Design of Clinical Trials in Acute Kidney Injury

Abstract

SummaryAcute kidney injury (AKI) remains a complex clinical problem associated with significant short-term morbidity and mortality and lacking effective pharmacologic interventions. Patients with AKI experience longer-term risks for progressive chronic ESRD, which diminish patients' health-related quality of life and create a larger burden on the healthcare system. Although experimental models have yielded numerous promising agents, translation into clinical practice has been unsuccessful, possibly because of issues in clinical trial design, such as delayed drug administration, masking of therapeutic benefit by adverse events, and inadequate sample size. To address issues of clinical trial design, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a workshop titled "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers" in December 2010. Workshop participants included representatives from academia, industry, and government agencies whose areas of expertise spanned basic science, clinical nephrology, critical care medicine, biostatistics, pharmacology, and drug development. This document summarizes the discussions of collaborative workgroups that addressed issues related to patient selection, study endpoints, the role of novel biomarkers, sample size and power calculations, and adverse events and pilot/feasibility studies in prevention and treatment of AKI. Companion articles outline the discussions of workgroups for model trials related to prevention or treatment of established AKI in different clinical settings, such as in patients with sepsis.

Association between AKI and Long-Term Renal and Cardiovascular Outcomes in United States Veterans

“…The second aim of our study was to determine the incidence of MAKE, MACE, and MARCE, because these are proposed composite endpoints of clinical trials (14,15). Our analysis showed that patients who experienced an episode of AKI were at significant risk for death and permanent loss of renal function.…”

“…Furthermore, poor outcomes associated with AKI exceed those of an MI, a disease that carries a much higher public health profile, and whose prevention attracts very high levels of government and nongovernment funding. We also propose that composite endpoints (MAKE, MACE, and MARCE) be used in future clinical trials of AKI, because they provide a method that improves the ability to detect meaningful differences in therapeutic interventions (14)(15)(16). Finally, improved prevention and therapy of AKI, as well as follow-up surveillance of this high-risk group, are urgently required.…”

“…More recently, multiple large cohort studies have demonstrated that patients who survive an episode of AKI are at risk for progression to advanced stages of CKD (7)(8)(9)(10)(11)(12). As a consequence of these findings, the composite endpoint of major adverse kidney events (MAKE) (13) has been endorsed by the National Institute of Diabetes and Digestive and Kidney Diseases clinical trials workgroup to harmonize and encourage future clinical trials (14)(15)(16).…”

Cellular and Molecular Mechanisms of AKI

“…80 The vast majority of successful preclinical experiments to date have been prophylactic, with exposure to the protective agent before an ischemic, septic, or nephrotoxic insult. 81 Fewer experimental models also include early postinsult exposures, which in some cases are successful. However, a major weakness of current preclinical experimental AKI models is that they do not routinely incorporate a more delayed secondary prevention/therapeutic component, with late addition of therapy when AKI is already developing.…”

Biomarkers of therapeutic response in primary nephrotic syndrome

“…However, following the lead of Devarajan and others [3] who have pioneered the use of urinary biomarkers in the diagnosis of acute kidney injury, I would suggest that investigators work together to develop a panel of suitable biomarkers that can be combined in an array and tested simultaneously in a single assay to enhance the sensitivity and specificity of these analytes in patients with new-onset primary nephrotic syndrome. Such an approach would be a welcome addition to the management of children and adolescents with this important clinical problem.…”