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

Abstract

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.

Keywords: adverse events; biomarker; hypertension; tubular secretion.

Graphical abstract

Figure 1.

Proportion of SPRINT participants with CKD experiencing AEs across secretion score quartiles. Secretion score ranges include 30.0–55.2 in quartile 1, 55.2–60.0 in quartile 2, 60.0–64.4 in quartile 3, and 64.4–81.7 in quartile 4. AE, adverse event.

Figure 2.

Restricted cubic splines of hazard ratios and 95% confidence intervals for the association of the summary secretion score with risk of the composite AE outcome. The composite AE outcome includes six serious AEs of interest (hypotension, syncope, bradycardia, AKI, electrolyte abnormalities, or injurious falls) and hyperkalemia and hypokalemia on routine laboratory monitoring at clinic visits. Hazard ratios with 95% confidence intervals were obtained from multivariable Cox proportional hazards models that included age, sex, race, intervention arm, prevalent cardiovascular disease, alcohol use, smoking, frailty index, body mass index, systolic BP, diastolic BP, heart rate, orthostatic hypotension at baseline visit, dizziness at baseline visit, number of antihypertensive medications, total medication burden, angiotensin-converting enzyme inhibitor use, angiotensin II receptor blocker use, diuretic use, calcium channel blocker use, β-blocker use, baseline eGFR, and urine albumin-creatinine ratio.

Figure 3.

Forest plot of the summary secretion score association with risk of the composite AE outcome in SPRINT participants with CKD. The composite AE outcome includes six serious AEs of interest (hypotension, syncope, bradycardia, AKI, electrolyte abnormalities, or injurious falls) and hyperkalemia and hypokalemia on routine laboratory monitoring at clinic visits. Hazard ratios per 1-SD lower secretion score with 95% confidence intervals were obtained from multivariable Cox proportional hazards models that included age, sex, race, intervention arm, prevalent cardiovascular disease, alcohol use, smoking, frailty index, body mass index, systolic BP, diastolic BP, heart rate, orthostatic hypotension at baseline visit, dizziness at baseline visit, number of antihypertensive medications, total medication burden, angiotensin-converting enzyme inhibitor use, angiotensin II receptor blocker use, diuretic use, calcium channel blocker use, β-blocker use, baseline eGFR, and urine albumin-creatinine ratio.