Bias in the composite outcomes of kidney-cardio protective randomized controlled trials in chronic kidney disease: a meta-epidemiological study v1

Chronic kidney disease (CKD) is characterized by a high burden of morbidity and mortality, associated with kidney failure and cardiovascular disease. Randomized controlled trials (RCTs) evaluating kidney–cardio protective therapies increasingly rely on composite primary endpoints that combine kidney disease progression, cardiovascular events, and death. While this strategy improves statistical efficiency and feasibility, it introduces important challenges in interpretation, as the individual components of these composites differ substantially in frequency, severity, and clinical relevance. A key limitation of composite outcomes is that the overall treatment effect may be disproportionately influenced by more frequent or less clinically consequential events, potentially obscuring the effect on the most meaningful outcomes such as end-stage kidney disease (ESKD) or death. The Bias Attributable to Composite Outcome (BACO) index has been proposed to quantify this phenomenon by comparing the treatment effect on the composite outcome with that on a key component. In CKD trials, where composite endpoints frequently span both kidney and cardiovascular domains, a clinically grounded application of BACO is required to ensure that interpretation reflects the dominant disease process and the most relevant hard outcomes.