Role of pharmacogenomics in dialysis and transplantation.
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ABSTRACT:
SUBMITTER: Birdwell K
PROVIDER: S-EPMC4220684 | biostudies-literature | 2014 Nov
REPOSITORIES: biostudies-literature
Publications
Role of pharmacogenomics in dialysis and transplantation.
Current opinion in nephrology and hypertension 20141101 6
<h4>Purpose of review</h4>Pharmacogenomics is the study of differences in drug response on the basis of individual genetic background. With rapidly advancing genomic technologies and decreased costs of genotyping, the field of pharmacogenomics continues to develop. Application to patients with kidney disease provides growing opportunities for improving drug therapy.<h4>Recent findings</h4>Pharmacogenomics studies are lacking in patients with chronic kidney disease and dialysis, but are abundant ...[more]
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Project description:INTRODUCTION:The new kidney allocation system (KAS) prioritizes patients based on date of dialysis initiation or waitlisting, whichever is earlier. We hypothesized that this change would increase transplant rates for patients with prolonged pretransplant dialysis times (DT) and aimed to assess the impact of prolonged DT on post-transplant outcomes. METHODS:We used United Network for Organ Sharing registry data to assess outcomes for patients added to the renal transplant waitlist from January 1, 1998 to December 31, 2010 and patients transplanted from January 1, 1998 to December 3, 2012. RESULTS:Compared with patients transplanted pre-emptively, patients with <5 years, 5-9 years, and ?10 years DT had progressively decreased graft and patient survival (P < .001). The rates of short-term complications including delayed graft function, graft loss within 30 days, and patient death within 30 days were significantly higher in cohorts with ?10 years DT than in cohorts with less DT (P < .001). CONCLUSIONS:Patients with pretransplant DT of ?10 years had worse outcomes than patients pre-emptively transplanted or transplanted with shorter DT. Durations of dialysis dependence beyond 10 years were associated with further deterioration in short-term but not long-term post-transplant outcomes.
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Project description:BackgroundChronic kidney disease following liver transplantation is a major long-term complication. Most liver transplant recipients with kidney failure will be treated with dialysis instead of kidney transplantation due to noneligibility and shortage in organ availability. In this population, the role of peritoneal dialysis (PD) as a modality of kidney replacement therapy (KRT) remains unclear.ObjectiveTo determine the feasibility regarding safety, technique survival, and dialysis efficiency of PD in liver transplant recipients requiring KRT for maintenance dialysis.DesignSystematic review.SettingInterventional and observational studies reporting the use of PD after liver transplantation.PatientsAdult liver transplant recipients with kidney failure treated with maintenance KRT.MeasurementsExtracted data included eligibility criteria, study design, demographics, and PD modality. The following outcomes of interest were extracted: rate of peritonitis and microorganisms involved, noninfectious peritoneal complications, technique survival, and kidney transplantation-censored technique survival. Non-PD complications included overall survival, liver graft dysfunction, and hospitalization rate.MethodsThe following databases were searched until July 2020: MedLine/PubMed, EMBASE, CINAHL, and Cochrane Library. Two reviewers independently screening all titles and abstracts of all identified articles. Due to the limited sample size, observational designs and study heterogeneity expected, no meta-analysis was pre-planned. Descriptive statistics were used to report all results.ResultsFrom the 5263 identified studies, 4 were included in the analysis as they reported at least 1 outcome of interest on a total of 21 liver transplant recipients, with an overall follow-up duration on PD of 19.0 (Interquartile range [IQR]: 9.5-29.5) months. Fifteen episodes of peritonitis occurred in a total cumulative PD follow-up of 514 patient-months, representing an incidence rate of 0.35 per year. These episodes did not result in PD technique failure, mortality, or impairment of liver graft function.LimitationsLimitations include the paucity of studies in the field and the small number of patients included in each report, a risk of publication bias and the impossibility to directly compare hemodialysis to PD in this population. These results, therefore, must be interpreted with caution.ConclusionsBased on limited data reporting the feasibility of PD in liver transplant recipients with kidney failure, no signal was associated with an increased risk of infectious complications. Long-term studies evaluating this modality need to be performed.Registration prosperoCRD42020218374.
