Impact of Pharmacogenetic Determinants of Tacrolimus and Mycophenolate on Adverse Events in Renal Transplant Patients

2021 ◽  
Vol 22 ◽  
Author(s):  
Kalluri Thishya ◽  
Boddupally Sreenu ◽  
Shree Bhushan Raju ◽  
Vijay Kutala
Keyword(s):  
Renal Transplant ◽  
Adverse Events ◽  
Metabolic Pathways ◽  
Early Stage ◽  
Maintenance Phase ◽  
Solid Organ ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Post Transplantation ◽  
Increased Risk

Background: Graft acceptance against immunity is one of themajor challenges in solid organ transplant. Immunosuppressive medications have effectively improved the post-transplantation outcome; however it has its own limitations. Genetic polymorphisms in drug-metabolizing enzymes have been identified as the potential targets in developing a pharmacogenetic strategy, to individualize drug dose and also in preventing the adverse events. Objective: The rationale of the study was to explore polymorphisms in tacrolimus and mycophenolate metabolic pathways that influence the adverse clinical outcomes in renal transplant recipients. Methods: A total of 255 renal transplant recipients were analyzed for the pharmacogenetic determinants of tacrolimus (CYP3A5*3, ABCB1 1236 T>C, ABCB1 2677 G>A/T, ABCB1 3435 T>C) and mycophenolate (UGT1A8*3, UGT1A9, IMPDH I, IMPDH II c.787C>T , ABCC2 -24 C>T and c.3972C>T) using Sanger sequencing. Results: Acute rejection (AR) was observed in 5.88% of the transplant recipients, whereas, acute tubular necrosis (ATNs) was observed in 7.45% of the patients, within early stage of the maintenance phase. Infections, such as urinary tract infection (UTI) and cytomegalovirus (CMV) infection were observed in 11.37% and 12.16% of the patients. The AUC of mycophenolate was significantly higher in patients with increased risk for infections. ABCC2 -24 C>T, c.3972C>T polymorphisms and ABCB1 3435 C-allele, were associated with reduced risk for infections. ABCC2 rs3740066 was associated with 2.06-fold all-cause mortality risk. CYP3A5 AG- and UGT1A9-440 CC-genotypes showed increased risk, and ABCC 3972C>T, CC-genotype showed protection against adverse events. Conclusion: Genetic variants in tacrolimus and mycophenolate metabolic pathways were found to influence the morbidity and mortality in renal transplant recipients.

P0863TYPE OF PROTON PUMP INHIBITOR AND RISK OF IRON DEFICIENCY IN RENAL TRANSPLANT RECIPIENTS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Rianne M. Douwes ◽  
Joanna Sophia Jacoline Vinke ◽  
António W Gomes-Neto ◽  
Hans Blokzijl ◽  
Stefan P Berger ◽  
...  
Keyword(s):  
Cohort Study ◽  
Renal Transplant ◽  
Iron Deficiency ◽  
Proton Pump ◽  
Ferritin Level ◽  
Solid Organ ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Increased Risk ◽  
Different Types

