Mycophenolate Discontinuation Research Articles

Worldwide variations in COVID-19 vaccination policies and practices in liver transplant settings: results of a multi-society global survey.

Despite the WHO's report of 24 available SARS-CoV-2 vaccines, limited data exist regarding vaccination policies for liver transplant (LT) patients. To address this, we conducted a global multi-society survey (EASL-ESOT-ELITA-ILTS) in LT centers. A digital questionnaire assessing vaccine policies, safety, efficacy, and center data was administered online to LT centers. Out of 168 responding centers, 46.4%, 28%, 13.1%, 10.7%, and 1.8% were from European, American, Western Pacific, Southeast Asian, and Eastern Mediterranean Regions. Most LT centers prioritized COVID-19 vaccine access for LT patients (76%) and healthcare workers (86%), while other categories had lower priority (30%). One-third of responders recommended mRNA vaccine exclusively, while booster doses were widely recommended (81%). One-third conducted post-vaccine liver function tests post COVID-19 vaccine. Only 16% of centers modified immunosuppression, and mycophenolate discontinuation or modification was the main approach. Side effects were seen in 1 in 1,000 vaccinated patients, with thromboembolism, acute rejection, and allergic reaction being the most severe. mRNA showed fewer side effects (-3.1, p = 0.002). COVID-19 vaccines and booster doses were widely used among LT recipients and healthcare workers, without a specific vaccine preference. Preventative immunosuppression adjustment post-vaccination was uncommon. mRNA vaccines demonstrated a favorable safety profile in this population.

Effect of SARS-CoV-2 infection on anti-HLA antibodies and de novo donor specific antibodies incidence in lung transplant recipients

PurposeThere are no clear guidelines on how to handle immunosuppression in lung transplant recipients (LTRs) infected by SARS-CoV-2. Antimetabolite reduction with corticosteroid escalation is the most frequent strategy. The aim of this study was to determine the effect of this therapeutic approach on the incidence of de novo donor specific-antibodies (dnDSA). MethodsWe retrospectively analysed a cohort of 27 LTRs diagnosed with SARS-CoV-2 infection between September 2020 and April 2021 with available anti-HLA antibodies screening before and after infection. Managed as per the centre's SARS-CoV-2 protocol, the treatment modalities included specific virostatic treatment, convalescent plasma administration, reduction or discontinuation of mycophenolate and transient corticosteroid escalation initiated in the second week post-infection. ResultsAll 27 patients received virostatics: 15 (55.6%) remdesivir and 12 (44.4%) favipiravir. In addition, 18 patients (66.7%) underwent convalescent plasma therapy. Of the 27 patients, 25 (92.6%) received mycophenolate as a part of their maintenance immunosuppressive regimen, which was temporarily reduced in 10 (37%) and discontinued in 15 LTRs (55.6%), the median resumption times for mycophenolate daily doses of at least 1000 mg being 13 days (IQR 11.0–63.5) and 59 days (IQR 26.0–130.0), respectively. Corticosteroids were escalated in 25 patients (92.6%), of whom 9 (33.3%) received IV methylprednisolone (median 80 mg/day; IQR 80–187.5) and 16 (59.3%) had oral prednisone adjusted (median 20 mg/day; IQR 16.3–38.8). The median time to revert to the corticosteroid dosage of ≤20 mg/day was 42 days (IQR 36.0–87.0). Notably, no dnDSA were detected in any LTR between 1 and 9 months from the onset of the SARS-CoV-2 infection. ConclusionOur findings suggest that antimetabolite cessation with a transient corticosteroid escalation is a safe therapeutic strategy regarding anti-HLA dynamics in SARS-CoV-2 infected LTRs.

Increased clonal hematopoiesis involving DNA damage response genes in patients undergoing lung transplantation.

