Comparison of the characteristics of adult liver transplant recipients with prope (almost) tolerance and full immunosuppression regimen

BackgroundThe liver transplant recipients are often subjected to excessive therapy by immunosuppressive drugs which produce several complications. Consequently, the minimization or even withdrawal of immunosuppression in selected patients is an attractive alternative. We investigated the frequency and characteristics of these near (or prope from Latin) tolerance in liver transplant recipients in Shiraz Organ Transplant Center.Material and methodsWe reviewed the medical records of over 3800 adult liver transplant recipients to select a group treated with a low-dose tacrolimus monotherapy (n = 90) between 1994 and 2017 in our transplant center. The patients with the best liver function parameters were selected; then, the clinician arbitrarily decided to withdraw steroids first and then mycophenolate mofetil and maintain each patient on a low dose tacrolimus.We compared the characteristics of prope tolerant recipients on a low-dose tacrolimus with those on standard immunosuppression, namely full-dose tacrolimus plus steroids and mycophenolate mofetil (n = 233). Data were analyzed by t-test, chi-square test using SPSS software version 16.ResultsOut of over 3800 liver transplant patients, 90 (2.34%) recipients were treated with a minimum dose of tacrolimus monotherapy. These recipients were compared to a selected group of 233 (6.1%) recipients treated with full-dose tacrolimus plus steroids and mycophenolate mofetil. In a prope tolerant group, there were 55 males (61.1%) and 35 females (38.9%) recipients. Mean age at the time of transplant was 39.92 ± (SD = 13.40) years with an average time from the transplantation time to completed weaning from triple immunosuppression to low-dose monotherapy of 41.35 months (SD = 17.27). The most common etiology of liver disease among both groups was viral hepatitis.ConclusionThe achievement of prope (almost) immune tolerance was possible only in some liver transplant recipients with a relatively low risk of rejection. Our analysis suggests that there is a difference in the underlying diseases and recipients' age and the number of rejections between the two groups.     

Higher mycophenolate dosage is associated with an increased risk of squamous cell carcinoma in kidney transplant recipients

BackgroundKidney transplant recipients are at increased risk of keratinocyte cancers, namely squamous cell and basal cell carcinomas (SCCs and BCCs). This is primarily due to the high levels of immunosuppression that are required to prevent allograft rejection. Different immunosuppressive medications confer different risks, and the effect of mycophenolate mofetil on SCC and BCC risk is unclear. We explored the relationship between mycophenolate dose prescribed over the entire transplant period and the risk of SCC and BCC.MethodsKidney transplant recipients from Queensland, Australia, were recruited between 2012 and 2014 and followed until mid-2016. During this time transplant recipients underwent regular skin examinations to diagnose incident SCCs and BCCs. Immunosuppressive medication regimens were obtained from hospital records, and the average mycophenolate dose/day over the entire transplantation period was calculated for each patient. Doses were divided into three ranked groups, and adjusted relative risks (RR_adj) of developing SCC and BCC tumours were calculated using negative binomial regression with the lowest dosage group as reference. Recipients who had used azathioprine previously were excluded; further sub-group analysis was performed for other immunosuppressant medications.ResultsThere were 134 kidney transplant recipients included in the study. The average age was 55, 31% were female and 69% were male. At the highest median mycophenolate dose of 1818 mg/day the SCC risk doubled (RR_adj 2.22, 95% CI 1.03–4.77) when compared to the reference group of 1038 mg/day. An increased risk persisted after accounting for ever-use of ciclosporin, ever-use of tacrolimus, and when excluding mammalian target of rapamycin users. This increased risk was mainly carried by kidney transplant recipients immunosuppressed for five or more years (RR_adj = 11.05 95% CI 2.50–48.81). In contrast, there was no significant association between BCC incidence and therapy with the highest compared with the lowest mycophenolate dosage (RR_adj = 1.27 95% CI 0.56–2.87).ConclusionHigher mycophenolate dosage is associated with increased SCCs in kidney transplant recipients, particularly those immunosuppressed for more than five years. The increased SCC risk persists after accounting for usage of other immunosuppressant medications.     

