Oral/oesophageal candidiasis is a risk factor for severe infection after kidney transplantation.

AIM: Bacterial and fungal infections are serious, life-threatening conditions after kidney transplantation. The development of oral/oesophageal candidiasis after kidney transplantation is not a reported risk factor for subsequent severe infection. This study was performed to investigate the relationship between oral/oesophageal candidiasis after kidney transplantation and the development of subsequent infection requiring hospitalization. METHODS: This retrospective study included 522 consecutive patients who underwent kidney transplantation at Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital from 1 January 2010 to 1 February 2019. Ninety-five percentage of patients were living donor transplant recipients. Visual examination was performed to detect oral candidiasis, beginning immediately after kidney transplantation; upper gastrointestinal endoscopy was performed 8-10 months after kidney transplantation. Twenty-five patients developed candidiasis (Candida-onset group) and 497 did not (non-Candida-onset group). The follow-up periods were 67 (37-86) months in the Candida-onset group and 55 (34-89) months in the non-Candida-onset group. Severe infection was defined as bacterial or fungal infection requiring hospitalization; viral infections were excluded. RESULTS: Severe infection developed in 9/25 (36%) patients in the Candida-onset group and in 77/497 (15%) patients in the non-Candida-onset group (p = .006). Binomial logistic analysis revealed that Candida infection (odds ratio [OR] 2.53, 95% confidence interval [CI] 1.06-6.06; p = .037) and use of rituximab (OR 1.81, 95% CI 1.12-2.93; p = .016) were significant predictors of subsequent severe infection. CONCLUSION: Oral/oesophageal candidiasis is a risk factor for severe infection after kidney transplantation and suggests an over-immunosuppressive state, which should prompt evaluation of immunosuppression.

Variation in immunosuppression practices among pediatric liver transplant centers-Society of Pediatric Liver Transplantation survey results.

BACKGROUND: Variation in IS exists among pediatric liver transplant centers. While individual centers may publish their practice paradigms, current data on practices as a whole are lacking. This study sought to ascertain the IS protocols of pediatric liver transplant centers within the SPLIT to better understand variability and similarities among peer institutions. METHODS: A 27-item questionnaire was developed within the SPLIT Quality Improvement and Clinical Care Committee. The survey collected data regarding center demographics, IS practices, and treatment of acute cellular rejection. RESULTS: Twenty-eight (64%) SPLIT centers responded with 22 (79%) centers performing more than 10 transplants per year and 17 (61%) following more than 100 post-transplant recipients. All centers use a written protocol, and 25 (89%) have a dedicated transplant pharmacist/PharmD. Twenty-five (89%) centers use steroids for induction alone or in combination with thymoglobulin/interleukin-2 antibodies. All centers use tacrolimus for initial maintenance therapy. Most centers have specialized protocols for ABO-incompatible transplants, recipients with renal dysfunction, autoimmune liver diseases, and liver tumors. Treatment of rejection varied but was associated with escalation in IS. CONCLUSION: IS practices among pediatric liver transplant centers are similar including the use of written protocols, pharmacy involvement, steroids for induction, tacrolimus as initial IS, tacrolimus reduction/delay for renal dysfunction, and escalation of IS with rejection severity. However, other IS practices show wide variability including treatment for ABO-incompatible grafts and presumed rejection. This study serves as a foundation to guide prospective research linking IS practice to outcomes to determine best practice.

Induction Immunosuppression and Renal Outcomes in Adult Heart Transplantation.

