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

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.

Fibroblast Growth Factor 23 Genotype and Cardiovascular Disease in Patients Undergoing Hemodialysis.

BACKGROUND: Elevated serum concentrations of fibroblast growth factor 23 (FGF23) are associated with cardiovascular mortality in patients with chronic kidney disease and those undergoing dialysis. OBJECTIVES: We tested the hypotheses that polymorphisms in FGF23, its co-receptor alpha-klotho (KL), and/or FGF23 receptors (FGFR) are associated with cardiovascular events and/or mortality. METHODS: We used 1,494 DNA samples collected at baseline from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events Trial, in which patients were randomized to the calcimimetic cinacalcet or placebo for the treatment of secondary hyperparathyroidism. We analyzed European and African Ancestry samples separately and then combined summary statistics to perform a meta-analysis. We evaluated single-nucleotide polymorphisms (SNPs) in FGF23, KL, and FGFR4 as the key exposures of interest in proportional hazards (Cox) regression models using adjudicated endpoints (all-cause and cardiovascular mortality, sudden cardiac death, and heart failure [HF]) as the outcomes of interest. RESULTS: rs11063112 in FGF23 was associated with cardiovascular mortality (risk allele = A, hazard ratio [HR] 1.32, meta-p value = 0.004) and HF (HR 1.40, meta-p value = 0.007). No statistically significant associations were observed between FGF23 rs13312789 and SNPs in FGFR4 or KL genes and the outcomes of interest. CONCLUSIONS: rs11063112 was associated with HF and cardiovascular mortality in patients receiving dialysis with moderate to severe secondary hyperparathyroidism.

Angiotensin-related genetic determinants of cardiovascular disease in patients undergoing hemodialysis.

BACKGROUND: Cardiovascular mortality in patients receiving dialysis remains unacceptably high, with unexplained ancestry differences suggesting a genetic component. METHODS: We analyzed DNA samples from 37% of subjects enrolled in the EValuation Of Cinacalcet Hydrochloride (HCl) Therapy to Lower CardioVascular Events (EVOLVE) trial, a randomized trial conducted in patients receiving hemodialysis with secondary hyperparathyroidism, comparing cinacalcet to placebo on a background of usual care. DNA was analyzed for single-nucleotide polymorphisms (SNPs) in the genes encoding the angiotensin-converting enzyme receptor type I (AGTR1) and angiotensin-converting enzyme (ACE). Survival analyses were conducted separately in European Ancestry (EA) and African Ancestry (AfAn) due to known differences in cardiovascular events, minor alleles for the same variant and the frequency of minor alleles. Our primary determination was a meta-analysis across both races. RESULTS: Meta-analysis showed significant associations between rs5186 in AGTR1 and increased rates by 25-34% for the primary endpoint (composite of death or nonfatal myocardial infarction, hospitalization for unstable angina, heart failure or peripheral vascular event), all-cause mortality, cardiovascular mortality and heart failure; all P < 0.001. Three correlated SNPs in ACE were associated with lower rates of sudden cardiac death (SCD) in EA samples. One ACE SNP, rs4318, only found in the AfAn samples, was associated with a lower rate of SCD in the AfAn samples. CONCLUSIONS: The C allele in rs5186 in AGTR1 was associated with higher rates of death and major cardiovascular events in a meta-analysis of EA and AfAn patients with end-stage kidney disease. SNPs in ACE were associated with SCD.

Triamterene Enhances the Blood Pressure Lowering Effect of Hydrochlorothiazide in Patients with Hypertension.

