Steroid Withdrawal Research Articles

A Comparative Effectiveness Analysis of Early Steroid Withdrawal in Black Kidney Transplant Recipients.

There is continued debate whether early steroid withdrawal is safe to use in high-immunologic risk patients, such as blacks. The goal of this study was to use comparative effectiveness methodology to elucidate the safety of early steroid withdrawal in blacks with kidney transplants. Our cohort study used United Network of Organ Sharing data including all adult black kidney transplant recipients from 2000 to 2009 followed through 2014. Propensity score matching was used to equalize baseline risk between continued steroid and early steroid withdrawal groups. Interaction terms were used to assess if the effect of early steroid withdrawal on outcomes varied by baseline and post-transplant factors. Of 26,582 eligible black patients with kidney transplants (5825 [21.9%] with early steroid withdrawal), 5565 patients with early steroid withdrawal were matched to 5565 blacks on continued steroid use. Black patients with early steroid withdrawal had similar risk of graft loss (hazard ratio, 0.98; 95% confidence interval, 0.92 to 1.04; P=0.42) and lower risk of death (hazard ratio, 0.91; 95% confidence interval, 0.84 to 0.99; P=0.02), primarily driven by a late mortality advantage (>4 years post-transplant). Delayed graft function, cytolytic induction, tacrolimus, and mycophenolate significantly modified the effect of early steroid withdrawal on outcomes (P<0.05). Acute rejection rates were slightly higher in the continued steroid group (13.0% versus 11.3%, respectively; P<0.01), but this was not associated with graft or patient survival. Overall, early steroid withdrawal in black kidney transplant recipients was not associated with graft loss but seemed to be associated with better long-term patient survival. Early steroid withdrawal in blacks not receiving cytolytic induction, tacrolimus, and mycophenolate or those with delayed graft function was associated with higher risk of graft loss and death.

Efficacy of rapid steroid withdrawal after induction therapy

Efficacy of rapid steroid withdrawal after induction therapy

Steroid Withdrawal related Relapse in a Patient with Neuro-Behçet’s Disease

Steroid Withdrawal related Relapse in a Patient with Neuro-Behçet’s Disease

Extracorporeal Photopheresis Is Effective in Treating Graft-Versus-Host Disease: A Retrospective Analysis

Introduction: Graft-versus-host disease (GVHD) remains the most common cause of morbidity and transplant-related mortality after allogeneic hematopoietic stem cell transplantation, despite significant advances in prophylaxis and treatment. Extracorporeal photopheresis (ECP) is an immunomodulatory therapy for which cutaneous T cell lymphoma is currently the only FDA-approved indication; it is, however, increasingly used as a second-line therapy for acute and chronic GVHD patients who are steroid-refractory or -dependent. Evidence suggests overall response rates of 60-80%, with better response rates among patients with cutaneous manifestations. This retrospective analysis reports our experience using ECP to treat adults with acute and chronic GVHD over a 5-year period.Methods: We identified 67 patients (age 21-69, 70% males) who underwent ECP therapy for GVHD between November 1, 2010 and June 2, 2016. Eleven patients were excluded based on exclusion criteria of fewer than 8 procedures, any part of ECP course performed at an outside institution, and inadequate documentation regarding GVHD response. Among the remaining 56 patients, 6 underwent more than one course of ECP, resulting in a total of 62 courses of ECP included in final analysis. Charts were reviewed for each of these 62 courses to obtain relevant demographic and transplant-related data, type of GVHD, and organs involved. Response was assessed separately for each involved organ using strict response criteria and was censored on the date of last ECP procedure. Hematology notes were reviewed for noted worsening or improvement of GVHD, and a response was counted only if it was maintained throughout the remainder of the ECP course, including the date of last procedure.Results: Results are summarized in Table 1. Tapering of immunosuppressive therapy by end of ECP course, defined as steroid tapering by at least 50% from baseline or steroid withdrawal and tapering of other immunosuppressive therapy, was successful in 43 out of 62 (69%) ECP courses. Overall response rate, defined as complete or partial response, was highest for skin GVHD (73%) and lowest for lung GVHD (27%). However, 6 out of 11 (54%) patients with lung involvement experienced no progression of disease, which may be considered a successful response in these difficult-to-manage patients. Twenty-two out of 62 courses did have a new immunosuppressive agent, such as mycophenylate mofetil, tacrolimus, or rituximab, introduced at the start of or during the ECP course, and 11 of these 22 courses achieved a response that may not reflect therapeutic effect of ECP alone. Four patients developed new progressive liver or lung involvement by GVHD even as other involved organs in these patients, such as skin, showed complete response.Conclusion: Response rates to ECP at our institution are similar to those reported in the literature; it is a useful therapeutic option in patients with acute or chronic GVHD, particularly those with skin involvement. ECP allows successful tapering or withdrawal of immunosuppressive therapy in the majority of patients, even in those who are steroid-refractory or steroid-dependent. [Display omitted] DisclosuresSarode:CSL Behring: Consultancy, Honoraria.

