Calcineurin Inhibitor Withdrawal Research Articles

Calcineurin inhibitor-related hyperkalemia is caused by hyporeninemic hypoaldosteronism and fludrocortisone is an effective treatment: Report of a case series and review of the literature.

Calcineurin inhibitors (CNIs) are widely used in transplantation. Although CNI-related hyperkalemia is common (10%-60.6%), the underlying pathogenetic mechanism is not well-elucidated and may lead to dose adjustment or treatment withdrawal. The aim of this study is to describe CNI-related hyperkalemia due to hyporeninemic hypoaldosteronism in pediatric transplant recipients who were successfully treated with fludrocortisone. In a total of 55 hematopoietic stem cell (HSCT) and 35 kidney transplant recipients followed according to institutional immunosuppression protocols, recipients diagnosed with CNI-related hyperkalemia were reviewed. Recipients who were receiving intravenous fluid, potassium, or were diagnosed with hemolysis, acute graft rejection, or had an eGFR < 30 mL/min/1.73m2, were excluded. A detailed analysis of clinical history as well as biochemical studies was carried out to reveal possible pathophysiology. Three pediatric transplant recipients (one HSCT, two kidney transplantation) with findings of hyperkalemia, hyponatremia, and a mild elevation in blood urea nitrogen while on CNIs were recruited. Urinary potassium excretion was diminished while sodium excretion was increased. Plasma aldosterone levels were low, and renin was not increased in response. Primary adrenal insufficiency was ruled out, and hyporeninemic hypoaldosteronism was diagnosed. CNI-related hyperkalemia was detected earlier in case 1, who had HSCT (22 days), than in the second and third cases, who had kidney transplantation (24 and 30 months post-transplantation, respectively). The discrepancy was hypothesized to be explained by higher overall CNI dose due to higher serum target CNI used in HSCT than kidney transplantation. Electrolyte imbalance was reversed upon administration of physiologic dose fludrocortisone (0.05 mg, daily), while fludrocortisone was ceased after CNI withdrawal in case 1, which is additional evidence for the etiological association of CNIs and hyporeninemic hypoaldosteronism. Our three cases strengthen the premise that CNI-related hyperkalemia may be due to hyporeninemic hypoaldosteronism, and the timing and severity may be related to CNI dose. Fludrocortisone is a safe and effective treatment in CNI-related hyperkalemia, providing maintenance of CNIs, which are one of the essential therapeutic agents for pediatric transplantation.

From the Clinical to the Bench: Exploring the Insulin Modulation Effects of Tacrolimus and Belatacept.

Calcineurin inhibitors (CNIs) are critical in preventing rejection posttransplantation but pose an increased risk of post-transplant diabetes (PTD). Recent studies show that late conversion from CNIs to belatacept, a costimulation blocker, improves HbA1c in kidney transplant recipients with PTD or de novo diabetes. This study investigates whether the observed effects on PTD stem solely from CNI withdrawal or if belatacept influences PTD independently. The study assessed the impact of tacrolimus and belatacept on insulin secretion in MIN6 cells (a beta cell line) and rat islets. Tacrolimus and belatacept were administered to the cells and islets, followed by assessments of cell viability and insulin secretion. Tacrolimus impaired insulin secretion without affecting cell viability, while belatacept showed no detrimental effects on either parameter. These findings support clinical observations of improved HbA1c upon switching from tacrolimus to belatacept. Belatacept holds promise in islet or pancreas transplantation, particularly in patients with unstable diabetes. Successful cases of islet transplantation treated with belatacept without severe hypoglycemia highlight its potential in managing PTD. Further research is needed to fully understand the metabolic changes accompanying the transition from CNIs to belatacept. Preserving insulin secretion emerges as a promising avenue for investigation in this context.

Early cessation of calcineurin inhibitors is feasible post–haploidentical blood stem cell transplant: the ANZHIT 1 study