BACKGROUND: Triamterene, because of its potassium-sparing properties, is frequently used in combination with hydrochlorothiazide (HCTZ) to treat patients with hypertension. By inhibiting the epithelial sodium channel (ENaC) in the cortical collecting duct, triamterene reduces potassium secretion, thus reducing the risk of hypokalemia. Whether triamterene has an independent effect on blood pressure (BP) has not been well studied. OBJECTIVE: To determine if triamterene provides an effect to further lower BP in patients treated with HCTZ. DESIGN: We conducted an observational study using electronic medical record data from the Indiana Network for Patient Care. Participants were 17,291 patients with the diagnosis of hypertension between 2004 and 2012. MAIN MEASURES: BP was the primary outcome. We compared the BP between patients who were taking HCTZ, with and without triamterene, either alone or in combination with other antihypertensive medications, by using a propensity score analysis. For each medication combination, we estimated the propensity score (i.e., probability) of a patient receiving triamterene using a logistic regression model. Patients with similar propensity scores were stratified into subclasses and BP was compared between those taking triamterene or not within each subclass; the effect of triamterene was then assessed by combining BP differences estimated from all subclasses. KEY RESULTS: The mean systolic BP in the triamterene + HCTZ group was 3.8 mmHg lower than in the HCTZ only group (p < 0.0001); systolic BP was similarly lower for patients taking triamterene with other medication combinations. Systolic BP reduction was consistently observed for different medication combinations. The range of systolic BP reduction was between 1 and 4 mm Hg, depending on the concurrently used medications. CONCLUSIONS: In the present study, triamterene was found to enhance the effect of HCTZ to lower BP. In addition to its potassium-sparing action, triamterene's ability to lower BP should also be considered.

Knowledge and Awareness Among Patients with Chronic Kidney Disease Stage 3.

Knowledge is a prerequisite for changing behavior, and is useful for improving outcomes and reducing mortality rates in patients diagnosed with chronic kidney disease (CKD). The purpose of this article is to describe baseline CKD knowledge and awareness obtained as part of a larger study testing the feasibility of a self-management intervention. Thirty patients were recruited who had CKD Stage 3 with coexisting diabetes and hypertension. Fifty-four percent of the sample were unaware of their CKD diagnosis. Participants had a moderate amount of CKD knowledge. This study suggests the need to increase knowledge in patients with CKD Stage 3 to aid in slowing disease progression.

Effects of chronic kidney disease on liver transport: quantitative intravital microscopy of fluorescein transport in the rat liver.

Clinical studies indicate that hepatic drug transport may be altered in chronic kidney disease (CKD). Uremic solutes associated with CKD have been found to alter the expression and/or activity of hepatocyte transporters in experimental animals and in cultured cells. However, given the complexity and adaptability of hepatic transport, it is not clear whether these changes translate into significant alterations in hepatic transport in vivo. To directly measure the effect of CKD on hepatocyte transport in vivo, we conducted quantitative intravital microscopy of transport of the fluorescent organic anion fluorescein in the livers of rats following 5/6th nephrectomy, an established model of CKD. Our quantitative analysis of fluorescein transport showed that the rate of hepatocyte uptake was reduced by ∼20% in 5/6th nephrectomized rats, consistent with previous observations of Oatp downregulation. However, the overall rate of transport into bile canaliculi was unaffected, suggesting compensatory changes in Mrp2-mediated secretion. Our study suggests that uremia resulting from 5/6th nephrectomy does not significantly impact the overall hepatic clearance of an Oatp substrate.

Principles and operational parameters to optimize poison removal with extracorporeal treatments.

A role for nephrologists in the management of a poisoned patient involves evaluating the indications for, and methods of, enhancing the elimination of a poison. Nephrologists are familiar with the various extracorporeal treatments (ECTRs) used in the management of impaired kidney function, and their respective advantages and disadvantages. However, these same skills and knowledge may not always be considered, or applicable, when prescribing ECTR for the treatment of a poisoned patient. Maximizing solute elimination is a key aim of such treatments, perhaps more so than in the treatment of uremia, because ECTR has the potential to reverse clinical toxicity and shorten the duration of poisoning. This manuscript reviews the various principles that govern poison elimination by ECTR (diffusion, convection, adsorption, and centrifugation) and how components of the ECTR can be adjusted to maximize clearance. Data supporting these recommendations will be presented, whenever available.

Gentamicin pharmacokinetics and pharmacodynamics during short-daily hemodialysis.