BACKGROUNDCellular stressors influence the development of clonal hematopoiesis (CH). We hypothesized that environmental, inflammatory, and genotoxic stresses drive the emergence of CH in lung transplant recipients. METHODSWe performed a cross-sectional cohort study of 85 lung transplant recipients to characterize CH prevalence. We evaluated somatic variants using duplex error-corrected sequencing and germline variants using whole exome sequencing. We evaluated CH frequency and burden using χ2 and Poisson regression, and we evaluated associations with clinical and demographic variables and clinical outcomes using χ2, logistic regression, and Cox regression. RESULTSCH in DNA damage response (DDR) genes TP53, PPM1D, and ATM was increased in transplant recipients compared with a control group of older adults (28% versus 0%, adjusted OR [aOR], 12.9 [1.7-100.3], P = 0.0002). Age (OR, 1.13 [1.03-1.25], P = 0.014) and smoking history (OR 4.25 [1.02-17.82], P = 0.048) were associated with DDR CH. Germline variants predisposing to idiopathic pulmonary fibrosis were identified but not associated with CH. DDR CH was associated with increased cytomegalovirus viremia versus patients with no (OR, 7.23 [1.95-26.8], P = 0.018) or non-DDR CH (OR, 7.64 [1.77-32.89], P = 0.024) and mycophenolate discontinuation (aOR, 3.8 [1.3-12.9], P = 0.031). CONCLUSIONCH in DDR genes is prevalent in lung transplant recipients and is associated with posttransplant outcomes including cytomegalovirus activation and mycophenolate intolerance. FUNDINGNIH/NHLBI K01HL155231 (LKT), R25HL105400 (LKT), Foundation for Barnes-Jewish Hospital (LKT), Evans MDS Center at Washington University (KAO, MJW), ASH Scholar Award (KAO), NIH K12CA167540 (KAO), NIH P01AI116501 (AEG, DK), NIH R01HL094601 (AEG), and NIH P01CA101937 (DCL).

249.2: Impact of COVID-19 Infection on Children and Adolescents After Liver Transplantation in a Latin American Reference Center

Background & Aims: Published studies suggest that children (<18 years) infected with COVID-19 are less likely to progress to the severe form of disease when compared to adults, however, scarce data are available on morbidity and mortality in immunocompromised children and adolescents. The aim of this study was to evaluate the outcomes of Pediatric Liver Transplant Recipients (PLTR) who were infected with COVID-19. Methods: Prospective longitudinal cohort study. Between 1st March 2020 and 31st October 2021 clinical, laboratory and evolution data from PLTR (<18 years) were collected in person or by remote telemedicine, who tested positive for COVID-19, for presenting symptoms suggestive of COVID-19 infection or positive epidemiological screening or for presenting positive in laboratory screening before procedure – incidental positive. Results: A total of 74 PLTR were diagnosed with COVID-19. The mean age was 8.2 years (SD 4.49) and 51.4% were girls. The prevalent indication for liver transplantation (LT) was biliary atresia 48 (64.8%) and in 69 (93.2%) patients LT was performed with a living donor. The mean time between LT and COVID-19 infection was 60 months (SD 57.7) and 5 (6.7%) patients became infected up to 3 months after LT, 2 in the early postoperative period. Most patients developed mild symptoms (66%) such as fever (25%), cough (20.2%) and runny nose (20.2%). Hospitalization of outpatients was necessary in 6 children (8.1%), all in hospital ward for suspected sepsis (1), respiratory distress (2), periorbital cellulitis requiring parenteral antibiotics (1), vomiting (1) and gum-stomatitis (1) both requiring hydroeletrolitic replacement. Only 1 child, previously admitted to hospital ward, required transfer to the ICU for respiratory support. The main comorbidities were atopic dermatitis in 5 patients (6.7%), asthma in 4 (5.4%), heart disease, neurological diseases and food allergy in 3(4%), none of which was related to the severity of presentation of COVID-19 infection. Baseline immunosuppression was based on tacrolimus, being associated with prednisone and mycophenolate in 28% and 13.7% respectively. Change in immunosuppression was required with mycophenolate discontinuation in 3 (4%) and a decrease tacrolimus level in 1 patient. Most patients had a good recovery, and only 1 child developed Multisystem Inflammatory Syndrome associated with COVID-19 infection. No child died in this study cohort. Conclusion: In pediatric population LT and immunosuppression cannot be considered independently as factors associated with the risk of severity and death due to COVID-19.

