention at Johns Hopkins University, Baltimore.
He presented an individual-level meta-analysis of 1.5 million participants in 28 cohorts. Among roughly half a million patients in the 19 cohorts with an initial eGFR below 60 mL/min per 1.73 m2, there were 7,523 ESRD events during a mean 2.4 years of follow-up beginning at the close of the 2-year baseline period. An additional 1,009 ESRD events occurred during the follow-up period in participants with an initial eGFR of 60 mL/min per 1.73 m2 or more.
This study grew out of a collaboration between the National Kidney Foundation and the Food and Drug Administration. Officials at the regulatory agency now accept that the established endpoint used to document CKD progression in clinical trials – that is, a doubling of serum creatinine concentration from baseline – has held back therapeutic progress in the field. That’s because this FDA-mandated surrogate endpoint is a late event and thus requires studies with large sample sizes and long follow-up times. The agency is eager for evidence in support of a better surrogate endpoint, explained Dr. Coresh, who is also director of the cardiovascular epidemiology training program at Johns Hopkins.
The new meta-analysis confirmed that a doubling of serum creatinine concentration over the course of 2 years is indeed a valid endpoint for CKD progression. It was associated with a 32-fold increased risk of developing ESRD in patients who started with an eGFR below 60 mL/min per 1.73 m2 and a 57-fold increased risk in patients with a higher starting eGFR. However, a doubling of serum creatinine in a 2-year time frame was also a rare outcome, occurring in less than 1% of patients with a low initial eGFR and in 0.1% of those with a higher initial value. In contrast, a 30% drop in eGFR over a 2-year period was 10 times more common.
"A doubling of serum creatinine captures only 10% of the excess or population-attributable risk of ESRD during follow-up, whereas a 30% decline in eGFR captures 44% of the population with ESRD in the baseline low-eGFR group and 28% in those with a baseline eGFR of 60 mL/min per 1.73 m2 or greater," Dr. Coresh said.
An impressive level of consistency in the results was seen across the 28 studies included in the meta-analysis, which featured adjustment for confounders.
"I think this level of remarkable consistency makes it safer to think that in many settings, if you have a 30% decline in eGFR over 2 years, you will have a substantially increased risk of ESRD of approximately 5-fold," according to the physician.
He stressed that the meta-analysis demonstrated that it’s not just the change in eGFR over the course of 2 years that’s important in determining risk, but that the starting eGFR level and duration of follow-up are also key in determining absolute risk.
"For example, someone who starts at 50 mL/min per 1.73 m2 and is stable for 2 years has a subsequent risk of ESRD 10 years later of only 5%. If, on the other hand, that patient had a 30% decline in eGFR during 2 years, the 10-year risk becomes 21%. And if you start out at an eGFR of 35 mL/min per 1.73 m2, your 10-year risk of ESRD goes from 18% if your eGFR is unchanged for 2 years to 64% if your eGFR falls by 30%. So within the first 2 years, you have the ability to detect things that will happen a long time from now, with pretty good power," Dr. Coresh said.