AbstractHaploidentical hematopoietic stem cell transplant (haplo-HSCT) using posttransplant cyclophosphamide (PTCy) is appropriate for those who lack matched donors. Most studies using PTCy have been retrospective making conclusions difficult. ANZHIT-1 was a phase 2 study conducted at 6 Australian allogeneic HSCT centers. The primary end points were disease-free and overall survival at 2 years after HSCT. The reduced-intensity conditioning (RIC) included fludarabine, cyclophosphamide, and 200 cGy total body irradiation, and the myeloablative conditioning (MAC) was IV fludarabine and busulfan. PTCy, MMF and a calcineurin inhibitor (CNI) were used for graft-versus-host disease (GVHD) prophylaxis. CNIs were weaned and ceased by day +120 in eligible patients on day 60. Patients (n = 78) with hematological malignancies were included in the study, with a median follow-up of 732 days (range, 28-1728). HSCT was RIC in 46 patients and MAC in 32 patients. Disease-free survival probability at 2 years was 67.5% (95% [CI], 53.2-85.6) for MAC recipients and 68.3% (95% CI, 56.3-83.01) for RIC recipients. Transplant-related mortality (TRM) on day 100 and year 1 was 4.9% (95% CI, 1.6-15.3) and 17.9% (95% CI, 8.8-36.5), respectively, in the MAC group compared with 3.1% (95% CI, 0.8.1-12) and 11.6% (95% CI, 6-22.4), respectively, in the RIC group. The median time for elective cessation of CNI was day 142.5 days, with no excess chronic GVHD (cGVHD) or mortality. Of the evaluable patients, 71.6% discontinued immunosuppression 12 months after transplant. This prospective haplo-HSCT trial using PTCY demonstrated encouraging survival rates, indicating that early CNI withdrawal is feasible and safe.

Left Atrial Structural and Functional Response in Kidney Transplant Recipients Treated With Mesenchymal Stromal Cell Therapy and Early Tacrolimus Withdrawal

Autologous bone marrow-derived mesenchymal stromal cell (MSC) therapy and withdrawal of calcineurin inhibitors (CNIs) has been shown to improve systemic blood pressure control and left ventricular hypertrophy regression in kidney transplant recipients. In the current subanalysis, we aimed to evaluate the impact of this novel immunosuppressive regimen on the longitudinal changes of left atrial (LA) structure and function after kidney transplantation. Kidney transplant recipients randomized to MSC therapy-infused at weeks 6 and 7 after transplantation, with complete discontinuation at week 8 of tacrolimus (MSC group)-or standard tacrolimus dose (control group) were evaluated with transthoracic echocardiography at weeks 4 and 24 after kidney transplantation. The changes in echocardiographic parameters were compared between the randomization arms using an analysis of covariance model adjusted for baseline variable. Fifty-four participants (MSC therapy=27; tacrolimus therapy=27) were included. There was no significant interaction between the allocated treatment and the changes of indexed maximal LA volume (LAVImax) over the study period. Conversely, between 4 and 24weeks post-transplantation, an increase in indexed minimal LA volume (LAVImin) was observed in control subjects, while it remained unchanged in the MSC group, leading to a significant difference between groups (P=.021). Additionally, patients treated with MSC therapy showed a benefit in LA function, assessed by a significant interaction between changes in LA emptying fraction and LA reservoir strain and the randomization arm (P=.012 and P=.027, respectively). The combination of MSC therapy and CNIs withdrawal prevents progressive LA dilation and dysfunction in the first 6months after kidney transplantation. LAVImin and LA reservoir strain may be more sensitive markers of LA reverse remodeling, compared with LAVImax.

Mesenchymal stromal cell therapy with early tacrolimus withdrawal prevents left atrial remodelling in renal transplant recipients: an analysis of the TRITON trial

Abstract Background After renal transplantation, there is a need for immunosuppressive regimens that effectively prevent allograft rejection, while minimizing cardiovascular side effects. The TRITON study is the first randomized clinical trial that tested a strategy with autologous bone marrow derived mesenchymal stromal cell (MSC) therapy and complete withdrawal of calcineurin inhibitors (CNIs). The combination of MSC therapy and CNIs discontinuation was associated with improved blood pression control and regression of left ventricular hypertrophy. Nevertheless, the impact of this immunosuppressive strategy on left atrial (LA) structural and functional remodelling, which has been proven as an independent predictor of cardiovascular outcomes, has not been investigated. Purpose To assess the effects of MSC therapy combined with CNIs withdrawal on longitudinal changes of LA structure and function, evaluated by two-dimensional transthoracic echocardiography. Methods The TRITON trial randomized renal transplant recipients to MSC therapy – infused at week 6 and 7 after transplantation, with complete withdrawal at week 8 of tacrolimus (MSC group) – or standard tacrolimus dose (control group). Patients who underwent transthoracic echocardiography with speckle-tracking analysis at week 4 and 24 after renal transplantation were included in this sub-analysis. Changes in echocardiographic variables between 4 and 24 weeks post-transplantation were evaluated and compared between randomization arms using an analysis of covariance model, adjusted for baseline variable. Results 54 patients (MSC group =27; control group =27) were included. Between 4 and 24 weeks after transplantation, an increase in indexed minimal LA volume (LAVImin) was observed in the control group, whereas in the MSC group there were no changes in LAVImin over the time, leading to a significant difference between groups (p=0.021). Moreover, patients randomized to MSC therapy showed a benefit in LA function, assessed by a significant interaction between changes in LA emptying fraction (LAEF) and LA reservoir strain and the treatment group (p=0.012 and p=0.027, respectively) (Table 1). The association between changes in LA structural and functional parameters and the randomization arm remained significant after adjustment for changes in systolic blood pressure, diastolic blood pressure and estimated glomerular filtration rate over the time (Figure 1). Conclusion The combination of MSC therapy and early CNIs withdrawal prevents LA structural and functional remodelling in the first six months after renal transplantation. MSC therapy appears a promising approach in renal transplant recipient, effective in the prevention of graft rejection, while exerting potential cardioprotective effects. Funding Acknowledgement Type of funding sources: None.

