Markers of Kidney Tubular Secretion and Risk of Adverse Events in SPRINT Participants with CKD

Abstract

Significance Statement

SPRINT demonstrated in individuals with hypertension and high cardiovascular disease (CVD) risk that intensive BP lowering was associated with decreased risk of CVD events and all-cause mortality. However, it was also associated with increased risk of adverse events (AEs), particularly among those with CKD. Thus, the ability to identify individuals at higher risk for these AEs is paramount. We used ten novel endogenous markers to evaluate the association between tubular secretion and elevated risk of AEs. We found that lower tubular secretion was associated with higher risk of AEs, independent of eGFR and albuminuria. Assessment of kidney tubule health, including tubular secretion, may provide new opportunities to understand the kidney’s role in adverse health outcomes. Background

Kidney tubular secretion is an essential mechanism for clearing many common antihypertensive drugs and other metabolites and toxins. It is unknown whether novel measures of tubular secretion are associated with adverse events (AEs) during hypertension treatment. Methods

Among 2089 SPRINT (Systolic Blood Pressure Intervention Trial) participants with baseline eGFR <60 ml/min per 1.73 m2, we created a summary secretion score by averaging across the standardized spot urine-to-plasma ratios of ten novel endogenous tubular secretion measures, with lower urine-to-plasma ratios reflecting worse tubular secretion. Multivariable Cox proportional hazards models were used to evaluate associations between the secretion score and risk of a composite of prespecified serious AEs (hypotension, syncope, bradycardia, AKI, electrolyte abnormalities, and injurious falls). The follow-up protocol for SPRINT routinely assessed two laboratory monitoring AEs (hyperkalemia and hypokalemia). Results

Overall, 30% of participants experienced at least one AE during a median follow-up of 3.0 years. In multivariable models adjusted for eGFR and albuminuria, lower (worse) secretion scores at baseline were associated with greater risk of the composite AE outcome (hazard ratio per 1-SD lower secretion score, 1.16; 95% confidence interval, 1.04 to 1.27). In analyses of the individual AEs, lower secretion score was associated with significantly greater risk of AKI, serious electrolyte abnormalities, and ambulatory hyperkalemia. Associations were similar across randomized treatment assignment groups. Conclusion

Among SPRINT participants with CKD, worse tubular secretion was associated with greater risk of AEs, independent of eGFR and albuminuria.