Steroid Avoidance Research Articles

Single‐center experience in pediatric renal transplantation using thymoglobulin induction and steroid minimization

Our center has offered thymoglobulin induction with steroid minimization to our pediatric renal transplant patients for the last 10yr. Steroid minimization or avoidance has shown favorable results in survival, kidney function, and growth in previous studies of pediatric patients. We report our experience with this protocol over the past 10yr with respect to patient/graft survival, acute rejection episodes, renal function, linear growth, bone density, cardiovascular risk factors, and opportunistic infections. A retrospective chart review was performed for pediatric renal transplant patients on the steroid-minimized protocol between January 2002 and December 2011 on an intention to treat basis. Patient demographics, height, weight, serum creatinine, iGFR, biopsies, and survival data were collected. Height and weight z-scores were calculated with EpiInfo 7, using the CDC 2000 growth charts. Survival was calculated using Kaplan-Meier analysis. eGFR was calculated using the original and modified Schwartz equations. Forty-four pediatric patients were identified, aged 13months to 19yr. Five-yr survival was 95.5% for males and 94.4% for females. Only five patients had biopsy-proven ACR, two of which were at more than 12months post-transplantation. Height delta z-scores from transplant to one, three, and fiveyr were 0.34, 0.38, and 0.79, respectively. Weight delta z-scores from transplant to one, three, and fiveyr were 0.87, 0.79, and 0.84, respectively. Mean original Schwartz eGFR was 84.3±15.8mL/min/1.73m(2) , modified Schwartz eGFR was 59.3±11.5mL/min/1.73m(2) , and iGFR was 64.2±8.5mL/min/1.73m(2) at threeyr. Of 18 subjects who had a bone density exam, none had a z-score less than -2 on DEXA exam at one-yr post-transplantation. Fifty-one percent of patients were on antihypertensives at the time of transplant compared with 43% at one-yr post-transplantation. Threeyr post-transplantation, the average LDL was <100mg/dL, and average total cholesterol was <200mg/dL. There were no clinical episodes of EBV or CMV infection. A steroid-minimized protocol with thymoglobulin induction is safe and provides favorable improvement in linear growth, stable graft function, stable or improved cardiovascular risk factors, and normal bone density in pediatric renal transplant patients.

Steroid avoidance or withdrawal for pancreas and pancreas with kidney transplant recipients.

