Relative carcinogenicity of tacrolimus vs mycophenolate after solid organ transplantation and its implications for liver transplant care

BACKGROUND De novo malignancy is a leading cause of late morbidity and mortality in liver transplant recipients.Cumulative immunosuppression has been shown to contribute to post-transplant malignancy(PTM)risk.There is emerging evidence on the differential carcinogenic risk profile of individual immunosuppressive drugs,independent of the net effect of immunosuppression.Calcineurin inhibitors such as tacrolimus may promote tumourigenesis,whereas mycophenolic acid(MPA),the active metabolite of mycophenolate mofetil,may limit tumour progression.Liver transplantation(LT)is relatively unique among solid organ transplantation in that immunosuppression monotherapy with either tacrolimus or MPA is often achievable,which makes careful consideration of the risk-benefit profile of these immunosuppression agents particularly relevant for this cohort.However,there is limited clinical data on this subject in both LT and other solid organ transplant recipients.AIM To investigate the relative carcinogenicity of tacrolimus and MPA in solid organ transplantation.METHODS A literature search was conducted using MEDLINE and Embase databases using the key terms“solid organ transplantation”,“tacrolimus”,“mycophenolic acid”,and“carcinogenicity”,in order to identify relevant articles published in English between 1st January 2002 to 11th August 2022.Related terms,synonyms and explosion of MeSH terms,Boolean operators and truncations were also utilised in the search.Reference lists of retrieved articles were also reviewed to identify any additional articles.Excluding duplicates,abstracts from 1230 records were screened by a single reviewer,whereby 31 records were reviewed in detail.Full-text articles were assessed for eligibility based on pre-specified inclusion and exclusion criteria.RESULTS A total of 6 studies were included in this review.All studies were large population registries or cohort studies,which varied in transplant era,type of organ transplanted and immunosuppression protocol used.Overall,there was no clear difference demonstrated between tacrolimus and MPA in de novo PTM risk following solid organ transplantation.Furthermore,no study provided a direct comparison of carcinogenic risk between tacrolimus and MPA monotherapy in solid organ transplantation recipients.CONCLUSION The contrasting carcinogenic risk profiles of tacrolimus and MPA demonstrated in previous experimental studies,and its application in solid organ transplantation,is yet to be confirmed in clinical studies.Thus,the optimal choice of immunosuppression drug to use as maintenance monotherapy in LT recipients is not supported by a strong evidence base and remains unclear.

Women’s health issues in solid organ transplantation:Breast and gynecologic cancers in the post-transplant population

The success of solid organ transplant has steadily improved which has led to a unique set of post-transplant issues.The rates of de novo cancer in the solid organ transplant recipient population are higher than those in the general population.There is growing evidence that breast and gynecologic cancers may have a higher mortality rate in post-transplant patients.Cervical and vulvovaginal cancers specifically have a significantly higher mortality in this population.Despite this increased mortality risk,there is currently no consistent standard in screening and identifying these cancers in post-transplant patients.Breast,ovarian and endometrial cancers do not appear to have significantly increased incidence.However,the data on these cancers remains limited.Further studies are needed to determine if more aggressive screening strategies would be of benefit for these cancers.Here we review the cancer incidence,mortality risk and current screening methods associated with breast and gynecologic cancers in the post-solid organ transplant population.

Current status of glucocorticoid usage in solid organ transplantation

Glucocorticoids(GCs)have been the mainstay of immunosuppressive therapy in solid organ transplantation(SOT)for decades,due to their potent effects on innate immunity and tissue protective effects.However,some SOT centers are reluctant to administer GCs long-term because of the various related side effects.This review summarizes the advantages and disadvantages of GCs in SOT.PubMed and Scopus databases were searched from 2011 to April 2021 using search syntaxes covering“transplantation”and“glucocorticoids”.GCs are used in transplant recipients,transplant donors,and organ perfusate solution to improve transplant outcomes.In SOT recipients,GCs are administered as induction and maintenance immunosuppressive therapy.GCs are also the cornerstone to treat acute antibody-and T-cell-mediated rejections.Addition of GCs to organ perfusate solution and pretreatment of transplant donors with GCs are recommended by some guidelines and protocols,to reduce ischemia-reperfusion injury peri-transplant.GCs with low bioavailability and high potency for GC receptors,such as budesonide,nanoparticle-mediated targeted delivery of GCs to specific organs,and combination use of dexamethasone with inducers of immuneregulatory cells,are new methods of GC application in SOT patients to reduce side effects or induce immune-tolerance instead of immunosuppression.Various side effects involving different non-targeted organs/tissues,such as bone,cardiovascular,neuromuscular,skin and gastrointestinal tract,have been noted for GCs.There are also potential drug-drug interactions for GCs in SOT patients.

