Mycophenolate Mofetil Withdrawal Research Articles

Mycophenolate mofetil withdrawal in patients with systemic lupus erythematosus: a multicentre, open-label, randomised controlled trial

Mycophenolate mofetil is an immunosuppressant commonly used to treat systemic lupus erythematosus (SLE) and lupus nephritis. It is a known teratogen associated with significant toxicities, including an increased risk of infections and malignancies. Mycophenolate mofetil withdrawal is desirable once disease quiescence is reached, but the timing of when to do so and whether it provides a benefit has not been well-studied. We aimed to determine the effects of mycophenolate mofetil withdrawal on the risk of clinically significant disease reactivation in patients with quiescent SLE on long-term mycophenolate mofetil therapy. This multicenter, open-label, randomised trial was conducted in 19 centres in the USA. Eligible patients were aged between 18 and 70 years old, met the American College of Rheumatology (ACR) 1997 SLE criteria, and had a clinical SLEDAI score of less than 4 at screening. Mycophenolate mofetil therapy was required to be stable or decreasing for 2 years or more if initiated for renal indications, or for 1 year or more for non-renal indications. Participants were randomly allocated in a 1:1 ratio to a withdrawal group, who tapered off mycophenolate mofetil over 12 weeks, or a maintenance group who maintained their baseline dose (1-3g per day) for 60 weeks. Adaptive random allocation ensured groups were balanced for study site, renal versus non-renal disease, and baseline mycophenolate mofetil dose (≥2 g per day vs <2 g per day). Clinically significant disease reactivation by week 60 following random allocation, requiring increased doses or new immunosuppressive therapy was the primary endpoint, in the modified intention-to-treat population (all randomly allocated participants who began study-provided mycophenolate mofetil). Non-inferiority was evaluated using an estimation-based approach. The trial was registered at ClinicalTrials.gov (NCT01946880) and is completed. Between Nov 6, 2013, and April 27, 2018, 123 participants were screened, of whom 102 were randomly allocated to the maintenance group (n=50) or the withdrawal group (n=52). Of the 100 participants included in the modified intention-to-treat analysis (49 maintenance, 51 withdrawal), 84 (84%) were women, 16 (16%) were men, 40 (40%) were White, 41 (41%) were Black, and 76 (76%) had a history of lupus nephritis. The average age was 42 (SD 12·7). By week 60, nine (18%) of 51 participants in the withdrawal group had clinically significant disease reactivation, compared to five (10%) of 49 participants in the maintenance group. The risk of clinically significant disease reactivation was 11% (95% CI 5-24) in the maintenance group and 18% (10-32) in the withdrawal group. The estimated increase in the risk of clinically significant disease reactivation with mycophenolate mofetil withdrawal was 7% (one-sided upper 85% confidence limit 15%). Similar rates of adverse events were observed in the maintenance group (45 [90%] of 50 participants) and the withdrawal group (46 [88%] of 52 participants). Infections were more frequent in the mycophenolate mofetil maintenance group (32 [64%]) compared with the withdrawal group (24 [46%]). Mycophenolate mofetil withdrawal is not significantly inferior to mycophenolate mofetil maintenance. Estimates for the rates of disease reactivation and increases in risk with withdrawal can assist clinicians in making informed decisions on withdrawing mycophenolate mofetil in patients with stable SLE. The National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Diarrhea after kidney transplantation: A study of risk factors and outcomes.

Diarrhea in kidney transplant recipients (KTRs) can be associated with significant morbidity. We evaluated 198 KTRs for a history of diarrhea post-kidney transplant at a tertiary care center in western India over 1 year. A protocol-based evaluation of diarrhea was done with respect to clinical features, diagnostic evaluation, associated acute allograft dysfunction, and its impact on long-term allograft function. Primary outcomes of interest were: chronic allograft injury (CAI) and the need for mycophenolate mofetil (MMF) withdrawal. We also assessed the effect of MMF withdrawal on the risk of the development of CAI. Eighty-five of 198 (42.5%) recipients experienced diarrhea and a total of 140 diarrheal episodes were evaluated. The mean age of these 85 recipients was 38 ± 12 years and 72 (84.7%) were males. 73 of 85 recipients were on MMF at the time of diarrhea and in 35 (48%) of them MMF withdrawal was needed for chronic and persistent symptoms. Diarrhea was attributed to infective etiologies in 90 of 140 (64.2%) cases. Among the microbiologically confirmed infective diarrheal episodes, giardia and cryptosporidium were the common pathogens in 11/28 (39%) and 6/28 (21.4%) episodes respectively. One hundred and twenty-eight episodes out of 140 (91.4%) episodes were complicated by acute allograft dysfunction. Forty-one of 85 recipients (48.2%) developed chronic allograft injury and 12 (14.1%) developed allograft rejection (acute and/or chronic). Probability of chronic allograft injury was higher in those with MMF withdrawal. Diarrhea post-kidney transplant adversely affects graft function, especially after MMF withdrawal.