Abstract Background and Aims Use of proton-pump inhibitors (PPIs) is common practice in renal transplant recipients (RTRs). Emerging data suggest several adverse effects of use of PPIs, including development of iron deficiency (ID). Although the latter has been shown with respect to PPIs, specific analyses for different types of PPIs and the associated risk of ID have not been performed. Method We used data from the TransplantLines Biobank and Cohort study, an ongoing prospective cohort study among all types of solid organ transplant recipients. For the current study, we used data from stable RTRs with a functional graft for more than 1 year post transplantation (n=795). We excluded RTRs who used any form of iron supplementation (n=54) and EPO-stimulating agents (n=24), resulting in 728 RTRs eligible for analyses. Use of PPIs was subdivided in different types of PPIs, i.e. omeprazole, esomeprazole, pantoprazole, and rabeprazole. ID was defined as TSAT<20% and ferritin <300 µg/L. Logistic regression analysis was used to assess the associations between PPIs and ID. Results We included 728 RTRs (age 56±13 years, 61% males), with a mean eGFR of 53±18 ml/min/1.73m2, a median [interquartile range] ferritin level of 96 (44 – 191) µg/L and mean TSAT of 24±10%. PPIs were used by 504 (69%) of the included RTRs, of which 398 (79%), 55 (11%), 49 (10%), and 2 (0.4%) respectively used omeprazole, pantoprazole, esomeprazole, and rabeprazole. Use of PPIs was strongly associated with ID (OR, 2.20; 95%CI 1.48 – 3.28; P<0.001), independent of adjustment for age, sex, BMI, eGFR, hs-CRP, smoking, alcohol use, use of calcineurine inhibitors, prednisolone, antiplatelet drugs, and antihypertensives. When subdividing the PPIs into the different types, both omeprazole (OR, 1.98; 95%CI 1.39 – 2.83; P<0.001) and esomeprazole (OR, 2.11; 95%CI 1.09 – 4.07; P=0.03) were independently associated with iron deficiency, whereas pantoprazole was not associated (OR, 0.89; 95%CI 0.47 – 1.70; P=0.73). Conclusion Omeprazole and esomeprazole, but not pantoprazole, are associated with an increased risk of ID. Our results are in line with previous reports that pantoprazole has the lowest potency with least increase in intragastric pH, thereby possibly interfering less with reduction of ferric to ferrous iron, and subsequently iron absorption. Future studies are warranted to confirm our present findings.

scholarly journals Initial mycophenolate dose in tacrolimus treated renal transplant recipients, a cohort study comparing leukopaenia, rejection and long-term graft function

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Vatsa Dave ◽  
Kevan R. Polkinghorne ◽  
Khai Gene Leong ◽  
John Kanellis ◽  
William R. Mulley
Keyword(s):  
Renal Function ◽  
Cohort Study ◽  
Renal Transplant ◽  
Graft Function ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Post Transplantation ◽  
Post Transplant ◽  
Increased Risk

Abstract The evidence supporting an initial mycophenolate mofetil (MMF) dose of 2 g daily in tacrolimus-treated renal transplant recipients is limited. In a non-contemporaneous single-centre cohort study we compared the incidence of leukopaenia, rejection and graft dysfunction in patients initiated on MMF 1.5 g and 2 g daily. Baseline characteristics and tacrolimus trough levels were similar by MMF group. MMF doses became equivalent between groups by 12-months post-transplant, driven by dose reductions in the 2 g group. Leukopaenia occurred in 42.4% of patients by 12-months post-transplant. MMF 2 g was associated with a 1.80-fold increased risk of leukopaenia compared to 1.5 g. Rejection occurred in 44.8% of patients by 12-months post-transplantation. MMF 2 g was associated with half the risk of rejection relative to MMF 1.5 g. Over the first 7-years post-transplantation there was no difference in renal function between groups. Additionally, the development of leukopaenia or rejection did not result in reduced renal function at 7-years post-transplant. Leukopaenia was not associated with an increased incidence of serious infections or rejection. This study demonstrates the initial MMF dose has implications for the incidence of leukopaenia and rejection. Since neither dose produced superior long-term graft function, clinical equipoise remains regarding the optimal initial mycophenolate dose in tacrolimus-treated renal transplant recipients.

scholarly journals Pharmacogenetics Based Dose Prediction Model for Initial Tacrolimus Dosing in Renal Transplant Recipients

2021 ◽  
Vol 12 ◽  
Author(s):  
Lekshmy Srinivas ◽  
Noble Gracious ◽  
Radhakrishnan R. Nair
Keyword(s):  
Renal Transplant ◽  
Adverse Effects ◽  
Allele Frequencies ◽  
Solid Organ ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Time Points ◽  
Post Transplant ◽  
Dose Prediction ◽  
Increased Risk