Solid organ transplantations and COVID-19 disease

Tens of thousands of people worldwide became infected with syndrome coronavirus-2(SARS-CoV-2).Death rate in general population is about 1%-6%,but this rate rises up to 15%in those with comorbidities.Recent publications showed that the clinical progression of this disease in organ recipients is more destructive,with a fatality rate of up to 14%-25%.We aimed to review the effect of pandemic on various transplantation patients.coronavirus disease 2019(COVID-19)has not only interrupted waiting list patients’lives;it has also impacted transplantation strategies,transplant surgeries and broke donation chains.COVID-19 was directly and indirectly accountable for 73%surplus in mortality of this population as compared to wait listed patients in earlier years.The impact of chronic immunosuppression on outcomes of COVID-19 remains unclear but understanding the immunological mechanisms related to the virus is critically important for the lifetime of transplantation and immune suppressed patients.It is hard to endorse changing anti-rejection therapy,as the existing data appraised is not adequate to advise substituting tacrolimus with cyclosporine during severe COVID-19 disease.

Chances and risks of sodium-glucose cotransporter 2 inhibitors in solid organ transplantation:A review of literatures

Solid organ transplantation offers life-saving treatment for patients with endorgan dysfunction.Patient survival and quality of life have improved over the past few decades as a result of pharmacological development,expansion of the donor pool,technological advances and standardization of practices related to transplantation.Still,transplantation is associated with cardiovascular complications,of which post-transplant diabetes mellitus(PTDM)is one of the most important.PTDM increases mortality,which is best documented in patients who have received kidney and heart transplants.PTDM results from traditional risk factors seen in patients with type 2 diabetes mellitus,but also from specific posttransplant risk factors such as metabolic side effects of immunosuppressive drugs,post-transplant viral infections and hypomagnesemia.Oral hypoglycaemic agents are the first choice for the treatment of type 2 diabetes mellitus in non-transplanted patients.However,the evidence on the safety and efficacy of oral hypoglycaemic agents in transplant recipients is limited.The favourable risk/benefit ratio,which is suggested by large-scale and long-term studies on new glucoselowering drug classes such as glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors,makes studies warranted to assess the potential role of these agents in the management of PTDM.

Kidney disease in non-kidney solid organ transplantation

Kidney disease after non-kidney solid organ transplantation(NKSOT)is a common post-transplant complication associated with deleterious outcomes.Kidney disease,both acute kidney injury and chronic kidney disease(CKD)alike,emanates from multifactorial,summative pre-,peri-and post-transplant events.Several factors leading to kidney disease are shared amongst solid organ transplantation in addition to distinct mechanisms unique to individual transplant types.The aim of this review is to summarize the current literature describing kidney disease in NKSOT.We conducted a narrative review of pertinent studies on the subject,limiting our search to full text studies in the English language.Kidney disease after NKSOT is prevalent,particularly in intestinal and lung transplantation.Management strategies in the peri-operative and post-transplant periods including proteinuria management,calcineurin-inhibitor minimization/sparing approaches,and nephrology referral can counteract CKD progression and/or aid in subsequent kidney after solid organ transplantation.Kidney disease after NKSOT is an important consideration in organ allocation practices,ethics of transplantation.Kidney disease after SOT is an incipient condition demanding further inquiry.While some truths have been revealed about this chronic disease,as we have aimed to describe in this review,continued multidisciplinary efforts are needed more than ever to combat this threat to patient and allograft survival.

