The Genetic Polymorphism of CYP3A4 rs2242480 is Associated with Sirolimus Trough Concentrations Among Adult Renal Transplant Recipients

Background:: The large interindividual variability in the genetic polymorphisms of sirolimus (SIR)- metabolizing enzymes, transporters, and receptors can lead to qualitatively and quantitatively distinct therapeutic responses. Objective:: We examined the impact of numerous candidate single-nucleotide polymorphisms (SNPs) involved in the trough concentration of SIR-based immunosuppressant regimen. Method:: This is a retrospective, long-term cohort study involving 69 renal allograft recipients. Total DNA was isolated from recipient blood samples and trough SIR concentrations were measured by microparticle enzyme immunoassay. Genome sequence reading was targeted based on next-generation sequencing. The association of tagger SNPs to SIR trough concentrations with non-genetic covariate adjusting was analyzed using logistic regression. Results:: A total of 300 SNPs were genotyped in the recipient DNA samples using target sequencing analysis. Only the SNP of CYP3A4 (Ch7: 99361466 C>T, rs2242480) had a significantly higher association with SIR trough concentration as compared to the other 36 tagger SNPs. The mean trough SIR concentration of patients in the CYP3A4 rs2242480-CC group was more significant compared to that of the CYP3A4 rs2242480-TC and TT group, respectively 533.3; 157.4 and 142.5 (ng/ml)/mg/kg, P<0.0001. After adjusting the SNPs, there was no significant association between clinical factors such as age, follow-up period, the incidence of delayed graft function, immunosuppression protocol, and sex with SIR trough concentration. Conclusion:: These findings indicated a significant association of polymorphism in the CYP3A4 (Ch7: 99361466 C>T, rs2242480) with SIR trough concentration after 1-year administration in patients who have undergone kidney transplantation.

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A comprehensive genotype–phenotype interaction of different Toll-like receptor variations in a renal transplant cohort

Clinical Science ◽

10.1042/cs20100190 ◽

2010 ◽

Vol 119 (12) ◽

pp. 535-544 ◽

Cited By ~ 28

Author(s):

Bernd Krüger ◽

Miriam C. Banas ◽

Andreas Walberer ◽

Carsten A. Böger ◽

Stefan Farkas ◽

...

Keyword(s):

Renal Transplant ◽

Acute Rejection ◽

Graft Function ◽

Major Adverse Cardiovascular Events ◽

Renal Transplant Recipients ◽

Nucleotide Polymorphisms ◽

Toll Like Receptor ◽

Receptor System ◽

Cardiovascular Morbidity And Mortality ◽

The Impact

To date, the impact of the TLR (Toll-like receptor) system on early and late kidney transplantation outcome, such as ARE (acute rejection episodes) or cardiovascular morbidity and mortality, has still not been elucidated conclusively. Genetically determined alterations in TLR expression exhibit a possibility to evaluate their role in transplantation. In the present study, we sought to determine a comprehensive genotype–phenotype association with early and late allograft outcomes. We studied 11 SNPs (single nucleotide polymorphisms) in TLR2, TLR3, TLR4, TLR5, TLR9 and within a co-molecule CD14 in 265 patients receiving their first kidney transplant and the association of these with the occurrence of DGF (delayed graft function), ARE or MACE (major adverse cardiovascular events). ARE were significantly more frequent in patients carrying the TLR3 TT/CT allele (43.8 compared with 25.8%; P=0.001) as were rates of DGF (21.4 compared with 12.0%; P=0.030). Furthermore, TLR9 was significantly involved in the occurrence of MACE (TLR9 −1237; P=0.030). Interestingly, there was no significant effect of any TLR polymorphism on graft survival or renal function and the incidence of any infection, including CMV (cytomegalovirus) infection. In conclusion, our present study in renal transplant recipients suggests that the TLR system may be involved in both acute rejection and MACE. Modulation of the TLR system may be a promising target in future therapeutic strategies.