Infliximab and Low Dose Alemtuzumab in Patients with Steroid-Refractory Acute Graft-Versus-Host Disease

Introduction:Steroid-refractory grade IV acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) carries a mortality rate of approximately 80%. Trials of novel therapies including antibodies directed against the T-cell immune response have generally failed to improve outcomes although may lead to responses. Infliximab, a chimeric monoclonal antibody to TNF alpha, and alemtuzumab another monoclonal antibody targeting CD52, an antigen expressed on T and B lymphocytes and other antigen presenting cells (APCs) both have produced response rates in the 50-75% range. However, few are long-term survivors as the majority die of opportunistic infections (OI). While steroids are ineffective in many series, they are continued when novel agents are employed. We have approached steroid-refractory aGVHD with a combination of rapid steroid discontinuation, standard doses of infliximab and short course low dose alemtuzumab with the hope for aGVHD control without early deaths from OIs.Methods:We identified all patients who were treated for steroid-refractory aGVHD between January 1, 2014 and March 1, 2016 at Loyola University Medical Center. The diagnosis of aGVHD was made by clinical criteria per the National Institutes of Health guidelines. The diagnosis was confirmed by endoscopic evaluation and biopsy of the affected organ. All patients received methylprednisolone 2 mg/kg/day IV given in twice daily dosing for at least 7 days prior to being considered steroid-refractory. Patients received infliximab 10 mg/kg IV infusion weekly x 2 then every other week until remission and alemtuzumab 3 mg IV test dose on day 1, followed by 10 mg IV daily for 4 days. At the same time steroids were reduced by 50% and further reductions of 50% were made every 4 days. Responses were assessed by daily grading of aGVHD per Glucksberg criteria after dosing of infliximab and alemtuzumab. A complete response (CR) was defined as full resolution of abdominal pain, diarrhea, rectal bleeding, liver function test abnormalities, or skin involvement. A partial response (PR) was defined as a 50% improvement in diarrhea, liver function abnormalities, or skin involvement with a decrease in 1 or more grade levels of aGVHD per Glucksberg criteria.Results:To date 6 patients have been treated for steroid-refractory aGVHD after matched related donor (MRD) or matched unrelated donor (MUD) HSCT. Patient characteristics are shown in Table 1. There were 5 patients who underwent a MRD or MUD HSCT for myelodysplastic syndrome (MDS), and 1 patient who underwent a MUD HSCT for B-cell acute lymphoblastic leukemia (B-ALL). Median age at treatment was 64 years. All patients had Glucksberg grade 4 aGVHD (Table 1). The overall response rate (ORR) was 83% with 4 patients achieving a PR, 1 patient achieving CR, and 1 patient with no response to treatment. Day 100 survival after dosing of alemtuzumab was 50% with deaths due to aGVHD in 2 patients and death due to septic shock in 1 patient. CMV reactivation occurred in 4 patients and EBV reactivation occurred in 1 patient.Conclusion:In our single institution analysis, the combination of infliximab and alemtuzumab with rapid steroid withdrawal achieved a high ORR of 83% in treatment of steroid-refractory aGVHD after MRD or MUD HSCT with an encouraging 50% survival at day 100. This approach will be continued to further define its efficacy and safety for the treatment of steroid-refractory aGVHD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Rapid steroid withdrawal in kidney transplantation: living in HARMONY?