Tacrolimus, an immunosuppressant used in solid organ transplantation, has a narrow therapeutic index and exhibits inter-individual pharmacokinetic variability. Achieving and maintaining a therapeutic level of the drug by giving appropriate doses is crucial for successful immunosuppression, especially during the initial post-transplant period. We studied the effect of CYP3A5, CYP3A4, and ABCB1 gene polymorphisms on tacrolimus trough concentrations in South Indian renal transplant recipients from Kerala to formulate a genotype-based dosing equation to calculate the required starting daily dose of tacrolimus to be given to each patient to attain optimal initial post-transplant period drug level. We also investigated the effect of these genes on drug-induced adverse effects and rejection episodes and looked into the global distribution of allele frequencies of these polymorphisms. One hundred forty-five renal transplant recipients on a triple immunosuppressive regimen of tacrolimus, mycophenolate mofetil, and steroid were included in this study. Clinical data including tacrolimus daily doses, trough levels (C0) and dose-adjusted tacrolimus trough concentration (C0/D) in blood at three time points (day 6, 6 months, and 1-year post-transplantation), adverse drug effects, rejection episodes, serum creatinine levels, etc., were recorded. The patients were genotyped for CYP3A5*3, CYP3A4*1B, CYP3A4*1G, ABCB1 G2677T, and ABCB1 C3435T polymorphisms by the PCR-RFLP method. We found that CYP3A5*3 polymorphism was the single most strongly associated factor determining the tacrolimus C0/D in blood at all three time points (p < 0.001). Using multiple linear regression, we formulated a simple and easy to compute equation that will help the clinician calculate the starting tacrolimus dose per kg body weight to be administered to a patient to attain optimal initial post-transplant period tacrolimus level. CYP3A5 expressors had an increased chance of rejection than non-expressors (p = 0.028), while non-expressors had an increased risk for new-onset diabetes mellitus after transplantation (NODAT) than expressors (p = 0.018). Genotype-guided initial tacrolimus dosing would help transplant recipients achieve optimal initial post-transplant period tacrolimus levels and thus prevent the adverse effects due to overdose and rejection due to inadequate dose. We observed inter-population differences in allele frequencies of drug metabolizer and transporter genes, emphasizing the importance of formulating population-specific dose prediction models to draw results of clinical relevance.

scholarly journals De-Novo Genitourinary Neoplasms in Transplant Recipients: The Present and Future

2020 ◽  
Vol 3 (1) ◽  
pp. 10-22
Author(s):  
K Regmi Subodh ◽  
◽  
Jiang Song ◽  
A. Warlick Christopher ◽  
◽  
...  
Keyword(s):  
Renal Transplant ◽  
Large Population ◽  
Renal Tumors ◽  
Solid Organ ◽  
Renal Transplant Recipients ◽  
Organ Transplants ◽  
Transplant Recipients ◽  
Post Transplant ◽  
Increased Risk ◽  
Risk Of Cancer

The risk of genitourinary cancers following transplantation is increased following majority of solid organ transplants but is best described following renal transplantation. Increasing average age of the transplant recipient as well as increases in post- transplant survival increases the risk of these malignancies. The risk of Kidney cancer is the highest following most solid organ transplants, whereas prostate cancer risk is lower than the general population in multiple large population-based studies. The etiology of increased risk of cancer following transplant is multifactorial with the predominant influence of immunosuppression and direct toxicity of immunosuppressants, however, the significance of end stage disease particularly in the causation of renal cancer in renal transplant recipients is undeniable. Modifications in immunosuppression regimens as well as changes in the standard treatment principles of some cancers may require changes in the management of some post-transplant malignancies. Standard screening guidelines have not been established but screening for renal tumors in renal transplant recipients is the only widely studied entity. Further work is needed to prepare the urologic oncological community with this once rare population group and standardized recommendations need to be established for screening and for the use of new age cancer therapeutics like immunotherapy.

scholarly journals Gut Microbiome Dysbiosis is Associated with Increased Mortality following Solid Organ Transplantation

2021 ◽  
Author(s):  
Rinse Weersma ◽  
J. Casper Swarte ◽  
Yanni Li ◽  
Shixian Hu ◽  
Johannes Björk ◽  
...  
Keyword(s):  
Organ Transplantation ◽  
Virulence Factors ◽  
Gut Microbiome ◽  
Metabolic Pathways ◽  
Solid Organ Transplantation ◽  
Solid Organ ◽  
Cell Transplant ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Post Transplantation

