Multinational Assessment of Accuracy of Equations for Predicting Risk of Kidney Failure: A Meta-analysis

Abstract

Importance: Identifying patients at risk of chronic kidney disease (CKD) progression may facilitate more optimal nephrology care. Kidney failure risk equations, including such factors as age, sex, estimated glomerular filtration rate, and calcium and phosphate concentrations, were previously developed and validated in 2 Canadian cohorts. Validation in other regions and in CKD populations not under the care of a nephrologist is needed.

Objective: To evaluate the accuracy of the risk equations across different geographic regions and patient populations through individual participant data meta-analysis.

Data sources: Thirty-one cohorts, including 721,357 participants with CKD stages 3 to 5 in more than 30 countries spanning 4 continents, were studied. These cohorts collected data from 1982 through 2014.

Study selection: Cohorts participating in the CKD Prognosis Consortium with data on end-stage renal disease.

Data extraction and synthesis: Data were obtained and statistical analyses were performed between July 2012 and June 2015. Using the risk factors from the original risk equations, cohort-specific hazard ratios were estimated and combined using random-effects meta-analysis to form new pooled kidney failure risk equations. Original and pooled kidney failure risk equation performance was compared, and the need for regional calibration factors was assessed.

Main outcomes and measures: Kidney failure (treatment by dialysis or kidney transplant).

Results: During a median follow-up of 4 years of 721,357 participants with CKD, 23,829 cases kidney failure were observed. The original risk equations achieved excellent discrimination (ability to differentiate those who developed kidney failure from those who did not) across all cohorts (overall C statistic, 0.90; 95% CI, 0.89-0.92 at 2 years; C statistic at 5 years, 0.88; 95% CI, 0.86-0.90); discrimination in subgroups by age, race, and diabetes status was similar. There was no improvement with the pooled equations. Calibration (the difference between observed and predicted risk) was adequate in North American cohorts, but the original risk equations overestimated risk in some non-North American cohorts. Addition of a calibration factor that lowered the baseline risk by 32.9% at 2 years and 16.5% at 5 years improved the calibration in 12 of 15 and 10 of 13 non-North American cohorts at 2 and 5 years, respectively (P = .04 and P = .02).

Conclusions and relevance: Kidney failure risk equations developed in a Canadian population showed high discrimination and adequate calibration when validated in 31 multinational cohorts. However, in some regions the addition of a calibration factor may be necessary.

Figure 1. Discrimination statistics (C statistics) for original 4-variable equation at 2 and 5 years by cohort

An asterisk indicates this cohorts measuring dipstick proteinuria. Due to a limited number of events, confidence intervals were wide in some studies and therefore capped at 1.00 (maximum value for C statistic). Size is proportional to the weight of the study in a random effects meta-analysis. Arrows indicate that the true values are beyond the range of the axis. Representative references and expanded acronyms for each cohort name are provided in eAppendix 3.

Figure 2. Discrimination statistics (C statistics) for original 4-variable and 8-variable equations at 2 and 5 years by subgroup

In the 4-variable equation analyses, 31 cohorts contributed for 2-year analysis and 26 cohorts for 5-year analysis. In the 8-variable equation analyses, 16 cohorts contributed for 2-year analysis and 11 cohorts contributed for 5-year analysis.

Figure 3. Refit baseline hazard of original 4-variable equation at 2 and 5 years in individual cohorts stratified by region

Horizontal gray line represents the centered baseline hazard for the original 4-variable KFRE (age 70 years, male 56%, eGFR 36 ml/min/1.73 m², ACR 170 mg/g); the red and green horizontal line represent the weighted mean refit baseline hazard within each region (North America and non-North America). NA: North America, NZ: New Zealand, E: Europe, I: Israel, A: Asia. The 25 cohorts included represent studies with available urine albumin-to-creatinine ratio. Studies with dipstick proteinuria were not included in the calculation. The North America cohorts include AASK, ARIC, BC CKD, CCF_ACR, CRIC, Geisinger, ICES-KDT, MDRD, Mt Sinai BioMe, Pima, REGARDS, Sunnybrook, and VA CKD. The New Zealand cohort is NZDCS. The Europe cohorts include CRIB, GCKD, GLOMMS-1, HUNT, MASTERPLAN, MMKD, Nephrotest, RENAAL, and SRR-CKD. The Israel cohort is Maccabi. The Asia cohort is Gonryo.