Pancreas or kidney-pancreas transplantation improves survival and quality of life for people with type 1 diabetes mellitus and kidney failure. Immunosuppression after transplantation is associated with complications. Steroids have adverse effects on cardiovascular risk factors such as hypertension, hyperglycaemia or hyperlipidaemia, increase risk of infection, obesity, cataracts, myopathy, bone metabolism alterations, dermatologic problems and cushingoid appearance. Whether avoiding steroids changes outcomes is unclear. We aimed to assess the safety and efficacy of steroid early withdrawal (treatment for less than 14 days after transplantation), late withdrawal (after 14 days after transplantation) or steroid avoidance in patients receiving a pancreas (including a vascularized organ) alone (PTA), simultaneous with a kidney (SPK) or after kidney transplantation (PAK). We searched the Cochrane Renal Group's Specialised Register (to 18 June 2014) through contact with the Trials' Search Co-ordinator. We handsearched: reference lists of nephrology textbooks, relevant studies, recent publications and clinical practice guidelines; abstracts from international transplantation society scientific meetings; and sent emails and letters seeking information about unpublished or incomplete studies to known investigators. We included randomised controlled trials (RCTs) or cohort studies of steroid avoidance (including early withdrawal) versus steroid maintenance or versus late withdrawal in pancreas or pancreas with kidney transplant recipients. We defined steroid avoidance as complete avoidance of steroid immunosuppression, early steroid withdrawal as steroid treatment for less than 14 days after transplantation and late withdrawal as steroid withdrawal after 14 days after transplantation. Two authors independently assessed the retrieved titles and abstracts, and where necessary the full text reports to determine which studies satisfied the inclusion criteria. Authors of included studies were contacted to obtain missing information. Statistical analyses were performed using random effects models and results expressed as risk ratio (RR) or mean difference (MD) with 95% confidence interval (CI). Cohort studies were not meta-analysed, but their findings summarised descriptively. Three RCTs enrolling 144 participants met our inclusion criteria. Two compared steroid avoidance versus late steroid withdrawal and one compared late steroid withdrawal versus steroid maintenance. All studies included SPK and only one also included PTA. All studies had an overall moderate risk of bias and presented only short-term results (six to 12 months). Two studies (89 participants) compared steroid avoidance or early steroid withdrawal versus late steroid withdrawal. There was no clear evidence of an impact on mortality (2 studies, 89 participants: RR 1.64, 95% CI 0.21 to 12.75), risk of kidney loss censored for death (2 studies, 89 participants: RR 0.35, 95% CI 0.04 to 3.09), risk of pancreas loss censored for death (2 studies, 89 participants: RR 1.05, 95% CI 0.36 to 3.04), or acute kidney rejection (1 study, 49 participants: RR 2.08, 95% CI 0.20 to 21.50), however results were uncertain and consistent with no difference or important benefit or harm of steroid avoidance/early steroid withdrawal. The study that compared late steroid withdrawal versus steroid maintenance observed no deaths, no graft loss or acute kidney rejection at six months in either group and reported uncertain effects on acute pancreas rejection (RR 0.88, 95% CI 0.06 to 13.35). Of the possible adverse effects only infection was reported by one study. There were significantly more UTIs reported in the late withdrawal group compared to the steroid avoidance group (1 study, 25 patients: RR 0.41, 95% CI 0.26 to 0.66).We also identified 13 cohort studies and one RCT which randomised tacrolimus versus cyclosporin. These studies in general showed that steroid-sparing and withdrawal strategies had benefits in lowering HbAc1 and risk of infections (BK virus and CMV disease) and improved blood pressure control without increasing the risk of rejection. However, two studies found an increased incidence of acute pancreas rejection (HR 2.8, 95% CI 0.89 to 8.81, P = 0.066 in one study and 43.3% in the steroid withdrawal group versus 9.3% in the steroid maintenance, P < 0.05 at three years in the other) and one study found an increased incidence of acute kidney rejection (18.7% in the steroid withdrawal group versus 2.8% in the steroid maintenance, P < 0.05) at three years. There is currently insufficient evidence for the benefits and harms of steroid withdrawal in pancreas transplantation in the three RCTs (144 patients) identified. The results showed uncertain results for short-term risk of rejection, mortality, or graft survival in steroid-sparing strategies in a very small number of patients over a short period of follow-up. Overall the data was sparse, so no firm conclusions are possible. Moreover, the 13 observational studies findings generally concur with the evidence found in the RCTs.

Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomised trial

Calcineurin inhibitors (CNIs) reduce short-term kidney transplant failure, but might contribute to transplant failure in the long-term. The role of alemtuzumab (a potent lymphocyte-depleting antibody) as an induction treatment followed by an early reduction in CNI and mycophenolate exposure and steroid avoidance, after kidney transplantation is uncertain. We aimed to assess the efficacy and safety of alemtuzumab-based induction treatment compared with basiliximab-based induction treatment in patients receiving kidney transplants. For this randomised trial, we enrolled patients aged 18 years and older who were scheduled to receive a kidney transplant in the next 24 h from 18 transplant centres in the UK. Using minimised randomisation, we randomly assigned patients (1:1; minimised for age, sex, and immunological risk) to either alemtuzumab-based induction treatment (ie, alemtuzumab followed by low-dose tacrolimus and mycophenolate without steroids) or basiliximab-based induction treatment (basiliximab followed by standard-dose tacrolimus, mycophenolate, and prednisolone). Participants were reviewed at discharge from hospital and at 1, 3, 6, 9, and 12 months after transplantation. The primary outcome was biopsy-proven acute rejection at 6 months, analysed by intention to treat. The study is registered at ClinicalTrials.gov, number NCT01120028, and isrctn.org, number ISRCTN88894088. Between Oct 4, 2010, and Jan 21, 2013, we randomly assigned 852 participants to treatment: 426 to alemtuzumab-based treatment and 426 to basiliximab-based treatment. Overall, individuals allocated to alemtuzumab-based treatment had a 58% proportional reduction in biopsy-proven acute rejection compared with those allocated to basiliximab-based treatment (31 [7%] patients in the alemtuzumab group vs 68 [16%] patients in the basiliximab group; hazard ratio (HR) 0·42, 95% CI 0·28-0·64; log-rank p<0·0001). We detected no between-group difference in treatment effect on transplant failure during the first 6 months (16 [4%] patients vs 13 [3%] patients; HR 1·23, 0·59-2·55; p=0·58) or serious infection (135 [32%] patients vs 136 [32%] patients; HR 1·02, 0·80-1·29; p=0·88). During the first 6 months after transplantation, 11 (3%) patients given alemtuzumab-based treatment and six (1%) patients given basiliximab-based treatment died (HR 1·79, 95% CI 0·66-4·83; p=0·25). Compared with standard basiliximab-based treatment, alemtuzumab-based induction therapy followed by reduced CNI and mycophenolate exposure and steroid avoidance reduced the risk of biopsy-proven acute rejection in a broad range of patients receiving a kidney transplant. Long-term follow-up of this trial will assess whether these effects translate into differences in long-term transplant function and survival. UK National Health Service Blood and Transplant Research and Development Programme, Pfizer, and Novartis UK.