Time-Limited Therapy with Belatacept in Kidney Transplant Recipients.

Introduction: In kidney transplant recipients, belatacept is usually pursued indefinitely after it has been started. In the setting of the belatacept shortage and after having evaluated the benefit–risk ratio, we established a strategy consisting of time-limited belatacept therapy/transient calcineurin inhibitor withdrawal, whose results are analyzed in that study. Methods: We considered all the kidney transplant recipients that had been switched from conventional immunosuppressive therapy to belatacept and then for whom belatacept has been withdrawn intentionally. Furthermore, in the first 8 patients, we assessed changes in peripheral blood mononuclear cells (PBMC) transcriptome using RNAseq before and 3 months after belatacept withdrawal. Results: Over the study period, 28 out of 94 patients had belatacept intentionally withdrawn including 25 (89%) switched to low-dose CNI. One rejection due to poor compliance occurred. The eGFR after 12 months remained stable from 48 ± 19 mL.1.73 m−2 to 46 ± 17 mL.1.73 m−2 (p = 0.68). However, patients that resumed belatacept/withdrew CNIs (n = 10) had a trend towards a better eGFR comparing with the others (n = 15): 54 ± 20 mL.1.73 m−2 vs. eGFR 43 ± 16 mL.1.73 m−2, respectively (p = 0.15). The only factor associated with belatacept resumption was when the withdrawal took place during the COVID-19 outbreak. Transcriptome analysis of PBMCs, did not support rebound in alloimmune response. Conclusions: These findings underpin the use of belatacept as part of a time-limited therapy, in selected kidney transplant recipients, possibly as an approach to allow efficient vaccination against SARS-CoV-2.

Tacrolimus-Induced Neurotoxicity in Early Post-Liver Transplant Saudi Patients: Incidence and Risk Factors.

BackgroundTacrolimus is a calcineurin inhibitor (CNI) commonly used as an immunosuppressant to prevent the rejection of organ transplants. After liver transplantation, it can cause early neurological complications, known as early calcineurin inhibitor-induced neurotoxicity (ECIIN). Its management requires CNI withdrawal, a measure that can affect post-transplant outcomes, primarily allograft rejection. In addition, it can negatively impact the quality of life. The incidence and risk factor of ECIIN has not been reported in the Saudi population. We investigated the incidence and risk factors of ECIIN after liver transplant in Saudi patients. We also looked at the length of stay in the Intensive Care Unit, hospital, and 30-day mortality as secondary endpoints.Material/MethodsThis was a retrospective cohort study of adult patients on tacrolimus with mild, moderate, or severe neurological events within the first month after liver transplantation at a single center of patients who meet the inclusion criteria and were over age 14 years. A total of 338 patients were included in the analysis, and the sample size was calculated based on a pilot study.ResultsAmong 338 liver transplantation patients, 63 patients (19%) developed ECIIN. Forty-eight percent of patients had seizures, 23% had agitation, 21% had psychosis, 10% had severe tremors, 13% had confusion, and 6% developed coma. The median time of the incident to develop ECIIN was 9 (IQR: 5–13.5) days after transplant. Thirty-eight patients were managed by switching to cyclosporine, 12 required a reduction in the dose, and 3 were managed temporarily by discontinuing therapy. Autoimmune hepatitis as an underlying liver disease was one of the statistically significant risk factors (P=0.0311). The median length of hospital stay was 31 (IQR: 21–75.5) days, ICU length of stay was 10 (IQR: 5–20.5) days, and 8 patients died within 30 days after transplant.ConclusionsThe incidence of ECIIN in Saud Arabia was similar to that reported in other populations with similar risk factors. Electrolyte imbalance, mainly hyponatremia, was significantly associated with developing ECIIN. Therefore, ECIIN may potentially increase hospital and ICU length of stay.