Abstract Organ transplantation is a life-saving treatment for patients with end-stage disease, but survival post-transplantation varies considerably. There is now increasing evidence that the gut microbiome is linked to the survival of hematopoietic cell transplant patients, yet little is known about the role of the gut microbiome in solid organ transplantation. We analyzed 1,370 fecal samples from liver and renal transplant recipients using shotgun metagenomic sequencing to assess microbial taxonomy, metabolic pathways, antibiotic resistance genes and virulence factors. To quantify taxonomic and metabolic dysbiosis, we analyzed 1,183 age-, sex- and BMI-matched subjects from the same population. A subset of patients were also followed longitudinally from pre- to post-transplantation. Our data show that transplant recipients suffer from gut dysbiosis—including lower microbial diversity, increased abundance of unhealthy microbial species, decreased abundance of important metabolic pathways, and increased prevalence and diversity of antibiotic resistant genes and virulence factors—that persist up to 20 years post-transplantation. Finally, we demonstrate that the use of immunosuppressive drugs is significantly associated with the observed dysbiosis and that the extent of dysbiosis is associated with increased post-transplant mortality.

scholarly journals Torquetenovirus Serum Load and Long-Term Outcomes in Renal Transplant Recipients

2020 ◽  
Vol 9 (2) ◽  
pp. 440 ◽  
Author(s):  
Edmund J. Gore ◽  
António W. Gomes-Neto ◽  
Lei Wang ◽  
Stephan J. L. Bakker ◽  
Hubert G. M. Niesters ◽  
...  
Keyword(s):  
Renal Transplantation ◽  
Renal Transplant ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Long Term Outcomes ◽  
Post Transplantation ◽  
Increased Risk ◽  
All Cause Mortality ◽  
One Year

Following transplantation, patients must take immunosuppressive medication for life. Torquetenovirus (TTV) is thought to be marker for immunosuppression, and TTV–DNA levels after organ transplantation have been investigated, showing high TTV levels, associated with increased risk of infections, and low TTV levels associated with increased risk of rejection. However, this has been investigated in studies with relatively short follow-up periods. We hypothesized that TTV levels can be used to assess long term outcomes after renal transplantation. Serum samples of 666 renal transplant recipients were tested for TTV DNA. Samples were taken at least one year after renal transplantation, when TTV levels are thought to be relatively stable. Patient data was reviewed for graft failure, all-cause mortality and death due to infectious causes. Our data indicates that high TTV levels, sampled more than one year post-transplantation, are associated with all-cause mortality with a hazard ratio (HR) of 1.12 (95% CI, 1.02–1.23) per log10 increase in TTV viral load, (p = 0.02). Additionally, high TTV levels were also associated with death due to infectious causes (HR 1.20 (95% CI 1.01–1.43), p = 0.04). TTV levels decrease in the years following renal transplantation, but remain elevated longer than previously thought. This study shows that TTV level may aid in predicting long-term outcomes, all-cause mortality and death due to an infectious cause in renal transplant patients sampled over one year post-transplantation.

scholarly journals Viral Enteritis in Solid-Organ Transplantation

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2019
Author(s):  
Anum Abbas ◽  
Andrea J. Zimmer ◽  
Diana Florescu
Keyword(s):  
Solid Organ Transplantation ◽  
Organ Transplant ◽  
Solid Organ Transplant ◽  
Solid Organ ◽  
Transplant Recipients ◽  
Post Transplantation ◽  
Organ Transplant Recipients ◽  
Increased Risk ◽  
Viral Enteritis ◽  
Solid Organ Transplant Recipients

Solid organ transplant recipients are at increased risk for infections due to chronic immunosuppression. Diarrhea is a commonly encountered problem post transplantation, with infectious causes of diarrhea being a frequent complication. Viral infections/enteritides in solid organ transplant recipients often result from frequently encountered pathogens in this population such as cytomegalovirus, adenovirus, and norovirus. However, several emerging viral pathogens are increasingly being recognized as more sensitive diagnostic techniques become available. Treatment is often limited to supportive care and reduction in immunosuppression, though antiviral therapies mayplay a role in the treatment in certain diseases. Viral enteritis is an important entity that contributes to morbidity and mortality in transplant recipients.

scholarly journals Exponentially increased risk of infectious death in older renal transplant recipients

2001 ◽  
Vol 59 (4) ◽  
pp. 1539-1543 ◽  
Author(s):  
Herwig-Ulf Meier-Kriesche ◽  
Akinlolu O. Ojo ◽  
Julie A. Hanson ◽  
Bruce Kaplan
Keyword(s):  
Renal Transplant ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Increased Risk

