Discontinuation Of Calcineurin Inhibitors Research Articles

Anuria after kidney transplantation diagnosed as early recurrence of focal segmental glomerulosclerosis combined with acute calcineurin inhibitor nephrotoxicity: a case report and literature review

BackgroundPrimary focal segmental glomerulosclerosis (FSGS) is a glomerular disease that sometimes recurs in patients after kidney transplantation (KT) and increases the risk of graft loss. Proteinuria is a common early sign of recurrent FSGS, but an abrupt decrease in urine volume is rare. Herein, we report a patient with early recurrence of FSGS with anuria following KT.Case presentationA 55-year-old man with end-stage kidney disease caused by primary FSGS experienced anuria on postoperative day 2 following deceased donor KT. Laboratory results revealed that serum tacrolimus trough levels were consistently elevated at the time of anuria. At first, we considered acute calcineurin inhibitor (CNI) nephrotoxicity based on graft biopsy on light microscopy, laboratory findings, and clinical courses. However, the allograft function did not recover even after discontinuation of CNI, and recurrent FSGS was diagnosed 2 weeks later on electron microscopy. A total of 13 sessions of plasmapheresis and two administrations of rituximab (375 mg/m2) were required to treat recurrent FSGS. The patient achieved a partial response, and the spot urine protein-to-creatinine ratio decreased from 15.5 g/g creatinine to 5.2 g/g creatinine. At 5 months following KT, the serum creatinine level was stable at 1.15 mg/dL.ConclusionsThese findings highlight that anuria can occur in cases of early recurrence of FSGS combined with acute CNI nephrotoxicity.

Short-term substitution of calcineurin inhibitors (CNI) with recombinant humanized anti-CD25 monoclonal antibody (Basiliximab) as aGVHD prophylaxis in CNI intolerant patients after allogeneic hematopoietic stem cell transplantation

Objectives: To investigate the efficacy of short-term substitution of recombinant humanized anti-CD25 monoclonal antibody (Basiliximab) as acute GVHD (aGVHD) prophylaxis in calcineurin inhibitors (CNI) intolerant patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: This study included 17 patients with refractory malignant hematological disorders who underwent salvage allo-HSCT at the Bone Marrow Transplantation Department of Shanghai Zhaxin Traditional Chinese and Western Medicine Hospital from August 2021 to August 2022 and were treated with Baliximab to prevent aGVHD due to severe adverse reactions to CNI. There were seven men and ten women, with a median age of 43 years (18-67). Following the discontinuation of CNI, Basiliximab was administered at a dose of 1 mg/kg once weekly until CNI or mTOR inhibitors were resumed. Results: Basiliximab was started at an average of 5 (1-32) days after HSCT. The median duration of substitution was 20 (7-120) days. All had neutrophil engraftment within a median of 12 (10-17) days. Thirteen patients had platelet engraftment after a median of 13 (11-20) days. Four patients did not develop stable platelet engraftment. Eight patients (47.1% ) developed Grade Ⅱ-Ⅳ aGVHD, while four (23.6% ) developed Grade Ⅲ/Ⅳ aGVHD. Only one patient died from aGVHD. Before the end of the followup period, seven of 17 patients died. The longest followup period of the survivors was 347 days, and the median survival rate was not met. The overall survival (OS) rate at six months was 62.6%. Among the 17 patients, 13 (76.4% ) experienced cytomegalovirus reactivation, 7 (41.2% ) experienced EB virus activation, and no cytomegalovirus disease was observed. Conclusions: When CNI intolerance occurs during allo-HSCT, short-term replacement with Baliximab can be used as an alternative to prevent aGVHD.

