scholarly journals Effects of Corticosteroid Treatment on Mycophenolic Acid Exposure in Renal Transplant Patients—Results From the SAILOR Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Nima Nourbakhsh ◽  
Jana Ekberg ◽  
Karin Skov ◽  
Christian Daugaard Peters ◽  
Aygen Øzbay ◽  
...  
Keyword(s):  
Body Weight ◽  
Renal Transplant ◽  
Mycophenolic Acid ◽  
Interindividual Variation ◽  
Fixed Dose ◽  
Therapeutic Drug ◽  
Solid Organ ◽  
Renal Transplant Recipients ◽  
Post Transplant

Background: Mycophenolic acid (MPA) is a potent immunosuppressive agent used in solid organ transplantation. MPA exhibits large interindividual variation in dose-normalized plasma concentrations but is nevertheless usually prescribed as a fixed dose without use of therapeutic drug monitoring (TDM). Data on the effect of corticosteroid (CS) treatment on MPA concentrations during concomitant tacrolimus treatment remains sparse.Methods: Data is based on TDM of MPA area under the concentration curve (AUC) in 210 renal transplant recipients participating in the prospective, randomized, controlled, multi-center trial (SAILOR) where a steroid-free immunosuppressive regimen with mycophenolate mofetil (MMF) and low-dose tacrolimus was compared with a conventional prednisolone-based treatment regimen. Multilevel mixed-effects linear regression post-hoc analyses of MPA AUC was performed.Results: Median MPA AUC at baseline (within the first 2 weeks post-transplant) in patients taking 2 g MMF daily was 53 mg*h/L (interquartile range: 43–69 mg*h/L, min: 24—max: 117 mg*h/L). Between-patient variation in MPA AUC was up to 5-fold on the same MMF dose. Patients in the steroid-free group had 12.5% lower (95% CI; 3.2–20.9%, p = 0.01) MPA AUC levels at baseline compared to the steroid treated group. During follow-up (14 days–2 years post-transplant) there were no significant differences in MPA AUC between the groups with MPA AUC being 4.2% lower (95% CI: −4.8%−12,5%, p = 0.35) in the steroid-free vs standard treatment group in restricted analysis after multivariate adjustment for tacrolimus trough level, body weight, time after transplantation and MMF dose. MMF dose was positively correlated with MPA AUC (p < 0.001) whereas body weight was negatively correlated with MPA AUC (p < 0.001). MPA AUC was 0.4% (95% CI: 0.2–0.6%, p < 0.001) lower per 1 kg increase in weight. Tacrolimus trough levels had no significant effect on MPA AUC.Conclusion: Immunosuppression with CS during concomitant tacrolimus treatment was shortly after transplantation associated with a significantly higher MPA exposure but the effect was small and not maintained during follow-up. Low body weight was associated with higher MPA exposure, which suggests a potential for weight adjusted MMF dosing.

scholarly journals Therapeutic monitoring of mycophenolic acid in renal transplanted patients by a validated HPLC method

Folia Medica ◽  
2021 ◽  
Vol 63 (5) ◽  
pp. 768-774
Author(s):  
Mikaela Kolaci ◽  
Leonard Deda ◽  
Alma Idrizi ◽  
Myftar Barbullushi ◽  
Dariel Thereska
Keyword(s):  
Renal Transplant ◽  
Mycophenolic Acid ◽  
Trough Concentration ◽  
Solid Organ Transplantation ◽  
Hplc Method ◽  
Therapeutic Monitoring ◽  
Therapeutic Drug ◽  
Solid Organ ◽  
Renal Transplant Recipients ◽  
Column Temperature