Effect of SARS-CoV-2 Infection on Anti-HLA Antibodies and De Novo DSA Incidence in Lung Transplant Recipients

PurposeThe SARS-CoV-2 pandemic has brought many challenges into the field of transplantation. The infection itself leads to a broad activation of B-lymphocytes, which in combination with reduced immunosuppression and systemic pro-inflammatory state may possibly lead to an alloimmune response. The main objective of this retrospective single-center study was to evaluate the effect of SARS-CoV-2 infection on anti-HLA antibody dynamics and development of de novo donor specific antibodies (dnDSA) in lung transplant recipients (LTRs). We also aimed to determine the outcomes of treatment with convalescent plasma (CP) and mycophenolate mofetil (MMF) reduction.MethodsA cohort of 27 LTRs infected by SARS-CoV-2 was retrospectively analyzed. The median age of LTRs at infection was 45.4 years (IQR 26.8-59.5) and median time between transplantation and infection was 16.8 months (IQR 8.0-56.9). The inclusion criteria were history of SARS-CoV-2 infection and screening for anti-HLA antibodies (Luminex technology, One Lambda) before and after infection (median 84, IQR 29-239 days and median 55, IQR 32-90 days resp.).ResultsNo dnDSA were detected after SARS-CoV-2 infection. De novo class II anti-HLA antibodies with low mean fluorescence intensity (MFI) were observed in 1 patient (3.7%) treated with favipiravir and MMF discontinuation without receiving CP. The standard therapeutic regimen consisted of specific antiviral therapy (remdesivir n=15, 55.6%; favipiravir n=12, 44.4%), reduced or discontinued MMF (n=10, 37.0% and n=17, 63.0%, resp.) and administration of CP (n=18, 66.7%) (Table 1).ConclusionIn this retrospective study we did not observe a significant effect of SARS-CoV-2 infection, MMF reduction or CP treatment on anti-HLA antibody dynamics and dnDSA incidence in LTRs. Therefore, CP and MMF withdrawal may be considered as safe therapeutic options regarding antibody-mediated rejection in LTRs affected by SARS-CoV-2. Future studies in larger cohorts are needed to confirm the findings.

Seroconversions After Withdrawal From Mycophenolate Mofetil in Solid Organ Transplant Recipients Without a Third Dose of BNT162b2 mRNA Coronavirus Disease 2019 Vaccine: A Case Series.

To control the burden of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, vaccines have emerged for preventing severe coronavirus disease 2019.1 Poor antibody response to 2 doses of vaccine against SARS-CoV-2 has been reported in solid organ transplants recipients.2-7 Mycophenolate mofetil is one of the key immunomodulators used by solid organ transplant recipients and it also provokes weak antibody responses to anti–SARS-CoV-2 vaccines.2 A third dose of BNT162b2 vaccine to solid organ transplant recipients has been considered as one alternative to achieve adequate antibody responses.3 In transplant patients, withdrawal of immunosuppressive drugs is impractical because of the risk of rejection of the transplanted organ, but other options include switching to other drugs, calcineurin inhibitor or steroid, reducing the dose of antimetabolites, or withdrawal from mycophenolate mofetil. We report the cases of 3 solid organ transplant recipients treated with mycophenolate mofetil at the Matsunami General Hospital (Gifu, Japan) who had each received a second dose of BNT162b2 mRNA (Pfizer/BioNTech) vaccine between March 2021 and October 2021 (Table 1). The SARS-CoV-2 S-immunoglobulin (Ig)G assay reagent kit (Fujirebio Co., Tokyo, Japan) was used to measure S receptor-binding domain IgG antibody titers. Titers >1.0 AU/mL were considered to represent seropositivity. None of the recipients received the third dose of vaccination or had developed prior clinically relevant and polymerase chain reaction–confirmed SARS-CoV-2 infection. All recipients completed their second dose of BNT162b2 mRNA vaccine at 21-d intervals. The institutional review board approval was obtained. TABLE 1. - Characteristics of solid organ transplant recipients who developed seroconversion after withdrawal from mycophenolic acid No. Age a/sex Organ/donor Years since transplant Days from second vaccination Immunosuppressive therapy Antibody titer b(AU/mL) Pre/post Pre/post 1 68/M Liver/deceased 16 103 Calcineurin inhibitor + mycophenolate mofetil/calcineurin inhibitor 0.2/2.4 2 67/F Kidney/deceased 15 110 Calcineurin inhibitor + mycophenolate mofetil/calcineurin inhibitor 0.8/36.7 3 63/M Liver/deceased 15 101 Calcineurin inhibitor + mycophenolate mofetil/calcineurin inhibitor <0.1/6.0 a Age at measurement.b RBD IgG antibody titer.F, female; M, male; RBD IgG, receptor-binding domain immunoglobulin G. In these 3 recipients, antibody titers 1 mo after the second vaccine administration showed seronegative antibody responses with a receptor-binding domain IgG antibody titer of 0.2, 0.8, and <0.1 AU/mL, respectively. The baseline characteristics and immunosuppression regimens are summarized in Table 1. All 3 recipients had received immunosuppression regimens including mycophenolate mofetil (1000 mg/d). After detailed discussions with attending physicians and solid organ transplant recipients regarding the potential risks and benefits, mycophenolate mofetil was tapered and terminated. The conversion to calcineurin inhibitor monotherapy was successful, with adequate control of rejection maintained. One month after withdrawal from mycophenolate mofetil, antibody titer had elevated to 2.4, 36.7, and 6.0 AU/mL, respectively, and seroconversion was confirmed in all 3 recipients. In solid organ transplant recipients requiring continuous immunosuppression, no specific alternatives to the standard immunization strategy have been proposed for these blunted antibody responses. Mycophenolate mofetil suppresses T-lymphocytic responses to allogeneic cells and also suppresses primary, but not secondary, antibody responses.8 In contrast, calcineurin inhibitors attenuated humoral immunity, cellular responses were preserved. We therefore assume that withdrawal from mycophenolic acid favors antibody production in solid organ transplant recipients. There may be cases where patients who have discontinued mycophenolate mofetil need to resume the drug afterward. In such cases, the possibility of a decline in antibody titers after restarting mycophenolate mofetil should be considered. The efficacy and safety of a third dose of mRNA coronavirus disease 2019 vaccine in solid organ transplant recipients have been studied.2,3 However, a large proportion of recipients failed to obtain sufficient antibody titers. Our therapeutic approach was well tolerated and led to serological recovery of antibody responses after withdrawal from mycophenolate mofetil without a third dose of vaccine. A point of notice for withdrawal of mycophenolate mofetil, we need to monitor the health of transplanted organs, particularly with respect to rejection by the host immune system. This case series could represent a useful alternative strategy for improving the immunogenicity of vaccines in solid organ transplant recipients. ACKNOWLEDGMENTS The authors are greatly indebted to the staff of Matsunami General Hospital and Matsunami Health Promotion Clinic for their generous cooperation in establishing the case report. They also gratefully acknowledge the special efforts of Matsunami Research Park.