Incidence of mTORi Associated BOOP in Cardiac Transplant Recipients – A Single Center Perspective

<h3>Purpose</h3> The incidence of mammalian target of rapamycin inhibitor (mTORi) associated bronchiolitis obliterans organizing pneumonia (BOOP) varies in the literature. We have previously reported a 24% incidence of BOOP in patients transitioned to sirolimus. This high rate was believed to be related to the full withdrawal of calcineurin inhibitor (CI) therapy. The aim of this study is to compare those results to our current practice of maintaining a low-dose CI with mTORi-based regimens <h3>Methods</h3> This was a single-center retrospective review of adult heart transplant recipients initiated on an mTORi at least six months post-transplant. The primary outcome of the study was incidence of BOOP. Secondary outcomes included timing of mTORi conversion post-transplant and associated tacrolimus concentrations. <h3>Results</h3> During the study period, none of the 61 included heart transplant patients developed BOOP. Late mTORi transition (>1 year post transplant) was more common (72%) than early conversion (6 months - 1 year post transplant; 28%), and sirolimus was more commonly utilized than everolimus (90% vs 10%). Following our centers mTORi conversion policy, all patients were maintained on low-dose tacrolimus at initiation, with 84% of patients continuing concomitant tacrolimus at one year. Of these patients, 46% had an FK goal < 4 mcg/mL and 38% had an FK goal 4-8 mcg/mL. <h3>Conclusion</h3> No patients at our center experienced mTORi related BOOP while maintaining a low dose CI. The results of this study suggest calcineurin inhibitors have a protective effect from BOOP, even at low concentrations.

Is the failure of recent trials on withdrawal of calcineurin inhibitors due to inadequate mycophenolic acid dosing?

Calcineurin inhibitors (CNIs) are the mainstay immunosuppressive therapy after kidney transplantation, despite their side effects. Recently, several randomized controlled trials attempting CNI withdrawal or minimization in stable, low-risk kidney transplant recipients led to an unacceptable risk of acute rejection and de novo HLA antibody formation. In the opinions of many, these trials definitively demonstrated that CNI-free regimens in the context of mycophenolate mofetil (MMF) maintenance are too risky. It can be argued, however, that the investigators failed to optimize the dose of the remaining immunosuppressive therapy. In particular, the potential benefit of MMF dosing based on the targeted mycophenolic acid (MPA) concentration was not taken into account. In this review, we present an overview of the studies on CNI withdrawal, both recent and older, paying specific attention to the MMF dose and elaborating on the possible benefit of MPA monitoring in this setting.

Clinical Course and Outcomes of COVID-19 in Kidney Transplant Recipients.

Kidney transplant recipients (KTR) are at increased risk of morbidity and mortality due to coronavirus disease 2019 (COVID-19). This study aimed to explore the clinical characteristics and outcomes of COVID-19 in KTR. We reviewed the clinical profile, outcomes, and immunological responses of recipients admitted with COVID-19. We determined the risk factors for mortality and severe COVID-19. Out of 452 recipients on follow-up, 60 were admitted with COVID-19. Prevalent comorbidities were hypertension (71%), diabetes (40%), lung disease (17%). About 27% had tuberculosis. The median Sequential Organ Failure Assessment score at presentation was 3 (interquartile range [IQR] 1-5). There was a high incidence of diarrhea (52%) and anemia (82%). Treatment strategies included antimetabolite withdrawal (85%), calcineurin inhibitor decrease or withdrawal (64%), increased steroids (53%), hydroxychloroquine (21%), remdesivir (28.3%), and tocilizumab (3.3%). Severe COVID-19 occurred in 34 (56.4%) patients. During a median follow-up of 42.5 days (IQR 21-81 days), 83% developed acute kidney injury (AKI) and eight (13%) died. Mortality was associated with the baseline graft dysfunction, hypoxia at admission, lower hemoglobin and platelets, higher transaminases, higher C reactive protein, diffuse radiological lung involvement, hypotension requiring inotropes, and Kidney Diseases Improving Global Outcomes (KDIGO) stage 3 AKI (univariate analysis). Around 57% of patients remained RT-PCR positive at the time of discharge. By the last follow-up, 66.6% of patients developed IgM (immunoglobulin M) antibodies and 82.3% of patients developed IgG antibodies. COVID-19 in kidney transplant recipients is associated with a high risk of AKI and significant mortality.