Outcomes Associated With Steroid Avoidance and Alemtuzumab Among Kidney Recipients in the United States.

Outcomes Associated With Steroid Avoidance and Alemtuzumab Among Kidney Recipients in the United States.

Steroid Avoidance Requires Adjustments in the Thymoglobulin Induction Therapy in Patients with Brittle T1DM and Pancreatic Islet Transplantation.

Steroid Avoidance Requires Adjustments in the Thymoglobulin Induction Therapy in Patients with Brittle T1DM and Pancreatic Islet Transplantation.

Long-Term Outcome of Steroid-Free vs Steroid-Based Maintenance Immunosuppression in Simultaneous Pancreas/Kidney Transplants (SPK).

Purpose: Over the last decade, steroid-free immunosuppressive maintenance protocols were used in about 30% of all primary SPKs to avoid the negative long-term side effects of steroid use. While the reported short-term results are excellent, no information is available for long-term steroid avoidance in SPKs. Method: The information of the International Pancreas Transplant Registry was used to match SPKs transplants performed between 2003-2012. Only primary, DD, ED SPK transplants were entered into the study. All patients received depleting antibodies with steroids for induction therapy and maintenance therapy consisting of mycophenolate mofetil in combination with tacrolimus. The transplants were matched for the most influential recipient (age, PRA, diabetes type, race), donor (age) and transplant factors (preservation time). In addition, the transplants were also matched according to the size of their transplant center. Patient survival and graft function were described using the Kaplan-Meier method and a multivariate analysis was performed. Result: We identified 817 transplants per group which were perfectly matched. Five year patient survival was 91% in the steroid-based (+Steroid) 92% in the steroid-free -Steroid group (p=0.48). Figure 1 shows SPK pancreas and kidney graft function.Figure: No Caption available.In both pancreas and kidney graft function no statistical significant differences between the 2 treatments could be found. Of interest is the slightly better early kidney graft function with steroids and the better long-term pancreas graft function without steroids. After 42 month the steroid-free group had significantly better pancreas graft function (p=0.01). Late differences in the kidney graft function did not reach significance. In the steroid-free group, the highest risk factors were increased PRA levels and recipient age. Conclusion: are safe in SPKs and did not show any negative impact on pancreas graft function. In contrast, steroid-free protocols resulted in early kidney graft function but the difference did not reach significance.

Comparative Effectiveness of Triple Immunosuppressive Therapy Versus Steroid Avoidance or Early Withdrawal Among Kidney Transplant Recipients Over Age 65.

Comparative Effectiveness of Triple Immunosuppressive Therapy Versus Steroid Avoidance or Early Withdrawal Among Kidney Transplant Recipients Over Age 65.