Detection of Toxoplasma Gondii Antibodies and DNA Among Renal Transplant Recipient and blood donor in Khartoum State, Sudan

2021 ◽  
pp. 135-141
Author(s):  
Elghazali Mohammed ◽  
Mustafa Yassin ◽  
Khalid Anan ◽  
Dina N Abdelrahman ◽  
Abdelrahim M. ElHussein ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Renal Transplant ◽  
Transplant Recipient ◽  
Renal Transplant Recipient ◽  
Blood Donor ◽  
Blood Donors ◽  
Solid Organ ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Toxoplasma Gondii Infection

Background and Aim: Toxoplasma gondii infection arises in transplant recipient groups, but at varying frequencies. Reactivation of latent T. gondii infection in transplant patients is uncommon, but does occur. The incidence of reactivation is greater in patient groups receiving more aggressive immunosuppressive therapy. Early diagnosis and treatment should be considered in T. gondii-antibody-positive patients subjected to solid organ transplantation. The aim of this study was to estimate the seroprevalence of Toxoplasma gondii infection in renal transplant recipients in Khartoum, Sudan, using serological and molecular methods. Methods: This was a descriptive cross sectional, hospital based study, blood sample were collected from 108 participants; out of them 58 renal transplant recipient individuals and 50 healthy Blood donor attending Sudanese Kidney Association Hospital and Sudan Heart Center Blood Bank. Demographic data were collected by structured questionnaire. All samples were tested for anti-Toxoplasma IgG and IgM antibodies using ELISA, and PCR for detection of Toxoplasma DNA was performed. Results: The seropositivity of IgG anti-T. gondii antibodies was higher in renal transplant recipients than in blood donors (36.2% vs 32.0%). Anti-toxoplasma IgM was positive in one renal transplant recipient individual (1.70%), and no samples exhibit reactive IgM antibody for blood donors. None of the samples exhibited positivity to T.gondii DNA. Conclusion: the study showed a relatively high seroprevalence of T.gondii antibodies in renal transplant recipients and blood donor volunteers, on the other hand, the prevalence was much higher in the study conducted in pregnant woman in Sudan. Our study highlighted that asymptomatic blood donors, may constitute a significant risk of transmitting toxoplasmosis to susceptible recipients.

scholarly journals Malignant and Noninvasive Skin Tumours in Renal Transplant Recipients

2014 ◽  
Vol 2014 ◽  
pp. 1-6
Author(s):  
Christopher D. Roche ◽  
Joelle S. Dobson ◽  
Sion K. Williams ◽  
Mara Quante ◽  
Joyce Popoola ◽  
...  
Keyword(s):  
Renal Transplant ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Skin Tumours ◽  
Skin Malignancy ◽  
Increased Risk ◽  
Malignant Skin ◽  
Risk Of Malignancy

Background.Transplant recipients require immunosuppression to prevent graft rejection. This conveys an increased risk of malignancy, particularly skin tumours. There is a need for up-to-date data for the South of England.Method.Pathology records were reviewed for 709 kidney transplant recipients on immunosuppression at our hospital from 1995 to 2008. Skin tumours were recorded/analysed.Results.Mean age at transplant was 46 years. Mean length of follow-up was 7.2 years and total follow-up was 4926 person-years. 53 (7.5%) patients (39/458 (8.5%) males and 14/251 (5.6%) females) developed ≥1 skin malignancy. Cumulative incidences of 4.0%, 7.5%, and 12.2% were observed for those with <5, <10, and ≥10 years follow-up, respectively. The rate was 45 tumours per 1000 person-years at risk. Additionally, 21 patients (3.0%) only had noninvasive tumours. 221 malignant skin tumours were found: 50.2% were SCCs, 47.1% BCCs, and 2.7% malignant melanomas. Mean years to first tumour were 5.8. Mean number of tumours per patient was 4, with mean interval of 12 months.Conclusions.Despite changes in transplantation practice during the time since the last data were published in this region, these findings are similar to previous studies. This adds to the evidence allowing clinicians to inform patients in this region of their risk.

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