Calcineurin Inhibitor Withdrawal Research Articles

Challenges in Calcineurin Inhibitor (CNI) Withdrawal in Conjunction with Co-Stimulation Blockade in Simultaneous Pancreas and Kidney Transplant (SPK)

Challenges in Calcineurin Inhibitor (CNI) Withdrawal in Conjunction with Co-Stimulation Blockade in Simultaneous Pancreas and Kidney Transplant (SPK)

Late Conversion to Everolimus with Calcineurin Inhibitor Minimization in Stable Kidney Transplant Recipients - Analysis of Factors Affecting ΔeGFR

Background Immunosuppressive regimens that minimize exposure to calcineurin inhibitors (CNIs) following kidney transplantation have been widely investigated in order to reduce the burden of CNI-related complications. Recent trials have focused on the use of everolimus to facilitate CNI withdrawal or minimization. Previous studies had shown that late conversion to everolimus had no overall renal benefit. However, late conversion of kidney transplant recipients to everolimus has demonstrated renal improvement in patients with a baseline estimated glomerular filtration rate (eGFR) of above 50 ml/min/1.73m2 or in patients who remained on everolimus medication. The aim of this study is to analyze the factors affecting graft function after late conversion to everolimus with CNI minimization in kidney transplant recipients. Patients and Methods A 1-year retrospective pilot study of 56 kidney recipients converted from antimetabolites with standard exposure CNIs to everolimus with CNI minimization was performed. The recipients enrolled in this study had normal or slightly impaired renal function defined as a serum creatinine (S-Cr) value<2.0 mg/dl, and normal or slightly increased albuminuria defined as a urinary albumin excretion rate <100 mg/g Cr. For the assessment of graft function, we used ΔeGFR according to the formula ΔeGFR=(eGFR at 12 months after conversion)-(eGFR at conversion). We evaluated the relationship betweenΔeGFR and clinical parameters in kidney transplant recipients enrolled in this study. Results The average time from transplant to conversion was 42.9±44.1 months, and treatment with everolimus was stopped due to adverse events in 17 patients (30.3%). ΔeGFR was significantly higher in patients who remained on everolimus than in those who discontinued everolimus medication. Univariate linear regression analysis revealed that ΔeGFR correlated negatively with urinary albumin excretion (R=0.479, p=0.000216) and kidney age (donor age at transplantation+time from transplantation to conversion)(R=0.275, p=0.048). Multivariate linear regression analysis indicated that urinary albumin excretion and everolimus continuation were independently associated with ΔeGFR. Conclusion Our results suggested that late conversion of kidney transplant recipients to everolimus with CNI minimization may lead to improvement in graft function compared to standard CNI therapy, if they remained on everolimus treatment. Urinary albumin excretion may be a marker of generalized endothelial or vascular damage, and graft function in patients with renal or systemic endothelial damage may deteriorate due to late conversion to everolimus with CNI minimization.

Dual antibody induction and de novo use of everolimus enable low-dose tacrolimus with early corticosteroid withdrawal in simultaneous pancreas-kidney transplantation

BackgroundTo be an optimal immunosuppressive regimen after simultaneous pancreas kidney transplantation (SPK), low dose calcineurin inhibitor and early withdrawal of corticosteroids are desired. MethodsImmunosuppressive regimen as such has been conducted consecutively in SPK recipients since 2009 in authors' institute. In addition to tacrolimus in low trough level and early corticosteroid withdraw, dual induction with basiliximab and low-dose thymoglobulin in combination with everolimus are the important components of the protocol. Results25 consecutive primary SPK recipients were included in the study. Lymphocyte depletion by low dose thymoglobulin was limited to two weeks, and CD25 coating with basiliximab was detectable for 4 weeks. The BPAR within the first 12 months was 13%. During a median follow-up of 58 months, new-onset diabetes mellitus and renal function deterioration were rare events. No cytomegalovirus activation was encountered. The patients, pancreas and kidney graft survival at 1-year and 5-year was 100% and 94.4%, 95.8% and 95.8%, 100% and 100% respectively.