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Calcium and phosphate levels after kidney transplantation and long-term patient and allograft survival

Clinical Kidney Journal ◽

10.1093/ckj/sfaa061 ◽

2020 ◽

Author(s):

Julio Chevarria ◽

Donal J Sexton ◽

Susan L Murray ◽

Chaudhry E Adeel ◽

Patrick O’Kelly ◽

...

Keyword(s):

Risk Factors ◽

Renal Transplant ◽

Graft Failure ◽

Graft Function ◽

Renal Transplant Recipients ◽

Post Transplant ◽

All Cause Mortality ◽

Transplant Function ◽

The Republic ◽

The Impact

Abstract Background Non-traditional cardiovascular risk factors, including calcium and phosphate derangement, may play a role in mortality in renal transplant. The data regarding this effect are conflicting. Our aim was to assess the impact of calcium and phosphate derangements in the first 90 days post-transplant on allograft and recipient outcomes. Methods We performed a retrospective cohort review of all-adult, first renal transplants in the Republic of Ireland between 1999 and 2015. We divided patients into tertiles based on serum phosphate and calcium levels post-transplant. We assessed their effect on death-censored graft survival and all-cause mortality. We used Stata for statistical analysis and did survival analysis and spline curves to assess the association. Results We included 1525 renal transplant recipients. Of the total, 86.3% had hypophosphataemia and 36.1% hypercalcaemia. Patients in the lowest phosphate tertile were younger, more likely female, had lower weight, more time on dialysis, received a kidney from a younger donor, had less delayed graft function and better transplant function compared with other tertiles. Patients in the highest calcium tertile were younger, more likely male, had higher body mass index, more time on dialysis and better transplant function. Adjusting for differences between groups, we were unable to show any difference in death-censored graft failure [phosphate = 1.14, 95% confidence interval (CI) 0.92–1.41; calcium = 0.98, 95% CI 0.80–1.20] or all-cause mortality (phosphate = 1.10, 95% CI 0.91–1.32; calcium = 0.96, 95% CI 0.81–1.13) based on tertiles of calcium or phosphate in the initial 90 days. Conclusions Hypophosphataemia and hypercalcaemia are common occurrences post-kidney transplant. We have identified different risk factors for these metabolic derangements. The calcium and phosphate levels exhibit no independent association with death-censored graft failure and mortality.

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The Prevalence of HBV Infection in Renal Transplant Recipients and the Impact of Infection on Graft Survival

ACTA MEDICA IRANICA ◽

10.18502/acta.v57i6.1884 ◽

2019 ◽

Author(s):

Nawfal R Hussein ◽

Zana SM Saleem ◽

Nashwan MR Ibrahim ◽

Mahde Saleh Assafi ◽

Shameran Daniel

Keyword(s):

Viral Load ◽

Renal Transplant ◽

General Population ◽

Serum Creatinine ◽

Graft Function ◽

Hbv Infection ◽

Renal Transplant Recipients ◽

Mortality And Morbidity ◽

Hbsag Positivity ◽

The Impact

Abstract- Hepatitis B virus infection (HBV) is a leading cause of increased mortality and morbidity in renal transplant subjects. The purpose of this project was to investigate the prevalence of HBV in patients with renal transplant and compare it with the general population in Duhok city, Iraq. Then, the impact of HBV infection on graft function was evaluated. A total of 560 renal transplant subjects and 2975 volunteers were recruited in this study. All subjects were examined for HB surface antigen (HBsAg) positivity. Then, all HBsAg positive subjects were tested for viral load, alanine transaminase (ALT), aspartate aminotransferase (AST), serum creatinine and HBV profile. All HBsAg positive renal transplant subjects received treatment and were followed up for 24 months. It was found that 6/560 (1.1%) of the renal transplant subjects were HBsAg positive while 30/2975 (1.09%) of the volunteers were positive for HBsAg (P>0.05). After initiation of medications, viral load became undetected within 6 months of treatment. Serum creatinine levels were normal at the end of the study. No major side effects were recorded. The prevalence of HBV in renal transplant subjects was similar to the prevalence in general population. HBV infection did not show any negative effect on the graft function. Further study is needed with a larger sample size to explore the long term effect of the infection on graft functionality.