| S-EPMC8293848 | biostudies-literature
Project description:Pharmacogenomics is increasingly important to guide objective, safe, and effective individualised prescribing. Personalised prescribing has revolutionised treatments in the past decade, allowing clinicians to maximise drug efficacy and minimise adverse effects based on a person's genetic profile. Opioids, the gold standard for cancer pain relief, are among the commonest medications prescribed in palliative care practice. This narrative review examines the literature surrounding opioid pharmacogenomics and its applicability to the palliative care cancer population. There is currently limited intersection between the fields of palliative care and pharmacogenomics, but growing evidence presents a need to build linkages between the two disciplines. Pharmacogenomic evidence guiding opioid prescribing is currently available for codeine and tramadol, which relates to CYP2D6 gene variants. However, these medications are prescribed less commonly for pain in palliative care. Research is accelerating with other opioids, where oxycodone (CYP2D6) and methadone (CYP2B6, ABCB1) already have moderate evidence of an association in terms of drug metabolism and downstream analgesic response and side effects. OPRM1 and COMT are receiving increasing attention and have implications for all opioids, with changes in opioid dosage requirements observed but they have not yet been studied widely enough to be considered clinically actionable. Current evidence indicates that incorporation of pharmacogenomic testing into opioid prescribing practice should focus on the CYP2D6 gene and its actionable variants. Although opioid pharmacogenomic tests are not widely used in clinical practice, the progressively reducing costs and rapid turnover means greater accessibility and affordability to patients, and thus, clinicians will be increasingly asked to provide guidance in this area. The upsurge in pharmacogenomic research will likely discover more actionable gene variants to expand international guidelines to impact opioid prescribing. This rapidly expanding area requires consideration and monitoring by clinicians in order for key findings with clinical implications to be accessible, meaningfully interpretable and communicated.
| S-EPMC9526685 | biostudies-literature
Project description:BackgroundThere is a paucity of evidence to inform the value of pharmacogenomic (PGx) results in patients after kidney transplant and how these results differ between Indigenous Americans and Whites. This study aims to identify the frequency of recommended medication changes based on PGx results and compare the pharmacogenomic (PGx) results and patients' perceptions of the findings between a cohort of Indigenous American and White kidney transplant recipients.MethodsThirty-one Indigenous Americans and fifty White kidney transplant recipients were studied prospectively. Genetic variants were identified using the OneOme RightMed PGx test of 27 genes. PGx pharmacist generated a report of the genetic variation and recommended changes. Pre- and post-qualitative patient surveys were obtained.ResultsWhite and Indigenous American subjects had a similar mean number of medications at the time of PGx testing (mean 13 (SD 4.5)). In the entire cohort, 53% received beta blockers, 30% received antidepressants, 16% anticoagulation, 47% pain medication, and 25% statin therapy. Drug-gene interactions that warranted a clinical action were present in 21.5% of patients. In 12.7%, monitoring was recommended. Compared to the Whites, the Indigenous American patients had more normal CYP2C19 (p = 0.012) and CYP2D6 (p = 0.012) activities. The Indigenous American patients had more normal CYP4F2 (p = 0.004) and lower VKORC (p = 0.041) activities, phenotypes for warfarin drug dosing, and efficacy compared to the Whites. SLC6A4, which affects antidepressant metabolism, showed statistical differences between the two cohorts (p = 0.017); specifically, SLC6A4 had reduced expression in 45% of the Indigenous American patients compared to 20% of the White patients. There was no significant difference in patient perception before and after PGx.ConclusionsKidney transplant recipients had several drug-gene interactions that were clinically actionable; over one-third of patients were likely to benefit from changes in medications or drug doses based on the PGx results. The Indigenous American patients differed in the expression of drug-metabolizing enzymes and drug transporters from the White patients.