Corticosteroids as graft-versus-host disease prophylaxis for allogeneic hematopoietic cell transplant recipients with calcineurin inhibitor intolerance

Background aimsAlthough calcineurin inhibitors (CNIs) have a well-established role in the prevention of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT), their use can be limited by significant toxicities, which may result in premature treatment discontinuation. The optimal management of patients with CNI intolerance is unknown. The objective of this study was to determine the effectiveness of corticosteroids as GVHD prophylaxis for patients with CNI intolerance. MethodsThis retrospective single-center study included consecutive adult patients with hematologic malignancies who underwent myeloablative peripheral blood allogeneic HCT with anti-thymocyte globulin, CNI, and methotrexate GVHD prophylaxis in Alberta, Canada. Multivariable competing-risks regression was used to compare cumulative incidences of GVHD, relapse, and non-relapse mortality between recipients of corticosteroid versus continuous CNI prophylaxis, and multivariable Cox proportional hazards regression was applied to compare overall survival, relapse-free survival (RFS) and moderate-to-severe chronic GVHD and RFS. ResultsAmong 509 allogeneic HCT recipients, 58 (11%) patients developed CNI intolerance and were switched to corticosteroid prophylaxis at median 28 days (range 1-53) after HCT. Compared with patients who received continuous CNI prophylaxis, recipients of corticosteroid prophylaxis had significantly greater cumulative incidences of grade 2-4 acute GVHD (subhazard ratio [SHR] 1.74, 95% confidence interval [CI] 1.08–2.80, P = 0.024), grade 3–4 acute GVHD (SHR 3.22, 95% CI 1.55–6.72, P = 0.002), and GVHD-related non-relapse mortality (SHR 3.07, 95% CI 1.54–6.12, P = 0.001). There were no significant differences in moderate-to-severe chronic GVHD (SHR 0.84, 95% CI 0.43–1.63, P = 0.60) or relapse (SHR 0.92, 95% CI 0.53–1.62, P = 0.78), but corticosteroid prophylaxis was associated with significantly inferior overall survival (hazard ratio [HR] 1.77, 95% CI 1.20–2.61, P = 0.004), RFS (HR 1.54, 95% CI 1.06–2.25, P = 0.024), and chronic GVHD and RFS (HR 1.46, 95% CI 1.04–2.05, P = 0.029). ConclusionsAllogeneic HCT recipients with CNI intolerance are at increased risks of acute GVHD and poor outcomes despite institution of corticosteroid prophylaxis following premature CNI discontinuation. Alternative GVHD prophylaxis strategies are needed for this high-risk population.

Antineoplastic chemotherapy and immunosuppression in liver transplant recipients: Squaring the circle?

Malignancies are a major cause of late death after liver transplantation (LT). In LT recipients presenting a malignancy, antineoplastic chemotherapy is central part of the therapeutic arsenal, but management of both immunosuppressive and antineoplastic chemotherapy can be very challenging. The aim of the present retrospective study was to describe a recent single center cohort of LT recipients treated with antineoplastic cytotoxic chemotherapy. All LT recipients who received antineoplastic chemotherapy in our center between 2005 and 2021 were included. The study population included 72 antineoplastic chemotherapy courses in 69 patients. There was a majority of men (81.9%); median age at LT was 54.9 (range 1-68) and was 63.0 (18-79) at the diagnosis of malignancy. Lung carcinomas (23.6%), head and neck carcinomas (20.8%), lymphomas (16.7%), and recurrent hepatocellular carcinoma (HCC) (8.3%) were the most frequent malignancies. Neoadjuvant (30.6%), adjuvant (12.5%) or palliative (54.2%) chemotherapy was performed. Immunosuppressive regimen was modified from a calcineurin inhibitor (CNI)-based to an everolimus-based regimen (63.5% of CNI discontinuation). Median survival after diagnosis of malignancy was 22.5 months and 5-year survival was 30.1%. Chemotherapy regimen was considered optimal in 81.9% of the cases. Multivariate analysis disclosed that non-PTLD N+ stage malignancy (HR=5.52 95%CI [1.40;21.69], p=.014), non-PTLD M+ stage malignancy (HR=10.55 95%CI [3.20;34.73], p=.0001), and suboptimal chemotherapy (HR=2.73 95%CI [1.34;5.56], p=.005) were significantly associated with poorer prognosis. No rejection episode occurred during chemotherapy. The present study is the first one focused on antineoplastic chemotherapy in LT recipients. Our results suggest that immunosuppressive drugs and antineoplastic chemotherapy can be managed satisfactorily in most cases but this needs confirmation from larger cohorts.