Optimal use of corticosteroids in nephrology

Abstract The usage of corticosteroids is widespread in nephrology both in the treatment of patients with native kidney diseases and of patients who have received a kidney transplant. In glomerular diseases, steroids are part of most immunosuppressive regimens applied nowadays, and only few steroid-free immunosuppressive regimens have been reported on. It is my hope that - with the introduction of more targeted therapies - corticosteroid dosage can be reduced or eliminated completely in the future. Although corticosteroids have been the mainstay in the immunosuppressive treatment of patients who received a kidney transplant, there has been a long-standing interest in steroid avoidance and withdrawal (SAW). However, there is an ongoing debate whether SAW can be considered to be the standard of care in kidney transplantation at this moment.

Alemtuzumab with corticosteroid minimization for pediatric deceased donor renal transplantation: A seven‐yr experience

Alemtuzumab is a monoclonal antibody targeting CD52 receptors on B and T lymphocytes and is an effective induction agent in pediatric renal transplantation. We report a seven-yr experience using alemtuzumab induction and steroid-free protocol in the pediatric population as safe and effective. Twenty-one pediatric deceased donor renal transplants were performed at a single academic institution. All received induction with single-dose alemtuzumab and were maintained on a steroid-free protocol using TAC and MMF immunosuppression. There were 15 males and six females in the study whose ages ranged from one to 19 yr. The average follow-up was 32 months (range from 12 to 78.2 months and median 33.7 ± 23.7 months). All patients had immediate graft function. Graft survival was 95%, and patient survival was 100%. Mean 12 and 36 months eGFR were 63.33 ± 21.01 and 59.90 ± 15.27 mL/min/1.73m(2), respectively. Three patients developed acute T-cell-mediated rejection due to non-adherence while no recipients developed cytomegalovirus infection, PTLD, or polyoma BK viral nephropathy. Steroid avoidance with single-dose alemtuzumab induction provides adequate and safe immunosuppression in pediatric deceased donor renal transplant recipients receiving TAC and low-dose MMF maintenance therapy.

A Single-Center Experience of the Use of Interleukin-2 Receptor Antagonists for Various Situations in Liver Transplant Recipients

BackgroundInterleukin-2 receptor antagonists (IL2Ra) are used mainly for (1) induction as an adjunct to conventional immunosuppression, (2) induction to facilitate calcineurin inhibitor (CNI) or steroid minimization, and (3) induction to facilitate steroid avoidance in hepatitis C virus (HCV)-positive recipients. The aim of this study was to present our strategy for IL2Ra rescue therapy and its outcome. MethodsA total of 20 patients were treated with IL2Ra at our institute for the following indications: (1) rescue for acute rejection (n = 13), (2) CNI sparing in cases of CNI toxicity (n = 5), and (3) induction for complicated cases (n = 2). ResultsRescue therapy for steroid-resistant rejection and rejection in HCV-positive recipients was successful in 11 cases, but 2 grafts were lost due to uncontrollable rejection. CNI cessation was successfully achieved with IL2Ra treatment in 3 cases with thrombotic microangiopathy and 2 cases of encephalopathy, with complete cure of these life-threatening complications of CNI. Induction with IL2Ra was successful in 2 complicated cases, 1 for CNI sparing due to renal failure and the other for adjunct immunosuppression in a case of positive lymphocytotoxic crossmatch. The overall patient/graft survival and the rate of infectious complications were comparable between those with and without IL2Ra treatment. ConclusionsIL2Ra could be safely and effectively used after liver transplantation in various situations.

Role of steroid minimization in the tacrolimus-based immunosuppressive regimen for liver transplant recipients: a systematic review and meta-analysis of prospective randomized controlled trials.

