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

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.