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.

Use of Basiliximab in Recipients Who Required Dose Reduction or Discontinuation of Calcineurin Inhibitors Early After Lung Transplantation

<h3>Purpose</h3> The standard immunosuppressive therapy after lung transplantation is a combination of calcineurin inhibitors (CNIs), antimetabolites, and corticosteroids. In the cases where CNIs need to be reduced or discontinued early after transplantation due to renal dysfunction or other side effects, basiliximab is used as an alternative at our hospital. In this study, we investigated the efficacy and safety of basiliximab administered early after transplantation as an alternative of CNIs. <h3>Methods</h3> All lung transplant recipients between April 2002 and April 2021 at our hospital were retrospectively reviewed. Among 272 lung transplant recipients (108 living-donor, 163 deceased-donor, and 1 hybrid), 18 recipients were treated with basiliximab due to the need for CNI reduction or discontinuation. We reviewed indications of basiliximab and the outcome. Acute rejection was diagnosed based on radiologic and clinical parameters without transbronchial biopsy. The incidence of clinically diagnosed acute rejection and that of chronic lung allograft dysfunction (CLAD) were compared between the basiliximab group (n = 18) and the non-basiliximab group (n = 254). <h3>Results</h3> The indications of basiliximab were preoperatively existing poor renal function (n = 11) postoperative acute kidney disease (eGFR < 50, n = 4), and posterior reversible encephalopathy syndrome (PRES, n = 3) due to CNIs. The first dose of basiliximab (20 mg for adults, 10 mg for children) was administered postoperatively (median 0, range 0-7 days) and the second dose was administered 4 days later. No apparent adverse effects were encountered. None of the recipients with poor renal function required dialysis in the perioperative period, and all the recipients with PRES showed complete recovery. The incidence of clinically diagnosed acute rejection before discharge was 44.4% in the basiliximab group and 41.3% in the non-basiliximab group (<i>p</i> = 0.81). Five-year CLAD-free survival was 50% in the basiliximab group and 60.6% in the non-basiliximab group (<i>p</i> = 0.41). <h3>Conclusion</h3> The use of basiliximab as an alternative of CNIs early after lung transplantation was safe and increased neither the risk of acute rejection nor CLAD.

Are Calcineurin Inhibitor-Free Protocols Safe and Effective in the Long-Term After Heart Transplant?

<h3>Purpose</h3> Calcineurin inhibitors (CNIs) tacrolimus and cyclosporine, have improved outcomes of heart transplant (HTx) patients but unfortunately have many side effects which include nephrotoxicity, hypertension, and malignancy. CNI-free regimens may protect the kidneys but at the risk of rejection. The purpose of this study was to assess our center's experience with CNI minimization and discontinuation. <h3>Methods</h3> We assessed 34 HTx patients transplanted between 2010-2020, who transitioned to CNI-free regimens 6m-2 years post HTx and 2-5 years post HTx. Outcomes assessed were any treated rejection (ATR; including acute cellular rejection [ACR], antibody-mediated rejection [AMR], and biopsy-negative rejection [BNR]), survival, cardiac dysfunction (ejection fraction ≤40%) in the 1 year following CNI-free initiation. We also assessed the need for antihypertensive medications, HgbA1c, and estimated glomerular filtration rate (eGFR). <h3>Results</h3> Of 34 HTx recipients, 89% of patients were successfully weaned off CNI at <2 years and 94% at 2-5 years after transplant. eGFR for both groups was markedly improved at 1-year post CNI-free initiation. There was no difference between groups in anti-hypertensive medications or HgbA1c. However, CNI had to be restarted in 50% of the CNI-free in <2 years group and in 31% of the CNI-free at 2-5 years group. Return to CNI was for: rejection, medication intolerance, and death. (Table). <h3>Conclusion</h3> CNI-free regimens are safe and efficacious for select patients but may not be sustainable. Additional strategies for renal protection and immunosuppression optimization are warranted.