Human Metapneumovirus and Parainfluenza Virus Infections in Lung Transplant Recipients: The Effects on Lung Allograft and Clinical Outcomes.

Human metapneumovirus (HMPVi) and parainfluenza virus (PIVi) infections are common community-acquired infections in lung transplant recipients (LTRs), but data are extremely limited. A retrospective study including all LTRs at the Johns Hopkins Hospital during July 2010-June 2019 with positive HMPV and PIV polymerase chain reaction respiratory specimens was performed. Thirty-one HMPV- and 53 PIV-infected LTRs were identified. LTRs with HMPVi and PIVi had similar baseline characteristics, infection parameters, treatment allocation, and allograft function outcomes. Among entire cohort, 31.6% had chronic allograft dysfunction (CLAD) stage progression within 1 y postinfections (29.2% versus 35.5% for PIVi versus HMPVi, respectively, P = 0.56). In forced expiratory volume in 1 s percent (FEV1%) trajectory analysis showed steadily decline of FEV1 across time among CLAD stage progressors from both viruses. FEV1% decline ≥10% at 90 d had adjusted hazard ratio for CLAD stage progression of 18.4 (4.98-67.76) and 4.6 (1.36-15.34) for PIVi and HMPVi, respectively. PIVi caused higher donor-specific antigen development (11.8% versus 3.2%, P = 0.18) and 1-y mortality (9.4% versus 0%, P = 0.11), compared with HMPVi, even though the results were not statistically significant. Ribavirin did not show protective effect, and mycophenolate discontinuation during infection did not increase risk of CLAD stage progression. One-third of HMPV- and PIV-infected LTRs developed CLAD stage progression within 1 y. The lack of early lung function recovery may predict long-term CLAD progression.

Guidance on the special care of liver or kidney transplant recipients diagnosed with COVID-19

Due to the COVID-19 pandemic caused by infection with the novel, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), transplant medicine also had to face a new, hitherto unknown challenge. To be prepared for any possibility, we consider it important to summarize the current knowledge regarding COVID-19 of liver and kidney transplant patients. Very early reports from Spanish and French registry recorded fatality rates of 18.6% and 13%, respectively, in renal patients which suggests a moderately worse outcome compared to the general population. In patients with positive PCR test but not showing clinical signs, the reduction of immunosuppression is not advised. In the case of gastrointestinal or respiratory signs with fever, the discontinuation of mycophenolate or mTOR inhibitors is recommended with decrease of the trough levels of calcineurin inhibitors to the lowest effective limit. Stop (kidney transplanted patients) or decrease (liver transplanted patients) immunosuppression and maintain corticosteroids when pulmonal injury develops and consider anti-IL1 and anti-IL6 monoclonal antibody use when hyperinflammatory syndrome is evolving. No proven effective treatment for SARS-CoV-2 exists currently. The use of lopinavir/ritonavir should be avoided because of the severe drug interaction with calcineurin inhibitors. The efficacy and tolerability of hidroxychloroquin remains to be also questionable; enroll patients into clinical trial with remdesivir or favipiravir if available. COVID-19 is characterized by virus-induced endothelial dysfunction, procoagulant state and renin-angiotensin-aldosteron system imbalance. Early thromboprofilaxis combination with low-molecular-weight heparin and low-dose aspirin is strongly recommended with the maintenance of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-II-receptor blocker (ARB) therapy when they were prescribed earlier. Orv Hetil. 2020; 161(32): 1310-1321.

