In December 2012, the NKF and FDA jointly co-sponsored a scientific workshop with the objective of  addressing the issues pertaining to use of various GFR definitions and their potential link with commonly designated outcomes and endpoints, e.g., ESKD, elevation in creatinine, death, etc. that are used in the design of clinical trials.

As clinical nephrologists, we know that GFR decline precedes ESKD. One of the goal of CKD treatment is to delay CKD progression, and eGFR has been used to estimate this. Traditionally, the FDA has identified eGFR decline of 57% (using the CKD-EPI formula), which corresponds to a doubling of serum creatinine, as a surrogate endpoint for assessing drug efficacy. Researchers have questioned the ability of lesser changes in eGFR to predict meaningful clinical outcomes. However, use of eGFR has its inherent limitations.

Coresh et al previously demonstrated that a decline in eGFR of ≥30% over a 2-year baseline period was associated with an adjusted hazard ratio for ESKD of approximately 5 in those with a baseline eGFR <60 mL/min/1.73 m², whereas a decline of ≥40% over 2 years was associated with an adjusted hazard ratio of ESKD of approximately 10.  As would be expected, the absolute risk of progression over 10 years was greater in those with a lower baseline eGFR than in those with a higher baseline eGFR.

After conducting an extensive review and analysis of current literature, the workgroup proposed that an eGFR decline of 30% as an alternative surrogate endpoint in trials of CKD, and an even stronger evidence for a 40% eGFR decline.

Results in simulations: summary of performance of alternative time-to-event end points for trials with 2- to 3-year durations of follow-up. Assumptions: glomerular filtration rate (GFR) based on estimated GFR from serum creatinine level, treatment effect is mixed proportional/uniform; acute effect attenuates to 0 at end-stage renal disease; follow-up duration 3 years for high GFR and 2 years for medium and low GFR. Key: acceptable type 1 error ≈ ≤10%; improved power = >15% smaller samples size for lesser versus 57% GFR decline in same trial duration. Baseline GFR (mL/min/1.73 m2): high, 67.5; medium, 42.5; low 27.5. Acute effect (mL/min/1.73 m2): moderate-to-large >±1.25; small, >0 to ±0.5-1.25; none, ≈ 0 (note: moderate-to-large positive acute effects are extrapolated from results from simulations). Fig 4 from Levey et al AJKD, © National Kidney Foundation.

We understand that eGFR is nonlinear, and in fact eGFRs tend to exhibit a variable pattern on multiple points of determination, being affected by many factors like glomerular hemodynamics, muscle mass, and nutritional states. The authors (table 6) recognize that the above surrogate endpoints may be limited in their applicability in certain situations. Certainly, this has significant implications on conducting clinical trials which provide the basis of evidence-based clinical guidelines that we use in the daily practice.

Edger Lerma, MD
AJKD Blog Advisory Board Member

AJKD’s Special Section on GFR Decline as an End Point for Clinical Trials in CKD is freely available for a limited time at AJKD.org.