Rapid steroid withdrawal in kidney transplantation: living in HARMONY?

Rabbit-ATG or basiliximab induction for rapid steroid withdrawal after renal transplantation (Harmony): an open-label, multicentre, randomised controlled trial

Standard practice for immunosuppressive therapy after renal transplantation is quadruple therapy using antibody induction, low-dose tacrolimus, mycophenolate mofetil, and corticosteroids. Long-term steroid intake significantly increases cardiovascular risk factors with negative effects on the outcome, especially post-transplantation diabetes associated with morbidity and mortality. In this trial, we examined the efficacy and safety parameters of rapid steroid withdrawal after induction therapy with either rabbit antithymocyte globulin (rabbit ATG) or basiliximab in immunologically low-risk patients during the first year after kidney transplantation. In this open-label, multicentre, randomised controlled trial, we randomly assigned renal transplant recipients in a 1:1:1 ratio to receive either basiliximab induction with low-dose tacrolimus, mycophenolate mofetil, and steroid maintenance therapy (arm A), rapid corticosteroid withdrawal on day 8 (arm B), or rapid corticosteroid withdrawal on day 8 after rabbit ATG (arm C). The study was done in 21 centres across Germany. Only participants aged between 18 and 75 years with a low immunological risk who were scheduled to receive a single-organ renal transplant from either a living donor or a deceased donor were considered for enrolment. Patients receiving a second renal transplant were eligible, provided that the first allograft was not lost due to acute rejection within the first year after transplantation. Donor and recipient had to be ABO compatible. Grafts with pre-transplant existing donor-specific human leukocyte antigen (HLA) antibodies were not eligible and the recipients had to have a panel-reactive antibody concentration of 30% or less. Pregnant women and nursing mothers were excluded from the study. The primary endpoint was the incidence of biopsy-proven acute rejection (BPAR) at 12 months. All analyses were done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00724022. Between Aug 7, 2008, and Nov 30, 2013, 615 patients were randomly assigned to arm A (206), arm B (189), and arm C (192). BPAR rates were not reduced by rabbit ATG (9·9%) compared with either treatment arm A (11·2%) or B (10·6%; A versus C: p=0·75, B versus C p=0·87). As a secondary endpoint, rapid steroid withdrawal reduced post-transplantation diabetes in arm B to 24% and in arm C to 23% compared with 39% in control arm A (A versus B and C: p=0·0004). Patient survival (94·7% in arm A, 97·4% in arm B, and 96·9% in arm C) and censored graft survival (96·1% in arm A, 96·8% in arm B, and 95·8% in arm C) after 12 months were excellent and equivalent in all arms. Safety parameters such as infections or the incidence of post-transplantation malignancies did not differ between the study arms. Rabbit ATG did not show superiority over basiliximab induction for the prevention of BPAR after rapid steroid withdrawal within 1 year after renal transplantation. Nevertheless, rapid steroid withdrawal after induction therapy for patients with a low immunological risk profile can be achieved without loss of efficacy and is advantageous in regard to post-transplantation diabetes incidence. Investigator Initiated Trial; financial support by Astellas Pharma GmbH, Sanofi, and Roche Pharma AG.

MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome.