Oral mycophenolate mofetil as a stabilizing treatment for progressive non-segmental vitiligo: results from a prospective, randomized, investigator-blinded pilot study

Dexamethasone oral mini-pulse (OMP) is commonly used to halt progression of non-segmental vitiligo (NSV). There is an unmet need for non-phototherapy, non-corticosteroid therapeutic options for stabilizing actively spreading NSV. To assess the efficacy of oral mycophenolate mofetil in stabilizing active NSV in comparison to OMP. In this prospective, randomized, investigator-blinded study, 50 patients of active vitiligo [baseline vitiligo disease activity (VIDA) score 4] were randomized into two groups in 1:1 ratio. Group A received oral dexamethasone (2.5mg on two successive days a week) and group B received mycophenolate mofetil (up to 2g) for 180days with a treatment-free follow-up period of 90days. Assessment was done using VIDA, number of new lesions in past 30days, and Vitiligo Area Scoring Index (VASI). Arrest of disease progression was defined as the absence of any new lesions in past 30days. Twenty-five patients received OMP (group A, 11 males, 14 females), and 25 received mycophenolate (group B, 12 males, 13 females). In both groups, Kruskal-Wallis revealed a significant trend for reduction in VIDA and the number of new lesions in last 30days, over the treatment and follow-up duration when compared to baseline (p < 0.001). The first significant reduction in VIDA was noticed on 90th day in groups A and B (p < 0.001). In both groups, VIDA reduced significantly at the 180th day compared to baseline (p < 0.001, WMP), only to increase significantly at the 270th day (p < 0.001, WMP). VIDA in group B was marginally higher at 270days than group A (p 0.03; Mann-Whitney). Eighteen and 17 patients achieved VIDA 2 + on the 180th day in groups A and B, respectively. The mean number of new lesions in last 30days reduced significantly in both groups at the 180th day (p < 0.001) and 270th day [p < 0.001; Wilcoxon matched pairs (WMP)] when compared to baseline; but increased significantly at the 270th day compared to the 180th day (p 0.006 WMP). Twenty patients in group A and 18 patients in group B had arrest of the disease activity with treatment. Mean duration to arrest disease progression was 47.2 ± 12.1days in group A, and 52.5 ± 9.3days in group B; p 0.21. The difference between VASI at baseline and VASI at the 180 and 270th days was non-significant in both groups (p 0.18 WMP). Five patients in each group failed the respective treatments. Acne (n = 3), weight gain (n = 3), headache, insomnia and menstrual irregularity (n = 1 each) were the important adverse effects noted with dexamethasone pulse; whereas nausea (n = 6) and diarrhea (n = 4) were the commonest adverse effects noted with mycophenolate. Two patients in group B discontinued treatment because of leucopenia (n = 1) and transaminitis (n = 1) that resolved after the discontinuation of mycophenolate. Both OMP and mycophenolate mofetil halt actively spreading vitiligo, and have distinct adverse effect profiles. These should be offered in progressive vitiligo, especially in circumstances precluding the use of phototherapy. Relapse occurred significantly earlier with mycophenolate, and relapse rate was higher (though non-significant) than dexamethasone OMP. The repigmentation potential is minimal for both therapies. This study was approved by Institute Ethics Committee, and retrospectively registered with clinical trial registry of India (CTRI/2018/02/011,664).

The role of mycophenolate in the treatment of antineutrophil cytoplasmic antibody-associated vasculitis.

Mycophenolic acid, the active metabolite for mycophenolate mofetil and mycophenolic sodium, is a strong, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase, the key enzyme in de novo synthesis of guanosine nucleotides leading to selective inhibition of lymphocyte proliferation. Mycophenolic acid has been evaluated as induction and remission maintenance agent in the treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Since the course of disease of AAV usually requires long term immunosuppression, mycophenolate has been explored as a less toxic agent compared to cyclophosphamide and azathioprine. Mycophenolate is a potent immunosuppressive agent in the therapy of AAV, non-inferior to other available drugs with comparable side effect profile. Therefore, it could be a valuable alternative in cases of toxicity with life threatening side effects or intolerance to cyclophosphamide or azathioprine, in cases with high cumulative dose of cyclophosphamide, but also in cases with insufficient response. Several studies have shown a higher relapse rate following discontinuation of mycophenolate or in mycophenolate treated subjects that raises concerns about its usefulness in the treatment of AAV. This review describes the efficacy of mycophenolate in AAV as remission induction agent, as remission maintenance agent, and as therapeutic option in relapsing AAV disease, the relapse rate following discontinuation of mycophenolate, and the adverse events related to mycophenolate treatment.

