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

Collins, Kimberly S.; Pratt, Victoria M.; Stansberry, Wesley M.; Medeiros, Elizabeth B.; Kannegolla, Karthik; Swart, Marelize; Skaar, Todd C.; Chapman, Arlene B.; Decker, Brian S.; Moorthi, Ranjani N.; Eadon, Michael T.

doi:10.1097/fpc.0000000000000361

Cited by 11 publications

(11 citation statements)

References 23 publications

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“…At present, there are many ways to treat CKD, including hypoglycemic [15], antihypertensive [16, 17], and control of urinary protein [18]. However, the treatment cost is high [19], the side effects are obvious [20], and the therapy is long-lasting [21] and ineffective [22].…”

Section: Introductionmentioning

confidence: 99%

Cordyceps militarisImproves Chronic Kidney Disease by Affecting TLR4/NF-κB Redox Signaling Pathway

Sun

Dong

Jiang

et al. 2019

Oxidative Medicine and Cellular Longevity

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Cordyceps militaris may show good promise in protecting against chronic kidney disease (CKD) but the molecular mechanism remains unclear. CKD risk is associated with the Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) signaling pathway. Cordycepin is the main component of Cordyceps militaris and may affect the TLR4/NF-κB pathway. Cordycepin was prepared by preparative HPLC. CKD patients were assigned into Cordyceps militaris (COG, 100 mg daily) and placebo (CG) groups. Cordycepin activity was measured using human embryo kidney cells (HEK293T). Biochemical indices, the levels of TLR4, NF-κB, cyclooxygenase-2 (COX2), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β), were measured by real-time qRT-PCR, or ELISA kits and or Western blot. After 3-month treatment, cordycepin reduced the levels of urinal protein, blood urea nitrogen (BUN), and creatinine by 36.7%±8.6%, 12.5%±3.2%, and 18.3%±6.6%, respectively (P<0.05). Cordyceps militaris improved lipid profile and redox capacity of CKD patients by reducing the serum levels of TG, TC, and LDL-C by 12.8%±3.6%, 15.7%±4.1%, and 16.5%±4.4% and increasing the HDL-C level by 10.1%±1.4% in the COG group when compared with the CG group, respectively (P<0.05). The serum levels of cystatin-C (Cys-C), myeloperoxidase (MPO), and malondialdehyde (MDA) were reduced by 14.0%±3.8%, 26.9%±12.3%, and 19.7%±7.9% while nitric oxide (NO) and superoxide dismutase (SOD) were increased by 12.5%±2.9% and 25.3%±13.4% in the COG group when compared with the CG group, respectively (P<0.05). Cordycepin reduced the levels of TLR4, NF-κB, COX2, TNF-α, and IL-1β in HEK293T cells too (P<0.05). However, cordycepin could not affect the levels anymore if TLR4 was silenced. Cordyceps militaris protected against CKD progression by affecting the TLR4/NF-κB lipid and redox signaling pathway via cordycepin.

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Section: Introductionmentioning

confidence: 99%

Cordyceps militarisImproves Chronic Kidney Disease by Affecting TLR4/NF-κB Redox Signaling Pathway

Sun

Dong

Jiang

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…Among the three studies assessed in this review with a phenotype-genotype concordance of less than 70%, one observed no separation in the distribution of its caffeine phenotyping results and the other two included the *12 and *13 variants [37, 44, 45]. As a result, our approach has been to adopt the 4-SNP model proposed by Hein et al [8, 33]. This 4-SNP model includes the *5, *6, *7, and *14 alleles and shows equivalent NAT2 phenotyping concordance (98.4%) compared to a 7-SNP model (98.4%) with the *11, *12, and *13 alleles included [33].…”

Section: Concordance Between Nat2 Phenotype and Genotypementioning

confidence: 99%

“…However, it is still commonly used in resistant hypertension and as a first-line therapy for afterload reduction in African Americans with heart failure [7]. In the Indiana University Healthcare system, NAT2 genotyping has been performed clinically as part of an antihypertensive pharmacogenetics panel since 2017, with results available to the clinician in the electronic health record [8, 9]. Among the 580 individuals who received antihypertensive pharmacogenetic testing in a kidney clinic, 13% of all renal patients were prescribed hydralazine (alone or in combination with isosorbide dinitrate), including 25% of all African Americans.…”

Section: Introductionmentioning

confidence: 99%

Genotype-Guided Hydralazine Therapy

et al. 2020

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Background: Despite its approval in 1953, hydralazine hydrochloride continues to be used in the management of resistant hypertension, a condition frequently managed by nephrologists and other clinicians. Hydralazine hydrochloride undergoes metabolism by the N-acetyltransferase 2 (NAT2) enzyme. NAT2 is highly polymorphic as approximately 50% of the general population are slow acetylators. In this review, we first evaluate the link between NAT2 genotype and phenotype. We then assess the evidence available for genotype-guided therapy of hydralazine, specifically addressing associations of NAT2 acetylator status with hydralazine pharmacokinetics, antihypertensive efficacy, and toxicity. Summary: There is a critical need to use hydralazine in some patients with resistant hypertension. Available evidence supports a significant link between genotype and NAT2 enzyme activity as 29 studies were identified with an overall concordance between genotype and phenotype of 92%. The literature also supports an association between acetylator status and hydralazine concentration, as fourteen of fifteen identified studies revealed significant relationships with a consistent direction of effect. Although fewer studies are available to directly link acetylator status with hydralazine antihypertensive efficacy, the evidence from this smaller set of studies is significant in 7 of 9 studies identified. Finally, 5 studies were identified which support the association of acetylator status with hydralazine-induced lupus. Clinicians should maintain vigilance when prescribing maximum doses of hydralazine. Key Messages: NAT2 slow acetylator status predicts increased hydralazine levels, which may lead to increased efficacy and adverse effects. Caution should be exercised in slow acetylators with total daily hydralazine doses of 200 mg or more. Fast acetylators are at risk for inefficacy at lower doses of hydralazine. With appropriate guidance on the usage of NAT2 genotype, clinicians can adopt a personalized approach to hydralazine dosing and prescription, enabling more efficient and safe treatment of resistant hypertension.

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“…We hypothesized that embedding a panel of pharmacogenomic predictors of antihypertensive response in routine clinical practice would aid patients and practitioners in arriving at an efficacious blood pressure regimen, either by identifying less efficacious medications in an individual’s current regimen or selecting an efficacious drug as the “next” antihypertensive agent. To facilitate this, a clinical genotyping assay was developed and implemented across multiple health systems, with results and recommendations recorded in the electronic health records (EHR) for 40 variants and 11 drug-gene pairs relevant to hypertension control 14 .…”

Section: Introductionmentioning

confidence: 99%

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

Maddatu

et al. 2021

Preprint

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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.

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

Cited by 11 publications

References 23 publications

Cordyceps militarisImproves Chronic Kidney Disease by Affecting TLR4/NF-κB Redox Signaling Pathway

Cordyceps militarisImproves Chronic Kidney Disease by Affecting TLR4/NF-κB Redox Signaling Pathway

Genotype-Guided Hydralazine Therapy

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

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