BackgroundA subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG).ObjectiveTo describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes.MethodsRetrospective multicenter study.ResultsThe sex ratio was 1:2.8 (m:f). Median age at onset was 31 years (range 6-70). The disease followed a multiphasic course in 80 % (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40 % (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36 %) and markedly impaired ambulation due to paresis or ataxia (25 %) as the most common long-term sequelae. Functional blindess in one or both eyes was noted during at least one ON attack in around 70 %. Perioptic enhancement was present in several patients. Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70 %). Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44 %. Fourty-one percent had a history of simultaneous ON and myelitis. Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50 %; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one). CSF pleocytosis (partly neutrophilic) was present in 70 %, oligoclonal bands in only 13 %, and blood-CSF-barrier dysfunction in 32 %. Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal. Full recovery was achieved by plasma exchange in some cases, including after IVMP failure. Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids. Methotrexate was effective in 5/6 patients. Interferon-beta was associated with ongoing or increasing disease activity. Rituximab and ofatumumab were effective in some patients. However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion. Coexisting autoimmunity was rare (9 %). Wingerchuk’s 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28 %, 32 %, 15 %, 33 %, respectively; MS had been suspected in 36 %. Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases.ConclusionOur findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD. The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis.

Ovarian steroid withdrawal results in GABAA receptor upregulation in the photoperiodic neuroendocrine pathways of the turkey hen

The mechanism(s) underlying photorefractoriness in temperate zone seasonally breeding birds remains undetermined. Our recent findings reveal a link between the upregulation of GABAA receptors (GABAARs) in the premammillary nucleus (PMM) and the state of photorefractoriness. Gonadal steroid levels fluctuate during the breeding season; increasing after gonadal recrudescence and declining sharply once gonadal regression begins. Here, we examined the effect of gonadal steroid withdrawal on the expression of GABAARs in the turkey PMM. Exogenous ovarian steroids were administered and then withdrawn from turkey hens to mimic the decline of ovarian steroids levels at the end of a breeding season. The upregulation of GABAAR α3, α4, δ, π, and γ2-subunits was observed in the PMM of the steroid withdrawal group when compared to the non-steroid treatment group. The level of tyrosine hydroxylase, photopigment melanopsin, and circadian clock genes in the PMM of the steroid withdrawal group resembled the levels observed in the natural photorefractory hens and were significantly lower than those of the short-day light stimulated group. A reduction in gonadotropin-releasing hormone-I mRNA expressed within the nucleus commissurae pallii was also observed in hens undergoing steroid withdrawal. These results suggest that the natural decline in circulating ovarian steroid levels may modulate the GABAergic system in the PMM through the upregulation of GABAA receptors. This, in turn, could diminish the reproductive neuroendocrine responses to light and favor a condition resembling the state of photorefractoriness.

Treatment efficacy and safety of low-dose azathioprine in chronic active ulcerative colitis patients: A meta-analysis and systemic review.

To evaluate the efficacy and safety of low-dose azathioprine (AZA) in treating patients with chronic active ulcerative colitis (UC). A literature search of Medline, Embase, the Cochrane Library, Web of Science, Wanfang Database, CNKI, SinoMed, VIP Chinese Science and the Technology Journals Database was conducted to identify eligible studies that evaluated the efficacy and safety of low-dose azathioprine (AZA) in treating patients with chronic active UC published up to 15 July 2015. Data were extracted from the studies, including clinical efficacy (response rate, adverse drug reaction [ADR] rate, steroid withdrawal rate and relapse rate) and endoscopic improvement (endoscopic remission rate and mucosal healing rate). Six studies with 211 patients were eligible for the analysis. The overall response rates after 6 and 12 months of treatment were 78.0% (95% confidence interval [CI] 71.0-85.0%) and 88.0% (95% CI 80.0-96.0%), respectively. The overall ADR rate was 25.0% (95% CI 18.0-31.0%). Endoscopic response rate was around 85.0%, while the endoscopic remission rates and mucosal healing rates after 6 and 12 months of treatment were above 60.0% and 70.0%, respectively. The steroid withdrawal rate and relapse rate were in moderate to high heterogeneity. Egger's test indicated that there was no publication bias for studies regarding the 6-month response rate and ADR rate. Low-dose AZA is effective and safe in the treatment of chronic active UC patients. However, randomized controlled trials with large sample sizes are needed to draw definitive conclusions.

Incidence and differential characteristics of culture-negative fever following pancreas transplantation with anti-thymocyte globulin induction.