Atypical Hemolytic Uremic Syndrome After Liver Transplant Treated With Eculizumab

Thrombotic microangiopathies (TMA) are a group of serious conditions that are characterized by microangiopathic hemolytic anemia and thrombocytopenia, and are often associated with acute kidney injury as well as neurologic abnormalities. There are multiple causes of TMA. TMA in a transplant patient is often attributed to calcineurin inhibitor (CNI) use and is usually treated with discontinuation of the drug. We report a case of TMA in a liver transplant patient who did not respond to CNI discontinuation or plasmapheresis but had great response to shorter than usual course of eculizumab. Eculizumab is a monoclonal antibody that prevents c5 cleavage and indirectly inhibits the formation of the membrane attack complex. Clinical response was sustained for nine months after discontinuation of eculizumab.

Long-Term Effects of the Replacement of Calcineurin Inhibitors With Everolimus and Mycophenolate in Patients With Calcineurin Inhibitor–Related Nephrotoxicity

BackgroundThere is little evidence on the long-term effects of calcineurin inhibitor (CNI) withdrawal and substitution with everolimus and mycophenolate mofetil in maintenance therapy of patients who have received heart transplants and have concurrent CNI nephrotoxicity. Aims of this study were to evaluate the progression of renal dysfunction after discontinuation of CNIs and to monitor for major adverse events after therapy change. MethodsData from 41 patients who underwent heart transplant and have different degrees of renal dysfunction (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), without evidence of proteinuria, and in whom CNI therapy was replaced by everolimus, were analyzed. At the time of CNI withdrawal, clinical parameters, echocardiographic data, blood tests of renal function, and monitoring of adverse events were recorded. The median follow-up period was 5 years ± 28 months. ResultsIn 52% of patients, there was a clear improvement in renal function (10.5 mL/min/1.73 m2 of extra eGFR on average). The former were characterized by less advanced age and a short time from the heart transplant. The echocardiographic parameters showed a significant reduction in septum thickness (11.58 ± 2 mm vs 10.29 ± 2 mm; P = .0001) and in left ventricle posterior wall thickness (10.74 ± 1 mm vs 9.74 ± 1 mm; P = .0004). The incidence of late acute rejection and cardiac allograft vasculopathy was similar in our population compared to literature data. ConclusionsA therapeutic switch from CNIs to everolimus and mycophenolate mofetil can improve renal function in patients with CNI nephrotoxicity, especially in those with a shorter time period from transplantation, without exposing them to a higher incidence of late acute rejection and cardiac allograft vasculopathy.

Glucose metabolism disorders in children with refractory nephrotic syndrome.

Patients with refractory nephrotic syndrome (NS) are at high risk of medication-induced glucose metabolism disorders, because of their long-term use of diabetogenic medications, particularly glucocorticoids and calcineurin inhibitors (CNIs). However, there have been no comprehensive evaluations of glucose metabolism disorders in pediatric patients with refractory NS. Moreover, glucocorticoids and CNIs could not be discontinued in these patients until the effectiveness of rituximab on refractory NS was shown, and therefore, there has been limited opportunity to evaluate glucose metabolism disorders after discontinuation of these medications. Consecutive pediatric patients who started rituximab treatment for refractory NS were enrolled. Their glucose metabolism conditions were evaluated using the oral glucose tolerance tests (OGTT) and HbA1c levels at the initiation of rituximab treatment. Patients with glucose metabolism disorders at the first evaluation were reevaluated after approximately 2years. Overall, 57% (20/35) of study patients had glucose metabolism disorders, and 40% (8/20) of these patients were detected only by their 2-h OGTT blood glucose levels and not by their fasting blood glucose or HbA1c levels. Non-obese/non-overweight patients had significantly more glucose metabolism disorders than obese/overweight patients (p = 0.019). In addition, glucose metabolism disorders in 71% (10/14) of patients persisted after the discontinuation of glucocorticoids and CNIs. Whether the patient is obese/overweight or not, patients with refractory NS are at high risk of developing glucose metabolism disorders, even in childhood. Non-obese/non-overweight patients who are at high risk of diabetes need extra vigilance.