BACKGROUND: This study explores the use of induction therapy in orthotopic heart transplantation as it relates to preoperative renal function and evaluates the impact of its utilization on post-transplant outcomes. METHODS: We conducted a retrospective analysis using the United Network for Organ Sharing database from 2000 to 2018 evaluating the initiation of de novo dialysis after transplantation. We examined the relationship between induction immunosuppression and pre-transplant estimated glomerular filtration rate with post-transplant outcomes, accounting for inter-center variability through a mixed-effects logistic regression model. RESULTS: In total, 16,201 patients were included with a median age of 57 y (interquartile range 47, 63); 26% were women (n = 4222) and 28% (n = 4552) had a history of diabetes mellitus. The median estimated glomerular filtration rate (eGFR) was 67.5 mL/min (interquartile range 53.1, 86.7); 51.2% (n = 3068) of the recipients with eGFR < 60 received induction therapy compared to 42.5% (n = 4336) within the eGFR ≥ 60 group (P < 0.001). Adjusted multivariable analysis found that induction therapy was associated with de novo dialysis (odds ratio 1.25, 95% confidence interval 1.10-1.43, P < 0.001), with the most significant effect on patients with eGFR ≥ 60. Although significant, there was a weak correlation between center-level induction utilization and mean eGFR (r = -0.2, P < 0.001). CONCLUSION: In this analysis, the use of induction immunosuppression in orthotopic heart transplantation varied widely between centers and did not correlate strongly with pre-transplant eGFR. In addition, its utilization did not mitigate the risk of renal replacement therapy after transplantation and in fact was associated with increased risk even after adjusting for confounders most notably in patients with eGFR ≥ 60.

COVID-19 in kidney transplant recipients: A multicenter experience in Istanbul.

INTRODUCTION: Management of COVID-19 in kidney transplant recipients should include treatment of the infection, regulation of immunosuppression, and supportive therapy. However, there is no consensus on this issue yet. This study aimed to our experiences with kidney transplant recipients diagnosed with COVID-19. MATERIAL AND METHODS: Kidney transplant recipients diagnosed with COVID-19 from five major transplant centers in Istanbul, Turkey, were included in this retrospective cohort study. Patients were classified as having moderate or severe pneumonia for the analysis. The primary endpoint was all-cause mortality. The secondary endpoints were acute kidney injury, the average length of hospital stay, admission to intensive care, and mechanical ventilation. RESULTS: Forty patients were reviewed retrospectively over a follow-up period of 32 days after being diagnosed with COVID-19. Cough, fever, and dyspnea were the most frequent symptoms in all patients. The frequency of previous induction and rejection therapy was significantly higher in the group with severe pneumonia compared to the moderate pneumonia group. None of the patients using cyclosporine A developed severe pneumonia. Five patients died during follow-up in the intensive care unit. None of the patients developed graft loss during follow-up. DISCUSSION: COVID-19 has been seen to more commonly cause moderate or severe pneumonia in kidney transplant recipients. Immunosuppression should be carefully reduced in these patients. Induction therapy with lymphocyte-depleting agents should be carefully avoided in kidney transplant recipients during the pandemic period.

Navigating immunosuppression in a pandemic: A guide for the dermatologist from the COVID Task Force of the Medical Dermatology Society and Society of Dermatology Hospitalists.

Dermatologists treating immune-mediated skin disease must now contend with the uncertainties associated with immunosuppressive use in the context of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Although the risk of infection with many commonly used immunosuppressive agents remains low, direct data evaluating the safety of such agents in coronavirus disease 2019 (COVID-19) are scarce. This article reviews and offers guidance based on currently available safety data and the most recent COVID-19 outcome data in patients with immune-mediated dermatologic disease. The interdisciplinary panel of experts emphasizes a stepwise, shared decision-making approach in the management of immunosuppressive therapy. The goal of this article is to help providers minimize the risk of disease flares while simultaneously minimizing the risk of iatrogenic harm during an evolving pandemic.

Steroid therapy in children with IgA nephropathy.

IgA nephropathy (IgAN) is one the most common primary glomerulonephritis in children and adolescents worldwide, with 20% of children developing end-stage kidney disease (ESKD) within 20 years of diagnosis. There is a need for treatment guidelines, especially for steroids in children with primary IgAN, since the STOP-IgA trial casts doubts on the use of steroids in adults with intermediate risk. Pediatricians are prone to prescribe steroids in addition to renin-angiotensin system blockade (RASB) when proteinuria is > 0.5 g/l, eGFR deteriorates < 70 ml/min/1.73 m2, or when a biopsy sample shows glomerular inflammation. Lack of randomized controlled trials (RCTs) in children with IgAN has led to an absence of consensus on the use of immunosuppressive agents in the treatment of progressive IgAN. This literature review evaluates the available evidence on steroid treatment in children with IgAN.