Identifying risk profiles in liver transplant candidates and implications for induction immunosuppression.

Changes in recipient and donor characteristics are redefining the role of induction in liver transplant recipients. Older recipients are more common, with greater concomitant comorbidity. Moderate or severe renal dysfunction is now estimated to affect 40% of liver transplant recipients. Donors are also becoming older, and other factors such as more frequent non-alcoholic fatty liver disease (NAFLD) compromise the quality of some grafts. Rejection rates are now relatively low (~10%) but some patients have a markedly increased risk such as younger recipients and those undergoing re-transplantation. Induction immunosuppression is associated with a significant reduction in rejection risk but due to various factors universal induction is not justified. Steroid-free therapy without induction increases the risk of biopsy-proven acute rejection (BPAR) but randomized trials have shown that induction with an interleukin-2 antagonist receptor (IL-2RA) agent or with rabbit antithymocyte globulin (rATG) maintains immunosuppressive efficacy in steroid-free regimens. Delayed calcineurin inhibitor (CNI) initiation (e.g. to days 4-5 post-transplant) can prevent deterioration of renal function during the first year post-transplant, but requires induction with an IL-2RA agent or rATG to maintain early immunosuppressive efficacy. IL-2RA induction may be inadequate to ensure a low risk of rejection in a steroid-free regimen combined with delayed tacrolimus. Randomized trials of CNI withdrawal at month 1 post-transplant have only achieved an acceptable rate of BPAR when induction is administered. In terms of safety, an increased rate of infection does not seem to be a concern. The most recent large-scale analyses have not indicated any evidence for an increased risk of malignancy, or specifically post-transplant lymphoproliferative disease. In summary, the place of induction in the management of liver transplant patients is becoming established. Selective use in high-risk individuals to avoid graft rejection is still relevant, but the key rationale for induction is to facilitate steroid-sparing and CNI-sparing regimens to reduce long-term complications.

The Effect of Everolimus Initiation and Early Calcineurin Inhibitor Withdrawal on Allograft Vasculopathy in De-Novo Heart Transplant Recipients: Results of the Schedule Trial after 6 Years

The SCHEDULE (Scandinavian heart transplant everolimus de-novo study with early calcineurin inhibitors avoidance) trial has sought to evaluate whether initiation of the proliferation signal inhibitor everolimus and total early cyclosporine elimination can significantly reduce the development of CAV in de-novo HTx recipients. We have previously reported that patients treated with everolimus demonstrated significantly reduced CAV progression when compared to cyclosporine therapy at both 12 and 36 months (12-month IVUS examination revealed ∆Maximal Intimal Thickness (MIT) 0.02±0.05 versus 0.08±0.12 mm (p<0.01), ∆Percent Atheroma Volume (PAV) 1.2±2.0 versus 3.7±4.1% (p<0.01), ∆Total Atheroma Volume (TAV) -0.13±20.5 mm3 versus 11.1±27.6 mm3 (p=0.08) and 36-month examination showed ∆MlT 0.09±0.05 versus 0.15±0.16 mm (p=0.01), ∆PAV 5.4±3.1 versus 7.6±5.9% (p=0.02), ∆TAV 33.9±71.2 mm3 versus 54.2±96.0 mm3 (p=0.26), respectively). Treatment according to study arm has been further extended to a total treatment period of 6 years and the IVUS results of this follow-up period will be presented. In addition, Virtual Histology (VH) data will be included to assess the morphological changes associated with everolimus treatment.

Adverse events linked with the use of chimeric and humanized anti-CD20 antibodies in children with idiopathic nephrotic syndrome.

