Re-Examining Adverse Outcomes of Chronic Kidney Disease in Ontario Adults: A Retrospective Cohort Study

Abstract

Background and rationale: Chronic kidney disease (CKD) has increased in prevalence over the last twenty years in Canada, now affecting up to one in ten Canadians (3). CKD is associated with adverse cardiovascular outcomes, end-stage kidney disease (ESKD) and all-cause mortality. CKD is diagnosed through blood and urine testing and is defined as a reduced estimated glomerular filtration rate (eGFR) of <= 60 ml/min/1.73 m2 for three months or more and albuminuria > 3 mg/mmol (4,5). The discrete eGFR cut-off for diagnosing CKD has been questioned due to physiologic changes in kidney function. Recent evidence suggests the CKD eGFR diagnostic threshold should be much higher in young adults (above 60 ml/min/1.7 3m2, e.g., 75 ml/min/1.73 m2), regardless of albuminuria and lower (< 60 ml/min/1.73 m2, e.g., < 45 ml/min/1.73 m2 in the absence of albuminuria) in older adults with CKD. Identifying age-specific, outcome-based threshold levels of eGFR would improve early CKD identification and treatment in the young, reduce overdiagnosis and overtreatment, and reduce inappropriate utilization of healthcare resources (6). Objectives: To examine the association of age-specific eGFR thresholds with mortality, major adverse cardiac events (MACE), and ESKD using population-based data from Ontario, Canada. Methods: Using linked, de-identified administrative datasets housed at ICES, we created a cohort of all adults (18-105) with at least two available eGFR measures between 90 and 730 days apart in Ontario, Canada, from January 2008 to December 2021, with a minimum follow-up of one year. We examined the associations of eGFR and age with adverse outcomes (all-cause mortality, MACE, MACE+, and ESKD) using Cox proportional hazards models and a regression discontinuity design (RDD) to identify specific risk-based eGFR thresholds in adults by age. Reclassification was used to examine event frequencies by eGFR in younger adults to determine an optimal eGFR cutoff for screening for adverse events associated with eGFR reduction. Results: The cohort included 8,388,340 individuals (mean age 51.27, SD 17.37, 62.3% female, mean baseline eGFR 92.59 +/- 20.17) with a median follow-up time of approximately 1 year. The age distribution was as follows: 27.28% from 18-39, 50.94% from 40-65, 16.68% from 66-80, and 5.11% 80 or older. In adjusted models, the risk of all-cause mortality, MACE, MACE+ and ESKD was higher in 18- to 30-year-olds at a threshold of eGFR 80-90, with a stepwise decline in risk with age. Among those aged 80 or older, the risk of adverse events was higher only when eGFR was 50 or lower. Cox proportional hazard analysis demonstrated that younger individuals had a discrete increase in all-cause mortality and adverse cardiac events at eGFR < 90 ml/min/1.73 m2. Adults over age 50 and older adults up to age 80 experienced adverse events at eGFR < 60 ml/min/1.73 m2 and at eGFR > 110 ml/min/1.73 m2. Sub-analyses for albuminuria and diabetes demonstrated similar results to the total population with modest reductions in risk; however, risk for younger individuals eGFR <90 ml/min were still present with albuminuria and diabetes. Regression discontinuity modelling did not identify a granular threshold by age for adverse outcomes; however, analyzing 3-, 5-, and 10-year risk for adverse outcomes in younger adults suggested that those with reductions in eGFR < 75 ml/min/1.73 m2 would benefit from closer monitoring. Conclusions: This retrospective cohort study of 8.3 million Ontario individuals has provided a novel and robust assessment of optimal risk-based eGFR cut-offs for CKD diagnosis and related adverse events. However, a definitive cut-off for the eGFR threshold by age could not be identified through Cox proportional hazards and RDD. In younger adults, an eGFR below 90 ml/min/1.73m2 consistently showed a significant association with adverse events at 3, 5, and 10 years. A U-shaped pattern for adverse cardiovascular events was observed in middle-aged to older adults, where hyperfiltration was linked to negative outcomes. Examining adverse event frequency by eGFR in younger adults suggests that screening individuals with eGFR 75 ml/min/1.73 m2 or lower would be optimal. Improved risk-based determination of eGFR thresholds for adverse events associated with CKD will guide primary care providers, specialists, and policymakers and may influence clinical practice.