Conversion from calcineurin inhibitors to mycophenolate mofetil in liver transplant recipients with diabetes mellitus

Diabetes mellitus, a frequent metabolic complication in liver transplant recipients, may be produced by the diabetogenic effect of calcineurin inhibitors cyclosporine and tacrolimus. The aim of this study was to investigate the safety and metabolic effects of a gradual switch from cyclosporine or tacrolimus to mycophenolate mofetil among 12 diabetic liver transplant recipients. One patient was withdrawn from the study due to gastrointestinal side effects. Of the 11 remaining patients, cyclosporine or tacrolimus was completely withdrawn in five patients. Two patients developed suspected acute rejection episodes that were controlled by increasing the tacrolimus dosage. Glycosylated hemoglobin A1C and C-peptide levels were significantly lower at 3 and 6 months after the initiation of mycophenolate mofetil (P<.03 in all cases). Furthermore, urea and uric acid levels were significantly reduced after the change of treatment. In conclusion, a switch from cyclosporine/tacrolimus to mycophenolate mofetil may produce beneficial metabolic effects in diabetic liver transplant recipients, but poses a risk of graft rejection.     

Gastrointestinal symptoms impair quality of life in Italian renal transplant recipients but are under‐recognized by physicians

We assessed patient‐ and physician‐reported prevalence of gastrointestinal symptoms and their impact on quality of life (QOL) in Italian renal transplant recipients with stable graft function. Patients ≥18 years with a renal allograft functioning for ≥6 months and stable serum creatinine levels of <2.5 mg/dl were enrolled. Physicians and patients completed an Italian translation of the Gastrointestinal Symptom Rating Scale (GSRS) and Gastrointestinal Quality of Life Index (GIQLI) questionnaires. The average time since transplantation (n = 1130) was 5.9 years. Forty‐two immunosuppressant drug regimens were reported. The top three regimens (cyclosporine/mycophenolate mofetil/steroids; tacrolimus/mycophenolate mofetil/steroids; cyclosporine/steroids) accounted for approximately 40% of patients. In the physician interview, 39.2% of patients had ≥1 gastrointestinal symptom vs. 88.3% of patients in the self‐administered questionnaire. The prevalence of GSRS symptoms was similar for each of the most frequently prescribed immunosuppressant drug regimens. GIQLI total score was significantly poorer in patients with versus those without gastrointestinal symptoms (121.8 ± 17.6 vs. 138.4 ± 3.7; P < 0.0001), and there was a strong inverse correlation between GIQLI and patient‐reported GSRS scores (Pearson’s correlation coefficient ?0.816; P < 0.0001). Gastrointestinal symptoms are frequent in renal transplant patients, are under‐evaluated by physicians and may adversely impact on patient QOL.     

A Case Report of the Resolution of Multiple Recalcitrant Verrucae in a Renal Transplant Recipient After a Mycophenolate Mofetil Dose Reduction

Renal transplant recipients are at an increased risk of developing verrucae due to chronic immunosuppression, and certain therapies may confer a greater risk. Herein, we describe a 51-year-old woman with a 10-year-old unrelated kidney transplant who developed numerous therapy-resistant verrucae while on mycophenolate mofetil and tacrolimus maintenance immunosuppression. Over several years of immunosuppressant therapy, she declined the approach of reducing her mycophenolate mofetil dose to potentially improve her verrucae. Unfortunately, she later developed graft rejection requiring reversion to peritoneal dialysis. Within months of reducing her mycophenolate mofetil dose (her tacrolimus dose remained unchanged), she experienced dramatic resolution of many of her verrucae. In the current case, the observed clinical improvement may have resulted from either the total reduction of immunosuppression or the specific reduction of mycophenolate mofetil. Consequently, mycophenolate mofetil may contribute to the refractory nature of verrucae within renal transplant recipients, and further research should determine the relationship between verrucae development and both specific immunosuppressant therapies and the degree of immunosuppression.     

