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Concept: Mycophenolate mofetil

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Preventing xenograft rejection is one of the greatest challenges of transplantation medicine. Here, we describe a reproducible, long-term survival of cardiac xenografts from alpha 1-3 galactosyltransferase gene knockout pigs, which express human complement regulatory protein CD46 and human thrombomodulin (GTKO.hCD46.hTBM), that were transplanted into baboons. Our immunomodulatory drug regimen includes induction with anti-thymocyte globulin and αCD20 antibody, followed by maintenance with mycophenolate mofetil and an intensively dosed αCD40 (2C10R4) antibody. Median (298 days) and longest (945 days) graft survival in five consecutive recipients using this regimen is significantly prolonged over our recently established survival benchmarks (180 and 500 days, respectively). Remarkably, the reduction of αCD40 antibody dose on day 100 or after 1 year resulted in recrudescence of anti-pig antibody and graft failure. In conclusion, genetic modifications (GTKO.hCD46.hTBM) combined with the treatment regimen tested here consistently prevent humoral rejection and systemic coagulation pathway dysregulation, sustaining long-term cardiac xenograft survival beyond 900 days.

Concepts: Immune system, DNA, Gene expression, Blood, Immunology, Organ transplant, Mycophenolic acid, Mycophenolate mofetil

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OBJECTIVES: To determine the mycophenolic acid pharmacokinetic profile early after transplant in Iranian kidney graft recipients. MATERIALS AND METHODS: A cross-sectional study was performed during 6 months in 31 patients who recently had kidney transplant and received fixed doses of mycophenolate mofetil (2 g/d). The plasma levels of mycophenolic acid were determined by high performance liquid chromatography. RESULTS: The mean first mycophenolic acid peak level was 10 ± 5 mg/L. The mean mycophenolic acid area under the curve was 26 ± 19 mgh/L and apparent clearance was 57 ± 55 L/h. The mycophenolic acid area under the curve values of only 8 patients (26%) were within the therapeutic range (30-60 mgh/L). The first, second, and third mycophenolic acid peak levels correlated significantly with mycophenolic acid area under the curve (P < .05). Mycophenolic acid concentration at 10 hours had the highest correlation with mycophenolic acid area under the curve (r=0.962; P < .05). No statistically significant differences were evident in the mean mycophenolic acid area under the curve between men and women. CONCLUSIONS: There was a high degree of variation between different patients in mycophenolic acid pharmacokinetics early after kidney transplant.

Concepts: Pharmacology, Statistics, Statistical significance, High performance liquid chromatography, Kidney transplantation, Pharmacokinetics, Mycophenolic acid, Mycophenolate mofetil

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Mycophenolate mofetil (MMF) is used for prevention of allograft rejection in transplantation medicine. In dermatology it is used as a corticosteroid-sparing agent. The pharmacokinetics of MMF are known to vary by individual. Therapeutic dose monitoring of mycophenolic acid (MPA), the active metabolite of MMF, is used as a guide in transplantation medicine, but limited data exist on the benefit of measuring MPA levels in the management of dermatologic disease.

Concepts: Pharmacology, Medicine, Disease, Organ transplant, Cyclophosphamide, Mycophenolic acid, Mycophenolate mofetil, Dermatology

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: The influence of the conversion from cyclosporine (CsA) to everolimus (EVR) on the chronopharmacokinetics of mycophenolic acid (MPA) and its glucuronide (MPAG) and acyl glucuronide (acyl-MPAG) metabolites in patients receiving enteric-coated mycophenolate sodium (EC-MPS) has not been studied.

Concepts: Organ transplant, Kidney transplantation, Transplant rejection, Immunosuppressants, Mycophenolic acid, Mycophenolate mofetil, Novartis

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Every month, new releases on the relationship between pharmacogenetic biomarkers and immunosuppressive drug therapy in kidney transplantation are published. However, the systematic clinical application of these discoveries occurs at a very slow pace, and the usefulness of knowing a patient’s genotype remains an important matter of debate. This can be partially ascribed to the lack of consistency when looking at the different associations reported across several studies but also the need for a broad-spectrum view and a rigorous analysis of the relevance of the different associations observed to date. For that purpose, we performed a comprehensive analysis of the strength of the different reported genetic associations, and in this article we discuss their potential for clinical implementation in kidney transplantation. For tacrolimus, it is likely that a genotype-based drug dosage can benefit patient outcome, while for ciclosporin A, the data appear less convincing. For the mammalian target of rapamycin inhibitors, sirolimus and everolimus - given the lack of data and the absence of large prospective studies - it is premature to implement pharmacogenetics, but some novel and promising leads have recently been reported. For mycophenolate mofetil, the complex metabolic pathways of its active moiety, mycophenolic acid, complicate analysis of the various published associations. However, at present, some interesting findings can be highlighted and offer potential value to assist clinicians in decision making.

