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

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.

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

10.46619/cmj.2020.3-1016 ◽

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.

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

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0863 ◽

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.

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

Scientific Reports ◽

10.1038/s41598-020-76379-6 ◽

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.

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

Current Drug Metabolism ◽

10.2174/1389200222666210114123349 ◽

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.

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Post-Renal Transplant De Novo Non-Skin Malignancies in Mycophenolate Mofetil- and Calcineurin Inhibitor-Based Immunosuppression.

Blood ◽

10.1182/blood.v114.22.1683.1683 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1683-1683

Author(s):

Lohith Bachegowda ◽

Diptesh Gupta ◽

Ajoy Bharadwaj ◽

Karthik Ranganna ◽

TIM Adamowicz ◽

...

Keyword(s):

Mycophenolate Mofetil ◽

Renal Transplant ◽

Calcineurin Inhibitor ◽

De Novo ◽

Calcineurin Inhibitors ◽

Solid Organ ◽

Renal Transplant Recipients ◽

Transplant Recipients ◽

Hla Antigen ◽

Post Transplant

Abstract Abstract 1683 Poster Board I-709 Introduction- Post-transplant malignancy is one of the major complications of immunosuppression in kidney transplant recipients. Mycophenolate Mofetil(MMF) and Calcineurin inhibitors(CNI) based immunosuppression is a well established combination in clinical practice. MMF has an action on cell proliferation by inhibiting Inosine Mono Phosphate dehydrogenase. However, its antitumor properties have been constantly debated. It is shown to have some antiproliferative effects in leukemias and lymphomas with a decreased incidence of PTLD. This single center study evaluated the effect of combining mycophenolate mofetil (MMF) with calcineurin inhibitors on the incidence of de novo post-transplant non skin malignancies in renal transplant recipients. We also compared the incidence of solid versus liquid cancers. Patients and Methods- Six hundred and fifty seven (657) consecutive kidney and kidney/pancreas recipients transplanted between January 2000 and December 2005 were analyzed for post-transplant malignancies. Three hundred and sixty two (362) recipients were maintained on a calcineurin inhibitor and MMF combination. The incidence of neoplasm in this group was monitored till June 2009. All patients received induction therapy with basiliximab and methylprednisolone. Steroid therapy was discontinued after the second dose in the withdrawal group. In the steroid treated group oral prednisone was initiated on day 2 at 30 mg per day and rapidly tapered to 5 mg per day at one month and continued for the life of the graft. Maintenance therapy in all recipients included both, a calcineurin inhibitor and mycophenolate mofetil (MMF). All clinical acute rejections were confirmed by biopsy and treated with intravenous methylprednisolone. Steroid unresponsive rejections were treated with Thymoglobulin Table 1 shows the demography in the CNI + MMF recipient group Recipient demography Calcineurin inhibitor/MMF group Number of recipients 362 Mean age in years 53 ± 3 Male gender 196 Deceased donor kidney recipients 305 Mean HLA antigen mismatch 3.95 ± 2.6 Pre-transplant malignancies 0 Number of recipients with rejection 71 Table 2 Incidence and type of malignancies in calcineurin inhibitor + MMF group Type of cancer Calcineurin inhibitor/MMF group Total number of recipients 362 Post transplant lymphoproliferative disease 1 Hodgkin's lymphoma 1 Renal cell cancer 6 Lung cancer 3 Prostate cancer 2 Colon cancer 2 Breast cancer 2 Bladder cancer 1 Pancreatic cancer 1 Leukemia 1 Thyroid cancer 1 Total cancers 21 (5.8%) Conclusion In our study on CNI/MMF based immunosuppression in renal transplant patients, 5.8% developed various neoplasms. There was a lower incidence of hematologic- malignancies 3/362(0.8%) in comparison to solid organ neoplasm 18/362(4.97%). The incidence of PTLD was 0.27%, which is similar to other observational studies. This could partly be due to greater expression of Inosine Monophosphate, inhibited by MMF in malignant hematologic cells. Further multicenter analysis needs to be done to detect the incidence of liquid and solid neoplasms, correlating with intracellular IMP levels with MMF usage in renal transplant recipients. Disclosures No relevant conflicts of interest to declare.