| S-EPMC10457738 | biostudies-literature
Project description:Variability in transplant rates between different dialysis units has been noted, yet little is known about facility-level factors associated with low standardized transplant ratios (STRs) across the United States End-stage Renal Disease (ESRD) Network regions. We analyzed Centers for Medicare & Medicaid Services Dialysis Facility Report data from 2007 to 2010 to examine facility-level factors associated with low STRs using multivariable mixed models. Among 4098 dialysis facilities treating 305 698 patients, there was wide variability in facility-level STRs across the 18 ESRD Networks. Four-year average STRs ranged from 0.69 (95% confidence interval [CI]: 0.64-0.73) in Network 6 (Southeastern Kidney Council) to 1.61 (95% CI: 1.47-1.76) in Network 1 (New England). Factors significantly associated with a lower STR (p?<?0.0001) included for-profit status, facilities with higher percentage black patients, patients with no health insurance and patients with diabetes. A greater number of facility staff, more transplant centers per 10 000 ESRD patients and a higher percentage of patients who were employed or utilized peritoneal dialysis were associated with higher STRs. The lowest performing dialysis facilities were in the Southeastern United States. Understanding the modifiable facility-level factors associated with low transplant rates may inform interventions to improve access to transplantation.
| S-EPMC4180229 | biostudies-literature
Project description:ImportanceFor-profit (vs nonprofit) dialysis facilities have historically had lower kidney transplantation rates, but it is unknown if the pattern holds for living donor and deceased donor kidney transplantation, varies by facility ownership, or has persisted over time in a nationally representative population.ObjectiveTo determine the association between dialysis facility ownership and placement on the deceased donor kidney transplantation waiting list, receipt of a living donor kidney transplant, or receipt of a deceased donor kidney transplant.Design, setting, and participantsRetrospective cohort study that included 1 478 564 patients treated at 6511 US dialysis facilities. Adult patients with incident end-stage kidney disease from the US Renal Data System (2000-2016) were linked with facility ownership (Dialysis Facility Compare) and characteristics (Dialysis Facility Report).ExposuresThe primary exposure was dialysis facility ownership, which was categorized as nonprofit small chains, nonprofit independent facilities, for-profit large chains (>1000 facilities), for-profit small chains (<1000 facilities), and for-profit independent facilities.Main outcomes and measuresAccess to kidney transplantation was defined as time from initiation of dialysis to placement on the deceased donor kidney transplantation waiting list, receipt of a living donor kidney transplant, or receipt of a deceased donor kidney transplant. Cumulative incidence differences and multivariable Cox models assessed the association between dialysis facility ownership and each outcome.ResultsAmong 1 478 564 patients, the median age was 66 years (interquartile range, 55-76 years), with 55.3% male, and 28.1% non-Hispanic black patients. Eighty-seven percent of patients received care at a for-profit dialysis facility. A total of 109 030 patients (7.4%) received care at 435 nonprofit small chain facilities; 78 287 (5.3%) at 324 nonprofit independent facilities; 483 988 (32.7%) at 2239 facilities of large for-profit chain 1; 482 689 (32.6%) at 2082 facilities of large for-profit chain 2; 225 890 (15.3%) at 997 for-profit small chain facilities; and 98 680 (6.7%) at 434 for-profit independent facilities. During the study period, 121 680 patients (8.2%) were placed on the deceased donor waiting list, 23 762 (1.6%) received a living donor kidney transplant, and 49 290 (3.3%) received a deceased donor kidney transplant. For-profit facilities had lower 5-year cumulative incidence differences for each outcome vs nonprofit facilities (deceased donor waiting list: -13.2% [95% CI, -13.4% to -13.0%]; receipt of a living donor kidney transplant: -2.3% [95% CI, -2.4% to -2.3%]; and receipt of a deceased donor kidney transplant: -4.3% [95% CI, -4.4% to -4.2%]). Adjusted Cox analyses showed lower relative rates for each outcome among patients treated at all for-profit vs all nonprofit dialysis facilities: deceased donor waiting list (hazard ratio [HR], 0.36 [95% CI, 0.35 to 0.36]); receipt of a living donor kidney transplant (HR, 0.52 [95% CI, 0.51 to 0.54]); and receipt of a deceased donor kidney transplant (HR, 0.44 [95% CI, 0.44 to 0.45]).Conclusions and relevanceAmong US patients with end-stage kidney disease, receiving dialysis at for-profit facilities compared with nonprofit facilities was associated with a lower likelihood of accessing kidney transplantation. Further research is needed to understand the mechanisms behind this association.