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Impact of Nursing Education on the Proportion of Appropriately Drawn Vancomycin Trough Concentrations

Journal of Pharmacy Practice ◽

10.1177/0897190014568381 ◽

2016 ◽

Vol 29 (5) ◽

pp. 472-474 ◽

Cited By ~ 10

Author(s):

Lindsay K. Coleman ◽

Ashley S. Wilson

Keyword(s):

Nursing Education ◽

Nursing Staff ◽

Trough Concentration ◽

Posttest Score ◽

Further Education ◽

Inpatient Setting ◽

Vancomycin Trough ◽

Trough Concentrations ◽

The Mean ◽

The Impact

Background: Few studies have investigated the timing of vancomycin trough concentration collection in the inpatient setting. To date, there are no published studies on the impact of targeted nursing staff education on the appropriate timing of vancomycin trough concentration collection. Objective: To evaluate the impact of educational sessions on nursing staff knowledge regarding vancomycin and proper collection of troughs. Methods: The nursing staffs of 5 hospital units with a high volume of vancomycin usage were targeted for voluntary vancomycin educational sessions. Comprehension of the educational content was measured by a 5-question pre-/posteducation quiz. Vancomycin trough concentrations were evaluated during a 2-month period pre-/posteducation for appropriate timing of sample draw, defined as ≤45 minutes prior to the next scheduled vancomycin dose. Results: A total of 114 nurses participated in the education sessions. The mean pretest score was 3.91 and the mean posttest score was 4.89 ( P < .001). Preeducation, 69% of trough concentrations were collected appropriately. Posteducation, 74% of samples were collected within the 45-minute time frame ( P = .20). Conclusions: A significant increase in short-term comprehension regarding vancomycin was seen posteducation. There was a nonsignificant increase in appropriately timed trough concentration collection posteducation. Further education of nursing staffs may be necessary to lessen timing errors.

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Ramadan Fasting in Kidney Transplant Recipients: A Single-Centre Retrospective Study

Journal of Transplantation ◽

10.1155/2018/4890978 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 3

Author(s):

Ihab A. Ibrahim ◽

Ehab A. Hassan ◽

Abdelrahman M. Alkhan ◽

Mohamed A. Hussein ◽

Ahmed F. Alhabashi ◽

...

Keyword(s):

Renal Transplant ◽

Kidney Transplant ◽

Graft Function ◽

Urinary Protein Excretion ◽

Urinary Protein ◽

Renal Transplant Recipients ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Protein Excretion ◽

The Impact

Background. Fasting during the lunar month of Ramadan is mandatory to all healthy adult Muslims. Renal transplant recipients are often worried about the impact of fluid and electrolyte deprivation during fasting on the function of their allograft. We aimed to examine the effect of fasting Ramadan on the graft function in renal transplant recipients. Methods. This retrospective cohort study included patients who underwent kidney transplantation in our tertiary referral center. Baseline pre-Ramadan estimated glomerular filtration rate (eGFR), mean arterial pressure (MAP), and urinary protein excretion were compared to those during and after Ramadan within and between the fasting and non-fasting groups. Results. The study population included 280 kidney transplant recipients who chose to fast during the Ramadan month (June-July 2014) and 285 recipients who did not fast. In the fasting group, baseline eGFR did not change from that during or post-Ramadan (72.6±23.7 versus 72.3±24.5 mL/min/1.73 m2, P=0.53; and 72.6±23.7 versus 72±23.2 mL/min/1.73 m2, P=0.14, respectively). Compared to baseline, there were no significant differences between the fasting and the non-fasting groups in terms of mean percent changes in eGFR, MAP, and urinary protein excretion. Conclusion. Fasting during the month of Ramadan did not have significant adverse effects on renal allograft function.

