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Reframing kidney outcomes in CKD trials: eGFR slopes, competing risks, and pragmatic trial design
Carmine Zoccali1,2,3, Adeera Levin4
1Institute of Molecular Biology and Genetics (BIOGEM), Ariano Irpino, Italy.
Abstract:
In both clinical research and study design, the definition of outcomes for chronic kidney disease (CKD) is changing. New molecules available for testing in humans, and the fact that kidney diseases are best treated earlier in their course, make the duration of studies requiring 'hard endpoints' longer than is feasible for registration purposes and funding agencies. Improved mathematical modelling and statistical analyses, and the availability of electronic medical records and registries have also impacted nephrology clinical research. Thus, eGFR slopes have been promoted as surrogate endpoints for kidney failure, competing-risk methods have exposed the limitations of standard survival analysis in high-mortality CKD and dialysis populations, and pragmatic, registry-based trials enroll patients who resemble those seen in daily practice. This review suggests that eGFR slopes, time to kidney failure, and competing risk factors must be considered in their totality, so that CKD and cardiovascular (CV) evidence can be understood in clinical practice by patients and clinicians. We propose that eGFR slopes may provide a clinically intuitive summary of 'kidney time', showing how, under appropriate conditions, chronic slope differences may be translated into approximate 'years of dialysis delayed' at the population level. We frame competing risks as a clinical, not only statistical, issue, and we examine how pragmatic CKD trials can and should integrate slope-based endpoints and competing-risk analyses into their design and reporting. To advance nephrology research, we must embrace these changes in study design and methodology to ensure that clinicians and patients understand them, and thus are more prepared to implement trial results.
Insights
Chronic kidney disease (CKD) research is evolving. New methods like eGFR slopes and competing-risk analyses offer better ways to measure treatment effectiveness and delay kidney failure, improving clinical trial design and patient understanding.
Area of Science:
- Nephrology
- Clinical Research Methodology
- Biostatistics
Background:
- Chronic kidney disease (CKD) outcome definitions are shifting due to new treatments and the need for earlier intervention.
- Traditional study designs with hard endpoints are often too long for current research and funding constraints.
- Advances in statistical modeling, electronic health records, and registries impact nephrology research.
Purpose of the Study:
- To review and propose updated methodologies for clinical research in chronic kidney disease.
- To integrate novel endpoints like eGFR slopes and competing-risk analyses into CKD trial design and interpretation.
- To ensure research findings are understandable and applicable for clinicians and patients in daily practice.
Main Methods:
- Review of current trends in CKD clinical research and study design.
- Discussion of the utility of estimated glomerular filtration rate (eGFR) slopes as surrogate endpoints.
- Examination of competing-risk methods and their application in high-mortality CKD populations.
- Analysis of pragmatic, registry-based trial designs.
Main Results:
- eGFR slopes can serve as surrogate endpoints for kidney failure, potentially estimating years of dialysis delayed.
- Competing-risk methods are crucial for accurately analyzing outcomes in CKD and dialysis populations, surpassing standard survival analysis.
- Pragmatic trials utilizing registries enroll representative patient populations, enhancing real-world applicability.
Conclusions:
- A holistic approach considering eGFR slopes, time to kidney failure, and competing risks is essential for understanding CKD and cardiovascular outcomes.
- eGFR slopes offer a clinically intuitive measure of kidney disease progression, translating to potential delays in dialysis.
- Integrating slope-based endpoints and competing-risk analyses into pragmatic CKD trials is vital for advancing nephrology research and clinical practice.
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