Design of clinical trials in acute kidney injury: report from an NIDDK workshop on trial methodology.

Acute 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.

Design of clinical trials in AKI: a report from an NIDDK workshop. Trials of patients with sepsis and in selected hospital settings.

AKI remains an important clinical problem, with a high mortality rate, increasing incidence, and no Food and Drug Administration-approved therapeutics. Advances in addressing this clinical need require approaches for rapid diagnosis and stratification of injury, development of therapeutic agents based on precise understanding of key pathophysiological events, and implementation of well designed clinical trials. In the near future, AKI biomarkers may facilitate trial design. To address these issues, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a meeting, "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers," in December of 2010 that brought together academic investigators, industry partners, and representatives from the National Institutes of Health and the Food and Drug Administration. Important issues in the design of clinical trials for interventions in AKI in patients with sepsis or AKI in the setting of critical illness after surgery or trauma were discussed. The sepsis working group discussed use of severity of illness scores and focus on patients with specific etiologies to enhance homogeneity of trial participants. The group also discussed endpoints congruent with those endpoints used in critical care studies. The second workgroup emphasized difficulties in obtaining consent before admission and collaboration among interdisciplinary healthcare groups. Despite the difficult trial design issues, these clinical situations represent a clinical opportunity because of the high event rates, severity of AKI, and poor outcomes. The groups considered trial design issues and discussed advantages and disadvantages of several short- and long-term primary endpoints in these patients.

Design of clinical trials in acute kidney injury: a report from an NIDDK workshop--prevention trials.

AKI is an important clinical problem that has become increasingly more common. Mortality rates associated with AKI remain high despite advances in supportive care. Patients surviving AKI have increased long-term mortality and appear to be at increased risk of developing CKD and progressing to ESRD. No proven effective pharmacologic therapies are currently available for the prevention or treatment of AKI. Advances in addressing this unmet need will require the development of novel therapeutic agents based on precise understanding of key pathophysiological events and the implementation of well designed clinical trials. To address this need, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored the "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers" workshop in December 2010. The event brought together representatives from academia, industry, the National Institutes of Health, and the US Food and Drug Administration. We report the discussions of workgroups that developed outlines of clinical trials for the prevention of AKI in two patient populations: patients undergoing elective surgery who are at risk for or who develop AKI, and patients who are at risk for contrast-induced AKI. In both of these populations, primary prevention or secondary therapy can be delivered at an optimal time relative to kidney injury. The workgroups detailed primary and secondary endpoints for studies in these groups, and explored the use of adaptive clinical trial designs for trials of novel preventive strategies to improve outcomes of patients with AKI.

Predictors of fatal and nonfatal cardiovascular events in patients with type 2 diabetes mellitus, chronic kidney disease, and anemia: an analysis of the Trial to Reduce cardiovascular Events with Aranesp (darbepoetin-alfa) Therapy (TREAT).

AIMS: This study aims to examine predictors of cardiovascular mortality and morbidity in patients with chronic kidney disease (CKD). Individuals with the triad of diabetes, CKD, and anemia represent a significant proportion of patients with cardiovascular disease and are at particularly high risk for adverse outcomes. METHODS AND RESULTS: Using Cox proportional hazards models, we identified independent predictors of the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for myocardial ischemia, or heart failure (HF) in 3,847 patients in the TREAT, 961 (25%) of whom experienced this outcome. The predictors (ranked by χ(2) value) were prior HF (hazard ratio [HR] 1.74, 95% CI 1.51-2.01), age (HR 1.03, 95% CI 1.02-1.04 per year), log urine protein/creatinine ratio (HR 1.19, 95% CI 1.13-1.26 per log unit ), C-reactive protein ≥6.6 mg/L (HR 1.44, 95% CI 1.23-1.69, compared with C-reactive protein ≤3.0 mg/L), and abnormal electrocardiogram (HR 1.42, 95% CI 1.21-1.66 ), all P < .0001. Addition of cardiac-derived biomarkers (subset of first 1,000 patients enrolled) significantly enhanced risk estimation, with N-terminal pro B-type natriuretic peptide becoming the highest ranked predictor of outcome (HR 1.30, 95% CI 1.15-1.46 per log unit, P < .001) and troponin T providing additional predictive information. These biomarkers improved risk classification in 17.8% (9.4%-26.2%) of patients. CONCLUSION: In patients with diabetes, CKD, and anemia, cardiovascular risk is most strongly predicted by age, history of HF, C-reactive protein, urinary protein/creatinine ratio, abnormal electrocardiogram, and 2 specific cardiac biomarkers, serum N-terminal pro B-type natriuretic peptide and troponin T, which are elevated in many. These findings suggest ways to improve cardiovascular risk stratification of patients with predialysis CKD, support the concept of cardiorenal syndrome, and may help target therapy.