A new analytic tool developed to assess safe use recommendations.

Develop a flexible analytic tool for the Food and Drug Administration's (FDA's) Sentinel System to assess adherence to safe use recommendations with two capabilities: characterize adherence to patient monitoring recommendations for a drug, and characterize concomitant medication use before, during, and/or after drug therapy. We applied the tool in the Sentinel Distributed Database to assess adherence to the labeled recommendation that patients treated with dronedarone undergo electrocardiogram (ECG) testing no less often than every 3months. Measures of length of treatment, time to first ECG, number of ECGs, and time between ECGs were assessed. We also assessed concomitant use of contraception among female users of mycophenolate per label recommendations (concomitancy 4weeks before through 6weeks after discontinuation of mycophenolate). Unadjusted results were stratified by age, month-year, and sex. We identified 21457 new episodes of dronedarone use of greater than or equal to 90days (July 2009 to September 2015); 86% had greater than or equal to one ECG, and 22% met the recommendation of an ECG no less often than every 3months. We identified 21942 new episodes of mycophenolate use among females 12 to 55years (January 2016 to September 2015); 16% had greater than or equal to 1day of concomitant contraception dispensed, 12% had concomitant contraception use for greater than or equal to 50% of the 4weeks before initiation through 6weeks after mycophenolate; younger females had more concomitancy. These results may be underestimates as the analyses are limited to claims data. We developed a tool for use in databases formatted to the Sentinel Common Data Model that can assess adherence to safe use recommendations involving patient monitoring and concomitant drug use over time.

Pregnancy Outcomes Related to Mycophenolate Exposure in Female Kidney Transplant Recipients.

In 2012, the U.S. Food and Drug Administration issued guidelines advising kidney transplant recipients (KTRs) to discontinue mycophenolate (MPA) in preparation for pregnancy. Little is known about how this guidance has affected pregnancy and graft outcomes. The purpose of this retrospective cohort study was to investigate any association between the discontinuation of MPA and KTR pregnancy and graft outcomes. Data from the National Transplantation Pregnancy Registry included 382 cases in which KTRs managed on MPA became pregnant. Overall, 22 variables, including the time in which a KTR discontinued MPA, were assessed across four end points: miscarriages, birth defects, and 2- and 5-year postpartum graft loss. Birth defects and miscarriages were similar among KTRs who discontinued MPA >6 and <6 weeks prior to pregnancy and during the first trimester. In contrast, discontinuing MPA during the second trimester or later significantly increased the risk of miscarriages (odds ratio [OR] 9.35, 95% confidence interval [CI] 4.31-20.00, p < 0.001) and birth defects (OR 6.06, 95% CI 1.96-18.87, p = 0.002). Discontinuing MPA <6 weeks prior to pregnancy was associated with an increased risk of 5-year graft loss. For the fetus, there is value to discontinuing MPA anytime prior to the second trimester. Adhering to current guidelines does not negatively affect graft survival.

BK Virus Infection in Pediatric Renal Transplantation

BackgroundPolyomavirus BK (BKV) is a common complication after renal transplantation and an important cause of graft loss. The purpose of this study was to determine the incidence of BKV infection (viremia) in our population and to describe clinical features, global outcomes, and potential correlations with clinical or epidemiologic factors. MethodsThis retrospective single-center study included 84 pediatric recipients of kidney transplantation from January 2006 to September 2012. BKV infection screening consisted of periodic determination of decoy cells in urine samples, confirmed by means of quantitative polymerase chain reaction test in blood. ResultsTwenty-two patients (26%) developed BKV viremia. BKV replication appeared early after renal transplantation (median, 2 months). One-third of patients remained asymptomatic, and 27% presented elevated serum creatinine. Immunosuppression was reduced in 90% of patients, and 83% achieved clearance of viremia within 6 months. There was only 1 case of histologically confirmed BKV nephropathy, which evolved to graft loss despite leflunomide, intravenous immunoglobulins, and mycophenolate discontinuation. Risk of BKV viremia was associated with younger age at transplantation (5.9 y vs 10.9 years; P = .001) and cadaveric donor (relative risk, 3.2; P < .05). BKV infection did not affect short-term renal function and graft survival. ConclusionsBKV viremia is very common in the pediatric renal transplant population, especially in younger children and in those receiving a kidney from cadaveric donors. It develops in the 1st months after transplantation. Reduction of immunosuppression seems to be a good therapeutic option, with high rates of clearance of the infection, although the only patient with confirmed BKV nephropathy had poor outcome.