Impact of immunosuppression on incidence of post-transplant diabetes mellitus in solid organ transplant recipients:Systematic review and meta-analysis

BACKGROUND Solid organ transplantation is a life-saving intervention for end-stage organ disease.Post-transplant diabetes mellitus(PTDM)is a common complication in solid organ transplant recipients,and significantly compromises long-term survival beyond a year.AIM To perform a systematic review and meta-analysis to estimate incidence of PTDM and compare the effects of the 3 major immunosuppressants on incidence of PTDM.METHODS Two hundred and six eligible studies identified 75595 patients on Tacrolimus,51242 on Cyclosporine and 3020 on Sirolimus.Random effects meta-analyses was used to calculate incidence.RESULTS Network meta-analysis estimated the overall risk of developing PTDM was higher with tacrolimus(OR=1.495%CI:1.0–2.0)and sirolimus(OR=1.8;95%CI:1.5–2.2)than with Cyclosporine.The overall incidence of PTDM at years 2-3 was 17%for kidney,19%for liver and 22%for heart.The risk factors for PTDM most frequently identified in the primary studies were age,body mass index,hepatitis C,and African American descent.CONCLUSION Tacrolimus tends to exhibit higher diabetogenicity in the short-term(2-3 years post-transplant),whereas sirolimus exhibits higher diabetogenicity in the longterm(5-10 years post-transplant).This study will aid clinicians in recognition of risk factors for PTDM and encourage careful evaluation of the risk/benefit of different immunosuppressant regimens in transplant recipients.

Hepatitis E in solid organ transplant recipients:A systematic review and meta-analysis

BACKGROUND Hepatitis E virus(HEV)infection is underdiagnosed due to the use of serological assays with low sensitivity.Although most patients with HEV recover completely,HEV infection among patients with pre-existing chronic liver disease and organ-transplant recipients on immunosuppressive therapy can result in decompensated liver disease and death.AIM To demonstrate the prevalence of HEV infection in solid organ transplant(SOT)recipients.METHODS We searched Ovid MEDLINE,EMBASE,and the Cochrane Library for eligible articles through October 2020.The inclusion criteria consisted of adult patients with history of SOT.HEV infection is confirmed by either HEV-immunoglobulin G,HEV-immunoglobulin M,or HEV RNA assay.RESULTS Of 563 citations,a total of 22 studies(n=4557)were included in this metaanalysis.The pooled estimated prevalence of HEV infection in SOT patients was 20.2%[95%confidence interval(CI):14.9-26.8].The pooled estimated prevalence of HEV infection for each organ transplant was as follows:liver(27.2%;95%CI:20.0-35.8),kidney(12.8%;95%CI:9.3-17.3),heart(12.8%;95%CI:9.3-17.3),and lung(5.6%;95%CI:1.6-17.9).Comparison across organ transplants demonstrated statistical significance(Q=16.721,P=0.002).The subgroup analyses showed that the prevalence of HEV infection among SOT recipients was significantly higher in middle-income countries compared to high-income countries.The pooled estimated prevalence of de novo HEV infection was 5.1%(95%CI:2.6-9.6)and the pooled estimated prevalence of acute HEV infection was 4.3%(95%CI:1.9-9.4).CONCLUSION HEV infection is common in SOT recipients,particularly in middle-income countries.The prevalence of HEV infection in lung transplant recipients is considerably less common than other organ transplants.More studies examining the clinical impacts of HEV infection in SOT recipients,such as graft failure,rejection,and mortality are warranted.

Renal manifestations of hepatitis E among immunocompetent and solid organ transplant recipients

Hepatitis E virus(HEV)infections are generally self-limited.Rare cases of hepatitis E induced fulminant liver failure requiring liver transplantation are reported in the literature.Even though HEV infection is generally encountered among developing countries,a recent uptrend is reported in developed countries.Consumption of unprocessed meat and zoonosis are considered to be the likely transmission modalities in developed countries.Renal involvement of HEV generally holds a benign and self-limited course.Although rare cases of cryoglobulinemia are reported in immunocompetent patients,glomerular manifestations of HEV infection are frequently encountered in immunocompromised and solid organ transplant recipients.The spectrum of renal manifestations of HEV infection include prerenal failure,glomerular disorders,tubular and interstitial injury.Kidney biopsy is the gold standard diagnostic test that confirms the pattern of injury.Management predominantly includes conservative approach.Reduction of immunosuppressive medications and ribavirin(for 3-6 mo)is considered among patients with solid organ transplants.Here we review the clinical course,pathogenesis,renal manifestations,and management of HEV among immunocompetent and solid organ transplant recipients.