Gastrointestinal Disorders After Renal Transplantation

BackgroundGastrointestinal disorders (GDs) are common in renal transplant recipients. The main cause of GDs seems to be the use of immunosuppressive medications, especially mycophenolic acid in the form of mycophenolate mofetil (MMF).ObjectiveThe aim of this study was to estimate the frequency and severity of GDs in renal allograft recipients with the use of the Gastrointestinal Symptom Rating Scale (GSRS).MethodsEighty-five renal allograft recipients, 50 ± 12 years old, treated with methylprednisolone, calcineurin inhibitor (cyclosporine [CsA], n = 42; tacrolimus (TAC), n = 43), and MMF were studied.ResultsAt the time of completion of the GSRS questionnaire, 38 of the 85 patients (45%) already had their MMF dose reduced because of GDs. Only 15 patients (18%) were totally free from GDs. The most frequent and severe GDs recorded were indigestion and diarrhea who were significantly more frequent in women (P = .045). GDs were recorded in patients receiving both standard and reduced dose of MMF. MMF dose was significantly associated only with diarrhea. Although TAC-treated patients had the highest mean GSRS scores, no statistically significant differences were observed compared with CsA-treated patients. In 31 patients, MMF was replaced by enteric-coated mycophenolate sodium (EC-MPS) and new questionnaires were completed 1 month later. Significant improvement in total and all subscores of GSRS was demonstrated (P < .001). Although EC-MPS dose tolerated by the patients was higher than MMF dose, the difference was not statistically significant.ConclusionsFemale sex and the use of MMF, especially in combination with TAC, are related to the occurrence of severe gastrointestinal symptoms. Substitution of MMF with EC-MPS significantly reduces the severity of symptoms and permits the use of higher doses.     

Post-transplant eosinophilic gastrointestinal disorders and lymphoproliferative disorder in pediatric liver transplant recipients on tacrolimus

AimTo examine and characterize post-transplant eosinophilic gastrointestinal disorders (PTEGID) and post-transplant lymphoproliferative disorder (PTLD) in pediatric liver transplant recipients.MethodsThis is a single center retrospective study of all liver transplant recipients aged 0–18 years from 1999 to 2019 who received tacrolimus as their primary immunosuppressant. Demographic data and clinical/laboratory data including PTEGID, PTLD, liver transplant types, Epstein-Barr virus status, and blood eosinophil count were reviewed. Analysis was done with logistic regression and Mann-Whitney U test.ResultsNinety-eight pediatric liver transplant recipients were included with median age at transplantation of 3.3 years (IQR: 1.1–9.3). The major indication for transplantation was biliary atresia, 51 (52%) cases. Eight (8%) children had PTLD and 14 (14%) had PTEGID. Receiving liver transplantation at an age of ≤1 year was associated with developing PTEGID (OR = 11.9, 95% CI = 3.5–45.6, p < 0.001). Additionally, eosinophilic count of ≥500/μL was associated with having PTLD (OR = 10.7, 95% CI = 1.8–206.0, p = 0.030) as well as having at least one liver rejection (OR = 2.8, 95% CI = 1.2–7.0, p = 0.024). The frequency of food-induced anaphylaxis significantly increased post-transplantation (p = 0.023).ConclusionsPTEGID and PTLD are common in this cohort and are associated with certain risk factors that help screen children to improve recipient survival. Further studies are needed to evaluate the clinical benefits of these findings.     

Risk Factors Associated With New-Onset Diabetes After Liver Transplant: A Case Control Study

BackgroundNew-onset diabetes after transplant is a severe complication that can present in liver transplant recipients, negatively impacting quality of life and graft survival. It also contributes to increased risk of infection, cardiovascular disease, and rejection, which are the main causes of death among liver transplant recipients. The aim of the present study was to assess the risk factors associated with new-onset diabetes after transplant.MethodThis was a case control study based on the data from 146 liver transplant patients at a reference hospital. The data from the charts were collected using a 2-part form: Part I (sociodemographic variables) and Part II (clinical variables).ResultsMultiple analysis showed that pre-existing systemic arterial hypertension (odds ratio [OR], 2.65; 95% CI, 1.12–6.28) and the use of sodium mycophenolate associated with tacrolimus (OR, 2.68; 95% CI, 1.02–7.06) increased the risk of new-onset diabetes after transplant. On comparing the anthropometric variables, lipid panel, and blood glucose levels of liver transplant patients with and without diabetes, higher glycemic levels were found in the group with diabetes (P < .001).ConclusionPre-existing systemic arterial hypertension and the associated use of sodium mycophenolate and tacrolimus increased the risk of new-onset diabetes after transplant.     

