Sunil Badve, MD

Dr. Badve is at St George Hospital in Sydney, Australia and Conjoint Associate Professor of Medicine at the University of New South Wales. Follow him @Badves.

Competitors for the Trial Outcomes Region

Doubling of Creatinine vs 40% Reduction in eGFR

Proteinuria vs Patient-Reported Outcomes

Currently established therapies for slowing the progression of chronic kidney disease (CKD) to end-stage kidney disease (ESKD) or death are limited to blood pressure lowering agents such as angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB). These agents each result in a modest (20%) relative risk reduction in adverse renal outcomes in CKD. Consequently, most people with CKD continue to suffer further declines in kidney function and unacceptably high rates of cardiovascular morbidity and mortality. The relative ineffectiveness of treatments targeting CKD to date may be due to the presence of multiple risk factors. However, there has been very little clinical research investigating novel therapeutic targets for slowing CKD progression.

There are many reasons for the shortage of high-quality trials in this area. One of the commonly cited reasons is that conducting trials in kidney disease progression is challenging because it frequently takes many years for CKD to progress to ESKD and because dropout rates from trials are often high due to the high number of cardiovascular events. Could the use of surrogate endpoints overcome this problem?

In the past, investigators have commonly used a composite endpoint of death, ESKD (typically defined as needing dialysis or kidney transplantation), and serum creatinine doubling. The comprehensive analytic work by the NKF-FDA Scientific Workshop concluded that the endpoint of a 40% decline in estimated glomerular filtration rate (eGFR) over 2 to 3 years was broadly acceptable as a substitute for doubling of serum creatinine in CKD progression trials. Some of the ongoing trials in CKD progression have already substituted 40% eGFR decline for doubling of serum creatinine.

Both outcomes (40% eGFR decline and doubling of serum creatinine) have the following drawbacks:

1. Serum creatinine doubling generally accounts for the bulk of the events comprising the composite kidney endpoint. The event rates of 40% eGFR decline are expected to be even higher.
2. The CKD Prognosis Consortium and NKF-FDA Scientific Workshop meta-analyses showed that the hazard ratio for the composite kidney endpoint decreased as the eGFR decline criterion progressively reduced from 57% to 40% to 30%.
3. Both doubling of serum creatinine and 40% eGFR decline are based on a biomarker. They do not provide any information on important aspects of patients’ health status, such as how they feel or function. They do not come directly from patients and need to be interpreted by clinicians. Therefore, their patient-level importance is limited.

While the use of 40% eGFR decline over 2 to 3 years in the kidney composite endpoint may be acceptable as a substitute for doubling of serum creatinine in CKD progression trials, investigators and clinicians should be aware of the strengths and limitations of clinical evidence based on eGFR decline as an outcome.

The patient-level importance, frequency of events, and treatment effect of 40% eGFR decline are not similar to those of the clinical endpoints of death and ESKD. Most CKD progression trials will enroll a heterogeneous study population including fast progressors as well as non-progressors. If the treatment effect is not uniform among the fast progressors and non-progressors, the utility of 40% eGFR decline will be uncertain. Treatment effect size on the surrogate endpoint may attenuate or accentuate depending on the type of intervention and duration of follow-up; the applicability of 40% eGFR decline endpoint is not uniform across all clinical settings and interventions. The decision to use a 40% eGFR decline as a surrogate endpoint should be considered on a case-by-case basis.

In my opinion, 40% Reduction in eGFR beats Doubling of Creatinine, but only narrowly. I would wait for the results of the ongoing CKD progression trials to see whether it lives up to our expectations.

Wait, the story is not yet over. Recently, the National Kidney Foundation, the US Food and Drug Administration, and the European Medicines Agency conducted a Scientific Workshop to review data concerning the use of albuminuria, changes in the rate/slope of GFR decline, and GFR and albuminuria in combination as predictors of a treatment’s effect on CKD progression in clinical trials for early stages of CKD. Their recommendations will be published in late 2018. It will be interesting to see whether the rate/slope of GFR decline will be the new kid on the block.

– Post written by Sunil Badve. Follow him @Badves. 

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.

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