BACKGROUND/AIMS: Gentamicin pharmacokinetics have not been described in patients undergoing short-daily hemodialysis (SDHD). The aim of this study is to describe gentamicin pharmacokinetics and dialytic clearance (Cl(dial)) in SDHD patients and simulate gentamicin exposure after six dosing regimens to help guide future dosing. METHODS: Six anuric patients undergoing SDHD were enrolled. Patients received intravenous infusion of 2 mg/kg gentamicin on day 1 after the first HD session followed by HD sessions on days 2, 3, and 4. Blood samples for determination of gentamicin concentrations were serially collected. Gentamicin pharmacokinetic parameters and Cl(dial) and interindividual variability terms (IIV) were estimated using NONMEM VII. Influence of patient weight on systemic clearance (Cl(s)) and central volume of distribution (V(c)) and influence of urea removal estimates on Cl(dial) were assessed. The model was used to simulate gentamicin concentrations after six dosing regimens including pre- and postdialysis as well as daily and every-other-day dosing. RESULTS: A two-compartment model with first-order elimination from central compartment described gentamicin pharmacokinetics. Population estimates for Cl(s) and Cl(dial) were 7.6 and 134 ml/min, respectively. Patient weight was statistically significantly associated with Cl(s) and V(c). Predialysis every-other-day regimens were as effective (C(max) ≥8 mg/l and AUC(48 h) ≥140 mg·h/l) and less toxic (C(min) <2 mg/l and AUC(48 h) <240 mg·h/l) than postdialysis regimens. CONCLUSIONS: Estimated gentamicin Cl(dial) is higher than previous estimates with thrice-weekly regimens. Predialysis every-other-day dosing may be recommended during SDHD.

Drug dosing consideration in patients with acute and chronic kidney disease-a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO).

Drug dosage adjustment for patients with acute or chronic kidney disease is an accepted standard of practice. The challenge is how to accurately estimate a patient's kidney function in both acute and chronic kidney disease and determine the influence of renal replacement therapies on drug disposition. Kidney Disease: Improving Global Outcomes (KDIGO) held a conference to investigate these issues and propose recommendations for practitioners, researchers, and those involved in the drug development and regulatory arenas. The conference attendees discussed the major challenges facing drug dosage adjustment for patients with kidney disease. In particular, although glomerular filtration rate is the metric used to guide dose adjustment, kidney disease does affect nonrenal clearances, and this is not adequately considered in most pharmacokinetic studies. There are also inadequate studies in patients receiving all forms of renal replacement therapy and in the pediatric population. The conference generated 37 recommendations for clinical practice, 32 recommendations for future research directions, and 24 recommendations for regulatory agencies (US Food and Drug Administration and European Medicines Agency) to enhance the quality of pharmacokinetic and pharmacodynamic information available to clinicians. The KDIGO Conference highlighted the gaps and focused on crafting paths to the future that will stimulate research and improve the global outcomes of patients with acute and chronic kidney disease.

Prediction of Nephropathy in Type 2 Diabetes: An Analysis of the ACCORD Trial Applying Machine Learning Techniques.

Applying data mining and machine learning (ML) techniques to clinical data might identify predictive biomarkers for diabetic nephropathy (DN), a common complication of type 2 diabetes mellitus (T2DM). A retrospective analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was intended to identify such factors using ML. The longitudinal data were stratified by time after patient enrollment to differentiate early and late predictors. Our results showed that Random Forest and Simple Logistic Regression methods exhibited the best performance among the evaluated algorithms. Baseline values for glomerular filtration rate (GFR), urinary creatinine, urinary albumin, potassium, cholesterol, low-density lipoprotein, and urinary albumin to creatinine ratio were identified as DN predictors. Early predictors were the baseline values of GFR, systolic blood pressure, as well as fasting plasma glucose (FPG) and potassium at month 4. Changes per year in GFR, FPG, and triglycerides were recognized as predictors of late development. In conclusion, ML-based methods successfully identified predictive factors for DN among patients with T2DM.