Anti-CD20 antibodies are increasingly being used to treat idiopathic nephrotic syndrome (INS) in children. While they may allow steroid and calcineurin inhibitor withdrawal, repeated infusions of anti-CD20 antibodies are often required to maintain remission. Data on their potential toxicity in INS are needed, to consider repeated infusions. We investigated the side effects associated with the use of rituximab (a chimeric antibody; 130 patients) and ofatumumab (a humanized antibody; 37 patients) in children with INS (steroid-dependent and steroid/calcineurin inhibitor-dependent disease) treated at a national referral centre over a 9-year period (400 treatments; follow-up 1-9years). Infusion reactions were mainly absent in children with steroid-dependent disease. Rash, dyspnoea, fever, cough and itchy throat (5% and 18% following rituximab and ofatumumab infusion, respectively) were resolved by using premedication with salbutamol. Other short-term reactions (up to 3months), including arthritis (2%) and lung injury (1%), were more common with rituximab. Infections were observed 3-9months following infusion, were similarly common in the two groups and resolved with targeted therapies [antibiotic, fluconazole, immunoglobulins (Igs), etc.]. The number of circulating CD19/20 cells fell to 0 at month 1 and were reconstituted at month 3; circulating IgG antibodies remained within the normal range for 1year. Tetanus and hepatitis B virus immunization was not modified by either treatment; Epstein-Barr virus and John Cunningham virus activation markers were occasionally observed. Overall, the toxicity of anti-CD20 monoclonal antibodies was limited to post-infusion side effects in children with more complex disease. The relatively safe profile of anti-CD20 antibodies supports their use as steroid-sparing agents in children with INS.

Subsequent nonmelanoma skin cancers and impact of immunosuppression in liver transplant recipients.

Nonmelanoma skin cancers (NMSCs) are the most frequent cancers in solid organ transplant recipients, with a high rate of subsequent tumors. To describe subsequent NMSCs in a large cohort of liver transplantrecipients (LTRs) with long follow-up and analyze the factors influencing it, including immunosuppressive regimen. A total of 96 LTRs (76 male) with a personal post-transplant history of squamous cell carcinoma, basal cell carcinoma or Bowen's disease were included, with a median follow-up of 12.4years (range, 1.5-27.8) after liver transplantation. The median follow-up after first NMSC was 6.4years (range, 0.17-22.1). In all, 52 patients (53.1%) developed 141 subsequent NMSCs with a basal cell carcinoma-to-squamous cell carcinoma ratio of 1.8:1. The actuarial risk for development of a second NMSC was 13.7% at 1year, 28.4% at 2years, 49.4% at 5years, 65.7% at 10years, and 88.4% at 15years. Multivariate analysis found that skin phototype I or II (vs III or IV) was a significant risk factor for development of a second NMSC (hazard ratio, 2.556; 95% confidence interval, 1.45-4.48; P=.001), whereas withdrawal of calcineurin inhibitors was significantly protective (hazard ratio, 0.358; 95% confidence interval, 0.142-0.902; P=.029). Retrospective analysis. Subsequent NMSCs are very frequent in LTRs, and conversion from a calcineurin inhibitor-based immunosuppressive regimen to a mammalian target of rapamycin inhibitor/antimetabolite-based immunosuppressive regimen can reduce subsequent NMSCs.

Effect of Calcineurin Inhibitor-Free, Everolimus-Based Immunosuppressive Regimen on Albuminuria and Glomerular Filtration Rate After Heart Transplantation.

Albuminuria in maintenance heart transplantation (HTx) is associated with poor renal response when switching to a calcineurin inhibitor (CNI)-lowered or CNI-free immunosuppressive regimen using everolimus (EVR), but the significance of albuminuria associated with EVR treatment after early CNI withdrawal in de novo HTx is unknown. We tested if measured glomerular filtration rate (mGFR, by chrome-ethylenediaminetetraacetic acid clearance) was associated with urine albumin/creatinine ratio (UACR) post-HTx in a subgroup of patients included in the Scandinavian Heart Transplant Everolimus De Novo Study With Early Calcineurin Inhibitor Avoidance trial, where de novo HTx patients (n = 115) were randomized to EVR with complete CNI elimination 7 to 11 weeks post-HTx or standard CNI immunosuppression. In 66 patients, UACR measures were available at 1 year. In 7 patients in the EVR group, a CNI was reintroduced within 12 months. Median mGFR was significantly higher in the EVR group both 1 and 3 years post-HTx (P = 0.0004 and P = 0.03, respectively). Median UACR at 1 year was significantly higher in the EVR group (P = 0.002). There was no correlation between log(UACR) at 1 year and mGFR at 1 or 3 years (r = -0.01, P = 0.9 and r = 0.15, P = 0.26, respectively) and in the EVR group between log(UACR) at 1 year and change in mGFR (Δ1-3 years) (r = 0.27, P = 0.14). Excluding patients in the EVR group in whom a CNI was reintroduced did not significantly change the results. The effects of EVR with early CNI withdrawal after HTx on albuminuria and renal function seem dissociated; hence, the clinical significance of albuminuria in this setting is uncertain and should not necessarily rule out EVR-based immunosuppression.