Prope tolerance after pediatric liver transplantation: Experience at Shiraz Organ Transplant Center

BackgroundChildren receive transplants at a younger age, and the period of immunosuppression therapy may extend over decades. However, immunosuppression seems to be responsible for long-term mortality and morbidity. Pediatric liver transplant recipients can benefit from achieving immune tolerance and the opportunity of freedom from lifelong immunosuppression. This study aimed to investigate the frequency of prope tolerance among pediatric liver transplant recipients and the characteristics of these patients.MethodsIn this retrospective cohort study of pediatric liver transplant recipients, the medical records of transplant recipients treated at Shiraz Organ Transplant Center between 1994 and 2017 were reviewed. Prope tolerance was defined as normal laboratory values and stable clinical status on low-dose monotherapy. Children treated with low-dose monotherapy were categorized as the prope tolerant group. We compared the characteristics of prope tolerant recipients on low-dose monotherapy with patients on standard immunosuppression, i.e. full-dose tacrolimus plus steroids and mycophenolate mofetil. The data were analyzed with the t-test, chi-squared test, and a Cox proportional hazard model at a 5% significance level in SPSS software version 16.ResultsA total of 585 children with a mean age of 8.32 ± 5.23 years were enrolled. 341 patients were categorized as prope tolerant and 244 comprised the full immunosuppression regimen group. Mean age at transplantation and rejection frequency were lower in the prope tolerant group (p < 0.001, p < 0.001). Based on the underlying diseases, metabolic/genetic, biliary tract, and cryptogenic liver diseases were significantly more prevalent in the prope tolerant group (p < 0.001). However, autoimmune liver disease was found to be more prevalent in the full immunosuppression regimen group. Also, those who received living organs (p = 0.001) and recipients of organs from female donors had a greater likelihood of achieving prope tolerant. According to the multiple Cox regression results, age at transplantation (p = 0.022), rejection frequency (p < 0.001), and autoimmune liver diseases (p = 0.028) had a prognostic effect on prope tolerance.ConclusionFactors as underlying disease, age at transplantation, and rejection frequency were factors that were predictive of prope tolerance in this sample of children. However, the risk of rejection should be considered during the tapering period.     

Retrospective Evaluation of the Effect of Mycophenolate Mofetil Dosage on Survival of Kidney Grafts Based on Biopsy Results

IntroductionPlasma concentration monitoring is commonly used to adjust immunosuppressant dosage in transplant recipients, but adjustment is often based on clinical experience rather than rigorous quantitative indicators.MethodsWe examined the effect of mycophenolate mofetil (MMF) dosage on graft survival by pathologic and immunologic analysis of 88 kidney recipients who were given a postoperative immunosuppressive regimen of tacrolimus (FK506), MMF, and corticosteroids. Patients were given a conventional dosage (≥1.5 g/d; n = 40) or a reduced dosage (n = 48) of MMF owing to postoperative adverse side effects.ResultsThe reduced-dose group included patients given low doses (≤1.0 g/d; n = 27), ultra-low doses (≤0.5 g/d; n = 15), and those who discontinued MMF (n = 6). The dose reduction group had increased acute rejection, chronic rejection, and graft dysfunction, poorer pathologic scores, and increased cell infiltration of graft tissue (CD4, CD8, CD68, and CD138 positivity) and expression of interleukin-2R and HLA-DR. Finally, hazard analysis indicated that patients given low doses and ultra-low doses of MMF had poorer long-term kidney grafts survival (hazard ratios of 1.52 and 1.78, respectively).ConclusionsThese results indicate the importance of using an appropriate dosage of MMF in kidney transplant recipients.     