To evaluate the efficacy and safety of early steroid withdrawal or steroid avoidance in the tacrolimus (Tac)-based immunosuppressive regimen for liver transplant recipients. According to the requirements of the Cochrane systematic review, a thorough literature search was performed in the PubMed/MEDLINE and Cochrane electronic databases between 1995 and 2011 using the key words “liver transplantation,” “Tac,” and “steroid free” or “steroid withdrawal,” restricting articles to the English language. Data were processed for a meta-analysis by Stata 12 software. Altogether 17 prospective randomized controlled trials containing 1,980 transplanted patients were included in this study. The overall pooled RR estimates of 1-, 2-, 3-, and 5-year patient and graft survival rates were 0.985, 0.998, 0.995, and 1.100 (95 % CI 0.925–1.048, 0.934–1.067, 0.894–1.107, and 0.968–1.250, respectively), as well as 0.998, 0.993, 0.945, and 1.053, respectively (95 % CI 0.928–1.072, 0.902–1.092, 0.833–1.072, and 0.849–1.307, respectively). The other pooled RR estimates of acute rejection and chronic rejection rates for all enrolled studies were 1.077 and 0.311 (95 % CI 0.864–1.343 and 0.003–37.207). As for secondary predictors, the pooled RR estimates such as HCV recurrence, HCC recurrence, diabetes, hypertension, kidney dysfunction, bacterial infection, and CMV were 1.101, 1.403, 1.836, 1.607, 0.842, 1.096, and 2.280, respectively (95 % CI 0.964–1.257, 0.422–4.688, 1.294–2.606, 0.926–1.228, 0.693–1.022, 0.783–1.533, and 1.500–3.465, respectively). There were no differences between the steroid group and steroid-free group for all clinical observational indices except for the incidence of diabetes (p = 0.001) and CMV infection (p < 0.001). In summary, our study indicate that rapid discontinuation of steroid in the Tac-based immunosuppressive regimen may not lead to an increased risk of morbidity and rejection rate.Electronic supplementary materialThe online version of this article (doi:10.1007/s12072-014-9523-y) contains supplementary material, which is available to authorized users.

Steroid Avoidance in Pediatric Heart Transplantation Results in Excellent Graft Survival

Maintenance steroid (MS) use in pediatric heart transplantation (HT) varies across centers. The purpose of this study was to evaluate the impact of steroid-free maintenance immunosuppression (SF) on graft outcomes in pediatric HT. Patients younger than 18 years in the United States undergoing a first HT during 1990 to 2010 were analyzed for conditional 30-day graft loss (death or repeat HT) and death based on MS use by multivariable analysis. A propensity score was then given to each patient using a logistic model, and propensity matching was performed using pre-HT risk factors, induction therapy, and nonsteroid maintenance immunosuppression. Kaplan-Meier graft and patient survival probabilities by MS use were then calculated. Of 4894 patients, 3962 (81%) were taking MS and 932 (19%) SF. Of the 4530 alive at 30 days after HT, 3694 (82%) and 836 (18%) were in the MS and SF groups, respectively. Unmatched multivariable analysis showed no difference in 30-day conditional graft survival between MS and SF groups (hazard ratio=1.08, 95% confidence interval=0.93-1.24; P=0.33). Propensity matching resulted in 462 patients in each MS and SF group. Propensity-matched Kaplan-Meier survival analysis showed no difference in graft or patient survival between groups (P=0.3 and P=0.16, respectively). We found no difference in graft survival between SF patients and those taking MS. An SF regimen in pediatric HT avoids potential complications of steroid use without compromising graft survival, even after accounting for pre-HT risk factors.

Regulation of Anti-HLA Antibody-Dependent Natural Killer Cell Activation by Immunosuppressive Agents

It was demonstrated that human natural killer (NK) cells, via antibody-dependent cellular cytotoxicity (ADCC)-like mechanism, increase IFNγ production after exposure to alloantigens. This finding was associated with an increased risk for antibody-mediated rejection (ABMR). Although the effects of various immunosuppressive drugs on T cells and B cells have been extensively studied, their effects on NK cells are less clear. This study reports the effect of immunosuppressive agents on antibody-mediated NK cell activation in vitro. Whole blood from normal individuals was incubated with irradiated peripheral blood mononuclear cells (PBMCs) pretreated with anti-HLA antibody+ sera (in vitro ADCC), with or without immunosuppressive agents. The %IFNγ+ and CD107a+ (degranulation marker) in CD56+ NK cells were enumerated by flow cytometry. Cyclosporine A and tacrolimus significantly reduced IFNγ production in a dose-dependent manner (53%-83%), but showed minimal effect on degranulation (20%). Prednisone significantly reduced both IFNγ production and degranulation (50%-66% reduction at maximum therapeutic levels). Calcineurin inhibitors (CNIs) in combination with prednisone additively suppressed IFNγ production and degranulation. The effect of sirolimus or mycophenolate mofetil on NK cells was minimal. These results suggest that potent suppressive effects of CNIs and prednisone on antibody-mediated NK cell activation may contribute to the reduction of ADCC in sensitized patients and possibly reduce the risk for ADCC-mediated ABMR. These further underscore the importance of medication compliance in prevention of ABMR and possibly chronic rejection, and suggest that ADCC-mediated injury may increase in strategies aimed at CNI or steroid minimization or avoidance.