Thrombotic microangiopathy following haematopoietic stem cell transplant

Thrombotic microangiopathy is a potentially lethal complication of haematopoietic stem cell (bone marrow) transplantation. The pathophysiology is incompletely understood, although endothelial damage appears to be central. Platelet activation, neutrophil extracellular traps and complement activation appear to play key roles. Diagnosis may be difficult and universally accepted diagnostic criteria are not available. Treatment remains controversial. In some cases, withdrawal of calcineurin inhibitors is adequate. Rituximab and defibrotide also appear to have been used successfully. In severe cases, complement inhibitors such as eculizumab may play a valuable role. Further research is required to define the pathophysiology and determine both robust diagnostic criteria and the optimal treatment.

Everolimus as a Calcineurin Inhibitor-Sparing Immunosuppressive Agent in Lung Transplant Recipients With Renal Impairment

SESSION TITLE: Transplant SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, November 1, 2017 at 01:30 PM - 02:30 PM PURPOSE: Calcineurin inhibitors (CNI) are considered a key component of maintenance immunosuppression following lung transplantation. However, CNI nephrotoxicity is a common and serious problem amongst lung transplant recipients. Everolimus (ERL), an inhibitor of the mechanistic target of rapamycin (mTOR), has been used as a CNI sparing immunosuppressive agent to allow renal recovery in patients with progressive renal impairment. Nevertheless, there is limited evidence to support the efficacy of this strategy to prevent rejection. This study aimed to evaluate the effect of ERL on renal and lung function in lung transplant recipients. METHODS: We conducted a retrospective analysis within a state-wide lung transplant service in Australia. Medical and pharmacy records were used to identify lung transplant recipients who were commenced on ERL from 2004 to 2015. Patients who received at least 6 consecutive months of ERL therapy during this period were included in the analysis. We recorded renal function and lung function 6 months before and 6 months after the initiation of ERL. Creatinine clearance (CrCl), derived from the Cockroft-Gault equation, was used as a measure of renal function. Lung function was reported as the percent predicted FEV1 and FVC. RESULTS: 44 patients were included in the analysis. The mean age was 49 ± 15 years. ERL was initiated at a median of 476 days (interquartile range 219-1247) post-transplant. The indication for ERL was renal impairment in 94%, malignancy in 4% and CNI related neurotoxicity in 2% of patients. After initiating ERL, 46% of patients had CNI ceased and the rest had a substantial dose reduction. At ERL initiation, mean CrCl was 52.6 ± 3.3 ml/min, mean percent predicted FEV1 70 ± 3% and FVC 77 ± 3%. In the 6 months prior to commencing ERL, there was a mean change in CrCl of -8.9 ± 2.4 ml/min (P=0.003), FEV1 -3.4 ± 1.9% (p=0.696), and FVC -1.2 ± 1.5% (p=1.000). 6 months after initiating ERL, the mean change in CrCl was +11.2 ± 2.4 ml/min (p<0.0001), FEV1 -5.3 ± 1.7% (p=0.024), and FVC -3.9 ± 1.4% (p=0.049). Excluded from the analysis were 8 patients who were on ERL for less than 6 months. 6 patients had ERL ceased; 2 for rejection, 2 for suspected pneumonitis, 1 for drug intolerance and 1 to aid wound healing after a motor vehicle accident. There were 2 deaths during this period; one due to chest sepsis and the other from liver failure, neither of which could be directly related to toxicity from ERL. These 8 patients received ERL for at least 3 months and were included in a 3-months analysis. At 3 months, there was a similar increase in CrCl of +11.6 ± 2.3 ml/min (p<0.0001) and no significant change in FEV1 and FVC. CONCLUSIONS: In lung transplant recipients with renal impairment, the use of ERL as a CNI sparing agent is associated with improvement in renal function. However, the efficacy of this maintenance immunosuppression strategy in preventing rejection requires elucidation with further studies. CLINICAL IMPLICATIONS: The use of ERL allows CNI withdrawal and renal recovery in lung transplant recipients with renal impairment. These patients should be closely followed up with frequent monitoring of lung function. DISCLOSURE: The following authors have nothing to disclose: Shaun Yo, Tim Coughlan, Steve Ivulich, Eldho Paul, Gregory Snell, Solomon Menahem No Product/Research Disclosure Information

Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients.

Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients.

Everolimus with cyclosporine withdrawal or low-exposure cyclosporine in kidney transplantation from Month 3: a multicentre, randomized trial.

Randomized trials have shown that early adoption of everolimus-based immunosuppressive regimens without a calcineurin inhibitor (CNI) improves long-term kidney graft function, but the optimal strategy for CNI minimization remains uncertain. In a prospective, randomized, multicentre, 12-month trial, 499 de novo kidney transplant patients were randomized at Month 3 to (i) remain on standard CNI (cyclosporine) therapy with mycophenolic acid, (ii) convert to everolimus with mycophenolic acid or (iii) start everolimus with reduced CNI and no mycophenolic acid (clinical trials registry: ClinicalTrials.gov-NCT00514514). The primary endpoint, change in estimated glomerular filtration rate (eGFR) (Nankivell) from randomization to Month 12, was significantly greater in the CNI-free arm versus standard CNI therapy: mean difference 5.6 mL/min/1.73 m 2 [95% confidence interval (CI) 2.8-8.3 mL/min/1.73 m 2 , P < 0.001]. The improvement in eGFR in the CNI-free arm was also higher than in the low-CNI group (mean difference 5.5 mL/min/1.73 m 2 , 95% CI 2.8-8.2 mL/min/1.73 m 2 , P < 0.001), while results were similar in the low-CNI and standard CNI arms. The post-randomization incidence of biopsy-proven acute rejection was 11.7%, 8.1% and 7.9% in the CNI-free, low-CNI and standard CNI groups, respectively (CNI-free versus standard CNI, P = 0.27; low-CNI versus standard CNI, P = 1.00). Adverse events led to study drug discontinuation in 28.7%, 15.5% and 15.2% of CNI-free, low-CNI and standard CNI patients, respectively. Everolimus initiation with CNI withdrawal at Month 3 after kidney transplantation achieves a significant improvement in renal function at 12 months, with a similar rate of acute rejection.

(925) - The Effect of Everolimus Initiation and Early Calcineurin Inhibitor Withdrawal on Exercise Capacity in De-Novo Heart Transplant Recipients: Results of the SCHEDULE Trial After 36 Months

(925) - The Effect of Everolimus Initiation and Early Calcineurin Inhibitor Withdrawal on Exercise Capacity in De-Novo Heart Transplant Recipients: Results of the SCHEDULE Trial After 36 Months

Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial.

SIMCER was a 6-mo, multicenter, open-label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low-exposure tacrolimus discontinued by month 4 (n=93) or to tacrolimus-based therapy (n=95), both with basiliximab induction and enteric-coated mycophenolate sodiumwith or withoutsteroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1vs. -13.3mL/min per 1.73m2 for everolimus vs. tacrolimus, respectively; difference 14.3 [95% confidence interval 7.3-21.3]; p<0.001). Mean eGFR at week 24 was 95.8versus 76.0mL/min per 1.73m2 for everolimus versus tacrolimus (p<0.001). Treatment failure (treated biopsy-proven acute rejection [BPAR; rejection activity index score >3], graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p=0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p=0.026); the rate of treated BPAR was 8.9% versus 2.2% (p=0.055). Sixteen everolimus-treated patients (17.8%) and three tacrolimus-treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI-based immunosuppression but more frequent BPAR.