Impact of Induction Immunosuppression Strategies in Simultaneous Liver/Kidney Transplantation.

BACKGROUND: There is scant data on the use of induction immunosuppression for simultaneous liver/kidney transplantation (SLKT). METHODS: We analyzed the Organ Procurement and Transplant Network registry from 1996 to 2016 to compare outcomes of SLKT, based on induction immunosuppression. RESULTS: Of 5172 patients, 941 (18%) received T-cell depletion induction, 1635 (32%) received interleukin 2 receptor antagonist (IL2-RA), and 2596 (50%) received no induction (NI). At 5 years, patient survivals were 68% in the T-cell group, 74% in the IL2-RA group, and 71% in the NI group (P = 0.0006). Five-year liver and kidney allograft survivals were 67% and 64% in the T-cell group, 73% and 70% in the IL2-RA group, and 70% and 68% in the NI group (P = 0.001 and 0.003), respectively. On multivariate analysis, the type of induction had no impact on patient or allograft survival. Maintenance steroids and calcineurin inhibitors (CNIs) at discharge were associated with improved patient and graft survival (steroids: patient survival hazard ratio [HR] 0.37 [0.27-0.52], liver survival HR 0.43 [0.31-0.59], kidney survival HR 0.46 [0.34-0.63]; P < 0.0001, CNI: patient survival HR 0.3 [0.21-0.43], liver survival HR 0.3 [0.2-0.44], kidney survival HR 0.4 [0.26-0.59]; P < 0.0001). CNI maintenance in patients who received T-cell induction was associated with decreased patient, liver, and kidney allograft survivals (respective HR: 1.4 [1.1, 1.8]; 1.5 [1.1, 1.9]; 1.3 [1.08, 1.7]; P < 0.05) CONCLUSION.: Induction immunosuppression had no impact on patient and allograft survival in SLKT, while maintenance steroids and CNI were associated with improved patient and graft survivals. Given the inherent limitations of a registry analysis, these findings should be interpreted with caution.

Optimizing Mycophenolic Acid Exposure in Kidney Transplant Recipients: Time for Target Concentration Intervention.

The immunosuppressive agent mycophenolate is used extensively in kidney transplantation, yet dosing strategy applied varies markedly from fixed dosing ("one-dose-fits-all"), to mycophenolic acid (MPA) trough concentration monitoring, to dose optimization to an MPA exposure target (as area under the concentration-time curve [MPA AUC0-12]). This relates in part to inconsistent results in prospective trials of concentration-controlled dosing (CCD). In this review, the totality of evidence supporting mycophenolate CCD is examined: pharmacological characteristics, observational data linking exposure to efficacy and toxicities, and randomized controlled trials of CCD, with attention to dose optimization method and exposure achieved. Fixed dosing of mycophenolate consistently leads to underexposure associated with rejection, as well as overexposure associated with toxicities. When CCD is driven by pharmacokinetic calculation to a target concentration (target concentration intervention), MPA exposure is successfully controlled and clinical benefits are seen. There remains a need for consensus on practical aspects of mycophenolate target concentration intervention in contemporary tacrolimus-containing regimens and future research to define maintenance phase exposure targets. However, given ongoing consequences of both overimmunosuppression and underimmunosuppression in kidney transplantation, impacting short- and long-term outcomes, these should be a priority. The imprecise "one-dose-fits-all" approach should be replaced by the clinically proven MPA target concentration strategy.

De novo malignancies after liver transplantation: The effect of immunosuppression-personal data and review of literature.