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The impact of CYP3A5 and MDR1 polymorphisms on tacrolimus dosage requirements and trough concentrations in pediatric renal transplant recipients

Saudi Journal of Kidney Diseases and Transplantation ◽

10.4103/1319-2442.121268 ◽

2013 ◽

Vol 24 (6) ◽

pp. 1125 ◽

Cited By ~ 5

Author(s):

Sireen Shilbayeh ◽

Rawan Zmeili ◽

RehamIssa Almardini

Keyword(s):

Renal Transplant ◽

Renal Transplant Recipients ◽

Transplant Recipients ◽

Tacrolimus Dosage ◽

Pediatric Renal Transplant ◽

Trough Concentrations ◽

Pediatric Renal Transplant Recipients ◽

The Impact

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Association of Genetic Variants in CYP3A4, CYP3A5, CYP2C8, and CYP2C19 with Tacrolimus Pharmacokinetics in Renal Transplant Recipients

Current Drug Metabolism ◽

10.2174/1389200220666190627101927 ◽

2019 ◽

Vol 20 (7) ◽

pp. 609-618

Author(s):

Zijie Wang ◽

Ming Zheng ◽

Haiwei Yang ◽

Zhijian Han ◽

Jun Tao ◽

...

Keyword(s):

Renal Transplant ◽

Graft Function ◽

Measurement Time ◽

Renal Transplant Recipients ◽

Nucleotide Polymorphisms ◽

Transplant Recipients ◽

Short Term ◽

Next Generation Sequencing Technology ◽

Time Points

Background: Our study aimed to investigate the pharmacogenetics of cytochrome P3A4 (CYP3A4), CYP3A5, CYP2C8, and CYP2C19 and their influence on TAC Pharmacokinetics (PKs) in short-term renal transplant recipients. Method: A total of 105 renal transplant recipients were enrolled. Target Sequencing (TS) based on next-generation sequencing technology was used to detect all exons, exon/intron boundaries, and flanking regions of CYP3A4, CYP3A5, CYP2C8, and CYP2C19. After adjustment of Minor Allele Frequencies (MAF) and Hardy-Weinberg Equilibrium (HWE) analysis, tagger Single-nucleotide Polymorphisms (SNPs) and haplotypes were identified. Influence of tagger SNPs on TAC concentrations was analyzed. Results: A total of 94 SNPs were identified in TS analysis. Nine tagger SNPs were selected, and two SNPs (rs15524 and rs4646453) were noted to be significantly associated with TAC PKs in short-term post-transplant follow-up. Measurement time points of TAC, body mass index (BMI), usage of sirolimus, and incidence of Delayed Graft Function (DGF) were observed to be significantly associated with TAC PKs. Three haplotypes were identified, and rs15524-rs4646453 was found to remarkably contribute to TAC PKs. Recipients carrying H2/H2 (GG-AA) haplotype also showed significantly high weight- and dose-adjusted TAC concentrations in posttransplant periods of 7, 14, and 30 days and 3 and 6 months. Conclusions: Two tagger SNPs, namely, rs15524 and rs4646453, are significantly related to the variability of TAC disposition, and TAC measurement time points, BMI, usage of sirolimus, and incidence of DGF contribute to this influence. Recipients carrying H2/H2 (GG-AA) haplotype in rs15524–rs4646453 may require a low dosage of TAC during 1-year follow-up posttransplant.

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A Quasi-Experiment To Study the Impact of Vancomycin Area under the Concentration-Time Curve-Guided Dosing on Vancomycin-Associated Nephrotoxicity

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01293-17 ◽

2017 ◽

Vol 61 (12) ◽

Cited By ~ 71

Author(s):

Natalie A. Finch ◽

Evan J. Zasowski ◽

Kyle P. Murray ◽

Ryan P. Mynatt ◽

Jing J. Zhao ◽

...