The Privilege of Induction Avoidance and Calcineurin Inhibitors Withdrawal in 2 Haplotype HLA Matched White Kidney Transplantation.

BackgroundWhite recipients of 2-haplotype HLA-matched living kidney transplants are perceived to be of low immunologic risk. Little is known about the safety of induction avoidance and calcineurin inhibitor withdrawal in these patients.MethodsWe reviewed our experience at a single center and compared it to Organ Procurement and Transplantation Network (OPTN) registry data and only included 2-haplotype HLA-matched white living kidney transplants recipients between 2000 and 2013.ResultsThere were 56 recipients in a single center (where no induction was given) and 2976 recipients in the OPTN. Among the OPTN recipients, 1285 received no induction, 903 basiliximab, 608 thymoglobulin, and 180 alemtuzumab. First-year acute rejection rates were similar after induction-free transplantation among the center and induced groups nationally. Compared with induction-free transplantation in the national data, there was no decrease in graft failure risk over 13 years with use of basiliximab (adjusted hazard ratio [aHR], 0.86; confidence interval [CI], 0.68-1.08), Thymoglobulin (aHR, 0.92; CI, 0.7-1.21) or alemtuzumab (aHR, 1.18; CI, 0.72-1.93). Among induction-free recipients at the center, calcineurin inhibitor withdrawal at 1 year (n = 27) did not significantly impact graft failure risk (HR,1.62; CI, 0.38-6.89).ConclusionsThis study may serve as a foundation for further studies to provide personalized, tailored, immunosuppression for this very low-risk population of kidney transplant patients.

Everolimus with early withdrawal or reduced‐dose calcineurin inhibitors improves renal function in liver transplant recipients: A systematic review and meta‐analysis

Calcineurin inhibitors (CNI) are the mainstay of immunosuppression after liver transplantation (LT), but CNIs are associated with significant nephrotoxicity. Recently, mTOR inhibitors such as sirolimus and everolimus (EVR) have been used with or without CNIs in LT recipients for their renal-sparing effect. We conducted a systematic review and meta-analysis of randomized controlled trials (RCT) that examined the effect of EVR with CNI minimization or withdrawal on renal function in LT recipients. RCT of primary adult LT recipients with baseline GFR >30mL/min who received EVR with CNI minimization or withdrawal were included. Four RCTs (EVR n=465, control n=428) were included. In three RCTs, EVR was initiated 4weeks following LT; these studies were used to assess the primary outcome. All four studies were used to assess the secondary outcomes. Based on this study, EVR use with CNI minimization in LT recipients is associated with improved renal function at 12months by GFR of 10.2mL/min (95% CI: 2.75-17.8). EVR use was not associated with an increased risk of biopsy-proven acute rejection (RR 0.68, 95% CI: 0.31-1.46), graft loss (RR 1.60, 95% CI: 0.51-5.00), or mortality (RR 1.34, 95% CI 0.62-2.90). However, it was associated with an increased risk of overall infections (RR 1.45, 95% CI: 1.10-1.91).

The CECARI Study: Everolimus (Certican®) Initiation and Calcineurin Inhibitor Withdrawal in Maintenance Heart Transplant Recipients with Renal Insufficiency: A Multicenter, Randomized Trial.

In this 3-year, open-label, multicenter study, 57 maintenance heart transplant recipients (>1 year after transplant) with renal insufficiency (eGFR 30–60 mL/min/1.73 m2) were randomized to start everolimus with CNI withdrawal (N = 29) or continue their current CNI-based immunosuppression (N = 28). The primary endpoint, change in measured glomerular filtration rate (mGFR) from baseline to year 3, did not differ significantly between both groups (+7.0 mL/min in the everolimus group versus +1.9 mL/min in the CNI group, p = 0.18). In the on-treatment analysis, the difference did reach statistical significance (+9.4 mL/min in the everolimus group versus +1.9 mL/min in the CNI group, p = 0.047). The composite safety endpoint of all-cause mortality, major adverse cardiovascular events, or treated acute rejection was not different between groups. Nonfatal adverse events occurred in 96.6% of patients in the everolimus group and 57.1% in the CNI group (p < 0.001). Ten patients (34.5%) in the everolimus group discontinued the study drug during follow-up due to adverse events. The poor adherence to the everolimus therapy might have masked a potential benefit of CNI withdrawal on renal function.