Growth following solid organ transplantation in childhood

One of the ultimate goals of successful transplantation in pediatric solid organ transplant recipients is the attainment of optimal final adult height. This manuscript will discuss the attainment of height following solid organ transplantation in pediatric recipients of kidney, liver, heart, lung, and small bowel transplantation. Age is a primary factor with younger recipients exhibiting the greatest immediate catch up growth. Graft function is a significant contributory factor with a reduction in glomerular filtration rate correlating with poor growth in kidney recipients and the need for re-transplantation with impaired growth in liver recipients. The known adverse impact of steroids on growth has led to modification of steroid dosage and even to steroid withdrawal and steroid avoidance. In kidney and liver recipients, this has been associated with the development on occasion of acute rejection episodes. In infant heart transplantation, avoidance of maintenance corticosteroid immunosuppression is associated with normal growth velocity in the majority of patients. With marked improvement in patient and graft survival rates in pediatric organ graft recipients, it is timely that the quality of life issues, such as normal adult height, receive paramount attention. In general, normal growth post-transplantation should be an achievable goal that results in normal adult height for many solid organ transplantation recipients.

No Association Between Cyclosporine Levels and Dyslipidemia?

Dear Editor, The recent manuscript analyzing whether there was a correlation between cyclosporine levels and dyslipidemia after renal transplantation in 1391 kidney transplant recipients (1) was read with great interest. Dyslipidemia is a common problem after renal transplantation and a potentially modifiable factor (2). This is particularly important because cardiovascular morbidity significantly contributes to the below-average life expectancy found in renal transplant patients (3). In their cross-sectional study of 1391 subjects, Hosseini et al. found a very high prevalence of hypercholesterolemia (58.8%) and hypertriglyceridemia (86.6%) (1). Using univariate correlation analysis, they found only a weak correlation between cyclosporine levels two hours post-intake (C2) and dyslipidemia (Pearson correlation coefficient 0.18 and 0.16 for hypercholesterolemia and hypertriglyceridemia, respectively). C2-monitoring is the preferred method for assessing cyclosporine exposure, although there are some challenges with timely C2 blood sampling, and some patients may suffer toxicity or rejection when switching from trough level (C0) to C2 monitoring (4). Using logistic multivariate regression, only serum creatinine was associated with hyperlipidemia. Hosseini’s study did not assess the correlation of steroid levels or the steroid dose and dyslipidemia, even though steroid therapy is a well-known risk factor for hyperlipidemia and steroid avoidance has been a powerful tool to reduce the prevalence of hyperlipidemia in liver transplantation (5). Hosseini’s study has several other limitations. No validation of the fasting state occurred. The results of the logistic regression were not well documented, and it is unclear what factors were included in the multivariate analysis. The limitations of the cross-sectional retrospective study are not well discussed, and such a study can only assess an association, no causality. Nonetheless, the stronger correlation of the hypertriglyceridemia with the GFR (measured as serum creatinine) is interesting; it is disappointing that targeting optimal calcineurin inhibitor exposure has little effect on hyperlipidemia. The authors call for prospective trials targeting better lipid control, with the hope that long-term outcomes will improve. The authors are correct in their assessment that chronic kidney disease (CKD)-related complications after renal transplantation are poorly managed (3, 6, 7). Often, there is undertreatment of dyslipidemia. Longevity after renal transplantation could be improved significantly if similar multidisciplinary clinics were introduced as for CKD in the primary kidneys (8). It is of the utmost importance to determine whether targeting conventional cardiovascular risk factors can effectively modify cardiovascular morbidity (9). In a large study of national data, Sciarretta et al. found no association of renal damage with cardiovascular disease and the individual cardiovascular risk profile (9). It is also important to determine which intervention is most effective and what novel therapies can be employed to lower triglycerides. There is no known effective treatment of hypertriglyceridemia. Dietary approaches such as supplementation with omega-3 fatty acids should be studied prospectively (10). Nonetheless, the undersigned is delighted that the attention is shifting towards modifiable long-term complications after renal transplantation. Cardiovascular risk factors are among the most significant factors affecting long-term outcomes in renal transplant recipients and are responsible for deaths with functioning graft. CKD is a major risk factor for cardiovascular morbidity following transplantation, and has a high prevalence in both renal and non-renal transplant patients. The relationship between impaired GFR and dyslipidemia needs to be studied further and effective therapeutic interventions have to be found.