Drug-gene and drug-drug interactions associated with tramadol and codeine therapy in the INGENIOUS trial.

Background: Tramadol and codeine are metabolized by CYP2D6 and are subject to drug-gene and drug-drug interactions. Methods: This interim analysis examined prescribing behavior and efficacy in 102 individuals prescribed tramadol or codeine while receiving pharmaco-genotyping as part of the INGENIOUS trial (NCT02297126). Results: Within 60 days of receiving tramadol or codeine, clinicians more frequently prescribed an alternative opioid in ultrarapid and poor metabolizers (odds ratio: 19.0; 95% CI: 2.8-160.4) as compared with normal or indeterminate metabolizers (p = 0.01). After adjusting the CYP2D6 activity score for drug-drug interactions, uncontrolled pain was reported more frequently in individuals with reduced CYP2D6 activity (odds ratio: 0.50; 95% CI: 0.25-0.94). Conclusion: Phenoconversion for drug-drug and drug-gene interactions is an important consideration in pharmacogenomic implementation; drug-drug interactions may obscure the potential benefits of genotyping.

Varying Influences of Aldosterone on the Plasma Potassium Concentration in Blacks and Whites.

BACKGROUND: Aldosterone acts to restrain the extracellular potassium (K+) concentration. Blacks have on average lower plasma aldosterone concentrations (PACs) than Whites. Whether this ethnic difference is associated with similar changes in the concentration of K+ is unclear. METHODS: Subjects were Blacks and Whites from an observational study of blood pressure regulation. PAC was known to be significantly lower in Blacks than Whites. We sought to test the hypothesis that the concentration of K+ remains constant despite variability in PAC. Initial enrollment took place in childhood in 1986. Some of the original enrollees were studied again in adulthood: 160 healthy Blacks and 271 healthy Whites (ages 5 to 39 years; all were studied as children and as adults). RESULTS: Plasma renin activity [a biomarker of angiotensin II and, more proximally, extracellular fluid volume (ECFV)] and PAC were lower in Blacks (P < 0.0354 and P < 0.001, respectively, for all ages). At the same time no ethnic difference in levels of K+ was observed regardless of age. Plasma K+ concentration and PAC associated differently based on ethnicity: PAC increased in Blacks by 1.5-2.0 and in Whites by 2.3-3.0 ng/dl per mmol/l increase in K+ (P < 0.001). CONCLUSIONS: Lower aldosterone levels in Blacks did not translate into higher K+ concentrations. We speculate that reaching the right concentration of K+ was an endpoint of aldosterone production in the presence of varying levels of ECFV and angiotensin II.

PATTERNS OF HEALTHCARE ENCOUNTERS EXPERIENCED BY PATIENTS WITH CHRONIC KIDNEY DISEASE.

BACKGROUND: Patterns of healthcare encounters by patients in each stage of chronic kidney disease (CKD) have not been fully described. OBJECTIVE: This study describes patterns of healthcare resource use by patients with CKD. DESIGN: A retrospective descriptive design was used. PARTICIPANTS: Patients with Stages 1-5 CKD were identified in five existing de-identified healthcare insurance claims databases in the United States using codes from the International Classification of Diseases (ICD-9-CM). MEASUREMENTS: The databases contained more than 23,660,000 claims records from over 11 million subscribers who were continuously enrolled in a single 2014 health plan. All CKD patients' 2014 claims were extracted, yielding 1,987 unique people with 110,594 healthcare encounters. RESULTS: Healthcare resources are used to manage the causes of CKD and its multiple effects on health, and thus the number of healthcare encounters among people with more advanced disease was, as expected, relatively higher. There were more hospitalisations, emergency department visits and specialist encounters in this group. Surprisingly, however, even people in earlier stages of kidney disease experienced a median of 14-17 healthcare encounters during a single calendar year. CONCLUSIONS: Understanding patterns of healthcare encounters provides important information about the transition experiences of patients with CKD. Exploring ways to reduce the risks associated with transitions in care may prevent problems with home medication management, frequent emergency department visits and potentially avoidable hospitalisations.