Changes in glomerular filtration rate in liver recipients after reduced exposure to calcineurin inhibitors with concomitant everolimus administration within the first year after immunosuppression conversion

Objective: to compare changes in estimated glomerular filtration rate (eGFR) in liver recipients with initially normal and impaired eGFR within the first year after immunosuppression conversion.Materials and methods. Enrolled in the study were 215 recipients of deceased-donor livers from February 2009 to February 2020, who received everolimus with dose reduction or complete withdrawal of calcineurin inhibitors (immunosuppression conversion, ISxC) for varying periods of time. GFR was measured using the MDRD-4 formula immediately before ISxC, then 3, 6, and 12 months after orthotopic liver transplantation (LTx). One month was considered an acceptable temporary deviation from the corresponding point.Results. At the time of ISxC, 32 (15%) of 215 recipients had normal renal function. Chronic kidney disease (CKD) increased in 60% of the recipients with normal eGFR by the end of the first year following ISxC; the fall in eGFR was particularly pronounced in older recipients. In the group with a baseline eGFR of 60–89 mL/min/1.73 m2, eGFR normalized in 62% of cases within 12 months; 28% of cases had no changes in renal function. In the subgroup with a pronounced decrease in eGFR at the time of ISxC, increased eGFR was observed as early as 1 month after ISxC, and the maximum was recorded after 3–6 months. The mean eGFR relative to baseline by month 3 after eGFR were higher for ISxC that was done in the first 2 months after LTx (19.7 ± 15.7 ml/minute/1.73 m2) than for ISxC done in the long-term period after LTx (10.1 ± 8.7 ml/minute/1.73 m2, p &lt; 0.05).Conclusion. Changes in eGFR in liver recipients receiving EVR plus low-dose calcineurin inhibitor (CNI) depend on baseline eGFR and are multidirectional. The use of ISxC in the early post-LTx period led to a more pronounced improvement in eGFR. Maximal changes in eGFR were observed by 3–6 months after ISxC.

Complete regression of generalized plasmacytoma of lymph nodes in a liver transplant recipient during the conversion of immunosuppressive therapy from tacrolimus to everolimus

Introduction. One of the serious complications after transplantation of solid organs and bone marrow is the development of post-transplant lymphoproliferative diseases.Clinical case. To evaluate the course of post-transplant lymphoproliferative diseases in the long-term in a liver transplant recipient after conversion of immunosuppressive therapy from tacrolimus to everolimus. We analyze a case of generalized primary plasmacytoma of lymph nodes with bone marrow involvement in a patient after liver transplantation.Results. After conversion of immunosuppression we observed a rapid positive trend: decreasing size of lymph nodes and regression of the level of paraprotein down to its complete disappearance. There were neither adverse events associated with everolimus for four years, nor signs of immunosuppression insufficiency.Conclusion. This Case Report is the first description of a long-term remission of nodal plasmacytoma that developed in a liver transplant recipient after complete withdrawal of calcineurin inhibitors and administration of everolimus. We suggest that the regression of post-transplant lymphoproliferative diseases after replacing calcineurin inhibitors with everolimus is associated not only with the minimization of calcineurin inhibitors exposure, but also with the antitumor effect of the everolimus itself, which prompts us to discuss the possibilities of expanding its clinical application.

Assessment of clinical outcomes in renal transplant recipients with COVID-19.

The coronavirus disease 2019 (COVID‐19) has affected more than a hundred million individuals and caused more than three million deaths worldwide. Specific risk groups were defined for increased risk of mortality and morbidity in COVID‐19, and renal transplant recipients are at a significantly increased risk regarding outcomes due to their immunosuppressed conditions. This study evaluated the general characteristics of kidney transplant recipients with COVID‐19 infection. Among 1257 transplant cases, 56 had COVID‐19 infection, and 23 (41%) were hospitalized during the 9‐month study period. Among all COVID‐19 cases, 58% were male with a mean age of 45.5 (±13.2, 19–71) years, and the most frequent comorbidities were hypertension (70.9%) and diabetes (23.6%). Hospitalized patients were older (p = 0.03) and had higher rates of hypertension (p = 0.008), diabetes (p = 0.002), and ischemic heart disease (p = 0.03). Therapeutic management included antimetabolite withdrawal and prednisolone increase in 71%, calcineurin inhibitor withdrawal in 8% and decrease in 58%, hydroxychloroquine in 17%, tocilizumab in 3%, and antivirals in 67% of patients. Acute kidney injury and respiratory failure developed in 34% and 85%, respectively. The mortality rate was 23%. These results emphasized that the COVID‐19 infection in renal transplant recipients significantly increases the risk of morbidity and mortality. Therefore, these patients should be intervened earlier and monitored closely to prevent poor outcomes.