Limited data are available on the incidence and characteristics of culture-negative fever following pancreas transplantation (PTx) with anti-thymocyte globulin (ATG) induction. Our study aims to better define the features of culture-negative fever, so it can be delineated from infectious fever, hopefully helping clinicians to guide antibiotic therapy in this high-risk patient population. We performed a retrospective cohort study of postoperative fever among 198 consecutive patients undergoing PTx at our center between August 1, 2004 and December 31, 2014. Fever was classified as culture-negative if there was neither a positive culture nor a documented clinical diagnosis of infection. Fever was identified in 113 patients; 66 were deemed to be infectious, 39 were culture-negative, and 8 were indeterminate. High body mass index of recipient (odds ratio 1.87, 95% confidence interval: 1.15-3.03, P = 0.011) was a significant factor associated with culture-negative fever in multivariate analysis. No patients with culture-negative fever were diagnosed with infiltrates or effusion on chest radiography. In addition, an increase in white blood cell count, C-reactive protein, and serum amylase was less prominent in culture-negative fever. Culture-negative fever developed most frequently at postoperative 7 or 14 days, showing a biphasic curve. Culture-negative fever develops in a substantial proportion of patients early after PTx. The awareness of the possibility and clinical features of post-transplant culture-negative fever might help clinicians to guide antibiotic therapy in this high-risk patient population, especially following ATG induction and early steroid withdrawal.

P08.62 Salvage chemotherapy with bevacizumab and fotemustine in temozolomide-pretreated patients with recurrent grade III gliomas: a phase II study

AbstractIntroduction:Fotemustine is a nitrosourea with elevated lipophilic properties, that has shown activity as monotherapy in recurrent grade III gliomas, but few data are available on the association with the antiangiogenic drug bevacizumab.Method:From July 2008 to November 2015 we accrued, in this single arm phase II study, patients with an histological diagnosis of grade III glioma (according to WHO, 2007) at relapse after radiotherapy and/or temozolomide and we treated them with a combination of bevacizumab and fotemustine. The primary endpoint was 6-month progression-free survival (PFS-6), while secondary endpoints were overall survival (OS), disease control rate and toxicity.Results:Forty-six patients with grade III glioma (22 astrocytomas, 10 oligodendrogliomas and 14 oligoastrocytomas, 67% MGMT methylated and 30% 1p/19q codeleted) were enrolled. Median age was 45 years and KPS ≥ 90 in 54%. PFS-6, median PFS and OS were 45%, 5 months and 9 months, respectively. Nineteen patients (41%) had already received prior chemotherapy lines and 35% a second surgery before inclusion into the trial. We observed a 95% disease control rate (response or stable disease on MRI) after the induction phase with a neurological improvement in 40% and steroid reduction or withdrawal in 67%. In a preliminary analysis we didn’t observe significant differences in terms of clinical and/or radiological response rate, in PFS or OS according to MGMT methylation and 1p/19q codeletion status. There was a better clinical improvement in oligodendroglial subtype after induction phase (75% of patients), while no differences emerged in radiological disease control rate, PFS6, PFS or OS compared to astrocitary histotype. Survival rates of the whole cohort were 34% at 1 year, 21% at 2 years, 14% at 3 years, 7% at 4 years and 5% at 5 years. The pattern of progression was focal enhancing in 73% of tumors, diffuse non-enhancing (gliomatosis-like) in 12%, multicentric in 10% and local plus leptomeningeal in 5%.Twenty-two percent of patients discontinued fotemustine for grade 3/4 myelotoxicity. We did not observe any additional toxicity from the combination.Conclusions:The combination of bevacizumab and fotemustine as salvage treatment for grade III gliomas is safe and somewhat active in this heavily pretreated cohort. Further clinical studies should explore alternative regimens of therapy in the different molecular subgroups.

