A Quantitative Analysis of the Role of Antihypertensive Drug Dose on Hypertension in Children with Chronic Kidney Disease

Abstract

Hypertension (HTN) is a highly prevalent and major risk factor for poor cardiovascular and kidney outcomes in chronic kidney disease (CKD). Prior research suggests that HTN is underdiagnosed and undertreated in children with CKD. Risk factors associated with HTN in CKD among children include worsening kidney function, African American race, primary glomerular disease, proteinuria, and non-use of renin-angiotensin-aldosterone system inhibitors (RAASi). However, the effect of antihypertensive dose on blood pressure control in this population is unknown. The objective of this study was to determine the effect of antihypertensive dose on blood pressure control in children with CKD. We hypothesize that uncontrolled hypertension (uHTN) is associated with lower antihypertensive dose. We developed a novel quantitative tool, the relative dose index (RDI), to analyze the effect of dose on blood pressure control, which expresses subject’s daily dose as a ratio between the current daily dose and the maximum potential daily dose, accounting for age, weight and if indicated, renal dose adjustments. Cumulative RDI (cRDI) is the sum RDI for all antihypertensive agents. This study was performed on data from the Chronic Kidney Disease in Children (CKiD) study, a large North American multicenter longitudinal study on children with CKD. A preliminary univariate analysis was performed on multiple clinical, demographic and pharmacological variables comparing outcomes of controlled vs. uncontrolled hypertension as well as on absence vs. presence left ventricular hypertrophy (LVH), considered a long-term sequela of uHTN. A multivariate logistic regression model was developed including relevant covariates. cRDI was not found to be significantly associated with uHTN or LVH, and therefore dose expressed as cRDI may be an indicator of disease severity. Similar to previous findings, non-use of RAASi was associated with uHTN. Non-use of diuretics and non-Caucasian, non-African American race were associated with higher odds of uHTN. Female sex, African American race, and use of a calcium channel blocker, diuretic or beta-blocker were associated with LVH. This study is the first quantitative analysis of the effect of antihypertensive dose on BP control in children with CKD. The cRDI has potential applications in research areas where multiple drugs are used for a single indication and quantitative analysis of the dose-effect relationship is needed.