Concepts: Pharmacology, Kidney transplantation, Transplant rejection, Immunosuppressive drug, Immunosuppressants, Mycophenolic acid, Mycophenolate mofetil, Liver transplantation

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BACKGROUND: Nephrotic syndrome (NS) is a recognized complication of immune tolerance induction (ITI) therapy, a treatment strategy used to treat inhibitors in patients with hemophilia B receiving factor IX concentrate. CASE DIAGNOSIS/TREATMENT: We present a 4-year-old boy with hemophilia B and an inhibitor who underwent ITI, and developed NS 19 months into this therapy. A percutaneous renal biopsy was safely performed with factor IX (FIX) concentrate administration both preceding and following the procedure. The patient’s inhibitor level had increased to 1.4-1.6 Bethesda Units just prior to the onset of proteinuria. Histology confirmed segmental membranous nephropathy (MGN). The patient was continued on FIX concentrate as ITI and also received 4 weekly doses of rituximab and ongoing immunosuppression with mycophenolate mofetil. This resulted in the complete resolution of his inhibitor and his NS. He continues with a modified ITI regimen and remains inhibitor-free without proteinuria >12 months post-biopsy. CONCLUSIONS: Hemophilia B patients undergoing ITI should be regularly screened for NS. At first detection of proteinuria, with proper precautions, a percutaneous kidney biopsy can be performed safely in patients with low levels of inhibitor. Our patient had segmental MGN with complete remission of NS.

Concepts: Kidney, Patient, Nephrotic syndrome, Proteinuria, Haemophilia B, Mycophenolic acid, Mycophenolate mofetil, Nephritic syndrome

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The efficacy of rituximab (RTX) as the sole therapy for preventing relapses of nephrotic syndrome (NS) is transient in most patients; therefore, the optimal therapy required for maintaining a successful response to a biological agent remains a challenge. We conducted a prospective study to compare the efficacy of cyclosporine (CsA) with that of mycophenolate mofetil (MMF) as maintenance therapy after a single infusion of RTX. Of 29 patients with persistent steroid-dependent NS despite the use of CsA and/or MMF, 13 without chronic nephrotoxicity continued CsA therapy, maintaining a 2-h post-dose CsA level of 400-500 ng/ml (CsA group). The remaining 16 were treated with MMF, maintaining a pre-dose level of 2-5 μg/ml of mycophenolic acid (MMF group). The median duration of CsA and MMF treatment was 18 and 19 months, respectively. Despite the mean number of relapses before RTX treatment being significantly lower in the MMF group than in the CsA group (2.3/year vs. 4.6/year, p < 0.01), treatment failure occurred more frequently in the MMF group (7/16) than in the CsA group (2/13). The rate of sustained remission was also significantly higher in the CsA group than in the MMF group (p < 0.05). Conclusion: In patients with severe steroid-dependent NS, CsA appears to be more effective than MMF for maintaining remission after a single infusion of RTX.

Concepts: Median, Arithmetic mean, Mean, Transplant rejection, Skewness, Immunosuppressants, Mycophenolic acid, Mycophenolate mofetil

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Intravenous (IV) cyclophosphamide has been first-line treatment for inducing disease remission in lupus nephritis. The comparative efficacy and toxicity of newer agents such as mycophenolate mofetil (MMF) and calcineurin inhibitors are uncertain.

Concepts: Systemic lupus erythematosus, Immunosuppressive drug, Lupus nephritis, Cyclophosphamide, Mycophenolic acid, Mycophenolate mofetil, Calcineurin

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Mycophenolic acid (MPA) is the active immunosuppressive substance in both mycophenolate mofetil and mycophenolate sodium and it is widely used after organ transplantation. In females taking MPA is teratogenic and may also influence spermatogenesis. There is a lack of knowledge regarding outcome of pregnancies fathered by males exposed to MPA.

Concepts: Organ transplant, Transplant rejection, Mycophenolic acid, Mycophenolate mofetil, Liver transplantation

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To report the 10-year follow-up of the MAINTAIN Nephritis Trial comparing azathioprine (AZA) and mycophenolate mofetil (MMF) as maintenance therapy of proliferative lupus nephritis, and to test different definitions of early response as predictors of long-term renal outcome.

Concepts: Systemic lupus erythematosus, Lupus nephritis, Immunosuppressants, Mycophenolic acid, Mycophenolate mofetil