Three-year outcomes in kidney transplant patients randomized to steroid-free immunosuppression or steroid withdrawal, with enteric-coated mycophenolate sodium and cyclosporine: the infinity study.

In a six-month, multicenter, open-label trial, de novo kidney transplant recipients at low immunological risk were randomized to steroid avoidance or steroid withdrawal with IL-2 receptor antibody (IL-2RA) induction, enteric-coated mycophenolate sodium (EC-MPS: 2160 mg/day to week 6, 1440 mg/day thereafter), and cyclosporine. Results from a 30-month observational follow-up study are presented. Of 166 patients who completed the core study on treatment, 131 entered the follow-up study (70 steroid avoidance, 61 steroid withdrawal). The primary efficacy endpoint of treatment failure (clinical biopsy-proven acute rejection (BPAR) graft loss, death, or loss to follow-up) occurred in 21.4% (95% CI 11.8–31.0%) of steroid avoidance patients and 16.4% (95% CI 7.1–25.7%) of steroid withdrawal patients by month 36 (P = 0.46). BPAR had occurred in 20.0% and 11.5%, respectively (P = 0.19). The incidence of adverse events with a suspected relation to steroids during months 6–36 was 22.9% versus 37.1% (P = 0.062). By month 36, 32.4% and 51.7% of patients in the steroid avoidance and steroid withdrawal groups, respectively, were receiving oral steroids. In conclusion, IL-2RA induction with early intensified EC-MPS dosing and CNI therapy in de novo kidney transplant patients at low immunological risk may achieve similar three-year efficacy regardless of whether oral steroids are withheld for at least three months.

Optimization of Bone Health in Children before and after Renal Transplantation: Current Perspectives and Future Directions.

The accrual of healthy bone during the critical period of childhood and adolescence sets the stage for lifelong skeletal health. However, in children with chronic kidney disease (CKD), disturbances in mineral metabolism and endocrine homeostasis begin early on, leading to alterations in bone turnover, mineralization, and volume, and impairing growth. Risk factors for CKD–mineral and bone disorder (CKD–MBD) include nutritional vitamin D deficiency, secondary hyperparathyroidism, increased fibroblast growth factor 23 (FGF-23), altered growth hormone and insulin-like growth factor-1 axis, delayed puberty, malnutrition, and metabolic acidosis. After kidney transplantation, nutritional vitamin D deficiency, persistent hyperparathyroidism, tertiary FGF-23 excess, hypophosphatemia, hypomagnesemia, immunosuppressive therapy, and alteration of sex hormones continue to impair bone health and growth. As function of the renal allograft declines over time, CKD–MBD associated changes are reactivated, further impairing bone health. Strategies to optimize bone health post-transplant include healthy diet, weight-bearing exercise, correction of vitamin D deficiency and acidosis, electrolyte abnormalities, steroid avoidance, and consideration of recombinant human growth hormone therapy. Other drug therapies have been used in adult transplant recipients, but there is insufficient evidence for use in the pediatric population at the present time. Future therapies to be explored include anti-FGF-23 antibodies, FGF-23 receptor blockers, and treatments targeting the colonic microbiota by reduction of generation of bacterial toxins and adsorption of toxic end products that affect bone mineralization.