SARS-CoV-2 in Solid Organ Transplant Recipients: A Structured Review of 2020

BackgroundThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is challenging health systems all over the world. Particularly high-risk groups show considerable mortality rates after infection. In 2020, a huge number of case reports, case series, and consecutively various systematic reviews have been published reporting on morbidity and mortality risk connected with SARS-CoV-2 in solid organ transplant (SOT) recipients. However, this vast array of publications resulted in an increasing complexity of the field, overwhelming even for the expert reader.MethodsWe performed a structured literature review comprising electronic databases, transplant journals, and literature from previous systematic reviews covering the entire year 2020. From 164 included articles, we identified 3451 cases of SARS-CoV-2–infected SOT recipients.ResultsInfections resulted in a hospitalization rate of 84% and 24% intensive care unit admissions in the included patients. Whereas 53.6% of patients were reported to have recovered, cross-sectional overall mortality reported after coronavirus disease 2019 (COVID-19) was at 21.1%. Synoptic data concerning immunosuppressive medication attested to the reduction or withdrawal of antimetabolites (81.9%) and calcineurin inhibitors (48.9%) as a frequent adjustment. In contrast, steroids were reported to be increased in 46.8% of SOT recipients.ConclusionsCOVID-19 in SOT recipients is associated with high morbidity and mortality worldwide. Conforming with current guidelines, modifications of immunosuppressive therapies mostly comprised a reduction or withdrawal of antimetabolites and calcineurin inhibitors, while frequently maintaining or even increasing steroids. Here, we provide an accessible overview to the topic and synoptic estimates of expectable outcomes regarding in-hospital mortality of SOT recipients with COVID-19.

P-17: Transplant Associated Thrombotic Microangiopathy and Immune Haematological Complications Following Intestine Containing Organ Transplantation: Experience from Over 100 Consecutive Cases

Descriptions of passenger lymphocyte syndrome (PLS), immune cytopenias and transplant associated thrombotic microangiopathy (TA-TMA) in patients with intestine-containing grafts remains scarce. We describe our experience of these complications in a retrospective chart review from 2007-2019. 96 patients received 103 transplants. PLS occurred in 9 (9%) patients (median 12 days post-transplant); all due to ABO antibodies. There were 31 minor ABO mismatch transplants. No patient required change in immunosuppression. Immune cytopenias (excluding PLS) occurred in 6 patients at an incidence of 1.6/100 years follow-up; 3 immune haemolysis, 1 immune thrombocytopenia, 1 acquired Glanzmann’s and 1 immune neutropenia; 50% occurred with other cytopenias. All cases responded to treatment, with a median of 5 treatments (range 1–8) and 5/6 required rituximab. 1 patient with immune haemolysis required bortezomib. Complications of infection or thrombosis were common. In 3/6 cases a secondary cause for the immune cytopenia was evident. Switching from tacrolimus to ciclosporin wasn’t necessary. There were 5 cases of TA-TMA (1.3/100 patient years) requiring calcineurin inhibitor withdrawal; 2 cases associated with acute rejection. 2 cases were managed with plasma exchange and 1 with eculizumab. We describe extensive experience for this patient group, in the largest published series, where further research collaboration or a research registry is needed.

Better outcome of COVID-19 positive kidney transplant recipients during the unremitting stage with optimized anticoagulation and immunosuppression.