Esophageal Stricture: Not Your Usual Culprit?

Question: A 60-year-old woman with past medical history of ATTR amyloidosis and status post heart and liver transplantation presented with complaints of progressive esophageal dysphagia to solids and liquids. She was on tacrolimus, mycophenolate mofetil (MMF), and prednisone. Other pertinent medications included trimethoprim sulfamethoxazole and valganciclovir for infection prophylaxis. Physical examination and laboratory data were unremarkable. Esophagogastroduodenoscopy (EGD) with histopathologic examination of biopsies from the middle third of the esophagus showed the findings presented in Figure A and B. Despite high-dose proton pump inhibitor therapy and repeated dilations, symptoms were unchanged and little progress was made in maintaining an increase in luminal diameter. What is the most likely diagnosis? Look on page 400 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. The EGD demonstrates a long, benign-appearing, intrinsic moderate stenosis with extensive fibrotic stricturing in the middle one-third of the esophagus (8 mm inner diameter × 4 cm in length) (Figure A). The stenosis was dilated with a through the scope dilator to 11 mm. Esophageal biopsies demonstrated extensive ulceration with fibrinopurulent exudate and inflamed granulation tissue (Figure B). No fungal or viral infection or malignancy was seen. The patient underwent placement of a percutaneous gastrostomy tube. Over the next year, despite continuous high-dose proton pump inhibitor therapy, she continued to experience dysphagia and required monthly dilations. After ruling out an infectious etiology, MMF was suspected as the possible culprit. Immediately upon withdrawal of MMF, the patient reported significant clinical improvement. A follow-up EGD 4 months later showed a widely patent esophageal lumen with only mild mucosal variance characterized by flattening and scarring in the mid esophagus. MMF has well-known gastrointestinal (GI) adverse effects, including nausea, vomiting and diarrhea. Although the entire GI tract is susceptible to MMF-related toxicity, the colon and, less commonly, the small bowel are the most affected areas.1Nguyen T. Park J.Y. Scudiere J.R. Montgomery E. Mycophenolic acid (CellCept and Myofortic) induced injury of the upper GI tract.Am J Surg Pathol. 2009; 33: 1355-1363Crossref PubMed Scopus (59) Google Scholar A variety of mucosal changes can be seen in the lower GI tract, ranging from inflammatory bowel disease–like changes to features akin to graft-versus-host disease. Upper GI tract toxicities of MMF have included features ranging from those compatible with nonsteroidal anti-inflammatory drug use with topical irritation and damage to ulcerative esophagitis, reactive gastropathy, and duodenal ulceration.2Panarelli N.C. Drug-induced injury in the gastrointestinal tract.Semin Diagn Pathol. 2014; 31: 165-175Crossref PubMed Scopus (24) Google Scholar MMF-related esophageal strictures are rare.3Kim J.J. Mulki R.H. Sebastian K.M. Recalcitrant esophageal stricture secondary to mycophenolate mofetil.Case Rep Gastrointest Med. 2020; 2020: 8817801PubMed Google Scholar This case highlights an uncommon cause of a refractory esophageal stricture that should be considered as a potential etiology for dysphagia, especially in a transplant recipient, when more common etiologies have been excluded or when esophagitis is refractory to proton pump inhibitor therapy.