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947. Nocardiosis in Renal Transplant Recipients Linked to Decreased Utilization of Trimethoprim/Sulfamethoxazole During COVID-19

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1142 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S566-S567

Author(s):

Terrence McSweeney ◽

Jennifer Marvin ◽

Elizabeth A Cohen ◽

Vincent Do ◽

Kristen Belfield ◽

...

Keyword(s):

Renal Transplant ◽

Organ Transplant ◽

Retrospective Chart Review ◽

Absolute Lymphocyte Count ◽

Cell Mediated Immunity ◽

Renal Transplant Recipients ◽

Transplant Recipients ◽

Post Transplant ◽

Aerosolized Pentamidine ◽

Increased Risk

Abstract Background The renal transplant population is at increased risk of Nocardiosis due to impaired T-cell mediated immunity with immunosuppression. Pneumocystis jirovecii (PJP) prophylaxis with trimethoprim/sulfamethoxazole (TMP/SMX) provides coverage against Nocardia spp. unlike alternative agents such as atovaquone (ATQ), aerosolized pentamidine (AP), and dapsone. During the COVID-19 pandemic, patients receiving AP were transitioned to ATQ to avoid the use of nebulized medication. This, in turn, led to decreased use of TMP/SMX as patients on oral ATQ were not reassessed for the use of TMP/SMX as would have occurred while on AP. Additionally, an increased incidence of Nocardia infections was observed during this time. The objective of this study was to determine the association between the incidence of Nocardia infections and number of TMP/SMX prophylaxis-days in pre- versus COVID-19 cohorts. Methods This was a single center retrospective chart review of all renal transplant recipients between September 2018 – August 2019 (pre-COVID-19 cohort) and April 2020 – March 2021 (COVID-19 cohort). Patients were included if they were at least 18 years of age and a recipient of a cadaveric or living donor kidney transplant. Exclusion criteria included multi-organ transplant, pediatric patients, and repeat transplants. The primary outcome was incidence of Nocardiosis within the first 6 months post-transplant in the pre- and COVID-19 cohorts. Results A total of 218 patients were included (Table 1). Induction therapy and initial immunosuppression did not differ significantly between groups, nor did rates of rejection within 180 days of transplant (Table 2). Although the pre-COVID-19 cohort had a higher rate of neutropenia, there was no difference in median absolute lymphocyte count between the two groups. The COVID-19 cohort had a decreased percentage of TMP/SMX prophylaxis-days (59.2% vs. 72.5%, p < 0.0001) and an increased incidence of Nocardia infections in the first 6 months post-transplant (4% vs. 0%, p=0.0292). All 4 cases of Nocardia infections occurred in patients receiving ATQ. Conclusion The increased incidence of Nocardiosis was associated with a decreased use of TMP/SMX for PJP prophylaxis which may have been an unintended consequence of increased use of ATQ in lieu of AP during COVID-19. Disclosures All Authors: No reported disclosures

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Post-Transplant Diabetes Mellitus and Prediabetes in Renal Transplant Recipients: An Update

Nephron ◽

10.1159/000514288 ◽

2021 ◽

pp. 1-13

Author(s):

Ana Elena Rodríguez-Rodríguez ◽

Esteban Porrini ◽

Mads Hornum ◽

Javier Donate-Correa ◽

Raúl Morales-Febles ◽

...

Keyword(s):

Diabetes Mellitus ◽

Renal Transplant ◽

Cell Function ◽

Cell Damage ◽

Current Evidence ◽

Renal Transplant Recipients ◽

Transplant Recipients ◽

Post Transplant ◽

Β Cell Function

Post-transplant diabetes mellitus (PTDM) is a frequent and relevant complication after renal transplantation: it affects 20–30% of renal transplant recipients and increases the risk for cardiovascular and infectious events. Thus, understanding pathogenesis of PTDM would help limiting its consequences. In this review, we analyse novel aspects of PTDM, based on studies of the last decade, such as the clinical evolution of PTDM, early and late, the reversibility rate, diagnostic criteria, risk factors, including pre-transplant metabolic syndrome and insulin resistance (IR) and the interaction between these factors and immunosuppressive medications. Also, we discuss novel pathogenic factors, in particular the role of β-cell function in an environment of IR and common pathways between pre-existing cell damage and tacrolimus-induced toxicity. The relevant role of prediabetes in the pathogenesis of PTDM and cardiovascular disease is also addressed. Finally, current evidence on PTDM treatment is discussed.

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