Introduction: Mycophenolate mofetil and its active metabolite mycophenolic acid are routinely used as immunosuppressant drugs in solid organ transplantation in a fixed daily dose regimen in association with cyclosporine, tacrolimus and steroids. Therapeutic drug monitoring for mycophenolic acid concentration has been suggested to optimize outcomes by reducing rejection and drug related toxicities in clinical renal transplantation. Aim: To determine the predose concentration of mycophenolic acid in renal transplanted patients by a validated proposed high-performance liquid chromatography (HPLC) method and to estimate the interindividual variability based on the therapeutic target. Materials and methods: An HPLC method combined with protein precipitation has been validated for mycophenolic acid determination in the human plasma obtained from 21 renal transplant recipients. HPLC analysis was carried out using the chromatographic system Agilent Technologies 1200 DAD. Samples were injected manually, and the compounds were separated on a LiChrosphere® select B C18 analytical column. The mobile phase was 45:55 (v/v) acetonitrile-buffer phosphate, pH 2.5, flow rate of 1.0 mL/min and column temperature of 30°C. Detection was performed at 215 nm. Whole blood samples were collected into vacutainers containing EDTA and separated at 6000 g for 10 minutes. A 200-μL aliquot of patient plasma was transferred to a tube, followed by addition of 10 μL of naproxen as internal standard and 400 μL of acetonitrile (v/v) as a protein precipitating agent. Each tube was vortex-mixed for 30 sec and then centrifuged for 10 min at 10000 rpm. 20 μL of the supernatant was injected into the HPLC system for analysis. Results: The method showed appropriate linearity for MPA with correlation coefficient greater than 0.999. High inter-patient variability is observed with 18% of patients within the target trough concentration range, 27% of patients below the target trough concentration range and 54% over the range with risk of toxicity. Conclusions: Therapeutic monitoring of MPA might contribute to a better management of renal transplant recipient with the goal of optimizing therapeutic regimens in order to reduce the risk of rejection and MPA‐related toxicity.

scholarly journals Tacrolimus concentration/dose ratio as a therapeutic drug monitoring strategy: The influence of gender and comedication

2015 ◽  
Vol 72 (9) ◽  
pp. 813-822 ◽  
Author(s):  
Nemanja Rancic ◽  
Viktorija Dragojevic-Simic ◽  
Neven Vavic ◽  
Aleksandra Kovacevic ◽  
Zoran Segrt ◽  
...  
Keyword(s):  
Gender Differences ◽  
Body Weight ◽  
Renal Transplant ◽  
Case Series ◽  
Tacrolimus Concentration ◽  
Therapeutic Drug ◽  
Channel Blockers ◽  
Renal Transplant Recipients ◽  
Dose Ratio ◽  
Case Series Study

Background/Aim. A combination of tacrolimus and other drugs such as corticosteroids has been commonly used immunosuppresive regimens. On the other hand, there is a growing body of evidence that male and female may differ in their response to the equal drug treatment. The aim of the study was to estimated the use of tacrolimus concentration/dose (C/D) ratio for the assessment of the influence of gender differences and comedication on tacrolimus exposure in renal transplant recipients. Methods. This prospective case series study included 54 patients, in which the unit of monitoring was outpatient examination (1,872) of the renal transplant patients. The patients were monitored in the period 2010-2014, starting one month after the transplantation. Tacrolimus trough concentrations (TTC) were measured by chemiluminescence microparticles immunoassay. Results. TTC and the tacrolimus C/D ratio were significantly lower in the females comparing with the males. Contrary to the males, in the females a significant increase of the tacrolimus daily dose (TDD) per body weight and TTC, along with the corticosteroid dose increase, was not accompanied by any significant changes in the tacrolimus C/D ratio; in different corticosteroid doses faster elimination of tacrolimus was found with the exception of the doses > 0.25 mg/kg. In the patients treated with proton pump inhibitors, mainly with pantoprazole TDD per body weight and TTC were significantly higher, while the tacrolimus C/D ratio was significantly lower compared to the patients without this treatment. In the patients treated with calcium channel blockers, TDD per body weight was significantly lower (particularly with amlodipine) while the tacrolimus C/D ratio was higher compared to the patients who were not treated by them. Conclusion. A lower tacrolimus exposure was detected in females in comparison to males. When gender differences were considered in the context of different corticosteroid doses, faster elimination of tacrolimus in the females was also seen, with the exception of the doses > 0.25 mg/kg. Tacrolimus exposure in the pantoprazole-treated patients was significantly less expressed, while in patients treated with CCB amplodipine the tacrolimus C/D ratio was significantly higher in comparison with the patients not treated with them.

scholarly journals High Plasma Branched-Chain Amino Acids Are Associated with Higher Risk of Post-Transplant Diabetes Mellitus in Renal Transplant Recipients