BACKGROUND: Immunosuppression has undoubtedly raised the overall positive outcomes in the post-operative management of solid organ transplantation. However, long-term exposure to immunosuppression is associated with critical systemic morbidities. De novo malignancies following orthotopic liver transplants (OLTs) are a serious threat in pediatric and adult transplant individuals. Data from different experiences were reported and compared to assess the connection between immunosuppression and de novo malignancies in liver transplant patients. AIM: To study the role of immunosuppression on the incidence of de novo malignancies in liver transplant recipients. METHODS: A systematic literature examination about de novo malignancies and immunosuppression weaning in adult and pediatric OLT recipients was described in the present review. Worldwide data were collected from highly qualified institutions performing OLTs. Patient follow-up, immunosuppression discontinuation and incidence of de novo malignancies were reported. Likewise, the review assesses the differences in adult and pediatric recipients by describing the adopted immunosuppression regimens and the different type of diagnosed solid and blood malignancy. RESULTS: Emerging evidence suggests that the liver is an immunologically privileged organ able to support immunosuppression discontinuation in carefully selected recipients. Malignancies are often detected in liver transplant patients undergoing daily immunosuppression regimens. Post-transplant lymphoproliferative diseases and skin tumors are the most detected de novo malignancies in the pediatric and adult OLT population, respectively. To date, immunosuppression withdrawal has been achieved in up to 40% and 60% of well-selected adult and pediatric recipients, respectively. In both populations, a clear benefit of immunosuppression weaning protocols on de novo malignancies is difficult to ascertain because data have not been specified in most of the clinical experiences. CONCLUSION: The selected populations of tolerant pediatric and adult liver transplant recipients greatly benefit from immunosuppression weaning. There is still no strong clinical evidence on the usefulness of immunosuppression withdrawal in OLT recipients on malignancies. An interesting focus is represented by the complete reconstitution of the immunological pathways that could help in decreasing the incidence of de novo malignancies and may also help in treating liver transplant patients suffering from cancer.

Mammalian Target of Rapamycin Inhibitors Combined With Calcineurin Inhibitors as Initial Immunosuppression in Renal Transplantation: A Meta-analysis.

BACKGROUND: The current standard of care immunosuppressive regimen in kidney transplantation (KT) includes a combination of mycophenolates (MMF/MPA) with a calcineurin inhibitor (CNI). METHODS: We designed a systematic review including all randomized clinical trials (RCTs) assessing the outcomes in KT recipients receiving mTORi + CNI compared with regimens containing MMF/MPA or azathioprine with CNI. RESULTS: A total of 24 studies with 7356 participants were included. The comparison between mTORi-CNI and MMF/MPA-CNI did not show differences in acute rejection, mortality, or graft loss rates. Better graft function was observed using MMF/MPA-CNI than using mTORi + CNI, but this difference was not evident when the mTORi was associated with reduced dose CNI in more recent studies with everolimus. Dyslipidemia, lymphoceles, and impaired wound healing were more frequent with mTORi-CNI and diarrhea and leukopenia were more frequent with MMF/MPA-CNI. Viral infections at any time and malignant neoplasia beyond 2 years were less frequent with mTORi-CNI. Rates of discontinuation because of adverse effects in the mTORi groups varied between 17% and 46% compared to 0%-26.6% in MMF/MPA groups. The current use of lower mTORi dosage has decreased the discontinuation rates. CONCLUSIONS: Efficacy is similar with mTORi + CNI and MMF/MPA-CNI. The safety profile is the predominant difference between the 2 regimens.

Development and evaluation of dedicated low clearance transplant clinics for patients with failing kidney transplants.

BACKGROUND: Recipients with failing kidney transplants (RFKTs) may receive sub-optimal care compared with patients with native kidney disease. The aim of this study is to compare the outcomes of RFKTs managed in a dedicated low clearance transplant clinic (LCTC) compared with those attending a general transplant clinic. METHODS: We undertook a retrospective analysis of patients with failing kidney transplants comparing two clinics-a LCTC versus a general transplant clinic. Kidney transplant recipients with an eGFR < 20 ml/min were included. A cross-sectional analysis was undertaken of all patients with two consecutive follow-up visits between the dates of January and July 2016 in either clinic, with follow-up to event or December 2017. RESULTS: Data were analysed for 141 kidney transplant recipients; 60 in the LCTC and 81 in the general transplant clinic. More patients in the LCTC cohort were non-white and early transplant recipients. A significantly greater proportion of LCTC versus general transplant patients had received documented discussions regarding their hepatitis vaccine status (63.3% vs. 17.3%, p < 0.001), counselled regarding dialysis modality (98.3% vs. 55.6%, p < 0.001) and had documented decision regarding re-transplantation (80.0% vs. 58.0%, p = 0.006). No difference was noted in the comparison of any clinical or biochemical parameters. More patients seen in the LCTC lost their kidney allograft (HR: 2.09, 95%CI: 1.17-3.72, p = 0.013) but patient survival was equivalent (p = 0.343). CONCLUSION: Our data suggest the management of RFKTs within LCTCs can focus attention on renal replacement therapy planning and counselling, but further work is warranted to investigate for any benefit in hard outcomes such as survival.