Gastrointestinal complications after kidney transplantation

Gastrointestinal complications are common after renal transplantation,and they have a wide clinical spectrum,varying from diarrhoea to post-transplant inflammatory bowel disease(IBD).Chronic immunosuppression may increase the risk of post-transplant infection and medication-related injury and may also be responsible for IBD in kidney transplant re-cipients despite immunosuppression.Differentiating the various forms of post-transplant colitis is challenging,since most have similar clinical and histological features.Drug-related colitis are the most frequently encountered colitis after kidney transplantation,particularly those related to the chronic use of mycophenolate mofetil,while de novo IBDs are quite rare.This review will explore colitis after kidney transplantation,with a particular focus on different clinical and histological features,attempting to clearly identify the right treatment,thereby improving the final outcome of patients.

Medical management of metabolic and cardiovascular complications after liver transplantation

Liver transplantation represents the only curative option for patients with endstage liver disease,fulminant hepatitis and advanced hepatocellular carcinoma.Even though major advances in transplantation in the last decades have achieved excellent survival rates in the early post-transplantation period,long-term survival is hampered by the lack of improvement in survival in the late post transplantation period(over 5 years after transplantation).The main etiologies for late mortality are malignancies and cardiovascular complications.The latter are increasingly prevalent in liver transplant recipients due to the development or worsening of metabolic syndrome and all its components(arterial hypertension,dyslipidemia,obesity,renal injury,etc.).These comorbidities result from a combination of pre-liver transplant features,immunosuppressive agent side-effects,changes in metabolism and hemodynamics after liver transplantation and the adoption of a sedentary lifestyle.In this review we describe the most prevalent metabolic and cardiovascular complications present after liver transplantation,as well as proposing management strategies.

Managing liver transplantation during the COVID-19 pandemic:A survey among transplant centers in the Southeast United States

BACKGROUND The coronavirus disease-2019(COVID-19)pandemic has had a profound worldwide impact.Indeed,it has led to a vast decrease in organ transplantation,including liver transplants(LT).There is little data regarding adjustments made by LT centers as a response to the COVID-19 pandemic.AIM To assess the experience of LT centers in the United States during the pandemic.METHODS We performed an observational survey study from May 11,2020 to June 5,2020.We sent out a 13 question survey to 15 LT centers across the southeastern United States.RESULTS Eleven LT centers responded to the survey.We found that(11/11)100%of transplant centers made adjustments because of the COVID-19 pandemic.At least 50%of transplant centers had at least one transplant recipient infected with COVID-19.To adjust,greater than 50%of centers performed fewer LT,100%of patients were tested for COVID-19,and most centers implemented a virtual platform.CONCLUSION The COVID-19 pandemic greatly affected liver transplantation in the southeastern United States.It was evident that a concerted effort was made by LT centers to protect their patients and employees from COVID-19 but also to continue the lifesaving procedure of LT in this sick patient population.Further studies are needed to assess how LT centers around the world managed the pandemic in order to learn strategies to continue life-saving procedures in this patient population.

Post-transplantation lymphoproliferative disorders:Current concepts and future therapeutic approaches

Transplant recipients are vulnerable to a higher risk of malignancy after solid organ transplantation and allogeneic hematopoietic stem-cell transplant.Posttransplant lymphoproliferative disorders(PTLD)include a wide spectrum of diseases ranging from benign proliferation of lymphoid tissues to frank malignancy with aggressive behavior.Two main risk factors of PTLD are:Firstly,the cumulative immunosuppressive burden,and secondly,the oncogenic impact of the Epstein-Barr virus.The latter is a key pathognomonic driver of PTLD evolution.Over the last two decades,a considerable progress has been made in diagnosis and therapy of PTLD.The treatment of PTLD includes reduction of immunosuppression,rituximab therapy,either isolated or in combination with other chemotherapeutic agents,adoptive therapy,surgical intervention,antiviral therapy and radiotherapy.In this review we shall discuss the prevalence,clinical clues,prophylactic measures as well as the current and future therapeutic strategies of this devastating disorder.

