Assessing the Validity of Surrogate Outcomes for ESRD

Abstract

Validation of current and promising surrogate outcomes for ESRD in randomized controlled trials (RCTs) has been limited. We conducted a systematic review and meta-analysis of RCTs to further inform the ability of surrogate outcomes for ESRD to predict the efficacy of various interventions on ESRD. MEDLINE, EMBASE, and CENTRAL (from inception through September 2013) were searched. All RCTs in adults with proteinuria, diabetes, or CKD stages 1-4 or renal transplant recipients reporting $10 ESRD events and a surrogate outcome (change in proteinuria or doubling of serum creatinine [DSCR]) for ESRD during a $1-year follow-up were included. Two reviewers abstracted trial characteristics and outcome data independently. To assess the correlation between the surrogate outcomes and ESRD, we determined the treatment effect ratio (TER), defined as the ratio of the treatment effects on ESRD and the effects on the change in surrogate outcomes. TERs close to 1 indicate greater agreement between ESRD and the surrogate, and these ratios were pooled across interventions. We identified 27 trials (97,458 participants; 4187 participants with ESRD). Seven trials reported the effects on change in proteinuria and showed consistent effects for proteinuria and ESRD (TER, 0.82; 95% confidence interval, 0.59 to 1.16), with minimal heterogeneity. Twenty trials reported on DSCR. Treatment effects on DSCR were consistent with the effects on ESRD (TER, 0.98; 95% confidence interval, 0.85 to 1.14), with moderate heterogeneity. In conclusion, DSCR is generally a good surrogate for ESRD, whereas data on proteinuria were limited. Further assessment of the surrogacy of proteinuria using prospective RCTs is warranted. CKD is commonly defined as a GFR,60 ml/min per 1.73 m 2 or the presence of markers of kidney damage, including proteinuria. 1 The global burden of CKD is increasing, with a prevalence of 10%-16% worldwide. 2 The clinical management of people with CKD has been difficult, particularly for those with irreversible kidney failure or ESRD. Preserving kidney function and slowing the progression of kidney disease is thus important. In measuring the efficacy of interventions in clinical trials focusing on this strategy, ESRD (defined as long-term dialysis or kidney transplantation) is the most definitive outcome in kidney disease. However, kidney disease often progresses slowly over many years. This presents logistic challenges in the conduct of randomized controlled trials (RCTs) because long follow-up and extensive resources are required. These considerations 4 There is considerable interest in using proteinuria or smaller changes in serum creatinine or eGFR as surrogate outcomes. 5-7 However, rigorous validation of a surrogate outcome is needed before it can be implemented in large-scale trials. We therefore conducted a systematic review and meta-analysis of RCTs, irrespective of intervention or comparator, in adults with proteinuria, diabetes, CKD stages 1-4, or renal transplant recipients to further inform the ability of surrogate...

Obesity, Renin-Angiotensin System Blockade and Risk of Adverse Renal Outcomes: A Population-Based Cohort Study

“…Existing literature supports that the hemodynamic effects of RAS blockade may contribute to up to 30% acute, reversible reduction in eGFR [58,59]. Nonetheless, in our study, the outcome of 50% reduction in eGFR across two consecutive values or ESRD suggests that RAS blockade does not protect against chronic adverse renal outcomes in obese, non-diabetic patients compared to other antihypertensive agents [60]. Additionally, our study corroborates existing data that RAS blockade is protective against the development of diabetes, but not mortality in this patient population [52].…”

Application of new acute kidney injury biomarkers in human randomized controlled trials

“…5 As noted by the FDA, these methods of biomarker use are not mutually exclusive; for example, in diabetic kidney disease trials, urine albumin is used as a prognostic biomarker to preferentially enroll patients at higher risk of reaching the trial’s end point, and as a pharmacodynamic biomarker to support proof-of-concept studies and aid in dose selection. 7 Novel biomarkers used in isolation may not perform as well as a composite biomarker score in combination with existing clinical information and traditional tests. 8,9 …”

Guidelines for clinical evaluation of chronic kidney disease

“…As evidence of this CQ, albuminuria/proteinuria at baseline and at the end of the study was measured, and six RCT articles [42][43][44][51][52][53] and four meta-analysis articles [45,46,54,55] using ESRD as the endpoint were adopted.…”

“…These randomized controlled trials and post hoc analysis results confirmed a relationship between the decrease in albuminuria/proteinuria as a result of treatment using RA inhibitors for diabetic nephropathy and prevention of progression to ESRD. On the other hand, there are four papers reporting systematic review/ meta-analysis reviewing the usefulness of decrease in albuminuria/proteinuria as a surrogate endpoint [45,46,54,55]. In a meta-analysis of 32 randomized controlled trials (9008 subjects) evaluating five treatment interventions (RA inhibitor, Ca antagonist, intensive depressor therapy, low protein diet, and immunosuppressive drug) with renal disease progression as an outcome, the relationships between changes in albuminuria 2.5-13 months later and composite endpoints (doubling of serum creatinine level, ESRD, death) were investigated [45].…”

“…As a result, the TER of proteinuria was 0.82 (95% CI 0.59-1.16), and changes in proteinuria were related to the treatment effects of ESRD. Since little data were obtained, it was concluded that there is a limit to evidence as a surrogate endpoint [55]. The results of these meta-analyses demonstrate that the decrease in albuminuria/proteinuria can be used as a surrogate endpoint for the progression of renal disease, not only for RA inhibitor for diabetic nephropathy accompanied by overt proteinuria but also treatment using RA inhibitor and corticosteroid for IgA nephropathy.…”