A Patient with Dermatomyositis Developing Steroid Induced Myopathy: A Case Report

Dermatomyositis is not a very uncommon disease affecting skin and muscles. Some varieties have atypical presentations and early diagnosis is pivotal to the effective management as it has significant morbidity and mortality including malignancy. Corticosteroids and other immunosuppressive is the mainstay of treatment; however, it should also be aimed to reduce the complications of steroid therapy as there is a possibility of steroid induced myopathy where withdrawal of steroid with introduction of other immunosuppressive drug is promptly warranted. Here, we presented a 60 year old lady with dermatomyositis who developed steroid induced myopathy.J Dhaka Medical College, Vol. 24, No.2, October, 2015, Page 156-159

Lymphocyte-depleting induction and steroid minimization after kidney transplantation: A review

Steroid minimization after kidney transplantation has become more widely practiced as transplant clinicians seek the potential benefits such as reduced cardiovascular risk factors, improved growth in pediatric patients, and improved compliance with the immunosuppression regimen. Steroid avoidance (i.e. no steroids after the first week) is generally favored compared to later withdrawal. Induction therapy is routine in this setting, frequently rabbit antithymocyte globulin (rATG, Thymoglobulin®) or off-license use of alemtuzumab. Direct comparisons of steroid minimization regimens versus standard steroid regimens are rare. However, the available data show that the risk of acute rejection is low when rATG or alemtuzumab induction is given to support steroid-avoidance regimens after kidney transplantation. Steroid avoidance may be inadvisable in patients at high immunological risk or at risk of recurrent glomerular disease. Steroid withdrawal after day 8 may be possible without additional risk of rejection in patients given rATG induction, but while encouraging, the data are too sparse for firm conclusions. In summary, steroid avoidance may be beneficial for patients after renal transplantation, with the potential to avoid or reduce steroid-related comorbidities. Whilst depleting induction therapy could be the treatment of choice, results of prospective randomized, controlled studies are eagerly awaited.

NIOX VERO: Individualized Asthma Management in Clinical Practice

As we move toward an era of precision medicine, novel biomarkers of disease will enable the identification and personalized treatment of new endotypes. In asthma, fractional exhaled nitric oxide (FeNO) serves as a surrogate marker of airway inflammation that often correlates with the presence of sputum eosinophils. The increase in FeNO is driven by an upregulation of inducible nitric oxide synthase (iNOS) by cytokines, which are released as a result of type-2 airway inflammation. Scientific evidence supports using FeNO in routine clinical practice. In steroid-naive patients and in patients with mild asthma, FeNO levels decrease within days after corticosteroid treatment in a dose-dependent fashion and increase after steroid withdrawal. In difficult asthma, FeNO testing correlates with anti-inflammatory therapy compliance. Assessing adherence by FeNO testing can remove the confrontational aspect of questioning a patient about compliance and change the conversation to one of goal setting and ways to improve disease management. However, the most important aspect of incorporating FeNO in asthma management is the reduction in the risk of exacerbations. In a recent primary care study, reduction of exacerbation rates and improved symptom control without increasing overall inhaled corticosteroid (ICS) use were demonstrated when a FeNO-guided anti-inflammatory treatment algorithm was assessed and compared to the standard care. A truly personalized asthma management approach—showing reduction of exacerbation rates, overall use of ICS and neonatal hospitalizations—was demonstrated when FeNO testing was applied as part of the treatment algorithm that managed asthma during pregnancy. The aim of this article is to describe how FeNO and the NIOX VERO® analyzer can help to optimize diagnosis and treatment choices and to aid in the monitoring and improvement of clinical asthma outcomes in children and adults.

Steroid avoidance or withdrawal for kidney transplant recipients.