Advances and effectiveness of the immunotherapy after liver transplantation

Transplant recipients usually have increased chances of graft rejection and graft vs host disease,requiring chronic immunosuppressive therapy.Nonetheless,longterm immunosuppression risks malignancies such as skin cancer,lymphoma,and Kaposi sarcoma.However,there are very few studies that included solid organ transplant recipients while studying the efficacy of immunotherapy.“Immunotherapy after liver transplantation:Where are we now?”is a study,where the authors described the mechanism of action and outcomes of immune checkpoint inhibitors specific to liver transplant recipients.The authors reported the graft rejection rates and the factors contributing to the rejection in the liver transplant recipients.

Post-transplant malignancy:Focusing on virus-associated etiologies,pathogenesis,evidence-based management algorithms,present status of adoptive immunotherapy and future directions

Modern immunosuppression has led to a decrease in rejection rates and improved survival rates after solid organ transplantation.Increasing the potency of immunosuppression promotes post-transplant viral infections and associated cancers by impairing immune response against viruses and cancer immunoediting.This review reflects the magnitude,etiology and immunological characteristics of various virus-related post-transplant malignancies,emphasizing the need for future research.A multidisciplinary and strategic approach may serve best but overall literature evidence targeting it is sparse.However,the authors attempted to provide a more detailed update of the literature consensus for the prevention,diagnosis,management and surveillance of post-transplant viral infections and associated malignancies,with a focus on the current role of adoptive immunotherapy and the way forward.In order to achieve long-term patient and graft survival as well as superior post-transplant outcomes,collaborative research on holistic care of organ recipients is imperative.

Tacrolimus-induced posterior reversible encephalopathy syndrome following liver transplantation

In this editorial,we talk about a compelling case focusing on posterior reversible encephalopathy syndrome(PRES)as a complication in patients undergoing liver transplantation and treated with Tacrolimus.Tacrolimus(FK 506),derived from Streptomyces tsukubaensis,is a potent immunosuppressive macrolide.It inhibits Tcell transcription by binding to FK-binding protein,and is able to amplify glucocorticoid and progesterone effects.Tacrolimus effectively prevents allograft rejection in transplant patients but has adverse effects such as Tacrolimus-related PRES.PRES presents with various neurological symptoms alongside elevated blood pressure,and is primarily characterized by vasogenic edema on neuroimaging.While computed tomography detects initial lesions,magnetic resonance imaging,especially the Fluid-Attenuated Inversion Recovery sequence,is superior for diagnosing cortical and subcortical edema.Our discussion centers on the incidence of PRES in solid organ transplant recipients,which ranges between 0.5 to 5+ACU-,with varying presentations,from seizures to visual disturbances.The case of a 66-year-old male status post liver transplantation highlights the diagnostic and management challenges associated with Tacrolimus-related PRES.Radiographically evident in the parietal and occipital lobes,PRES underlines the need for heightened vigilance among healthcare providers.This editorial emphasizes the importance of early recognition,accurate diagnosis,and effective management of PRES to optimize outcomes in liver transplant patients.The case further explores the balance between the efficacy of immunosuppression with Tacrolimus and its potential neurological risks,underlining the necessity for careful monitoring and intervention strategies in this patient population.

Epstein-Barr virus-associated smooth muscle tumors in immunocompromised patients:Six case reports

BACKGROUND Epstein-Barr virus associated smooth muscle tumor(EBV-SMT)is a rare oncological entity.However,there is an increasing incidence of EBV-SMTs,as the frequency of organ transplantation and immunosuppression grows.EBV-SMT diagnosis relies on histopathology and immunochemical staining to distinguish it from post-transplant lymphoproliferative disorder(PTLD).There is no clear consensus on the treatment of EBV-SMTs.However,surgical resection,chemotherapy,radiation therapy,and immunosuppression reduction have been explored with varying degrees of success.CASE SUMMARY Our case series includes six cases of EBV-SMTs across different age groups,with different treatment modalities,adding to the limited existing literature on this rare tumor.The median latency time between immunosuppression and disease diagnosis is four years.EBV-SMTs present with variable degrees of aggressiveness and seem to have worse clinical outcomes in patients with tumor multiplicity and worse immunocompetency.CONCLUSION It is imperative to continue building on this knowledge and keeping EBV-SMTs on the differential in immunocompromised individuals.