IntroductionCOVID‐19 is an ongoing pandemic with high morbidity and mortality and with a reported high risk of severe disease in kidney transplant recipients (KTR).AimWe aimed to report the largest number of COVID‐19‐positive cases in KTR in a single center and to discuss their demographics, management, and evolution.MethodsWe enrolled all the two thousand KTR followed up in our center in Kuwait and collected the data of all COVID‐19‐positive KTR (104) from the start of the outbreak till the end of July 2020 and have reported the clinical features, management details, and both patient and graft outcomes.ResultsOut of the one hundred and four cases reported, most of them were males aged 49.3 ± 14.7 years. Eighty‐two of them needed hospitalization, of which thirty‐one were managed in the intensive care unit (ICU). Main comorbidities among these patients were hypertension in 64.4%, diabetes in 51%, and ischemic heart disease in 20.2%. Management strategies included anticoagulation in 56.7%, withdrawal of antimetabolites in 54.8%, calcineurin inhibitor (CNI) withdrawal in 33.7%, the addition of antibiotics in 57.7%, Tocilizumab in 8.7%, and antivirals in 16.3%. During a follow‐up of 30 days, the reported number of acute kidney injury (AKI) was 28.7%, respiratory failure requiring oxygen therapy 46.2%, and overall mortality rate was 10.6% with hospital mortality of 13.4% including an ICU mortality rate of 35.5%.ConclusionBetter outcome of COVID‐19‐positive KTR in our cohort during this unremitting stage could be due to the younger age of patients and early optimized management of anticoagulation, modification of immunosuppression, and prompt treatment of secondary bacterial infections. Mild cases can successfully be managed at home without any change in immunosuppression.

Prospective Measures of Adherence by Questionnaire, Low Immunosuppression and Graft Outcome in Kidney Transplantation.

Background: Non-adherence with immunosuppressant medication (MNA) fosters development of de novo donor-specific antibodies (dnDSA), rejection, and graft failure (GF) in kidney transplant recipients (KTRs). However, there is no simple tool to assess MNA, prospectively. The goal was to monitor MNA and analyze its predictive value for dnDSA generation, acute rejection and GF. Methods: We enrolled 301 KTRs in a multicentric French study. MNA was assessed prospectively at 3, 6, 12, and 24 months (M) post-KT, using the Morisky scale. We investigated the association between MNA and occurrence of dnDSA at year 2 post transplantation, using logistic regression models and the association between MNA and rejection or graft failure, using Cox multivariable models. Results: The initial percentage of MNA patients was 17.7%, increasing to 34.6% at 24 months. Nineteen patients (8.4%) developed dnDSA 2 to 3 years after KT. After adjustment for recipient age, HLA sensitization, HLA mismatches, and maintenance treatment, MNA was associated neither with dnDSA occurrence, nor acute rejection. Only cyclosporine use and calcineurin inhibitor (CNI) withdrawal were strongly associated with dnDSA and rejection. With a median follow-up of 8.9 years, GF occurred in 87 patients (29.0%). After adjustment for recipient and donor age, CNI trough level, dnDSA, and rejection, MNA was not associated with GF. The only parameters associated with GF were dnDSA occurrence, and acute rejection. Conclusions: Prospective serial monitoring of MNA using the Morisky scale does not predict dnDSA occurrence, rejection or GF in KTRs. In contrast, cyclosporine and CNI withdrawal induce dnDSA and rejection, which lead to GF.

POS-753 LONG TERM BENEFITS OF PRESERVED GRAFT FUNCTIONS AFTER LATE WITHDRAWAL OF CALCINEURIN INHIBITORS IN LIVE DONOR KIDNEY TRANSPLANT RECIPIENTS.