[Stem cell transplantation unit: Guidelines from the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC)]. / Unité de greffe : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Allogeneic hematopoietic cell transplantation (HCT) is part of the standard of care for many hematological diseases. Over the last decades, significant advances in patient and donor selection, conditioning regimens as well as supportive care of patients undergoing allogeneic HCT leading to improved overall survival have been made. In view of many new treatment options in cellular and molecular targeted therapies, the place of allogeneic transplantation in therapy concepts must be reviewed. Most aspects of HCT are well standardized by national guidelines or laws as well as by certification labels such as FACT-JACIE. However, the requirements for human resources, construction and layout of a unit treating patients during the transplantation procedure and for different complications are not well defined. Here, we describe the process of planning a transplant unit in order to open a discussion that could lead to more precise guidelines in the field of personnel and infrastructural requirements for hospitals caring for people with severe immunosuppression.

Pro: Steroids Can Be Withdrawn After Transplant in Recipients With Autoimmune Hepatitis.

Corticosteroids have been a mainstay of immunosuppression following liver transplantation. However, evolution in the field of transplant immunology has produced steroid-free options, resulting in most transplant centers weaning steroids after transplant within days to months-an evidence-based management decision. Patients with autoimmune hepatitis (AIH), however, receive corticosteroids prior to transplant. This raises the question of whether these patients should also be weaned from corticosteroids. In this review, we discuss the benefits of avoiding steroid use in this population of patients-an approach that not only avoids the adverse effects of corticosteroids but does so without risking graft failure from recurrent AIH or from acute cellular rejection.

Con: Steroids Should Not Be Withdrawn in Transplant Recipients With Autoimmune Hepatitis.

Autoimmune liver diseases (AILDs) can recur following liver transplantation (LT) despite immunosuppressive therapy, with implications for graft survival. Although the evidence is not robust, disease recurrence seems to occur in the presence of less intense and/or steroid-free immunosuppression (IS) in particular in the case of autoimmune hepatitis (AIH). The main risk factor for AIH recurrence is the severity of disease activity in the explant and potential donor/recipient human leukocyte antigen D-related 3 (DR3) mismatch. The treatment for AIH recurrence includes reintroduction or increase in the dose of steroids with or without the addition of azathioprine. T cell-mediated rejection episodes are also more common in AILD. Steroid withdrawal is the common practice in LT for non-AILD, eliminating the risks associated with longterm exposure to steroids. In AILD, maintenance of steroids at a low dose in the long term may reduce the risk of disease recurrence and rejection. This strategy is safe when there is vigilance for steroid-related adverse effects. Alternatively, identifying patients who are at the greatest risk for disease recurrence and who would benefit from intensified IS might be an option.

[Adherence to Immunosuppressive Medication Following Organ Transplantation]. / Immunsuppressiva-Adhärenz nach Transplantation.

Organ transplantation is the best and to some extent only option for many patients with chronic organ failure. Usually after successful transplantation patients experience a significant improvement of their condition. Nevertheless, they are not cured but still chronically ill. Living with an organ transplant requires consequent immunosuppression intake, regular physician visits and following the recommendations regarding infection prevention. These factors are important to secure a long transplant survival. Especially non-adherence to immunosuppressants is known as a risk factor for transplant rejection. There are several reasons for non-adherent behavior. However identifying the individual motivations is crucial for addressing them correctly. The aim of this article is to give an overview of factors influencing adherence, to introduce options to assess adherence and to present ways to improve adherence. Randomized-controlled intervention studies are presented and on that basis recommendations for clinical practice are derived.

Generic immunosuppressants.