Steroid-sparing strategies have been attempted in recent decades to avoid morbidity from long-term steroid intake among kidney transplant recipients. Previous systematic reviews of steroid withdrawal after kidney transplantation have shown a significant increase in acute rejection. There are various protocols to withdraw steroids after kidney transplantation and their possible benefits or harms are subject to systematic review. This is an update of a review first published in 2009. To evaluate the benefits and harms of steroid withdrawal or avoidance for kidney transplant recipients. We searched the Cochrane Kidney and Transplant Specialised Register to 15 February 2016 through contact with the Information Specialist using search terms relevant to this review. All randomised and quasi-randomised controlled trials (RCTs) in which steroids were avoided or withdrawn at any time point after kidney transplantation were included. Assessment of risk of bias and data extraction was performed by two authors independently and disagreement resolved by discussion. Statistical analyses were performed using the random-effects model and dichotomous outcomes were reported as relative risk (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals. We included 48 studies (224 reports) that involved 7803 randomised participants. Of these, three studies were conducted in children (346 participants). The 2009 review included 30 studies (94 reports, 5949 participants). Risk of bias was assessed as low for sequence generation in 19 studies and allocation concealment in 14 studies. Incomplete outcome data were adequately addressed in 22 studies and 37 were free of selective reporting.The 48 included studies evaluated three different comparisons: steroid avoidance or withdrawal compared with steroid maintenance, and steroid avoidance compared with steroid withdrawal. For the adult studies there was no significant difference in patient mortality either in studies comparing steroid withdrawal versus steroid maintenance (10 studies, 1913 participants, death at one year post transplantation: RR 0.68, 95% CI 0.36 to 1.30) or in studies comparing steroid avoidance versus steroid maintenance (10 studies, 1462 participants, death at one year after transplantation: RR 0.96, 95% CI 0.52 to 1.80). Similarly no significant difference in graft loss was found comparing steroid withdrawal versus steroid maintenance (8 studies, 1817 participants, graft loss excluding death with functioning graft at one year after transplantation: RR 1.17, 95% CI 0.72 to 1.92) and comparing steroid avoidance versus steroid maintenance (7 studies, 1211 participants, graft loss excluding death with functioning graft at one year after transplantation: RR 1.09, 95% CI 0.64 to 1.86). The risk of acute rejection significantly increased in patients treated with steroids for less than 14 days after transplantation (7 studies, 835 participants: RR 1.58, 95% CI 1.08 to 2.30) and in patients who were withdrawn from steroids at a later time point after transplantation (10 studies, 1913 participants, RR 1.77, 95% CI 1.20 to 2.61). There was no evidence to suggest a difference in harmful events, such as infection and malignancy, in adult kidney transplant recipients. The effect of steroid withdrawal in children is unclear. This updated review increases the evidence that steroid avoidance and withdrawal after kidney transplantation significantly increase the risk of acute rejection. There was no evidence to suggest a difference in patient mortality or graft loss up to five year after transplantation, but long-term consequences of steroid avoidance and withdrawal remain unclear until today, because prospective long-term studies have not been conducted.

Pulsatile Cortisol Feedback on ACTH Secretion Is Mediated by the Glucocorticoid Receptor and Modulated by Gender

Factors that regulate physiological feedback by pulses of glucocorticoids on the hypothalamic-pituitary unit are sparsely defined in humans in relation to gluco- or mineralocorticoid receptor pathways, gender, age, and the sex steroid milieu. The objective of the study was to test (the clinical hypothesis) that glucocorticoid (GR) and mineralocorticoid (MR) receptor-selective mechanisms differentially govern pulsatile cortisol-dependent negative feedback on ACTH output (by the hypothalamo-pituitary unit) in men and women studied under experimentally defined T and estradiol depletion and repletion, respectively. The study was conducted at the Mayo Center for Translational Science Activities. Healthy middle-aged men (n = 16) and women (n = 25) participated in the study. This was a randomized, prospective, double-blind, placebo- and saline-controlled study of pulsatile cortisol infusions in low cortisol-clamped volunteers with and without eplerenone (MR blocker) and mifepristone (GR blocker) administration under a low and normal T and estradiol clamp. During frequent sampling, a bolus of CRH-arginine vasopressin was infused to assess corticotrope responsiveness. Analytical Methods and Outcomes: Deconvolution and approximate entropy of ACTH profiles were measured. Infusion of cortisol (but not saline) pulses diminished ACTH secretion. The GR antagonist, mifepristone, interfered with negative feedback on both ACTH burst mass and secretion regularity. Eplerenone, an MR antagonist, exerted no detectable effect on the same parameters. Despite feedback imposition, CRH-arginine vasopressin-stimulated ACTH secretion was also increased by mifepristone and not by eplerenone. Withdrawal vs addback of sex steroids had no effect on ACTH secretion parameters. Nonetheless, ACTH secretion was greater (P = .006) and more regular (P = .004) in men than women. Pulsatile cortisol feedback on ACTH secretion in this paradigm is mediated by the glucocorticoid receptor, in part acting at the level of the pituitary, and influenced by sex.