Pharmacogenomically actionable medications in a safety net health care system.

OBJECTIVE: Prior to implementing a trial to evaluate the economic costs and clinical outcomes of pharmacogenetic testing in a large safety net health care system, we determined the number of patients taking targeted medications and their clinical care encounter sites. METHODS: Using 1-year electronic medical record data, we evaluated the number of patients who had started one or more of 30 known pharmacogenomically actionable medications and the number of care encounter sites the patients had visited. RESULTS: Results showed 7039 unique patients who started one or more of the target medications within a 12-month period with visits to 73 care sites within the system. CONCLUSION: Findings suggest that the type of large-scale, multi-drug, multi-gene approach to pharmacogenetic testing we are planning is widely relevant, and successful implementation will require wide-scale education of prescribers and other personnel involved in medication dispensing and handling.

1-Alpha, 25-dihydroxyvitamin D3 alters the pharmacokinetics of mycophenolic acid in renal transplant recipients by regulating two extrahepatic UDP-glucuronosyltransferases 1A8 and 1A10.

Mycophenolic acid (MPA) is an important immunosuppressant broadly used in renal transplantation. However, the large inter-patient variability in mycophenolic acid (MPA) pharmacokinetics (PK) limits its use. We hypothesize that extrahepatic metabolism of MPA may have significant impact on MPA PK variability. Two intestinal UDP-glucuronosyltransferases 1A8 and 1A10 plays critical role in MPA metabolism. Both in silico and previous genome-wide analyses suggested that vitamin D (VD) may regulate intestinal UGT1A expression. We validated the VD response elements (VDREs) across the UGT1A locus with chromatin immunoprecipitation (ChIP) and luciferase reporter assays. The impact of 1-alpha,25-dihydroxyvitamin D3 (D3) on UGT1A8 and UGT1A10 transcription and on MPA glucuronidation was tested in human intestinal cell lines LS180, Caco-2 and HCT-116. The correlation between transcription levels of VD receptor (VDR) and the two UGT genes were examined in human normal colorectal tissue samples (n = 73). PK alterations of MPA following the parent drug, mycophenolate mofetil (MMF), and D3 treatment was assessed among renal transplant recipients (n = 10). Our ChIP assay validate three VDREs which were further demonstrated as transcriptional enhancers with the luciferase assays. D3 treatment significantly increased transcription of both UGT genes as well as MPA glucuronidation in cells. The VDR mRNA level was highly correlated with that of both UGT1A8 and UGT1A10 in human colorectal tissue. D3 treatment in patients led to about 40% reduction in both AUC0-12 and Cmax while over 70% elevation of total clearance of MPA. Our study suggested a significant regulatory role of VD on MPA metabolism and PK via modulating extrahepatic UGT activity.

Self-management interventions in stages 1 to 4 chronic kidney disease: an integrative review.

The prevalence, effect on health outcomes, and economic impact of chronic kidney disease (CKD) have created interest in self-management interventions to help slow disease progression to kidney failure. Seven studies were reviewed to identify knowledge gaps and future directions for research. All studies were published between 2010 and 2013; no investigations were conducted in the United States. Knowledge gaps included the focus on medical self-management tasks with no attention to role or emotional tasks, lack of family involvement during intervention delivery, and an inability to form conclusions about the efficacy of interventions because methodological rigor was insufficient. Educational content varied across studies. Strategies to improve self-management skills and enhance self-efficacy varied and were limited in scope. Further development and testing of theory-based interventions are warranted. There is a critical need for future research using well-designed trials with appropriately powered sample sizes, well-tested instruments, and clear and consistent reporting of results.

Extracorporeal Treatment for Lithium Poisoning: Systematic Review and Recommendations from the EXTRIP Workgroup.