2020 ◽  
Vol 9 (2) ◽  
pp. 511 ◽  
Author(s):  
Maryse C. J. Osté ◽  
Jose L. Flores-Guerrero ◽  
Eke G. Gruppen ◽  
Lyanne M. Kieneker ◽  
Margery A. Connelly ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Amino Acids ◽  
Renal Transplant ◽  
Branched Chain Amino Acids ◽  
Resonance Spectroscopy ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Post Transplant ◽  
Branched Chain

Post-transplant diabetes mellitus (PTDM) is a serious complication in renal transplant recipients. Branched-chain amino acids (BCAAs) are involved in the pathogenesis of insulin resistance. We determined the association of plasma BCAAs with PTDM and included adult renal transplant recipients (≥18 y) with a functioning graft for ≥1 year in this cross-sectional cohort study with prospective follow-up. Plasma BCAAs were measured in 518 subjects using nuclear magnetic resonance spectroscopy. We excluded subjects with a history of diabetes, leaving 368 non-diabetic renal transplant recipients eligible for analyses. Cox proportional hazards analyses were used to assess the association of BCAAs with the development of PTDM. Mean age was 51.1 ± 13.6 y (53.6% men) and plasma BCAA was 377.6 ± 82.5 µM. During median follow-up of 5.3 (IQR, 4.2–6.0) y, 38 (9.8%) patients developed PTDM. BCAAs were associated with a higher risk of developing PTDM (HR: 1.43, 95% CI 1.08–1.89) per SD change (p = 0.01), independent of age and sex. Adjustment for other potential confounders did not significantly change this association, although adjustment for HbA1c eliminated it. The association was mediated to a considerable extent (53%) by HbA1c. The association was also modified by HbA1c; BCAAs were only associated with renal transplant recipients without prediabetes (HbA1c < 5.7%). In conclusion, high concentrations of plasma BCAAs are associated with developing PTDM in renal transplant recipients. Alterations in BCAAs may represent an early predictive biomarker for PTDM.

Therapeutic Drug Monitoring of Mycophenolic Acid in Renal Transplant Recipients

2005 ◽  
Vol 37 (2) ◽  
pp. 859-860 ◽  
Author(s):  
M. Okamoto ◽  
Y. Wakabayashi ◽  
A. Higuchi ◽  
Y. Kadotani ◽  
S. Ogino ◽  
...  
Keyword(s):  
Renal Transplant ◽  
Therapeutic Drug Monitoring ◽  
Mycophenolic Acid ◽  
Drug Monitoring ◽  
Therapeutic Drug ◽  
Renal Transplant Recipients ◽  
Transplant Recipients

scholarly journals Long-term follow-up of renal transplant recipients treated with losartan for post-transplant erythrosis

1998 ◽  
Vol 11 (4) ◽  
pp. 312-315 ◽  
Author(s):  
Didier Ducloux ◽  
Véronique Fournier ◽  
Catherine Bresson-Vautrin ◽  
Jean-Marc Chalopin
Keyword(s):  
Renal Transplant ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Post Transplant ◽  
Long Term Follow Up

scholarly journals Comparison of the Emit Immunoassay with HPLC for Therapeutic Drug Monitoring of Mycophenolic Acid in Pediatric Renal-Transplant Recipients on Mycophenolate Mofetil Therapy

2002 ◽  
Vol 48 (3) ◽  
pp. 517-525 ◽  
Author(s):  
Lutz T Weber ◽  
Maria Shipkova ◽  
Victor W Armstrong ◽  
Natalie Wagner ◽  
Ekkehard Schütz ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Renal Transplant ◽  
Acute Rejection ◽  
Mycophenolic Acid ◽  
Therapeutic Drug ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Increased Risk ◽  
Pediatric Renal Transplant ◽  
Pediatric Renal Transplant Recipients

