Many kidney diseases progress slowly, and trials to evaluate treatments for kidney disease require extensive durations of follow-up to determine if the treatment has been effective, increasing expense and complexity, and are usually infeasible for early stage disease. This problem has likely contributed to the small number of RCTs in nephrology compared to other fields, and the paucity of therapies to slow kidney disease progression.
Proteinuria has been established as a marker of kidney damage in experimental studies and has been widely reported to be prognostic for long-term disease progression at all stages of kidney disease. However, there is only preliminary empirical evidence in support of this hypothesis. Our work attempts to provide integrated, systematic evaluation of an early change in proteinuria as a surrogate endpoint for trials of kidney disease progression using individual patient meta-analysis.
We performed a comprehensive evaluation of this hypothesis based on a joint analysis of 9,008 individuals from 32 randomized control trials provide of 5 types of interventions in progressive kidney disease. The results provide new evidence supporting the use of an early reduction in proteinuria as a surrogate endpoint, but do not provide sufficient evidence to establish its validity in all settings. However, due to limitations of the data, we are not able definitely refute the validity of proteinuria as a surrogate end point. It may be reasonable to recommend proteinuria in early-phase clinical trials for new therapies and for exploratory analyses (eg, subgroup analyses). In addition, in kidney diseases and populations where proteinuria is high, it is a rare diseases where adequate sample sizes for clinical outcomes are infeasible, and experimental evidence for a pathological role of proteinuria is strong, use of proteinuria as a surrogate endpoint may be warranted in certain Phase III clinical trials, especially when the risks of adverse outcomes of the intervention are low . For populations with high levels of proteinuria and high GFR, it may also be reasonable to use reduction in proteinuria for initial acceptance of an intervention.