Predictive factors for the recurrence of anti-aminoacyl-tRNA synthetase antibody-associated interstitial lung disease.

Anti-synthetase syndrome (ASS) is characterized by the presence of anti-aminoacyl-tRNA synthetase antibody and ASS-associated interstitial lung disease (ILD) often recurs. The effectiveness of remission induction therapy with corticosteroids and calcineurin inhibitor (CNI) and the predictive factors for ASS-ILD recurrence were examined. We retrospectively identified consecutive patients with ASS-ILD treated with corticosteroids and CNI during 2006-2017 and evaluated the predictive factors for recurrence using logistic regression analysis. Of the 57 patients included in this study, 54 (94.7%) exhibited improved response to remission induction therapy. There were 32 recurrence patients during maintenance therapy. The median period until recurrence was 27 months. There were no significant differences in the baseline characteristics between the recurrence and nonrecurrence groups. In the recurrence group, respiratory function and St. George's Respiratory Questionnaire score deteriorated over the clinical course. The Krebs von den Lungen-6 (KL-6) level changed with disease behavior. The multivariate analysis revealed that KL-6 increase rate from remission (odds ratio: 3.21, 95% CI: 1.17-8.86, p=0.02) and CNI discontinuation (odds ratio: 8.09, 95% CI: 1.39-47.09, p=0.02) were independent predictive factors for recurrence. The receiver operating characteristics analysis revealed that the optimal cut-off point of KL-6 increase rate was 2.0. The positive predictive values of the KL-6 increase rate from remission of >2.0 and CNI discontinuation were 90.0 and 88.9%, respectively. The CNI treatment duration and recurrence were not related. Recurrence influenced long-term deterioration. KL-6 was a serum biomarker for disease behavior and recurrence prediction. The results suggest the importance of CNI continuation.

Prevalence and Risk Factors of BK Viremia and Clinical Impact of BK Virus Surveillance on Outcomes in Kidney Transplant Recipients: A Single-Center Cross-Sectional Study.

BK virus is a polyomavirus that can cause nephropathy and graft loss after kidney transplant. The aim of our study was to screen the BK viremia prevalence, to understand the value of the inter-vention for BK virus nephropathy, and to determine the risk factors associated with BK viremia after kidney transplant in our center. Our retrospective cross-sectional study included 91 adult kidney transplant recipients who were seen between 2015 and 2017 and who had follow-up from 1 month to over 2 years. BK viremia was evaluated by use of plasma quantitative polymerase chain reaction. The prevalence of BK viremia and the clinical treatments and outcomes of BK virus nephropathy were assessed. The prevalence of BK viremia was 5.5% (5/91 patients). BK virus nephropathy was confirmed by allograft biopsy in 4.4% (4/91 patients) of all patients. Delayed graft function was found to be an independent risk factor for BK viremia (P < .001). Patients with BK viremia had significantly higher serum creatinine levels (P = .04). Patients who were diagnosed with BK viremia at 1 to 5 years after kidney transplant had higher serum creatinine (P = .02) and uric acid levels (P = .02). After reduction or discontinuation of calcineurin inhibitor, BK virus was cleared in all patients with BK virus nephropathy, with higher level of serum creatinine but no graft loss. Delayed graft function was considered as a risk factor for viremia. Early detection of BK viremia replication is important. The strategy of reduction of immunosuppression was effective for BK virus nephropathy and graft function improvement.

Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial.

