Pharmacogenomics of hypertension in chronic kidney disease: the CKD-PGX study

Abstract

Background: Patients with chronic kidney disease (CKD) often have uncontrolled hypertension despite polypharmacy. Pharmacogenomic drug-gene interactions (DGIs) may impact the metabolism or efficacy of antihypertensive agents. We hypothesized that providing a panel of 11 pharmacogenomic predictors of antihypertensive response would improve hypertension control. Methods: A prospective cohort with CKD and hypertension was followed to assess the effect of pharmacogenomic testing on blood pressure control. The analysis population included 382 hypertensive subjects genotyped for cross-sectional assessment of drug-gene interactions and 335 subjects followed for 1 year to assess systolic (SBP) and diastolic blood pressure (DBP). Results: Most participants (58.2%) with uncontrolled hypertension had a DGI reducing the efficacy of one or more antihypertensive agents. Subjects with a DGI had 1.88-fold (95% CI 1.2-2.8) higher odds of uncontrolled hypertension as compared to those without a DGI, adjusted for race and CKD grade. CYP2C9 reduced metabolism genotypes were associated with losartan response and uncontrolled hypertension (Odds Ratio 5.2, CI 1.9 -14.7). CYP2D6 intermediate or poor metabolizers had less frequent uncontrolled hypertension compared to normal metabolizers taking metoprolol or carvedilol (OR 0.55, CI 0.3-0.95). In 335 subjects completing 1 year follow-up, SBP (-4.0 mmHg, CI 1.6- 6.5) and DBP (-3.3 mmHg, CI 2.0-4.6) were improved. The magnitude of reductions in SBP (-14.8 mmHg, CI 10.3-19.3) and DBP (-8.4 mmHg, CI 5.9-10.9) were greatest in the 90 individuals with uncontrolled hypertension and an actionable genotype. Conclusions: There is a potential role for the addition of pharmacogenomic testing to optimize antihypertensive regimens in patients with CKD.

Hypertension Pharmacogenomics in CKD: The Clinical Relevance and Public Health Implications

“…In this issue of Kidney360 , Eadon et al . (19) evaluated the association of DGIs with uncontrolled hypertension among 382 adults with hypertension and/or CKD. A clinical genotyping assay was developed for 40 variants and 11 drug-gene pairs relevant to hypertension control, selected on the basis of the strength of evidence, minor allele frequency, Food and Drug Administration label annotations, and guidelines including the Dutch Pharmacogenomic Working Group and Clinical Pharmacogenomics Implementation Consortium (20).…”