Keyword(s):

Trough Concentration ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Time Curve ◽

Cox Proportional Hazards Regression ◽

Proportional Hazards Regression ◽

Concentration Time ◽

Trough Concentrations ◽

The Impact ◽

Quasi Experiment

ABSTRACT Evidence suggests that maintenance of vancomycin trough concentrations at between 15 and 20 mg/liter, as currently recommended, is frequently unnecessary to achieve the daily area under the concentration-time curve (AUC24) target of ≥400 mg · h/liter. Many patients with trough concentrations in this range have AUC24 values in excess of the therapeutic threshold and within the exposure range associated with nephrotoxicity. On the basis of this, the Detroit Medical Center switched from trough concentration-guided dosing to AUC-guided dosing to minimize potentially unnecessary vancomycin exposure. The primary objective of this analysis was to assess the impact of this intervention on vancomycin-associated nephrotoxicity in a single-center, retrospective quasi-experiment of hospitalized adult patients receiving intravenous vancomycin from 2014 to 2015. The primary analysis compared the incidence of nephrotoxicity between patients monitored by assessment of the AUC24 and those monitored by assessment of the trough concentration. Multivariable logistic and Cox proportional hazards regression examined the independent association between the monitoring strategy and nephrotoxicity. Secondary analysis compared vancomycin exposures (total daily dose, AUC, and trough concentrations) between monitoring strategies. Overall, 1,280 patients were included in the analysis. After adjusting for severity of illness, comorbidity, duration of vancomycin therapy, and concomitant receipt of nephrotoxins, AUC-guided dosing was independently associated with lower nephrotoxicity by both logistic regression (odds ratio, 0.52; 95% confidence interval [CI], 0.34 to 0.80; P = 0.003) and Cox proportional hazards regression (hazard ratio, 0.53; 95% CI, 0.35 to 0.78; P = 0.002). AUC-guided dosing was associated with lower total daily vancomycin doses, AUC values, and trough concentrations. Vancomycin AUC-guided dosing was associated with reduced nephrotoxicity, which appeared to be a result of reduced vancomycin exposure.

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Right Ventricular Dysfunction and Adverse Outcomes after Renal Transplantation

Cardiorenal Medicine ◽

10.1159/000515124 ◽

2021 ◽

Vol 11 (2) ◽

pp. 109-118

Author(s):

Megan S. Joseph ◽

Francis Tinney ◽

Abhijit Naik ◽

Raviprasenna Parasuraman ◽

Milagros Samaniego-Picota ◽

...

Keyword(s):

Renal Transplant ◽

Right Ventricular ◽

Graft Failure ◽

Graft Function ◽

Systolic Pressure ◽

Right Ventricular Dysfunction ◽

Adverse Outcomes ◽

Renal Transplant Recipients ◽

End Point ◽

The Impact

Introduction: Pulmonary hypertension is common among patients with end-stage renal disease, although data regarding the impact of right ventricular (RV) failure on postoperative outcomes remain limited. We hypothesized that echocardiographic findings of RV dilation and dysfunction are associated with adverse clinical outcomes after renal transplant. Methods: A retrospective review of adult renal transplant recipients at a single institution from January 2008 to June 2010 was conducted. Patients with transthoracic echocardiograms (TTEs) within 1 year leading up to transplant were included. The primary end point was a composite of delayed graft function, graft failure, and all-cause mortality. Results: Eighty patients were included. Mean follow-up time was 9.4 ± 0.8 years. Eight patients (100%) with qualitative RV dysfunction met the primary end point, while 39/65 patients (60.0%) without RV dysfunction met the end point (p = 0.026). Qualitative RV dilation was associated with a significantly shorter time to all-cause graft failure (p = 0.03) and death (p = 0.048). RV systolic pressure was not measurable in 45/80 patients (56%) and was not associated with outcomes in the remaining patients. Conclusion: RV dilation and dysfunction are associated with adverse outcomes after renal transplant. TTE assessment of RV size and function should be a standard part of the pre-kidney transplant cardiovascular risk assessment.

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