With the use of calcineurin inhibitors (CNI) and induction therapy , graft survival has reached over 90% at 1 year. Despite short and medium term improvement , long term graft survival has not shown proportionate improvement. There is debate about role of CNI induced nephrotoxicity and long term graft dysfunction and there is no uniformity in renal outcome after CNI minimization or withdrawal 1 year after transplantation, especially in live donor transplants and well matched kidneys. This retrospective data analyses the long term outcome of patient and graft survival after CNI withdrawal from triple drug therapy of CNI, prednisolone and azathioprine /mycophenolate mofetyl (MMF) Twenty two adults (M:F- 16: 6) who had kidney from live donor and no rejections with stable renal function at one year after transplant were evaluated in this retrospective study. 6 recipients for financial reasons opted for CNI withdrawal which was done over 8 weeks. In the transition period prednisolone and azathioprine dose was stepped up. In another 12 patients CNI was withdrawn over 1-2 years post transplantation for gradually rising serum creatinine. In the remaining 4 patients CNI was withdrawn after graft biopsy revealed no evidence of rejection and histological changes suggestive of CNI toxicity,48-140 months( mean 90 +/-40) after transplant.Patients were followed up regularly for estimation of renal functions. Withdrawal of CNI after 12 months and even in late withdrawal did not result in graft rejection and all patients tolerated the intervention well. At time of early withdrawal at 12 months in 6 patients(Group A) serum creatinine ranged from 1.12 –1.6 mg/dl (Mean1.28 +/-0.16) and eGFR of 65.16 +/-12.81ml/mt. In12 patients (Group-B) in whom CNI was withdrawn between12-24 months serum creatinine ranged from 1.3-1.75 mg/dl (mean 1.51+/- 0.15) and eGFR 56.16 +/-7.1 ml/mt. In remaining 4 patients (group 3) who had evidence of toxicity,CNI was withdrawn 48 to140 months after transplant.Their serum creatinine was1.3 -1.75 mg/dl (mean 1.57+/-0.19) and eGFR 47+/-7.63ml/mt. At the end of follow up ranging from 60-348 months (mean 170+/-72 months ) all the patients had well preserved renal functions with their mean GFR of 65, 56 and 47 ml/mt in respective group with serum creatinine1.02 to 5.2 mg/dl (mean 1.86 +/- 0.99) There were 9 deaths after a follow up of 82-300 months (mean 200 +/- 75.2 )months.Three patients had carcinoma tongue of whom one had achieved prolonged remission after therapy but during follow up along with 2others reached ESRD and were initiated on hemodialysis.Cardiovascular events in 3 and infections in other 2 patients accounted for their mortality. Recipients of kidney from live donors with at least 1 haplo match and who did not have rejections in the1st year of transplant had excellent long term graft survival with 2 drugs only without CNI.In selected live donor transplant recipients who do not have rejection in first year calceinurin inhibitors can safely be withdrawn at least one year after transplant which helps in ameliorating CNI induced renal injury and prevents further deterioration of renal functions. In patients with graft dysfunction with histological features of CNI toxicity this beneficial effect of CNI withdrawal can sometimes be seen even many years after transplantation.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome after hematopoietic stem cell transplantation for thalassemia major: incidence, management, and outcome

Hepatic veno-occlusive disease or sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the present prospective study, we aimed to investigate the incidence, management, and outcome of VOD/SOS in patients with thalassemia major (TM) who received allo-HSCT. VOD/SOS was diagnosed and classified based on the modified Seattle criteria. The prophylactic regimen for VOD/SOS was a combination treatment of dalteparin and lipo-PGE1. VOD/SOS was managed through an approach consisting of adequate supportive measures, short-term withdrawal of calcineurin inhibitors (CNIs), and the use of methylprednisolone and basiliximab for graft-versus-host disease prophylaxis. VOD/SOS was found in 54 of 521 patients (10.4%) at a median time of 12 days after allo-HSCT. The cumulative incidence of all-grade and moderate VOD/SOS was 10.4% and 4.2%, respectively. Among the 54 VOD/SOS patients, no patient developed severe grade and died from VOD/SOS. Besides, the cumulative incidence of transplant-related mortality on day 100 for patients with or without VOD/SOS was 0% vs. 4.0% (P = 0.187), respectively, and the 3-year overall survival rates were 94.3% vs. 93.2% (P = 0.707), respectively. Collectively, we concluded that appropriate symptomatic therapy and short-term withdrawal of CNIs safely mitigated the mortality of VOD/SOS in TM patients who underwent allo-HSCT.

Comparison of two strategies based on mammalian target of rapamycin inhibitors in secondary prevention of non-melanoma skin cancer after kidney transplantation, a pilot study.

After kidney transplantation, withdrawal of calcineurin inhibitors (CNI) and conversion to sirolimus (SRL) may reduce the occurrence of new non-melanoma skin cancer (NMSC). Conversely, a reduced CNI exposure with everolimus (EVR) is an alternative strategy that has not been thoroughly evaluated. We retrospectively compared the occurrence of newly diagnosed NMSCs in two cohorts of kidney transplant recipients (KTR) with at least one NMSC: 35 patients were converted to EVR with reduced CNI exposure (CNI/EVR group), whereas 46 patients were converted to SRL in association with mycophenolic acid (MPA) (SRL/MPA group). Two years after conversion, survival free of new NMSC was similar between the two cohorts (p=.37), with 19 KTR (54.3%) in the CNI/EVR group and 22 (47.8%) in the SRL/MPA group being diagnosed of at least one new NMSC. Half of the KTR from both groups showed adverse events, leading to mTORi discontinuation for 37.1% of KTR in the CNI/EVR group and 21.7% in the SRL/MPA group (p=.09). The incidence of rejections was similar between the two groups. In a retrospective cohort of KTR with at least one post-transplant NMSC, the outcome of the patients converted to a CNI/EVR regimen was not different from those converted to a SRL/MPA regimen.