Finally, a sensitivity analysis excluding the Study of Heart and Renal Protection, which contributed a large number of events to the meta-analysis, did not alter the conclusions. analysis revealed that the placebo-adjusted treatment effect on albuminuria significantly correlated with the treatment effect on ESRD: for each 30% reduction in albuminuria, the risk of ESRD decreased by 23. 7% (95% confidence interval, 11. 4% to 34. 2%; P=0. 001). The association was consistent regardless of drug class (P=0. 73) or other patient or trial characteristics. These findings suggest albuminuria may be a valid substitute for ESRD RepSox (SJN 2511) RepSox (SJN 2511) in many circumstances, even taking into account possible other drug-specific effects that may alter renal outcomes. Keywords: albuminuria, clinical trial, ESRD, proteinuria CKD receives growing attention as a major public health concern. Clinical practice guidelines advocate early detection and appropriate treatment based on the rationale that RepSox (SJN 2511) intervention in the early course of disease may be more advantageous. 1, 2To establish drug efficacy in clinical trials of progression of Igfbp2 CKD doubling of serum creatinine and ESRD are used as clinical end points. However , progression of kidney disease to ESRD takes many years to manifest. Clinical trials enrolling patients at early stages of disease would therefore require a long follow-up or an impractical large sample size to establish drug efficacy. The use of surrogate end points may be a solution to this problem. However , rigorous validation is required before a surrogate end point is used in clinical trials. The criteria for validation are defined in the International Conference of Harmonization RepSox (SJN 2511) statistical principles of clinical trials. 3First, prognostic evidence of the surrogate end point with patient outcome must be available. Second, a biologically plausible relationship between the surrogate and outcome should exist. Third, clinical trial data must demonstrate that the effect of interventions that change the surrogate end point is directly associated with the same change in clinical outcomes. A typical example is BP, because high BP is associated with cardiovascular risk and reduction of BP, by whatever means, lowers cardiovascular risk. Albuminuria has been proposed as a surrogate end point in clinical trials of CKD progression. 4Multiple clinical studies have shown a strong and independent association between albuminuria and ESRD, 5whereas experimental studies have documented the causal mechanisms through which increased urinary albumin leakage aggravates kidney damage. 6In addition, analyses from several clinical trials have shown that the initial treatment-induced change in albuminuria predicts subsequent renal risk change. 712Although the consistency of these studies supports the validity of albuminuria as a surrogate, the correlation analyses from randomized controlled trials between changes in albuminuria and ESRD were conductedpost hocand were no longer based on randomized comparisons. Therefore , the possibility that the lower risk of ESRD among patients with a reduction in albuminuria was caused by factors unrelated to the antialbuminuric effect of the intervention cannot be excluded. To minimize this type of bias, it is necessary to associate the placebo-controlled treatment effects on albuminuria with the placebo-controlled treatment effects on ESRD. This approach requires a combined analysis of multiple randomized controlled trials. A combined analysis of multiple clinical trials allows assessment of whether the reductions in albuminuria and ESRD are independent of the interventions that are used. If so , it would support the RepSox (SJN 2511) idea that the reduction in albuminuria is the determinant of renoprotection rather than the interventionper se. Therefore , the aim of this study was to conduct a systematic review and meta-analysis to reliably examine the treatment effects of various interventions on an initial change in albuminuria as a predictor of the treatment effect on ESRD. == Results == == Literature Search and Characteristics of Studies == The combined literature search in EMBASE and MEDLINEviaPubMed yielded 3412 articles, of which 626 articles were duplicates identified in both databases. Sixty-four articles were reviewed in full text on the basis of our inclusion criteria (Figure 1). Of these, 21 randomized clinical trials provided information on 78, 342 patients and 4183 ESRD events and were eligible for inclusion. All trials were published in peer-reviewed journals. The majority of other studies identified by our search but not included in the meta-analysis were randomized clinical trials in dialysis, renal transplant, or acute kidney populations or trials that had insufficient patient follow-up to be eligible. == Figure 1 . == Identification process for eligible studies. CVD, cardiovascular disease; RCT, randomized controlled trial. Table 1summarizes the characteristics of the included studies. These were reported between 1994 and 2013, with a.
