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Analytical validity of a genotyping assay for use with personalized antihypertensive and chronic kidney disease therapy.

ABSTRACT: Hypertension and chronic kidney disease are inextricably linked. Hypertension is a well-recognized contributor to chronic kidney disease progression and, in turn, renal disease potentiates hypertension. A generalized approach to drug selection and dosage has not proven effective in managing these conditions, in part, because patients with heterogeneous kidney disease and hypertension etiologies are frequently grouped according to functional or severity classifications. Genetic testing may serve as an important tool in the armamentarium of clinicians who embrace precision medicine. Increasing scientific evidence has supported the utilization of genomic information to select efficacious antihypertensive therapy and understand hereditary contributors to chronic kidney disease progression. Given the wide array of antihypertensive agents available and diversity of genetic renal disease predictors, a panel-based approach to genotyping may be an efficient and economic means of establishing an individualized blood pressure response profile for patients with various forms of chronic kidney disease and hypertension. In this manuscript, we discuss the validation process of a Clinical Laboratory Improvement Amendments-approved genetic test to relay information on 72 genetic variants associated with kidney disease progression and hypertension therapy. These genomic-based interventions, in addition to routine clinical data, may help inform physicians to provide personalized therapy.

SUBMITTER: Collins KS

PROVIDER: S-EPMC6358457 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Analytical validity of a genotyping assay for use with personalized antihypertensive and chronic kidney disease therapy.

Collins Kimberly S KS Pratt Victoria M VM Stansberry Wesley M WM Medeiros Elizabeth B EB Kannegolla Karthik K Swart Marelize M Skaar Todd C TC Chapman Arlene B AB Decker Brian S BS Moorthi Ranjani N RN Eadon Michael T MT

Pharmacogenetics and genomics 20190101 1

Hypertension and chronic kidney disease are inextricably linked. Hypertension is a well-recognized contributor to chronic kidney disease progression and, in turn, renal disease potentiates hypertension. A generalized approach to drug selection and dosage has not proven effective in managing these conditions, in part, because patients with heterogeneous kidney disease and hypertension etiologies are frequently grouped according to functional or severity classifications. Genetic testing may serve ...[more]

PMID: 30489456

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Project description:Background and objectivesThe transition from CKD to ESRD can be particularly unstable, with high rates of death and hospitalizations. Few studies have examined medication use during this critical period. We examined patterns of antihypertensive medication use from the four quarters before and eight quarters after incident ESRD treated with maintenance dialysis.Design, setting, participants, & measurementsWe used the US Renal Data System to identify patients aged ≥67 years initiating dialysis for ESRD between January 2008 and December 2010 with Medicare Part D and a low-income subsidy. We ascertained the incidence of AKI and hyperkalemia during each quarter on the basis of having at least 1 payment claim for the condition. We used Poisson regression with robust SEMs to formally test for changes in the trend and level of antihypertensive medication use in a series of intervention analyses.ResultsThe number of antihypertensive drugs used increased as patients neared ESRD, peaking at an average of 3.4 in the quarter immediately preceding dialysis initiation, then declining to 2.2 medications by 2 years later. Angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use was stable at approximately 40%, even among patients with coronary disease and systolic heart failure, and did not correlate with AKI or hyperkalemia. Dialysis initiation was associated with a 40% (95% confidence interval, 38% to 43%) lower adjusted level of diuretic use, which continued to decline after ESRD. Three- and four-drug combinations that included a diuretic were most common before ESRD, whereas after ESRD, one- and two-drug β-blocker or calcium-channel blocker-based combinations were most common.ConclusionsThe use of antihypertensive medications, particularly angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers and diuretics, may be suboptimal during the transition from CKD to ESRD, especially in patients with coronary disease or systolic heart failure. Future studies are needed to identify strategies to increase the appropriate use of antihypertensive medications during this critical transition period.

Project description:Background The implementation of genotyping for anti-hypertensive drugs in clinical practice remains a challenge. We conducted this study to analyze the distribution of polymorphisms of antihypertensive drug-related genes in Changsha County in China and compare the clinical effectiveness of genotype-guided and clinical experience-guided antihypertensive therapy in hypertensive individuals. Methods A total of 9,933 essential hypertensive participants from Changsha County were consecutively enrolled in our study, and 7 genetic polymorphic loci (CYP2D6*10, ADRB1, CYP2C9*3, AGTR1, ACE, CYP3A5*3 and NPPA) were detected by a polymerase chain reaction (PCR)-fluorescence probe. From an available sample of 660 hypertensive participants, 495 cases were randomly identified by genotype-guided therapy and 165 cases by clinical experience-guided therapy. We performed 24-hour ambulatory blood pressure (BP) monitoring on each of these cases, pre- and post-intervention. Results In the enrolled 9,933 cases, the mutation frequencies of CYP2C9*3, ADRB1(1165G>C), AGTR1(1166A>C), CYP2D6*10, ACE(I/D), CYP3A5*3 and NPPA(2238T>C) were 4.41%, 74.60%, 5.55%, 57.08%, 30.94%, 69.03% and 1.19%, respectively. In both genotype-guided and clinical experience-guided groups, the comparisons of intra-group pre-and post-treatments showed significant decreases in diastolic blood pressure (DBP) (P<0.01) and significant increases in the control rate of BP (47.1% vs. 38.6% and 37.5% vs. 33.9%, P<0.05) in response to adjusted antihypertensive agents. Correspondingly, the extent of the reduction of systolic blood pressure (SBP; 3.52±11.72 vs. 0.92±9.14 mmHg), the extent of the increase in the rate of BP control (8.5% vs. 3.6%) and the percentage rate of decrease of grades 2 and 3 hypertensive individuals were more significant in the genotype-guided group than that in the clinical experience-guided group (P<0.01). Conclusions While prescribing anti-hypertensive drugs, appropriate dosage and type adjustments should be made according to the gene mutation frequency and individual circumstances. Pharmacogenomics-guided personalized treatment of hypertensive patients is likely to be a more effective strategy, especially in those with significantly elevated SBP.

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Analytical validity of a genotyping assay for use with personalized antihypertensive and chronic kidney disease therapy.

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Analytical validity of a genotyping assay for use with personalized antihypertensive and chronic kidney disease therapy.

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