Alemtuzumab Induction in Renal Transplantation Permits Safe Steroid Avoidance with Tacrolimus Monotherapy

The use of alemtuzumab as induction immunosuppression for renal transplantation introduces the possibility of long-term tacrolimus monotherapy, avoiding maintenance with both corticosteroids and mycophenolate mofetil (MMF). We conducted a single-center, prospective, open-label, randomized controlled trial comparing two steroid avoidance regimens between December 2006 and November 2010. One hundred and sixteen adult patients were randomized to either basiliximab induction followed by tacrolimus and MMF maintenance or to alemtuzumab induction followed by tacrolimus monotherapy. The primary endpoint was noninferiority of isotopic glomerular filtration rate at 1 year; secondary endpoints included patient and graft survival, incidence of delayed graft function, and incidence and severity of biopsy-proven acute rejection. The two groups were well matched for all baseline demographics. Isotopic glomerular filtration rate was comparable between the groups at 1 year (57±26 mL/min for alemtuzumab group and 53±21 mL/min for basiliximab group; P=0.42). Secondary endpoints were also similar between the groups. The rate of biopsy-proven acute rejection by 12 months was lower in the alemtuzumab group (n=6 vs. n=14 in basiliximab arm) just reaching statistical significance (P=0.049); however, a single extra case in the alemtuzumab arm included when considering clinically treated rejection removes this significance (P=0.082). Similar rates of cardiovascular, infective, and neoplastic complications were observed in both groups. Forty-seven (81.0%) of the patients in the alemtuzumab group remained on tacrolimus monotherapy at 12 months. Renal transplantation with alemtuzumab induction followed by tacrolimus monotherapy leads to good graft and patient outcomes, with no major differences detected compared with basiliximab induction and tacrolimus/MMF maintenance at 1 year.

Long‐term experience of steroid‐free pediatric renal transplantation: Effects on graft function, body mass index, and longitudinal growth

Increased focus on the potential negative side effects of steroid usage in pediatric transplantation has led to steroid minimization or steroid-free transplantation. In this study, we report results after complete steroid avoidance in renal transplantation in the period 1994-2009. We evaluate the effects of complete steroid avoidance on allograft function, BMI, and linear growth. The majority of transplanted children were induced with antithymocyte globulin and immunosuppressed with a calcineurin inhibitor and mycophenolate mofetil. Steroids were given only when rejection occurred or due to comorbidities. Anthropometric data were collected from 65 transplantations in 60 children. Patient survival was 93%; graft survival was 81% after five yr (N = 42) and 63% after 10 yr (N = 16). Acute rejection within the first year of transplantation was 9%. The distribution of the children's BMI before transplantation was normal; the mean BMI-SDS was 0.21 before transplantation, and this value remained stable during the next five yr. Post-transplantation the children demonstrated significant improved growth as the mean height-SDS increased significantly from -1.7 to -1.1. Catch-up growth was most pronounced in the youngest (< six yr). Steroid-free immunosuppression in pediatric renal transplantation is safe and protects against steroid-induced obesity and short stature.

Current trends in immunosuppression following organ transplantation in children

To highlight the current trends in immunosuppression and their application to paediatric transplantation informed by the systematic reviews and randomized controlled trials: new induction agents, steroid avoidance, calcineurin minimization and desensitization protocols. Newer induction agents, belatacept and alemtuzumab, are associated with serious side-effects, and interleukin-2 receptor antagonists remain the preferred agents in children. Steroid-free regimens may improve growth and, compared with steroid-containing regimens, have similar short to medium term graft survival, although long-term outcomes are uncertain. Mammalian target of rapamycin inhibitors, sirolimus and everolimus, when used in recipients as primary immunosuppression to avoid calcineurin exposure, results in poorer graft survival. Although desensitization is being performed more frequently, the relative benefits and harms of regimens used are uncertain. There is growing evidence for the use of steroid-free immunosuppression regimens in children to maximize growth. Further trials with a focus on long-term graft survival are needed to establish the role of desensitization protocols in organ transplantation in children.