Biomarkers of Tolerance in Kidney Transplantation: Are We Predicting Tolerance or Response to Immunosuppressive Treatment?

We and others have previously described signatures of tolerance in kidney transplantation showing the differential expression of B cell–related genes and the relative expansions of B cell subsets. However, in all of these studies, the index group—namely, the tolerant recipients—were not receiving immunosuppression (IS) treatment, unlike the rest of the comparator groups. We aimed to assess the confounding effect of these regimens and develop a novel IS‐independent signature of tolerance. Analyzing gene expression in three independent kidney transplant patient cohorts (232 recipients and 14 tolerant patients), we have established that the expression of the previously reported signature was biased by IS regimens, which also influenced transitional B cells. We have defined and validated a new gene expression signature that is independent of drug effects and also differentiates tolerant patients from healthy controls (cross‐validated area under the receiver operating characteristic curve [AUC] = 0.81). In a prospective cohort, we have demonstrated that the new signature remained stable before and after steroid withdrawal. In addition, we report on a validated and highly accurate gene expression signature that can be reliably used to identify patients suitable for IS reduction (approximately 12% of stable patients), irrespective of the IS drugs they are receiving. Only a similar approach will make the conduct of pilot clinical trials for IS minimization safe and hence allow critical improvements in kidney posttransplant management.

Short-Term Estrogen Withdrawal Increases Adiposity in Healthy Men.

T deprivation increases risk of insulin resistance in men, but whether this risk is independent of changes in body composition is unknown. Further, the metabolic roles of T and its metabolite estradiol have not been clearly defined in men. This study sought to establish the effects of selective sex steroid withdrawal on insulin sensitivity in healthy men. This was a double-blinded, placebo-controlled, randomized trial at an academic medical center of 56 healthy men, 19-55 years of age. Subjects received the GnRH antagonist acyline plus one of the following: placebo gel (Castrate), 1.25 g testosterone gel (Low T/E), 5 g testosterone gel (Normal T/E), or 5 g testosterone gel with letrozole (Normal T/Low E) daily for 4 weeks. Body composition and glucose tolerance were assessed at baseline and end of treatment. Insulin sensitivity was quantified by the Matsuda index. Predicted circulating sex steroid concentrations were achieved in all treatment groups. The time-by-group interaction for Matsuda index did not achieve significance in overall repeated measures ANOVA (baseline vs week 4; P = .16). A significant time-by-group interaction was observed for fat mass (P = .003), with changes in fat mass attributable predominantly to estrogen exposure in linear regression analysis (P = .016). A time-by-group interaction also was observed for lean mass (P = .03) and influenced by androgen exposure (P = .003). Short-term sex steroid withdrawal in healthy men causes adverse changes in body composition. These findings support the role of estradiol as a determinant of adiposity in men.

Pubertal development in children with chronic kidney disease.

Impairment of pubertal growth and sexual maturation resulting in reduced adult height is an significant complication in children suffering from chronic kidney disease (CKD). Delayed puberty and reduced pubertal growth are most pronounced in children with pre-existing severe stunting before puberty, requiring long-term dialysis treatment, and in transplanted children with poor graft function and high glucocorticoid exposure. In pre-dialysis patients, therapeutic measures to improve pubertal growth are limited and mainly based on the preservation of renal function and the use of growth hormone treatment. In patients with end-stage CKD, early kidney transplantation with steroid withdrawal within 6months of renal transplantation allows for normal pubertal development in the majority of patients. This review focuses on the underlying pathophysiology and strategies for improving height and development in these patients.