In a 12-month, multicenter, open-label study, 106 children were randomized at 4 to 6 weeks after kidney transplantation to switch to everolimus with reduced TAC (EVR/rTAC) and steroid elimination from month 5 posttransplant or to continue standard tacrolimus with mycophenolate mofetil (sTAC/MMF) and steroids. The cumulative incidence of a co-primary efficacy end point (biopsy-proven acute rejection [BPAR], graft loss, or death from randomization to month 12) was 10.3% with EVR/rTAC and 5.8% with sTAC/MMF (difference 4.4%; P = .417). BPAR occurred in 9.6% and 5.6% of patients, respectively. Patient and renal allograft survival were 100%. The co-primary end point of mean estimated glomerular filtration rate at month 12 was 76.2 mL/min/1.73 m2 with EVR/rTAC and 72.5 mL/min/1.73 m2 for sTAC/MMF (difference 3.8 mL/min/1.73m2 ; P = .49). One EVR/rTAC patient developed posttransplant lymphoproliferative disease. Longitudinal growth and sexual maturation were equivalent between groups. The randomized drug regimen was discontinued in 34.6% and 13% of patients in the EVR/rTAC and sTAC/MMF groups, respectively (P = .024), and discontinued due to adverse events/infections in 25.0% and 11.1% of patients (P = .062). In conclusion, early conversion of pediatric kidney transplant patients from TAC, MMF, and steroids to EVR/rTAC and steroid withdrawal maintains immunosuppressive efficacy and preserves renal function.

Periodically repeated rituximab administrations in children with refractory nephrotic syndrome: 2-year multicenter observational study.

Rituximab (RTX) is effective in maintaining remission in patients with nephrotic syndrome (NS), but a standard protocol of RTX administration has not been established. This study was a 2-year multicenter observational study, in which consistent treatments and evaluations were performed. We enrolled pediatric patients with refractory NS between January 2015 and December 2015. RTX infusion was performed four times at 6-month intervals, followed by mizoribine pulse therapy with early discontinuation of calcineurin inhibitor (CNI). Primary endpoints were the relapse-free survival rate and the number of relapses after RTX administration. Secondary endpoints were changes in side effects associated with long-term steroid administration. Twenty-two patients were analyzed. The relapse-free survival rate at 1year and 2years was 50 and 46%, respectively. Twenty-one patients accomplished our protocol and the frequency of relapse was reduced under the discontinuation of CNI. Although two patients were diagnosed with frequent relapse and/or steroid dependency during the observation period, the frequency of relapse decreased with each rituximab dose. Statistically significant improvements in all steroid complications were observed in the final examination, but no significant improvements were observed from 1 to 2years after RTX administration. One patient had agranulocytosis, and three patients showed electrocardiographic abnormalities. Our protocol was useful and safe for refractory NS. However, RTX administration four times might have been excessive in patients who had no relapse by 1year after the initial RTX administration. Further investigation of the most appropriate method of RTX administration is required.

Predictors and Outcome of Pericardial Effusion After Hematopoietic Stem Cell Transplantation in Children

Pericardial Effusion (PE) is a potentially life-threatening complication of Hematopoietic Cell Transplantation (HCT). Our study aim was to identify incidence, risk factors, response to treatment, and outcome of PE after pediatric HCT. All patients after HCT at our tertiary center between 2005 and 2010 were included. Endpoints were PE development and overall survival. We analyzed patient factors, HCT details, and complications and used Cox proportional hazard regression modeling to identify predictors for PE. Twelve out of 129 patients (9.3%) developed PE. Multivariate analysis demonstrated that young age at HCT was a predictor for PE: expressed per year increase in age HR = 0.66 (95% CI 0.46–0.95, p = 0.03). PE had no impact on overall mortality of HCT. Mild respiratory symptoms and vomiting were presenting symptoms for PE. Discontinuation of calcineurin inhibitors—with or without pericardiocentesis—was the only effective treatment for PE, in contrast to diuretics or increased immunosuppression. Seven of 12 PE patients had pericardiocentesis, which was safe and effective in all. Pericardial effusion is not rare after HCT, and young age is the only significant risk factor. Calcineurin inhibitor toxicity appears to be the primary cause of PE after HCT, and discontinuation is effective in the reduction of PE. Pericardiocentesis for PE is a safe and effective procedure. Pericardial effusion did not have an impact on survival after HCT.

Calcineurin inhibitor-free strategies for prophylaxis and treatment of GVHD in children with posterior reversible encephalopathy syndrome after stem cell transplantation.