Overview of tacrolimus-based immunosuppression after heart or lung transplantation.

Transplantation has evolved into an accepted treatment for end-stage heart or lung disease. Acute rejection, complications related to immunosuppressive protocols, and the development of chronic rejection continue to challenge the long-term success of heart and lung transplantations. Wide acceptance of tacrolimus as an important immunosuppressant in renal and hepatic transplantations has led subsequently to its investigation as primary immunosuppression in heart and lung transplant recipients, either combined with azathioprine or with the newer agents mycophenolate mofetil or rapamycin. Studies have shown that tacrolimus is an effective therapeutic alternative to cyclosporine for primary immunosuppression in heart or lung transplantation and demonstrates equivalent if not improved prophylaxis of acute rejection, and more recently demonstrates a potential influence on chronic rejection, particularly in lung transplant recipients. Of importance, the enhanced immunosuppressive activity of tacrolimus is achieved without increased risk of infection or malignancy. Differences in tolerability profiles and side effects between tacrolimus and cyclosporine may be used in selecting the optimal immunotherapy after thoracic transplantation. In particular, the lesser propensity of tacrolimus to cause hypertension and hyperlipidemia potentially offers decreased cardiovascular risk for heart and lung transplant recipients.     

Second Kidney Transplant Outcomes in Dialysis Dependent Recipients by Induction Type in the United States

BackgroundWe examined the association between induction type for a second kidney transplant in dialysis-dependent recipients and the long-term outcomes.MethodsUsing the Scientific Registry of Transplant Recipients, we identified all second kidney transplant recipients who returned to dialysis before re-transplantation. Exclusion criteria included: missing, unusual, or no-induction regimens, maintenance regimens other than tacrolimus and mycophenolate, and positive crossmatch status. We grouped recipients by induction type into 3 groups: the anti-thymocyte group (N = 9899), the alemtuzumab group (N = 1982), and the interleukin 2 receptor antagonist group (N = 1904). We analyzed recipient and death-censored graft survival (DCGS) using the Kaplan-Meier survival function with follow-up censored at 10 years post-transplant. We used Cox proportional hazard models to examine the association between induction and the outcomes of interest. To account for the center-specific effect, we included the center as a random effect. We adjusted the models for the pertinent recipient and organ variables.ResultsIn the Kaplan-Meier analyses, induction type did not alter recipient survival (log-rank P = .419) or DCGS (log-rank P = .146). Similarly, in the adjusted models, induction type was not a predictor of recipient or graft survival. Live-donor kidneys were associated with better recipient survival (HR 0.73, 95% CI [0.65, 0.83], P < .001) and graft survival (HR 0.72, 95% CI [0.64, 0.82], P < .001). Publicly insured recipients had worse recipient and allograft outcomes.ConclusionIn this large cohort of average immunologic-risk dialysis-dependent second kidney transplant recipients, who were discharged on tacrolimus and mycophenolate maintenance, induction type did not influence the long-term outcomes of recipient or graft survival. Live-donor kidneys improved recipient and graft survival.     

Analysis of Acquisition of COVID-2019 Neutralizing Antibodies in Organ Transplant Recipients

BackgroundThis study confirmed the kinetics of antibodies acquired by SARS-CoV-2 vaccination in solid-organ transplant recipients and examined their association with the development of COVID-19 and immunosuppressive status in organ transplant recipients.MethodsWe measured COVID-19 neutralizing antibody titer in 21 organ transplant recipients vaccinated with the COVID-19 vaccine and 14 nontransplant recipients (control group) 3 times before and at 1 and 6 months after the third dose of vaccine. By confirming the kinetics of the acquired antibodies, we examined the relevance of the background characteristics of organ transplant recipients, such as the development of infectious diseases and immunosuppressive status.ResultsThe proportion of patients with neutralizing antibodies was significantly higher in the nontransplant group than in the transplant group. Neutralizing antibody titers were significantly lower in transplant recipients when they were compared before the third dose and 1 month later. In the transplant recipient group, 11 patients were positive, and 10 were negative for neutralizing antibodies. When the causal relationship between the neutralizing antibody titer and background was examined, a positive correlation was found between the antibody titer and the number of years since transplantation, and a negative correlation was found between the tacrolimus trough values, amount of mycophenolate mofetil or steroids taken internally, and antibody titer.ConclusionThis study suggests that the effectiveness of vaccination in transplant recipients is associated with the post-transplant period before vaccination and the dose of immunosuppressive agents.     