Impact of Mycophenolate Mofetil Dose Reduction on Allograft Outcomes in Kidney Transplant Recipients on Tacrolimus-Based Regimens: A Systematic Review

To systematically evaluate the clinical consequences of mycophenolate dose reduction in renal transplant recipients on tacrolimus-based regimens. PubMed (1949-July 2010), EMBASE (1980-July 2010), Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts, and Web of Science were searched using the terms mycophenolate mofetil, tacrolimus, dose reduction, and kidney and/or renal transplant. References from publications identified were reviewed. Studies reporting on rejection rate, allograft survival, or renal function were included and ranked according to the US Preventive Services Task Force classification; excluded were studies that were dose-finding or used cyclosporine only, involved patients on enteric-coated mycophenolate sodium or those with multiorgan transplant, or provided no information on concomitant immunosuppressants. Data extracted were study design, sample size, immunosuppression regimen, type of transplant, and allograft outcomes. Of 13 studies included, 1 was level I evidence, 3 were level II-2, 6 were level II-3, and 3 were level III evidence. Three focused on tacrolimus-based regimens, whereas 7 included either cyclosporine or tacrolimus. The only prospective, randomized, multicenter trial demonstrated that early taper of mycophenolate dosage to 1 g/day can be utilized without increased risk of rejection, compared with late tapering, but the rejection rate was high (30-40%). Overall, we found conflicting evidence regarding the impact of mycophenolate dose reduction on rejection rate and allograft loss and that discontinuing mycophenolate led to an increased risk of graft loss as high as 8 fold. Allograft survival was lowest in patients with gastrointestinal complications and those in whom mycophenolate was discontinued, compared with patients with neither gastrointestinal complications nor mycophenolate discontinuation. Weak evidence suggests that mycophenolate dose modifications, either reduction or discontinuation, may increase rejection rate and graft loss; however, this is more apparent in cyclosporine-based regimens. Prospective, well-designed trials are necessary to definitively determine the impact of dose reduction in renal transplant recipients on tacrolimus-based regimens.

Incidence of BK with Tacrolimus Versus Cyclosporine and Impact of Preemptive Immunosuppression Reduction

Our purposes were to determine the incidence of BK viruria, viremia or nephropathy with tacrolimus (FK506) versus cyclosporine (CyA) and whether intensive monitoring and discontinuation of mycophenolate (MMF) or azathioprine (AZA), upon detection of BK viremia, could prevent BK nephropathy. We randomized 200 adult renal transplant recipients to FK506 (n = 134) or CyA (n = 66). Urine and blood were collected weekly for 16 weeks and at months 5, 6, 9 and 12 and analyzed for BK by polymerase chain reaction (PCR). By 1 year, 70 patients (35%) developed viruria and 23 (11.5%) viremia; neither were affected independently by FK506, CyA, MMF or AZA. Viruria was highest with FK506-MMF (46%) and lowest with CyA-MMF (13%), p = 0.005. Viruria >/= 9.5 log(10) copies/mL was associated with a 3-fold increased risk of viremia and a 13-fold increased risk of sustained viremia. After reduction of immunosuppression, viremia resolved in 95%, without increased acute rejection, allograft dysfunction or graft loss. No BK nephropathy was observed. Choice of calcineurin inhibitor or adjuvant immunosuppression, independently, did not affect BK viruria or viremia. Viruria was highest with FK506-MMF and lowest with CyA-MMF. Monitoring and preemptive withdrawal of immunosuppression were associated with resolution of viremia and absence of BK nephropathy without acute rejection or graft loss.