Dr. Bakris is a nephrologist/hypertension specialist who dedicates his time to the diagnosis and reduction of high blood pressure, particularly in complicated and refractory cases. He is also skilled in the treatment of kidney disease, with special expertise in diabetes-related kidney disease, where he has spent over 25 years on clinical trials focused on slowing its progression. In his research activities, Dr. Bakris explores why the rate of kidney disease is significantly higher in the African American population compared to other ethnic groups.
Many of us were at the FDA in 2012 when NIDDK, academia, and industry came together with the FDA to find a more plausible method of detecting changing GFR progression by a given therapy. All parties (including the FDA) conceded that the triple Ds (death, dialysis, and doubling of serum creatinine) were a very high bar to meet but this was established in the early 1990s.
An excellent tour de force presentation by both Tom Greene and Joe Coresh clearly indicated that we didn’t need a 57% reduction in GFR (doubling of creatinine) to reliably prove renoprotection but that 50% and even 40% was reasonable. Thus, ultimately the FDA agreed with 40% as a low bar but still wanted mortality as part of the outcome. This was all published in a special report (freely available) in AJKD a couple of years ago. A 30% change in GFR was viewed as an early signal of benefit, although sufficiently long follow-up was required to show sustainability of this benefit.
Change in albuminuria is at best a surrogate marker and has not reliably shown a strong correlation with outcome. Moreover, there are several studies of patients with both Type 1 and Type 2 diabetes that have progressed to dialysis with, at most, microalbuminuria. Maybe these patients don’t follow the typical “playbook” but there are enough of them out there to discourage using albuminuria as a reliable long-term marker of preserved kidney function. While all agree progressive increases in proteinuria over time are associated with higher incidence of CV, death, and CKD progression, a reduction does not have the same reliability.
Competitors for the Trial Outcomes Region
Of these choices, I think the 40% change is the most reasonable. I would argue that as there is some evidence to support a >30% decline as preliminary evidence of benefit, it should be the earliest marker allowed, with continual follow-up of patients for a period until 40% change is seen.
It is clear that certain approaches reduce mortality but do not slow CKD progression (eg SPRINT, although it was underpowered for a CKD benefit). Depending on the etiology of CKD, progression rates are variable and one needs to account for this if designing outcome trials.
Also, clinical researchers need to keep in mind financial feasibility and the changing standard of care when comparing trials. We needed only 400+ patients for the captopril trial in 1993 and now have over 6,000 for the ongoing Fidelio trial of diabetic nephropathy progression.
– Post written by George Bakris
As with all content on the AJKD Blog, the opinions expressed are those of the author of each post, and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.