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

2020-04-02T14:42:46Z (GMT) by Josef Coresh Hiddoj L Heerspink Yingying Sang Kunihiro Matsushita Johan Arnlov Brad C Astor Corti Black Nigel J Brunskill Juan-Jesus Carrero Harold Feldman Caroline S Fox Lesley A Inker Areef Ishani Sadayoshi Ito Simerjot Jassal Tsuneo Konta Kevan Polkinghorne Solfrid Romundstad Marit D Solbu Nikita Stempniewicz Benedicte Stengel Marcello Tonelli Mitsumasa Umesawa Sushruts Waikar Chi-Pang Wen Jack FM Wetzels Mark Woodward Morgan E Grams Csaba P Kovesdy Andrew S Levey Ron T Gansevoort Stein Hallan Varda Shalev John Chalmers Hisatomi Arima Vlado Perkovic Adeera Levin Ognjenka Djurdjev Mila Tang Joseph Nally Sankar Navaneethan Jesse Schold Misghina Weldegiorgis William Herrington Margaret Smith Yenchih Hsu Caroline Fox Shih-Jen Hwang Alex R Chang H Lester Kirchner Jamie Green Kevin Ho Corri Black Angharad Marks Gordon Prescott Laura Clark Nick Fluck Gabriel Chodick Jack Wetzels Peter Blankestijn Arjan van Zuilen Jan van den Brand Mark Sarnak Lesley Inker Erwin Bottinger Girish N Nadkarni Stephen B Ellis Rajiv Nadukuru Marie Metzger Martin Flamant Pascal Houillier Jean-Philippe Haymann Marc Froissart Timothy Kenealy C Raina Elley John F Collins Paul L Drury John Cuddeback Elizabeth Ciemins Rich Stempniewicz Robert G Nelson William C Icnowler Hiddo JL Heerspink Stephen JL Bakker Nigel Brunsldll Rupert Major James F Medcalf David Shepherd Simerjot K Jassal Elizabeth Barrett-Connor Jaclyn Bergstrom Joe Ix Csaba Kovesdy Miklos Z Molnar Keiichi Sumida Dick de Zeeuw Barry Brenner Abdul Rashid Qureshi Carl-Gustaf Elinder Blorn Runesson Marie Evans Marten Segelmark Maria Stendahl Staffan Schon David Naimark Navdeep Tangri Maneesh Sud Atsushi Hirayama Kazunobu Ichikawa Henk JG Bilo Gijs WD Landman Komelis JJ van Hateren Shoshana H Ballew Jingsha Chen Lucia Kwak Aditya Surapaneni Hans-Henrik Parving Roger A Rodby Richard D Rohde Julia B Lewis Edmund Lewis Ronald Perrone Kaleab Z Abebe Fan Fan Hou Di Xie Lawrence G Hunsicker Enyu Imai Fumiald Kobayashi Hirofumi Makino Giuseppe Remuzzi Piero Ruggenenti
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 (pinteraction<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.