Posterior reversible encephalopathy syndrome (PRES) is a distinct clinico-radiologic entity that can occur following allogeneic hematopoietic stem cell transplantation, often in the context of treatment with calcineurin inhibitors (CNIs). We describe the results of CNI-free management of 14 children with PRES and review the clinical and radiologic manifestations of their presentation. Discontinuation of CNIs usually resulted in remission of PRES, but patients with established graft versus host disease (GVHD) at the time when treatment was changed often experienced progressive GVHD despite administration of immune suppressive and modulating treatments. All but three patients experienced full neurologic recovery. Nine children died as a result of either GVHD, disease relapse, or severe infection. Discontinuation of CNIs results in neurologic improvement in most cases, but superior alternative immune modulatory treatment is needed to prevent progression of established GVHD.

T Lymphocyte Activation Markers as Predictors of Responsiveness to Rituximab among Patients with FSGS.

Rituximab is used with variable success in difficult FSGS. Because B cell depletion significantly affects T cell function, we characterized T cell subsets in patients with FSGS to determine if an immunologic signature predictive of favorable response to rituximab could be identified. Twenty-two consecutive patients with FSGS (median age =14.4 years old; range =6.2-25.0 years old) and age of onset of nephrotic syndrome 1-18 years old receiving rituximab for clinical indications between October of 2009 and February of 2014 were studied. Indications for rituximab were lack of sustained remission despite calcineurin inhibitors (CNIs) and mycophenolate in steroid-resistant patients and lack of steroid-sparing effect with cyclophosphamide and CNI or CNI toxicity in steroid-dependent patients. Exclusion criteria were infantile onset, known genetic mutations, and secondary causes. Rituximab (375 mg/m(2)) was given fortnightly up to a maximum of four doses. Immunologic subset monitoring was performed at baseline and regular intervals until relapse. Median follow-up duration postrituximab was 26.7 months (range =6.5-66.5 months). Baseline immunologic subsets were examined for association with rituximab response defined as resolution of proteinuria with discontinuation of prednisolone and CNI 3 months postrituximab. Twelve patients (54.5%) responded to rituximab. Mitogen-stimulated CD154(+)CD4(+)CD3(+) subset before rituximab was significantly lower in FSGS responders compared with nonresponders (54.9%±28.1% versus 78.9%±16.4%; P=0.03). IFN-γ(+)CD3(+) and IL-2(+)CD3(+) were similarly decreased in responders compared with nonresponders (0.6%±0.8% versus 7.5%±6.1%; P=0.003 and 0.2%±0.5% versus 4.0%±4.7%; P<0.01, respectively). Recovery of all three activation subsets occurred 6 months postrituximab treatment (CD154(+)CD4(+)CD3(+), 74.8%±17.2%; IFN-γ(+)CD3(+), 7.1%±7.7%; and IL-2(+)CD3(+), 7.9%±10.9%; P<0.01). Receiver-operating characteristic analysis using optimal cutoff values showed that activated CD154(+)CD4(+)CD3(+) <83.3% (area under the curve [AUC], 0.81; 95% confidence interval [95% CI], 0.61 to 1.00), IFN-γ(+)CD3(+)<2.5% (AUC, 0.90; 95% CI, 0.75 to 1.00), and IL-2(+)CD3(+)<0.3% (AUC, 0.78; 95% CI, 0.57 to 0.98) were good predictors of rituximab response. We have identified prognostic markers that define a subset of patients with FSGS bearing an immunologic signature representing hyporesponsiveness to T cell stimulation and therefore, who respond better to rituximab.

A Randomized 2x2 Factorial Clinical Trial of Renal Transplantation: Steroid-Free Maintenance Immunosuppression with Calcineurin Inhibitor Withdrawal after Six Months Associates with Improved Renal Function and Reduced Chronic Histopathology.