Fatal outcome in a patient under immunosuppressant therapy infected with human T-lymphotropic virus type 1 (HTLV-1), cytomegalovirus (CMV) and Strongyloides stercoralis: a case report

BackgroundStrongyloidiasis is a gastrointestinal parasitic infection caused by percutaneous infection with Strongyloides stercoralis. Digestive symptoms such as diarrhea and abdominal pain are the main manifestation, but serious infections such as septicemia, purulent meningitis, and bacterial pneumonia may occur in individuals harboring human T-lymphotropic virus type 1 (HTLV-1) or who are immunocompromised. Although coinfection with Strongyloides stercoralis and HTLV-1 can lead to chronic strongyloidiasis and a disseminated form of the disease, there is a high rate of response to the anthelmintic ivermectin.Case presentationWe report a case of strongyloidiasis infection syndrome that was difficult to differentiate from immune reconstitution inflammatory syndrome (IRIS) for various reasons. The patient had been treated with the corticosteroids tacrolimus (Tac) and mycophenolate mofetil (MMF) for systemic lupus erythematosus (SLE) with lupus nephritis and pancytopenia. When the steroid was reduced, she developed cytomegalovirus (CMV) enteritis, and her respiratory status rapidly deteriorated immediately after the withdrawal of Tac and MMF. It was difficult to distinguish immune reconstitution inflammatory syndrome from strongyloidiasis infection syndrome because stool cultures were negative and eosinophils were not increased. Bronchoscopy revealed viable Strongyloides, leading to a diagnosis of strongyloidiasis infection syndrome, but the patient died despite treatment.ConclusionsBoth corticosteroid therapy and HTLV-1 infection can be associated with a decrease of eosinophils, despite the presence of parasitic infection. In conclusion, even if multiple culture tests are negative, the risk of parasitic infection should be assessed in patients receiving immunosuppressants and steroids even in non-endemic areas.

Pure Red Cell Aplasia Related to Parvovirus B19 Infection in Simultaneous Pancreas and Kidney Recipient: A Case Report

A 42-year-old woman received a simultaneous pancreas and kidney transplantation (SPK). Immunosuppression consisted of tacrolimus modified release, prednisone, mycophenolate mofetil (MMF), and thymoglobulin as induction. The function of both grafts was good. Eight months after SPK, the patient suffered from weakness and arthralgia. Normocytic anemia with reticulocytopenia was revealed. In a bone marrow examination, giant pronormoblasts were found. Immunohistochemical staining of bone marrow and serum examination were positive for Parvovirus B19 (Parvo B19) confirming diagnosis of pure red cell aplasia (PRCA).The treatment consisted of MMF withdrawal, red-cell transfusions, immunoglobulins subcutaneously (SCIg) and immunosuppression reduction. Rapid improvement was observed with the rise of reticulocyte count and hemoglobin. Two months after the achievement of remission, the low dose of everolimus was added considering the high risk of rejection and antiviral potential of mTOR inhibitors. Three months later, PRCA relapsed. Retherapy with SCIg was still effective. Subsequent SCIg was supplemented due to low reticulocyte count and recurrent herpes zoster. The replication of Parvo B19 was persistent (serum qualitative test). Everolimus was withdrawn after 9 months of therapy due to the recurrence of PRCA and serious infections. The observation period after PRCA diagnosis lasts for 15 months. The patient is in good condition with no anemia and excellent grafts function. In conclusion, pure red cell aplasia related to Parvo B19 infection should be considered in transplant recipients with normocytic anemia and reticulocytopenia. The treatment with immunoglobulin G and immunosuppression reduction is an effective therapy. The role of everolimus in Parvo B19 infection requires future studies.

OP0167 SUCCESSFUL WITHDRAWAL OF MYCOPHENOLATE MOFETIL IN QUIESCENT SLE: RESULTS FROM A RANDOMIZED TRIAL

Background:Trials and clinical observations have demonstrated the efficacy of mycophenolate mofetil (MMF) for SLE treatment. Long-term use of MMF is associated with adverse events, pregnancy risks, drug monitoring, and increased cost. Current management continues therapy indefinitely. Whether immunosuppression may be safely withdrawn or whether risks of withdrawal outweigh the benefits of continuation is unknown.Objectives:To compare rates of clinically significant disease reactivation (CSDR), major flares, and all flares in patients with quiescent SLE on stable MMF randomized to maintain or withdraw MMF. The goal is to provide guidance for clinicians and patients on the risks of MMF withdrawal.Methods:Adults with quiescent SLE (SELENA-SLEDAI without serologies &lt;4) receiving MMF for ≥2 years for nephritis or ≥ 1 year for non-nephritis were randomized 1:1 to unblinded MMF (maintenance arm, MA) or to a 12-week taper off MMF (withdrawal arm, WA) and followed through 60 weeks. Subjects were on stable hydroxychloroquine; steroids limited to ≤ 10 mg. CSDR, defined as a SLEDAI flare requiring immunosuppression, BILAG flares and adverse events were assessed. Event rates and time to flare were compared using Kaplan-Meier.Results:102 subjects were randomized (50 MA, 52 WA); 1 subject in each arm was ineligible and 10 terminated early (7 MA, 3 WA). Mean disease duration was 13 years; 76% had a history of nephritis; mean baseline SLEDAI was 2.2. 5 MA subjects (10%) had CSDR, compared to 9 WA (17%). Median time to CDSR was 38 weeks in both arms. BILAG A flares occurred in 1MA subject (pancreatitis) vs. 4 WA (cranial neuropathy, panniculitis, 2 nephritis). Kaplan-Meier curves overlapped for CDSR, BILAG A flares, and all SLEDAI flares (Figure). Based on these data, we are 86% confident that the increased risk of CDSR with MMF withdrawal is less than 15% over 60 weeks. AEs were similar between groups; infections occurred more commonly in MA (63 vs. 49).Conclusion:In this cohort of subjects with quiescent SLE on long term MMF serious flares occurred infrequently in subjects continuing or withdrawing MMF without differences in time to flare. MMF withdrawal may be considered in subjects with prolonged quiescent disease.Table 1.Baseline and Demographic CharacteristicsMaintenance armWithdrawal armTotalRandomized5052102Female, n (%)39 (78)47 (90)86 (84)White, n (%)25 (50)19 (37)44 (43)Black, n (%)19 (38)22 (42)41 (40)Hispanic/Latino, n (%)10 (20)12 (23)22 (22)Age, Years, mean (SD)42.4 (12.9)41.6 (12.5)42.0 (12.6)Disease Duration, Years, mean (SD)13.6 (8.2)12.2 (7.9)12.9 (8.0)H/O Lupus Nephritis, n (%)40 (80)38 (73)78 (76.5)On Baseline Steroids, n (%)18 (36)23 (44)41 (40)Prednisone Dose, mg, mean (SD)4.8 (2.7)3.3 (1.7)4.0 (2.3)MMF Duration, Years, mean (SD)6.8 (4.3)6.4 (4.3)6.6 (4.3)Baseline MMF Dose, mg, mean1,6121,6681,640SELENA-SLEDAI*, mean (SD)2.4 (1.76)1.9 (1.76)2.2 (1.77)Positive DsDNA, n (%)35 (70)27 (52)62 (61)Low C31, n (%)14 (28)9 (17)23 (23)Low C41, n (%)6 (12)5 (10)11 (11)Figure.Kaplan-Meier Estimates of Flare EndpointsDisclosure of Interests:Eliza Chakravarty: None declared, Tammy Utset: None declared, Diane L Kamen Consultant of: Consulted on SLE survey development for Lilly and consulted on SLE trial protocol development for EMD Serono in 2019, Gabriel Contreras Grant/research support from: Genentech, Merck, Consultant of: Genentech, Merck, William Joseph McCune: None declared, Kenneth C Kalunian: None declared, Cynthia Aranow: None declared, Megan Clowse Grant/research support from: GSK, Pfizer, Consultant of: UCB, Astra-Zeneca, Speakers bureau: UCB, Ellen Goldmuntz: None declared, Jessica Springer: None declared, Lynette Keyes-Elstein: None declared, Bill Barry: None declared, Ashley Pinckney: None declared, Judith James: None declared

