Kidney Function Measures and Mortality: A Mendelian Randomization Study

Rationale & ObjectiveIndividuals with a low estimated glomerular filtration rate (eGFR) are at a high risk of death. Yet, the causes underpinning this association are largely uncertain. This study aimed to assess the causal relationship of low eGFR with all-cause and cause-specific mortality.Study DesignRetrospective cohort study incorporating Mendelian randomization (MR).Setting & ParticipantsIndividual-level data from 436,214 White participants (54.3% females, aged 56.8 ± 8.0 years) included in the United Kingdom (UK) Biobank.ExposuresEGFR estimated using cystatin C (eGFRcyst).OutcomesThe outcomes of interest included all-cause mortality, cardiovascular mortality, cancer mortality, infection mortality, and other-cause mortality.Analytical ApproachCox proportional hazards analysis for the conventional observational analyses. Linear and nonlinear MR analyses implemented using genetic allele scores as instrumental variables representing kidney function to estimate the effect of kidney function on the survival outcomes.ResultsDuring a median follow-up of 12.1 years, 30,489 participants died, including 6,098 attributed to cardiovascular events, 15,538 to cancer, 1,516 to infection, and 7,227 to other fatal events. In the conventional observational analysis, eGFRcyst exhibited a nonlinear association with all the outcomes. MR analysis suggested that genetically predicted lower eGFRcyst was linearly associated with a higher rate of cardiovascular mortality (hazard ratio [HR] 1.43, 95% confidence interval [CI] 1.18-1.75) across the entire measurement range (every 10 ml/min/1.73 m2 decrement). Nonetheless, no causal associations between eGFRcyst and all-cause mortality (HR 1.07, 95% CI 0.98-1.17) or any types of noncardiovascular mortality were detected.LimitationsPotential misclassification of the actual cause of death, a non-representative sample, and potential error in the interpretation of magnitude of associations generated in MR analyses.ConclusionsThese findings suggest a potential causal association between low eGFR and cardiovascular mortality in the general population, yet no causal relationship with all-cause mortality or noncardiovascular mortality was observed. Further studies in other populations are warranted to confirm these findings.