Impact of COVID-19 on liver transplant recipients: A nationwide cohort study evaluating hospitalization, transplant rejection, and inpatient mortality

BACKGROUND The coronavirus disease 2019(COVID-19)pandemic has posed a major public health concern worldwide.Patients with comorbid conditions are at risk of adverse outcomes following COVID-19.Solid organ transplant recipients with concurrent immunosuppression and comorbidities are more susceptible to a severe COVID-19 infection.It could lead to higher rates of inpatient complications and mortality in this patient population.However,studies on COVID-19 outcomes in liver transplant(LT)recipients have yielded inconsistent findings.AIM To evaluate the impact of the COVID-19 pandemic on hospital-related outcomes among LT recipients in the United States.METHODS We conducted a retrospective cohort study using the 2019–2020 National Inpatient Sample database.Patients with primary LT hospitalizations and a secondary COVID-19 diagnosis were identified using the International Classi-fication of Diseases,Tenth Revision coding system.The primary outcomes included trends in LT hospitalizations before and during the COVID-19 pandemic.Secondary outcomes included comparative trends in inpatient mortality and transplant rejection in LT recipients.RESULTS A total of 15720 hospitalized LT recipients were included.Approximately 0.8% of patients had a secondary diagnosis of COVID-19 infection.In both cohorts,the median admission age was 57 years.The linear trends for LT hospitalizations did not differ significantly before and during the pandemic(P=0.84).The frequency of in-hospital mortality for LT recipients increased from 1.7% to 4.4% between January 2019 and December 2020.Compared to the pre-pandemic period,a higher association was noted between LT recipients and in-hospital mortality during the pandemic,with an odds ratio(OR)of 1.69[95% confidence interval(CI):1.55-1.84),P<0.001].The frequency of transplant rejections among hospitalized LT recipients increased from 0.2%to 3.6% between January 2019 and December 2020.LT hospitalizations during the COVID-19 pandemic had a higher association with transplant rejection than before the pandemic[OR:1.53(95%CI:1.26-1.85),P<0.001].CONCLUSION The hospitalization rates for LT recipients were comparable before and during the pandemic.Inpatient mortality and transplant rejection rates for hospitalized LT recipients were increased during the COVID-19 pandemic.

Primary Aspergillus spondylodiscitis in a liver transplant recipient

Solid organ transplant recipients are at increased risk for Aspergillus infections. However, the cases of Aspergillus spondylodiscitis are rare and mostly resulted from the hematogenous spread of invasive pulmonary Aspergillosis. Here, we report a case of primary spondylodiscitis in a liver transplant recipient. Six months after transplantation, a chronic and progressive lumbar back pain was presented. The patient had no fever and the white blood cell count was normal. High plasma （l^3）-beta-d-glucan （BDG） level was detected at the time of back pain. The pathogen was Aspergillus flavus. Clinical and radiological healing was achieved through posterior only debridement and voriconazole therapy.

Safety and immunogenicity of COVID-19 vaccination in immunocompromised patients

The coronavirus disease 2019(COVID-19)pandemic poses a great threat to public health.Individuals who are immunocompromised because of the progression of the primary disease or receiving immunosuppressive medications are prone to severe COVID-19 complications and poor outcomes.Abundant data have shown that many COVID-19 vaccines are safe and effective in large-scale populations;however,these clinical trials have excluded immunocompromised populations.Available evidence indicates that immunocompromised populations have a blunted immune response to other vaccines,raising concerns regarding the efficacy of COVID-19 vaccination in these populations.Thus,there is an urgent need to delineate the efficacy of COVID-19 vaccines in these vulnerable populations.Here,we review the characteristics of specific humoral and cellular responses to COVID-19 vaccination in immunocompromised populations,including HIV-infected patients and those receiving immunosuppressive treatment,especially solid organ transplant recipients and those undergoing anti-CD20 treatment.We also addressed the challenges that immunocompromised populations will face in the future pandemic and the need for basic and clinical translational studies to highlight the best vaccination strategies for these populations.