Abstract Background: HPLC is currently the preferred method for accurate measurement of mycophenolic acid (MPA). This study was designed to validate the Emit compared with HPLC in relation to clinical outcome measurements. Methods: Pediatric renal-transplant recipients (n = 50) on an immunosuppressive triple regimen consisting of cyclosporin A, prednisone, and mycophenolate mofetil (600 mg/m2 twice per day) were investigated in an open-label prospective study. Pharmacokinetic profiles over 12 h were obtained at 1 week, 3 weeks, 3 months, and 6 months posttransplant. Plasma MPA was measured by both reversed-phase HPLC and the Emit immunoassay. Results: There was an association between the risk of acute rejection episodes and low area under the curve values from t0 to t12h (AUC0–12) for MPA (MPA-AUC0–12) or predose concentrations of MPA derived from both HPLC and Emit measurements. According to ROC analysis, an AUC value of 33.8 mg · h/L for MPA from t0 to t12h (MPA-AUC0–12) determined by HPLC had a diagnostic sensitivity of 80% and a diagnostic specificity of 57%. The corresponding value of the Emit was 36.1 mg · h/L. For the predose concentration (MPA-c12), a concentration of 1.2 mg/L determined by HPLC and 1.4 mg/L determined by Emit gave a sensitivity of 80% and a specificity of 60%, respectively. There was no association of any pharmacokinetic variables derived from total MPA measurements with an increased risk of side effects related to mycophenolate mofetil. Conclusions: The Emit assay appears to have a comparable diagnostic efficacy to HPLC for assessing the risk of acute rejection in pediatric renal-transplant recipients. However, because of the cross-reactivity of the antibody used in the Emit assay with the active MPA acyl glucuronide metabolite, the decision thresholds for the Emit were higher than those calculated from HPLC measurements.

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

Blood ◽  
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.

A Single-Centre Experience of Clinico-Pathological Features, Risk Factors and Treatment Outcome of Posttransplant Lymphoproliferative Disorders (PTLD) after Renal Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4421-4421
Author(s):  
Esben Sondergaard ◽  
Charlotte Strandhave ◽  
Robert S. Pedersen ◽  
Kaj A. Jorgensen ◽  
Knud Bendix ◽  
...  
Keyword(s):  
T Cell ◽  
Renal Transplant ◽  
B Cell ◽  
Graft Function ◽  
B Cell Lymphoma ◽  
Solid Organ ◽  
Renal Transplant Recipients ◽  
Early Lesions ◽  
Anti Cd20

Abstract Background: PTLD is a lymphoid proliferation that develops as a consequence of immunosuppression and represents monoclonal B-cell, or rarely T-cell proliferations, occurring in a setting of decreased T-cell immune surveillance. PTLD is a major complication after solid organ transplantation. The disease is often unpredictable and devastating of nature resulting in a high rate of morbidity and patient mortality. Methods: Between 1990 and 2005 872 renal transplantations in 793 patients were performed at Skejby University Hospital in Aarhus and 11 cases of PTLD were identified retrospectively. PTLD Patients were investigated according to transplantation procedure, patient characteristics, type of lymphoma, treatment and outcome. Results: 11 of 793 renal transplant recipients (1,4%) developed PTLD. Patients (7 male, 4 female) ranged from 19 to 73 years of age at the time of diagnosis (mean age: 42 years). 8 had a cadaveric renal transplant while 3 received a transplant from related donor. Lymphomas were classified as diffuse large B-cell lymphoma in 10 cases and as Burkitt lymphoma in 1 case. No cases were of T-cell origin or Hodgkins lymphomas. Six cases were EBV positive (54%). Out of 11 cases, 5 were diagnosed within 1 year after transplantation, among which 4 were EBV positive, whereas 6 had a latency period of more than 1 year, among which only 2 were EBV positive. The mean latency time between grafting and diagnosis of PTLD among the early lesions was 7 months and among late lesions 6 years and 2 months (ranging from 1 month to 10 years and 8 months). Sites involved in PTLD were renal graft in 2 cases (both early lesions), lungs in 1 case, bowel system in 4 cases, CNS in 1 case, isolated lymph nodes in 1 case, widespread disease in 1 case and uncertain location in 1 case. All patients were treated by tapering of the immunosuppressive regimen. Two were treated with additional surgery and 3 with chemotherapy - all 5 of them are alive and in complete remission. Among those 5 patients 3 have preserved graft function (60%) and 2 returned to dialysis. One patient was treated with anti-CD20 monoclonal antibody, 3 had both conventional chemotherapy and anti-CD20 immunotherapy and 2 did not receive additional treatment. All 6 were dead at the end of the study period. With a median follow-up period of 5 years and 2 months (ranging from 6 months to 11½ years) 5 patients of 11 PTLD cases (45%) were alive with no sign of lymphoma relapse. Conclusions: PTLD is a severe complication, usually running an aggressive course and the outcome remains poor. The incidence in our population-based regional study material is 1,4%. Overall survival after a median follow-up of 62 months was 45%, with 60% of survivors maintaining graft function.

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