The Extracorporeal Treatments in Poisoning Workgroup was created to provide evidence-based recommendations on the use of extracorporeal treatments in poisoning. Here, the EXTRIP workgroup presents its recommendations for lithium poisoning. After a systematic literature search, clinical and toxicokinetic data were extracted and summarized following a predetermined format. The entire workgroup voted through a two-round modified Delphi method to reach a consensus on voting statements. A RAND/UCLA Appropriateness Method was used to quantify disagreement, and anonymous votes were compiled and discussed in person. A second vote was conducted to determine the final workgroup recommendations. In total, 166 articles met inclusion criteria, which were mostly case reports, yielding a very low quality of evidence for all recommendations. A total of 418 patients were reviewed, 228 of which allowed extraction of patient-level data. The workgroup concluded that lithium is dialyzable (Level of evidence=A) and made the following recommendations: Extracorporeal treatment is recommended in severe lithium poisoning (1D). Extracorporeal treatment is recommended if kidney function is impaired and the [Li(+)] is >4.0 mEq/L, or in the presence of a decreased level of consciousness, seizures, or life-threatening dysrhythmias irrespective of the [Li(+)] (1D). Extracorporeal treatment is suggested if the [Li(+)] is >5.0 mEq/L, significant confusion is present, or the expected time to reduce the [Li(+)] to <1.0 mEq/L is >36 hours (2D). Extracorporeal treatment should be continued until clinical improvement is apparent or [Li(+)] is <1.0 mEq/L (1D). Extracorporeal treatments should be continued for a minimum of 6 hours if the [Li(+)] is not readily measurable (1D). Hemodialysis is the preferred extracorporeal treatment (1D), but continuous RRT is an acceptable alternative (1D). The workgroup supported the use of extracorporeal treatment in severe lithium poisoning. Clinical decisions on when to use extracorporeal treatment should take into account the [Li(+)], kidney function, pattern of lithium toxicity, patient's clinical status, and availability of extracorporeal treatments.

Needs, concerns, strategies, and advice of daily home hemodialysis caregivers.

Improved patient outcomes have led to increased international interest in daily home hemodialysis as a kidney replacement therapy. Daily home hemodialysis often requires the assistance of a caregiver during and between treatments. Understanding the needs and concerns of caregivers of persons on daily home hemodialysis will inform the design of supportive interventions to improve caregiver retention and maintain their health and well-being. Using a descriptive qualitative design, the purpose of this study was to identify and describe the needs, concerns, strategies, and advice of family caregivers. Twenty-one caregivers were interviewed; five of these individuals were former caregivers of patients who had returned to outpatient hemodialysis. Data were collected via audio-recorded telephone interviews following a semistructured interview guide with five open-ended questions. A content analysis approach was used to code and analyze the data. Caregivers described needs, concerns, and strategies and offered advice in five predetermined major categories. Major findings included a need for respite services and a need for interventions to manage the emotional responses to caregiving. This study provides valuable information about relevant areas to consider when developing an intervention program for daily home hemodialysis caregivers.

Hemodialysis does not alter in vitro hepatic CYP3A4 and CYP2D6 metabolic activity in uremic serum.

There is a paucity of studies evaluating the change in liver metabolism in subjects receiving hemodialysis. The purpose of this study was to compare the effect of uremic toxins on hepatic cytochrome P450 (CYP)3A4 and CYP2D6 metabolism before and after a 4-hour hemodialysis session. Midazolam and dextromethorphan were incubated with uremic serum collected from subjects before and after the 4-hour hemodialysis session. Analysis and quantification of the 1'-OH-midazolam and 4-OH-midazolam and dextrorphan metabolites were performed by high-pressure liquid chromatography/mass spectrometry. Statistical analysis using the Student's t-test (paired) was used to compare the amount of metabolite formed. The mean amount of 1'-OH-midazolam, 4-OH-midazolam, and dextrorphan metabolites formed before and after hemodialysis did not significantly differ. There was no significant difference in CYP3A4 and CYP2D6 metabolic activity in uremic serum before and after hemodialysis.