P1636THE IMPACT OF CALCINEURIN INHIBITOR WITHDRAWAL ON DE NOVO DSA PRODUCTION IN LIVING DONOR KIDNEY TRANSPLANTATION

Abstract Background and Aims Chronic antibody mediated rejection caused by de novo donor specific antibody (dnDSA) is one of the biggest reasons for graft failure. At present, because it is difficult to treat CAMR, prevention of de novo DSA production is important. We investigated the risk factor for dnDSA production in living donor kidney transplantation. Method 807 patients underwent living donor kidney transplantation between January 2008 and December 2016. 159 recipients were excluded because of preformed DSA (58 recipients), pediatric transplantation (35 recipients), pancreas transplantation after kidney transplantation (4 recipients), and insufficient data on DSA after transplantation (62 recipients). 648 recipients were enrolled in this study. In 84 out of 648 recipients, dnDSA were detected until December 2018. With cox regression analysis, the risk factors for de novo DSA production were investigated between dn DSA positive and negative groups. The impact of donor characteristics including age and sex, and recipient characteristics including age, sex, hemodialysis vintage, cold ischemic time, past history of transfusion, pregnancy, and transplantation, HLA mismatch, pre-operative Flow PRA results, ABO incompatibility, rituximab induction, splenectomy, pre-operative plasmapheresis, transplantation from first-degree relatives, conversion of calcineurin inhibitor (CNI), conversion of mycophenolate mofetil, mizoribin, and everolimus, CNI used for induction, induction with mycophenolate mofetil, mizoribin, and everolimus, CNI withdrawal, withdrawal of mycophenolate mofetil, mizoribin, and everolimus, and rejection within 6 months after transplantation were investigated. Results In the univariate analysis, male recipient, male donor, and CNI withdrawal were the significant risk factors (P=0.020, HR 1.795, 95%CI 1.095-2.942; P=0.027, HR 0.568, 95%CI 0.344-0.938; P&amp;lt;0.001, HR 6.346, 95%CI 2.560-15.730, respectively). In the multivariate analysis, calcineurin inhibitor withdrawal was significant risk factor with P&amp;lt;0.001, HR 6.374, 95%CI 2.567-15.828. Conclusion Calcineurin inhibitor withdrawal was the significant risk factor for de novo DSA production in living donor kidney transplantation

Immunological risk stratification and tailored minimisation of immunosuppression in renal transplant recipients