IntroductionThe two most significant impediments to renal allograft survival are rejection and the direct nephrotoxicity of the immunosuppressant drugs required to prevent it. Calcineurin inhibitors (CNI), a mainstay of most immunosuppression regimens, are particularly nephrotoxic. Until less toxic antirejection agents become available, the only option is to optimize our use of those at hand.AimTo determine whether intensive rabbit anti-thymocyte globulin (rATG) induction followed by CNI withdrawal would individually or combined improve graft function and reduce graft chronic histopathology–surrogates for graft and, therefore, patient survival. As previously reported, a single large rATG dose over 24 hours was well-tolerated and associated with better renal function, fewer infections, and improved patient survival. Here we report testing whether complete CNI discontinuation would improve renal function and decrease graft pathology.MethodsBetween April 20, 2004 and 4-14-2009 we conducted a prospective, randomized, non-blinded renal transplantation trial of two rATG dosing protocols (single dose, 6 mg/kg vs. divided doses, 1.5 mg/kg every other day x 4; target enrollment = 180). Subsequent maintenance immunosuppression consisted of tacrolimus, a CNI, and sirolimus, a mammalian target of rapamycin inhibitor. We report here the outcome of converting patients after six months either to minimized tacrolimus/sirolimus or mycophenolate mofetil/sirolimus. Primary endpoints were graft function and chronic histopathology from protocol kidney biopsies at 12 and 24 monthsResultsCNI withdrawal (on-treatment analysis) associated with better graft function (p <0.001) and lower chronic histopathology composite scores in protocol biopsies at 12 (p = 0.003) and 24 (p = 0.013) months, without affecting patient (p = 0.81) or graft (p = 0.93) survival, or rejection rate (p = 0.17).ConclusionCNI (tacrolimus) withdrawal at six months may provide a strategy for decreased nephrotoxicity and improved long-term function in steroid-free low immunological risk renal transplant patients.Trial RegistrationClinicalTrials.gov NCT00556933

Conversion to mammalian target of rapamycin inhibitors and calcineurin inhibitor discontinuation in liver transplantation: A systematic review and meta-analysis of randomised controlled trials

Conversion to mammalian target of rapamycin inhibitors and calcineurin inhibitor discontinuation in liver transplantation: A systematic review and meta-analysis of randomised controlled trials

Renal, efficacy and safety outcomes following late conversion of kidney transplant patients from calcineurin inhibitor therapy to everolimus: the randomized APOLLO study.

The primary objective of this trial was to demonstrate, based on the estimated glomerular filtration rate (eGFR), superior renal function at month 12 after conversion of maintenance kidney transplant patients from calcineurin inhibitor (CNI) therapy to everolimus, compared to continuing a standard CNI regimen. APOLLO was an open-label, 12-month, prospective, multicenter study in which 93 maintenance kidney transplant patients were randomized to convert from CNI to everolimus (n = 46) or remain on standard CNI-based immunosuppression (n = 47). The primary efficacy variable was eGFR (Nankivell formula) 12 months after randomization. The study was terminated prematurely due to slow recruitment and was thus underpowered. Mean time post-transplant was 83.5 months with everolimus and 70.1 months with CNI. Adjusted values for eGFR (Nankivell) at month 12 were 61.6 (95% CI 58.1, 65.1) mL/ min/1.73 m² with everolimus and 58.8 (95% CI 55.2, 62.3) mL/min/1.73 m² with CNI, a difference of 2.8 (95% CI -1.0, 6.7) mL/ min/1.73 m² (p = 0.145) i.e., the primary objective was not met. Using the modification of diet in renal disease (MDRD) formula, adjusted eGFR at month 12 was significantly higher with everolimus (p = 0.030). In the subpopulation who remained on the study drug (n = 52), the difference in the adjusted change from randomization was 6.6 (95% CI 1.5, 11.6) mL/min/1.73 m² (p = 0.013) in favor of everolimus. There was no biopsyproven acute rejection and no graft losses. Adverse events led to discontinuation of everolimus and CNI in 32.6% and 10.6% of patients, respectively. Conversion from CNI to everolimus to preserve renal function can be considered several years after kidney transplantation and does not compromise immunosuppressive efficacy.