Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studies

Abstract

Background: Change in albuminuria as a surrogate endpoint for progression of chronic kidney disease is strongly supported by biological plausibility, but empirical evidence to support its validity in epidemiological studies is lacking. We aimed to assess the consistency of the association between change in albuminuria and risk of end-stage kidney disease in a large individual participant-level meta-analysis of observational studies.

Methods: In this meta-analysis, we collected individual-level data from eligible cohorts in the Chronic Kidney Disease Prognosis Consortium (CKD-PC) with data on serum creatinine and change in albuminuria and more than 50 events on outcomes of interest. Cohort data were eligible if participants were aged 18 years or older, they had a repeated measure of albuminuria during an elapsed period of 8 months to 4 years, subsequent end-stage kidney disease or mortality follow-up data, and the cohort was active during this consortium phase. We extracted participant-level data and quantified percentage change in albuminuria, measured as change in urine albumin-to-creatinine ratio (ACR) or urine protein-to-creatinine ratio (PCR), during baseline periods of 1, 2, and 3 years. Our primary outcome of interest was development of end-stage kidney disease after a baseline period of 2 years. We defined an end-stage kidney disease event as initiation of kidney replacement therapy. We quantified associations of percentage change in albuminuria with subsequent end-stage kidney disease using Cox regression in each cohort, followed by random-effects meta-analysis. We further adjusted for regression dilution to account for imprecision in the estimation of albuminuria at the participant level. We did multiple subgroup analyses, and also repeated our analyses using participant-level data from 14 clinical trials, including nine clinical trials not in CKD-PC.

Findings: Between July, 2015, and June, 2018, we transferred and analysed data from 28 cohorts in the CKD-PC, which included 693 816 individuals (557 583 [80%] with diabetes). Data for 675 904 individuals and 7461 end-stage kidney disease events were available for our primary outcome analysis. Change in ACR was consistently associated with subsequent risk of end-stage kidney disease. The adjusted hazard ratio (HR) for end-stage kidney disease after a 30% decrease in ACR during a baseline period of 2 years was 0·83 (95% CI 0·74-0·94), decreasing to 0·78 (0·66-0·92) after further adjustment for regression dilution. Adjusted HRs were fairly consistent across cohorts and subgroups (ie, estimated glomerular filtration rate, diabetes, and sex), but the association was somewhat stronger among participants with higher baseline ACR than among those with lower baseline ACR (p_interaction<0·0001). In individuals with baseline ACR of 300 mg/g or higher, a 30% decrease in ACR over 2 years was estimated to confer a more than 1% absolute reduction in 10-year risk of end-stage kidney disease, even at early stages of chronic kidney disease. Results were generally similar when we used change in PCR and when study populations from clinical trials were assessed.

Interpretation: Change in albuminuria was consistently associated with subsequent risk of end-stage kidney disease across a range of cohorts, lending support to the use of change in albuminuria as a surrogate endpoint for end-stage kidney disease in clinical trials of progression of chronic kidney disease in the setting of increased albuminuria.

Funding: US National Kidney Foundation and US National Institute of Diabetes and Digestive and Kidney Diseases.

Figure 1.

Adjusted hazard ratio of ESKD and population distribution of change in albuminuria. Top row ACR, bottom row PCR, left to right 1, 2, and 3-year baseline period. Two-year albuminuria change is used for the primary analysis with 7,461 ESKD cases among 675,904 individuals in 20 cohorts. Black circles denote −30% and +43% change in albuminuria.

Figure 2.

Forest plot showing the individual study and meta-analyzed estimate of adjusted hazard ratio of ESKD associated with 2-year ACR change (top row) and PCR change (bottom row) for a 30% reduction (left side) 43% increase (right side)

Figure 3.

Interaction analysis of the adjusted hazard ratio of ESKD associated with 2-year change in ACR by baseline level of ACR, eGFR, and diabetes.*

Figure 4.

Adjusted hazard ratio of cardiovascular (CVM), non-cardiovascular (Non-CVM) and all-cause mortality by 2-year change in albuminuria (ACR). 3,443 CVM, 13,175 non-CVM and 75,761 ACM cases among 125,000, 125,000 and 690,513 individuals in 11, 11 and 25 cohorts.

Figure 5.

Risk of ESKD by years of follow-up for three levels of baseline albuminuria (ACR, panel A; PCR, panel B) and a 30% decline in albuminuria (dashed lines). Differences between lines with the same level of albuminuria indicate attributable risk for change in albuminuria adjusted for regression dilution. Analysis includes the competing risk of mortality with baseline subhazards meta-analyzed in 18 cohorts including 6,799 ESKD events and 584,489 individuals.