BackgroundThe efficacy and safety of minimisation of immunosuppression including early steroid withdrawal in kidney transplant recipients treated with Basiliximab induction remains unclear.MethodsThis retrospective cohort study reports the outcomes from 298 consecutive renal transplants performed since 1st July 2010–June 2013 treated with Basiliximab induction and early steroid withdrawal in low immunological risk patients using a simple immunological risk stratification and 3-month protocol biopsy to optimise therapy. The cohort comprised 225 low-risk patients (first transplant or HLA antibody calculated reaction frequency (CRF ≤50% with no donor specific HLA antibodies) who underwent basiliximab induction, steroid withdrawal on day 7 and maintenance with tacrolimus and mycophenolate mofetil (MMF), and 73 high-risk patients who received tacrolimus, MMF and prednisolone for the first 3 months followed by long term maintenance immunosuppression with tacrolimus and prednisolone. High-risk patients not undergoing 3-month protocol biopsy were continued on triple immunosuppression.ResultsSteroid withdrawal could be safely achieved in low immunological risk recipients with IL2 receptor antibody induction. The incidence of biopsy-proven acute rejection was 15.1% in the low-risk and 13.9% in the high-risk group (including sub-clinical rejection detected at protocol biopsy). One- year graft survival was 93.3% and patient survival 98.5% in the low-risk group, and 97.3 and 100% respectively in the high-risk group. Graft function was similar in each group at 1 year (mean eGFR 61.2 ± 23.4 mL/min low-risk and 64.6 ± 19.2 mL/min high-risk).ConclusionsImmunosuppression regimen comprising basiliximab induction, tacrolimus, MMF and prednisolone with early steroid withdrawal in low risk patients and MMF withdrawal in high risk patients following a normal 3-month protocol biopsy is effective in limiting acute rejection episodes and produces excellent rates of patient survival, graft function and complications.

Clinical Significance of Mycophenolate Mofetil Withdrawal in Kidney Transplant Recipients

IntroductionThe most effective immunosuppressant protocol in kidney transplantation (KT) is the combination of a calcineurin inhibitor, steroid, and mycophenolate mofetil (MMF) until now. However, MMF withdrawal (MW) is performed for many reasons, and the clinical course of the KT recipients after MW is not clearly known. The purpose of this study was to investigate the clinical outcomes of KT after MW. Materials and MethodsWe retrospectively analyzed the medical records of 626 KT recipients between 2000 and 2016. We evaluated the incidence of biopsy-proven acute rejection (BPAR), graft and patient survival rates, and risk factors related with graft failure. ResultsThe proportion of MW was 33.2% (208 of 626 patients). The median time between KT and MW was 6.4 months (range, 3.2–32.1 months). The common causes of MW were infection (70.7%), hematologic abnormalities (9.1%), and gastrointestinal trouble (7.7%). The incidence of BPAR was significantly higher in the MW group compared with the MMF continuation group (27.4% vs 8.9%, respectively, P < .001). Death-censored graft survival and patient survival rates were significantly lower in the MW group compared with the MMF continuation group (P < .001; P < .001, respectively). In the multivariate analysis, BPAR after MW was an independent risk factor for graft failure (hazard ratio 6.058, 95% confidence interval, 3.172–11.569, P < .001). ConclusionsThe incidence of rejection, graft failure, and patient mortality in KT were high after MW. Therefore, MW should be considered carefully.

Mycophenolate Mofetil Withdrawal With Conversion to Everolimus to Treat BK Virus Infection in Kidney Transplant Recipients

BackgroundBK virus (BKV) is a significant post-transplant infection. Mammalian target of rapamycin inhibitors (mTORis) reduce BKV large T antigen expression in vitro and are associated with lower rates of BKV infection when used as de novo immunosuppression in clinical studies. MethodsWe performed a prospective, single-center, randomized, open label pilot trial to evaluate the impact of mycophenolate mofetil (MMF) withdrawal with conversion to the mTORi everolimus versus a 50% reduction of the MMF dose for the treatment of BKV infection after kidney transplantation. Patients maintained on tacrolimus, MMF, and corticosteroids that developed BK viremia or BK viruria ≥1 × 106 copies/mL were eligible. The primary endpoint was a >50% reduction of BK viruria or clearance of viremia at 3 months postrandomization. ResultsForty patients were enrolled and randomized in a 1:1 manner; 11 (55%) and 8 patients (40%) reached the primary endpoint in the everolimus group and the MMF group, respectively (P = .53). Of those with BK viremia at the time of enrollment, 8 of 16 (50%) and 5 of 15 (33.3%) cleared the viremia by month 3 in the everolimus conversion and MMF dose reduction groups, respectively (P = .47). ConclusionConversion from MMF to everolimus in BKV infection demonstrated a trend toward improved viral clearance but did not reach statistical significance.

Long-term outcome after early cyclosporine withdrawal in kidney transplantation: ten years after.

Despite long-term side effects, calcineurin inhibitors (CNI) remain a cornerstone of immunosuppression in renal transplantation. Few trials assessed the long-term outcome after early CNI withdrawal. This intention-to-treat study assessed the 10-year outcome of 108 patients randomly converted from a cyclosporine (CsA)-mycophenolate mofetil (MMF)-prednisone regimen to a dual therapy (CsA-prednisone or MMF-prednisone) at 3months postgraft. At 10years, 3.7% in the CsA group and 35.2% in the MMF group remained on the protocol regimen (P<.001). eGFR was higher in the MMF group (64.4±21 vs 49.7±14.7 mL/min/1.73 m², P<.001), although acute rejection (12 vs 4 in the CsA group, P=.03) and Class II DSA incidences were increased. CNI-related toxicity (P=.019) and moderate-to-severe IF/TA (P=.004) were higher in the CsA group. Ten-year graft and patient survivals were not different. In multivariate analysis, acute rejection remained the strongest predictor of graft loss (HR=11.64, 95% CI [5.05-26.79], P<.0001). MMF withdrawal largely failed due to CNI toxicity, while CsA withdrawal led to increased graft failure due to uncontrolled acute rejection without increasing graft survival. From this study, it remains unclear which patients could benefit from limiting CNI exposure.