Reversible encephalopathy associated with tacrolimus in pediatric renal transplants

Neurological complications post transplant have been described with the use of calcineurin inhibitors. Although tacrolimus may be a better immunosuppressant than cyclosporine, its neurological side effects may be worse. Two children, living-related kidney transplant recipients, were treated with antibody induction, mycophenolate mofetil, prednisone, and tacrolimus. Soon after transplant, they each developed an encephalopathy, which when visualized by magnetic resonance imaging showed that it affected both white and grey matter of the brain. Although the encephalopathy was associated with the use of tacrolimus, there was a complete neurological recovery without cessation of the drug. Received: 7 September 2000 / Revised: 2 January 2001 / Accepted: 30 January 2001     

Gastrointestinal side effects in liver transplant recipients taking enteric‐coated mycophenolate sodium vs. mycophenolate mofetil

In the setting of liver transplantation, mycophenolate mofetil (MMF) may be used as an adjuvant therapy for immunosuppression to prevent graft rejection; however, its use may be limited due to severe gastrointestinal (GI) side effects. In contrast, enteric‐coated mycophenolate sodium (EC‐MPS) may be associated with less severe side effects and hence better tolerability. We compared the side effects of EC‐MPS to MMF in liver transplant patients in a de novo study (Study I—randomized, prospective, double‐blinded) and a conversion study (Study II). In both studies, the severity of GI symptoms was assessed at various time points using the Gastrointestinal Symptoms Rating Scale (GSRS) survey, a validated survey of GI symptoms (abdominal pain, reflux, indigestion, diarrhea, and constipation). In Study I, the symptoms of 30 recipients receiving EC‐MPS (n = 15) were compared to 15 recipients receiving MMF. A multivariate analysis of variance (MANOVA) of the total GSRS scores and symptom syndrome subscores revealed no significant difference (p > 0.05) between the two medications over time. A conversion study (Study II) with 29 participants, however, showed that over time, all GI symptoms improved significantly (p < 0.001) when the patients were treated with EC‐MPS instead of MMF.     

Preemptive Second Kidney Transplant Outcomes by Induction Type in the United States

BackgroundThe role of induction in preemptive second kidney recipients is unclear. We examined the association between induction therapy and the long-term graft and recipient survival in the settings of tacrolimus and mycophenolate maintenance.MethodsWe identified all preemptive second kidney transplant recipients between 2000 and 2020 in the Scientific Registry of Transplant Recipients. We excluded those with missing or mixed induction regimens and positive crossmatch. We grouped recipients by induction type into 3 groups: anti-thymocyte globulin (n = 1442), alemtuzumab (n = 362), and interleukin-2 receptor antagonist (IL-2RA; n = 481). We generated Kaplan-Meier curves of the recipient and death-censored graft survival (DCGS) with follow-up censored at 10 years. We used multivariable Cox proportional hazards models to examine the association between induction and the above outcomes. We adjusted the models for recipient and donor variables.ResultsRates of delayed graft function, rejection, hospitalization, and post-transplant lymphoproliferative disorder at one year were not statistically different. Recipient survival did not vary by induction type in the Kaplan-Meier analysis (log-rank P = .189) or in the multivariable model. However, DCGS was the lowest in the Alemtuzumab group (log-rank P = .01). In the multivariable models, alemtuzumab was associated with a 57% increased risk of graft loss (1.57, 95% confidence interval (1.08, 2.30), P = .019) compared to anti-thymocyte. Live-donor kidneys were associated with significantly better recipient survival and DCGS.ConclusionsCompared to anti-thymocyte induction, alemtuzumab, but not IL-2RA, was associated with inferior graft survival in preemptive second transplant recipients discharged on tacrolimus and mycophenolate.