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Project description:Recent studies have pointed out the essential role of genetic ancestry in population pharmacogenetics. In this study, we analyzed the whole-genome sequencing data from The 1000 Genomes Project (Phase 3) and the pharmacogenetic information from Drug Bank, PharmGKB, PharmaADME, and Biotransformation. Here we show that ancestry-informative markers are enriched in pharmacogenetic loci, suggesting that trans-ancestry differentiation must be carefully considered in population pharmacogenetics studies. Ancestry-informative pharmacogenetic loci are located in both protein-coding and non-protein-coding regions, illustrating that a whole-genome analysis is necessary for an unbiased examination over pharmacogenetic loci. Finally, those ancestry-informative pharmacogenetic loci that target multiple drugs are often a functional variant, which reflects their importance in biological functions and pathways. In summary, we develop an efficient algorithm for an ultrahigh-dimensional principal component analysis. We create genetic catalogs of ancestry-informative markers and genes. We explore pharmacogenetic patterns and establish a high-accuracy prediction panel of genetic ancestry. Moreover, we construct a genetic ancestry pharmacogenomic database Genetic Ancestry PhD ( http://hcyang.stat.sinica.edu.tw/databases/genetic_ancestry_phd/ ).
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Project description:Genetic polymorphisms in metabolizing enzymes and drug transporters have been shown to significantly impact the exposure of drugs having a high dependence on a single mechanism for their absorption, distribution or clearance, such that genotyping can lead to actionable steps in disease treatment. Recently, global regulatory agencies have provided guidance for assessment of pharmacogenomics during early stages of drug development, both in the form of formal guidance and perspectives published in scientific journals. The Industry Pharmacogenomics Working Group (I-PWG), conducted a survey among member companies to assess the practices relating to absorption, distribution, metabolism, excretion pharmacogenomics) during early stages of clinical development, to assess the impact of the recent Regulatory Guidance issued by the US FDA and EMA on Industry practices.
| S-EPMC5558530 | biostudies-literature
Project description:Background:Data on dialysis and renal transplantation (RT) after intestinal transplantation (IT) are sparse. Whether changes in immunosuppression and surgical techniques have modified these outcomes is unknown. Methods:Two hundred eighty-eight adult intestinal transplants performed between 1990 and 2014 at the University of Pittsburgh were analyzed for incidence, risk factors and outcomes after dialysis and RT. Cohort was divided into 3 eras based on immunosuppression and surgical technique (1990-1994, 1995-2001, and 2001-2014). Receiving RT, or dialysis for 90 days or longer was considered as end-stage renal disease (ESRD). Results:During a median follow-up of 5.7 years, 71 (24.7%) patients required dialysis, 38 (13.2%) required long-term dialysis and 17 (6%) received RT after IT. One-, 3-, and 5-year ESRD risk was 2%, 7%, and 14%, respectively. No significant era-based differences were noted. Higher baseline creatinine (hazard ratio [HR], 3.40 per unit increase, P < 0.01) and use of liver containing grafts (HR, 2.01; P = 0.04) had an increased ESRD risk. Median patient survival after dialysis initiation was 6 months, with a 3-year survival of 21%. Any dialysis (HR, 12.74; 95% CI 8.46-19.20; P < 0.01) and ESRD (HR, 9.53; 95% CI, 5.87-15.49; P < 0.01) had higher mortality after adjusting for covariates. For renal after IT, 1- and 3-year kidney and patient survivals were 70% and 49%, respectively. All graft losses were from death with a functioning graft, primarily related to infectious complications (55%). Conclusions:In intestinal transplant recipients, renal failure requiring dialysis or RT is high and is associated with increased mortality. Additionally, the outcomes for kidney after IT are suboptimal due to death with a functioning graft.
| S-EPMC6092176 | biostudies-literature