Efficacy and Safety of Monotherapy With Mycophenolate Mofetil in Liver Transplantation Patients With Nephrotoxicity.

Calcineurin inhibitors (CNI) are the base of immunosuppressive regimens in liver transplantation but they are associated with significant side effects, namely nephrotoxicity, which leads to increased morbidity and mortality. Through time, mycophenolate mofetil (MMF) as monotherapy has been suggested as an alternative in patients with CNI-related toxicity, but still no consensus has been reached as to its efficacy. We have evaluated the safety, efficacy, and tolerability of MMF monotherapy in selected patients, developing CNI-associated events, focusing primarily on kidney dysfunction. Thirty patients were selected (60% men) with a mean age of 48.5 years. Four patients (13%) were initially on a multidrug regimen that included MMF ad initio due to increased risk of kidney dysfunction. CNI tapering was initiated 5.1 years after liver transplantation (5 months to 13.9 years). The mean time of follow-up after conversion to monotherapy with MMF was 5.6 years (14 months to 12 years). Kidney function analysis accessed by creatinine values and glomerular filtration rate measurement showed a gradual improvement (P< .01). Graft dysfunction after conversion to monotherapy was observed in three patients who required reintroduction of the previous immunosuppressive regimen. Four patients referred minor side effects that were managed with dose reduction. None required MMF withdrawal. Ten patients died during follow up, mainly due to disease progression, 6.8 years after MMF conversion. In conclusion, MMF monotherapy seems to be safe, effective, and well tolerated in selected patients.

Mycophenolate mofetil in systemic lupus erythematosus: results from a retrospective study in a large monocentric cohort and review of the literature.

In the present study, we performed a retrospective study on the indication, efficacy and causes of withdrawal of mycophenolate mofetil (MMF) in patients with systemic lupus erythematosus (SLE). Moreover, a review of the literature concerning the use of MMF in the real life was performed. We recorded data about indications, mean dosage, duration of treatment and reasons for drug withdrawal. The efficacy was evaluated according to changes in SLE Disease Activity Index 2000 (SLEDAI-2K), renal SLEDAI-2K and daily proteinuria, after 4 and 12 months of treatment. Six hundred and nine SLE patients were evaluated; among them, 109 patients (17.9 %) were treated with MMF (mean treatment duration 33.9 ± 31.2 months, mean dosage 28.1 ± 10.6 mg/kg). The most frequent indications for using MMF were lupus nephritis (55.9 %) and musculoskeletal manifestations (33.0 %). After 4 and 12 months, a significant reduction of mean SLEDAI-2K, renal SLEDAI and daily proteinuria, compared with baseline, was demonstrated. Thirty-one patients (28.4 %) discontinued MMF therapy (mean treatment duration at the time of discontinuation 17.5 ± 21.2 months). The incidence risks of MMF discontinuation due to inefficacy and side effects were 0.09 and 0.1, respectively. Patients with disease duration longer than 36 months (70.6 %) had a significant increased risk of MMF withdrawal (RR 0.4, P = 0.03). The results of the present study demonstrated that MMF should be considered a treatment option for SLE manifestation other than renal involvement in daily clinical practice.

Hand Transplantation in Its Fourteenth Year: The Innsbruck Experience

Five patients received a bilateral hand (n = 3), a bilateral forearm (n = 1) and a unilateral hand transplant (n = 1) between 03/2000 and 03/2014. We herein describe the long-term outcome with emphasis on function, immunosuppression (IS), histomorphology and graft vascular changes.Induction therapy with antithymocyte globulin or alemtuzumab was followed by tacrolimus, prednisolone ± mycophenolate mofetil (MMF) or tacrolimus and MMF maintenance IS. Later, an mTOR-Inhibitor was added under simultaneous withdrawal or dose reduction of tacrolimus or MMF. Steroids were avoided in one and withdrawn in 2 patients.Range of motion reached up to 70% of normal with a grip strength up to 10kg. Hand function correlated with time after transplantation and amputation level and remained stable after year 5 in all cases. Intrinsic hand muscle function recovery, discriminative sensation and temperature sensation were observed after hand transplantation. Three, 7, 6, 3 and one rejection episodes were successfully treated wi...

Impact of Late Calcineurin Inhibitor Withdrawal on Ambulatory Blood Pressure and Carotid Intima Media Thickness in Renal Transplant Recipients

Calcineurin inhibitors (CNIs) have an unfavorable cardiovascular risk profile in renal transplant recipients. The aim of this substudy was to assess the effects of late CNI or mycophenolate mofetil (MMF) withdrawal on ambulatory blood pressure monitoring and carotid intima media thickness. A total of 119 stable renal transplant recipients on triple regimen with steroids, a CNI and MMF were randomized into either the concentration-controlled CNI or MMF withdrawal groups. Patients were treated for traditional cardiovascular risk factors according to predefined targets. Ambulatory blood pressure monitoring and measurements of intima media thickness were performed at baseline and after 1, 2, and 3 years after randomization. CNI withdrawal resulted in a significant decline in both ambulatory day- and nighttime blood pressures (daytime: systolic blood pressure, -1.6 mm Hg/y, P=0.018; diastolic blood pressure, -1.3 mm Hg/y, P=0.002; nighttime systolic blood pressure: -1.9 mm Hg/y, P=0.008; diastolic blood pressure: -1.3 mm Hg/y, P=0.014), which was not observed after MMF withdrawal. There was no difference in the proportion of nocturnal nondippers (both groups, 69%, P=0.95). Despite the reduction in ambulatory blood pressure, no effect of CNI withdrawal on carotid intima media thickness was found. In stable renal transplant recipients, late CNI withdrawal from a triple drug regimen decreased blood pressure in comparison with MMF withdrawal but had no specific impact on carotid intima media thickness. Considering the high prevalence of hypertension in patients on CNI therapy, most stable renal transplant recipients may benefit from late CNI withdrawal by improved blood pressure control.