Systemic meta-analysis assessing the short term applicability of early conversion to mammalian target of rapamycin inhibitors in kidney transplant.

AIMTo consolidate the present evidence of effectiveness in renal functioning and graft survival following early introduction of mammalian target of rapamycin (mTOR) inhibitors with or without calcineurin inhibitors (CNIs) in renal transplant recipients.METHODSWe analysed the current literature following PROSPERO approval describing the role of immunosuppressive agent, mTOR inhibitors as an alternative to CNI within six months of renal transplant by searching the PubMed, EMBASE, Cochrane, Crossref, and Scopus using MeSH terms.RESULTSSix articles of early withdrawal of CNI and introduction of mTOR-inhibitors within six months of renal transplantation were sought. Glomerular filtration rate (GFR) and serum creatinine were significantly better in mTOR inhibitor group with equivalent survival at 12 mo, even though Biopsy Proven Acute rejection was significantly higher in mTOR-inhibitor group.CONCLUSIONThe evidence reviewed in this meta-analysis suggests that early introduction mTOR-inhibitors substantial CNI minimization. The mTOR inhibitors such as everolimus and sirolimus, due to their complementary mechanism of action and favourable nephrotoxicity profile; better glomerular filtration, lower serum creatinine with equivalent survival. Having said that, due to the higher rejection rate, may influence the use of these regimens to patients with moderate to high immunological risk patients.

The Use of Everolimus for Renal-Transplant Patients with Nephrotoxicity by Calcineurin Inhibitors in our Center: Case Report

Introduction: Long-term renal-transplantation outcomes are reportedly impaired by acute and chronic nephrotoxicity caused by calcineurin inhibitors (CNI), while recent renal transplant results have improved remarkably due to progress in the development of immunosuppressive drugs. Everolimus (EVL) belongs to a novel class of immunosuppressive agents, known as mammalian target of rapamycin (mTOR) inhibitor or proliferation signal inhibitor, which allow dose reduction or even complete withdrawal of CNI. mTOR inhibitor, such as EVL appear to exacerbate pre-existing proteinuria and may ameliorate nephrotoxicity caused by CNI. We describe herein one patient showing histological improvement of CNI nephrotoxicity with EVL. Patient: A 53-year-old, female underwent her third living-donor transplantation. We used cyclosporine (CsA), mycophenolate mofetil (MMF), prednisolone (PSL) and basiliximab. Diuresis was obtained immediately, but on post-operative day 3 (POD 3), urine volume decreased and renal function gradually deteriorated. On POD 14, renal biopsy (BTx) revealed CsA-induced nephrotoxicity. Renal function improved with a reduction in the CsA dose, and the patient was subsequently discharged on POD 30 with a serum creatinine level (S-Cr) 1.07 (mg/dL). Acute r rejection occurred three times, but each time renal function was improved by anti-rejection therapy, and subsequently stabilized with S-Cr levels in the 1.4-1.6 range. S-Cr suddenly rose to 4.03 on POD 293. Histopathological examination showed CsA nephrotoxicity. Although we reduced the CsA dose, her renal function remained unstable. We changed CsA to EVL on POD 341, and renal function subsequently stabilized. On POD 420, her S-Cr level was 1.17, and BTx showed amelioration of nephrotoxicity findings. Conclusion: In this patient, we obtained improvement of renal dysfunction caused by CsA nephrotoxicity without rejection by switching CsA to EVL (EVL +MMF+PSL). EVL can be safely used as an alternative to CsA, and it is anticipated that EVL+MMF+PSL will become one of the choices for immunosuppressive therapy in the future.