Immunosuppressive drugs for solid organ transplantation are critical dose drugs with a narrow therapeutic index. Many of the most commonly used innovator drugs are off patent and have been replicated by generic counterparts, often at substantial cost-savings to the patient. However, serious adverse events caused by the transition from innovator to generic medications, specifically in pediatric solid organ transplant recipients, have questioned these autosubstitutions. The purpose of this review is to summarize the criteria set forth by the regulatory bodies, and to examine how major immunosuppressive drugs conform to these recommendations. Regulatory bodies have established inconsistent criteria to demonstrate bioequivalence between innovator and generic medications, causing approved generic variations to have varying levels of equivalence with the innovator drugs. In order to minimize the risk for under-immunosuppression, the following recommendations have been concluded. Brand prescribing of cyclosporine and tacrolimus are recommended due to evidence of adverse events after conversion to generic formulations and differences in dissolution parameters. Mycophenolate mofetil (MMF) shows better bioequivalence between innovator and generic formulations, however caution should be advised when switching between formulations. The institution of 'innovator only' policies may be appropriate at this time in order to minimize the risk of under-immunosuppressing patients until the evidence of more stringent bioequivalence has been established.

Meeting report: FDA public meeting on patient-focused drug development and medication adherence in solid organ transplant patients.

The Food and Drug Administration (FDA) held a public meeting and scientific workshop in September 2016 to obtain perspectives from solid organ transplant recipients, family caregivers, and other patient representatives. The morning sessions focused on the impact of organ transplantation on patients' daily lives and the spectrum of activities undertaken to maintain grafts. Participants described the physical, emotional, and social impacts of their transplant on daily life. They also discussed their posttransplant treatment regimens, including the most burdensome side effects and their hopes for future treatment. The afternoon scientific session consisted of presentations on prevalence and risk factors for medication nonadherence after transplantation in adults and children, and interventions to manage it. As new modalities of Immunosuppressive Drug Therapy are being developed, the patient perceptions and input must play larger roles if organ transplantation is to be truly successful.

Renal allograft rejection, lymphocyte infiltration, and de novo donor-specific antibodies in a novel model of non-adherence to immunosuppressive therapy.

BACKGROUND: Non-adherence has been associated with reduced graft survival. The aim of this study was to investigate the immunological mechanisms underlying chronic renal allograft rejection using a model of non-adherence to immunosuppressive therapy. We used a MHC (major histocompatibility complex) -mismatched rat model of renal transplantation (Brown Norway to Lewis), in which rats received daily oral cyclosporine A. In analogy to non-adherence to therapy, one group received cyclosporine A on alternating days only. Rejection was histologically graded according to the Banff classification. We quantified fibrosis by trichrome staining and intra-graft infiltration of T cells, B cells, and monocytes/macrophages by immunohistochemistry. The distribution of B lymphocytes was assessed using immunofluorescence microscopy. Intra-graft chemokine, chemokine receptor, BAFF (B cell activating factor belonging to the TNF family), and immunoglobulin G transcription levels were analysed by RT-PCR. Finally, we evaluated donor-specific antibodies (DSA) and complement-dependent cytotoxicity using flow cytometry. RESULTS: After 28 days, cellular rejection occurred during non-adherence in 5/6 animals, mixed with humoral rejection in 3/6 animals. After non-adherence, the number of T lymphocytes were elevated compared to daily immunosuppression. Monocyte numbers declined over time. Accordingly, lymphocyte chemokine transcription was significantly increased in the graft, as was the transcription of BAFF, BAFF receptor, and Immunoglobulin G. Donor specific antibodies were elevated in non-adherence, but did not induce complement-dependent cytotoxicity. CONCLUSION: Cellular and humoral rejection, lymphocyte infiltration, and de novo DSA are induced in this model of non-adherence.

[Management of the chronic graft versus host disease: Guidelines from the Francophone society of bone marrow transplantation and cellular therapies (SFGM-TC)]. / Prise en charge de la maladie du greffon contre l'hôte chronique : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

The Francophone society of bone marrow transplantation and cellular therapy (SFGM-TC) organized the 7th allogeneic hematopoietic stem cell transplantation clinical practices harmonization workshop series in September 2016 in Lille, France. The objective of our workshop is to discuss chronic graft versus host disease and to provide recommendations for the indications and treatment of this condition.