Long‐term outcomes after cyclosporine or mycophenolate withdrawal in kidney transplantation – results from an aborted trial

Long-term triple immunosuppressive therapy with cyclosporine (CsA), mycophenolate mofetil (MMF) and prednisolone may be excessively powerful for many transplant recipients. We compared withdrawal of either MMF or CsA in stable kidney transplants on triple immunosuppression. The study was a prospective, randomized, controlled 12-months trial in stable kidney transplants. The patients who withdrew CsA were given MMF 2 g/d, and CsA troughs were between 75 and 125 ng/mL in MMF withdrawal. Planned inclusion was 298 patients. The study was prematurely aborted after inclusion of 39 patients. Acute rejection rates were 6/20 (30%) in the MMF group compared with 0/19 (0%) in the CsA group (p = 0.02). Time to acute rejections was 4.0-28.7 months after withdrawal. Trough concentrations of mycophenolic acid (MPA) and CsA showed therapeutic levels. The subjects have been observed for eight yr, and of the 28 patients remaining on randomized therapy, the MMF patients preserved graft function better than CsA patients. Death-censored graft survival was 75% and 95% (p = 0.18) and patient survival was 70% and 68% (p = 0.99) in the MMF and CsA groups, respectively, at the end of long-term follow-up. CsA withdrawal was associated with a high rate of acute rejections. Initially, the treatment of acute rejections was successful. However, five of six lost their grafts in the long term.

Mycophenolate mofetil in liver transplantation: A review

Liver transplantation is the only live-saving, curative treatment for various end-stage liver diseases, and it has excellent survival rates. Mycophenolate mofetil is widely used as co-medication for immunosuppression after liver transplantation, especially to allow a sparing effect on calcineurin-inhibitors, thus reducing their numerous adverse effects. It improves both graft and patient survival. The properties of its active metabolite, mycophenolic acid, are diverse: inhibition of de novo purine synthesis and selective lymphocyte inhibition, anti-tumoral, antiviral, anti-angioneoplastic, and vasculoprotective mechanisms are described and summarized in this review. The most common adverse effects of mycophenolate mofetil are gastrointestinal complaints such as diarrhea, which often lead to dose-reduction or withdrawal of mycophenolate mofetil. A newer, enteric-coated formulation is available, which is meant to reduce the gastrointestinal adverse effects. Mycophenolate mofetil does not relevantly interact with other common drugs. The question of whether therapeutic drug monitoring allows optimized dosing strategies cannot be satisfyingly answered yet. The optimal partner-immunosuppressant seems to be tacrolimus, especially in low doses. This tutorial review provides an overview of recent studies exploring the role of mycophenolate mofetil in liver transplantation with regards to its development, mechanism of action, and actual controversies such as therapeutic drug monitoring or de novo malignancy after transplantation.

Late Calcineurin Inhibitor Withdrawal Prevents Progressive Left Ventricular Diastolic Dysfunction in Renal Transplant Recipients

Calcineurin inhibitor (CNI)-based therapy is associated with adverse cardiovascular effects. We examined the effects of late CNI or mycophenolate mofetil (MMF) withdrawal on echocardiographic parameters. This study was conducted as a substudy of a randomized trial in stable renal transplant recipients who were on a triple CNI-based regimen with prednisone and MMF that evaluated late concentration-controlled withdrawal of CNI or MMF on renal function. A total of 108 patients (age, 52.3±11.5 years; 67% male; at a median of 2.0 years post-transplantation, (interquartile range 1.3-3.3 years); estimated glomerular filtration rate, 57±16 mL/min/1.73 m; 66% on cyclosporine and 34% on tacrolimus) entered the cardiovascular substudy examining echocardiographic parameters at baseline and 2 years after randomization. In all patients, traditional cardiovascular risk factors were treated according to predefined targets. Late CNI withdrawal prevented progressive development of left ventricular (LV) diastolic dysfunction, as assessed by markers of LV diastolic function (mitral deceleration time and mitral annular e' velocity). Conversely, in the MMF-withdrawal group, the left atrial volume index (an indicator of chronic LV diastolic dysfunction) was significantly increased at 2 years (from 24.1±6.7 to 27.0±7.0 mL/m, P<0.05). In addition, CNI withdrawal resulted in a higher proportion of patients achieving the predefined blood pressure targets (<130/85 mm Hg: 41.5% vs. 12.7%, P=0.001) at 2 years while requiring less antihypertensive drugs. Changes in the left atrial volume index were significantly associated with treatment arm (P=0.03) and changes in systolic (P=0.005) and diastolic (P=0.005) blood pressure. Late CNI withdrawal, from a triple-drug regimen in stable renal transplant recipients, prevented progressive deterioration of LV diastolic function and facilitated better blood pressure control.