Transplant-Associated Thrombotic Microangiopathy: Prevalence, Prognostic Factors and Treatment Outcomes in Unrelated Allogeneic Transplant for Hematologic Diseases

Introduction: Transplant-associated thrombotic microangiopathy (TA-TMA) represents a devastating and life-threatening complication occurring more frequently in allogeneic compared to autologous hematopoietic cell transplantation (HCT). Although it has been a well-recognized syndrome for decades, our understanding in terms of epidemiology and more importantly, treatment options remains unclear. Therefore, we aimed to retrospectively investigate the incidence of TA-TMA in patients undergone HCT from unrelated donors and identify prognostic factors and treatment outcomes.Methods: We enrolled consecutive patients who underwent HCT from unrelated donors from 2003 to 2015. TA-TMA diagnosis was based on EBMT (European Bone Marrow Transplantation) criteria: increased (>4%) schistocytes in peripheral blood, thrombocytopenia, increased lactade dehydrogenase, decreased Hb. Anti-thymocyte globulin (ATG, rabbit) was used as standardised part of the conditioning in almost all patients (total dose of 5-7.5mg/kg). Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporine or tacrolimus plus methotrexate in myeloablative and mycophenolate mofetil plus cyclosporine in reduced intensity conditioning transplants. Upon identification of TA-TMA, all possible causative factors were fully investigated. The mainstay of treatment strategy was withdrawal of calcineurin inhibitors, plasma infusion and plasma exchange combined with corticosteroid administration and in refractory cases, humanized anti-CD20 monoclonal antibody (Rituximab).Results: In total, we studied 179 patients, 74 male:105 female, aged 37±14 years, who underwent HCT from matched HLA A/B/C/DRB1 (8/8, n=88) and allele or antigen mismatched (n=91) grafts. Grafts derived from peripheral blood (157), bone marrow (18) and umbilical stem cells (4). Conditioning regimens were myeloablative (139), reduced intensity (28) and toxicity (12). Median follow-up was 11.5 (0.1-147.4) months.TA-TMA was diagnosed in 29 (16.2%) patients, 12 male:17 female, aged 34±12 years, 78 (9-721) days post-HCT for acute leukemia (21), Hodgkin (3) and non-Hodgkin (1), lymphoma, MDS (2), aplastic anemia (1) and MPN (1). Conditioning regimens were myeloablative in 24 (12 based on total body irradiation/TBI) and reduced intensity in 5 patients. Among patients with TA-TMA, 10 (34%) presented severe (grade III-IV) acute GVHD, 15 (52%) extensive chronic GVHD, 12 (41%) bacterial, 2 (7%) fungal and 21 (71%) viral (Cytomegalovirus and/or Epstein-Barr viremia) infectious episodes.In univariate analysis, age, gender, diagnosis, disease phase, previous lines of treatment, conditioning (intensity and TBI-based), ABO and HLA incompatibility, infections, acute and chronic GVHD were studied. The presence of TA-TMA was associated with severe acute and extensive chronic GVHD (p=0.001 and p=0.035 respectively) and TBI-based conditioning (p=0.043). In multivariate analysis, severe acute GVHD was the only independent factor associated with TA-TMA (β=3.4, p=0.038).Regarding treatment outcomes, 8 (28%) patients responded to cyclosporine cessation and plasma infusions. The rest 21 out of 29 patients underwent plasma exchange sessions; 14 (48%) of them responded to plasma exchange treatment. One patient that did not respond to plasma exchange received additional Rituximab treatment and the syndrome resolved. The other 6 (20.6%) patients were refractory and eventually succumbed. Treatment-related mortality was 33.3% (9/29) in TA-TMA patients and was directly associated with refractory microangiopathic syndrome in 6/29.Conclusion: Our results suggest that TA-TMA is not rare in unrelated transplant recipients and can be managed in a portion of patients that respond to cyclosporine cessation and plasma exchange. GVHD was the only independent predictor for the development of TA-TMA and therefore, successful prevention and treatment strategies for GVHD need to be timely employed to prevent complications. More importantly, transplanted patients with refractory microangiopathic syndrome showed increased TRM indicating that conventional treatment is inadequate. Recent data of increased complement activation in TA-TMA pave the way for targeted treatment with complement inhibitors in these patients. DisclosuresNo relevant conflicts of interest to declare.