Britta Höcker

Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy.

Alport syndrome inevitably leads to end-stage renal disease and there are no therapies known to improve outcome. Here we determined whether angiotensin-converting enzyme inhibitors can delay time to dialysis and improve life expectancy in three generations of Alport families. Patients were categorized by renal function at the initiation of therapy and included 33 with hematuria or microalbuminuria, 115 with proteinuria, 26 with impaired renal function, and 109 untreated relatives. Patients were followed for a period whose mean duration exceeded two decades. Untreated relatives started dialysis at a median age of 22 years. Treatment of those with impaired renal function significantly delayed dialysis to a median age of 25, while treatment of those with proteinuria delayed dialysis to a median age of 40. Significantly, no patient with hematuria or microalbuminuria advanced to renal failure so far. Sibling pairs confirmed these results, showing that earlier therapy in younger patients significantly delayed dialysis by 13 years compared to later or no therapy in older siblings. Therapy significantly improved life expectancy beyond the median age of 55 years of the no-treatment cohort. Thus, Alport syndrome is treatable with angiotensin-converting enzyme inhibition to delay renal failure and therapy improves life expectancy in a time-dependent manner. This supports the need for early diagnosis and early nephroprotective therapy in oligosymptomatic patients.

Successful withdrawal of steroids in pediatric renal transplant recipients receiving cyclosporine A and mycophenolate mofetil treatment : results after four years

Background. Despite their numerous systemic side effects, glucocorticoids (steroids) still form a cornerstone in immunosuppressive regimens in pediatric renal transplant recipients. The addition of mycophenolate mofetil (MMF) to a cyclosporine A (CsA)-based immunosuppressive regimen after renal transplantation may allow steroid withdrawal and amelioration or avoidance of steroid-specific side effects. Methods. In a retrospective case-control study, covering a mean follow-up period of 46±2.3 months and 40 patients aged 11.4±4.9 years, we analyzed the safety and efficacy of steroid withdrawal in pediatric renal transplant recipients receiving CsA micoroemulsion, MMF, and low-dose prednisone treatment. Results. Steroid withdrawal in all 20 pediatric renal transplant recipients receiving CsA and MMF was successful and not associated with an acute rejection episode; graft function remained stable. At baseline, the degree of growth retardation was comparable between the groups (mean height standard deviation scores [SDSs] −1.60±0.30 [withdrawal group] and −1.32±0.39 [case-control group]). After steroid withdrawal, prepubertal patients exhibited a significant catch-up growth with a mean height gain of 1.47±0.32 SDS, whereas height SDS did not improve in patients receiving steroids. Growth was also improved in pubertal patients who stopped taking steroids. Standardized body mass index in patients who stopped taking steroids decreased significantly by 49% from 0.87±0.31 SDS to 0.45±0.30 SDS. After steroid withdrawal, mean arterial blood pressure SDS decreased significantly by 45%. Moreover, the need for antihypertensive medication declined significantly in patients who stopped taking steroids. The white blood cell counts and hemoglobin levels were comparable between the groups. Conclusions. This study suggests that steroids can be safely and successfully withdrawn in selected pediatric renal transplant recipients receiving immunosuppressive maintenance therapy consisting of CsA and MMF.

Molecular Evidence of Pneumocystis Transmission in Pediatric Transplant Unit

We describe an outbreak of Pneumocystis jirovecii pneumonia in a pediatric renal transplant unit, likely attributable to patient-to-patient transmission. Single-strand conformation polymorphism molecular typing showed that 3 affected patients had acquired the same 2 strains of Pneumocystis, which suggests interhuman infection. An infant with mitochondriopathy was the probable index patient.

Improved growth and cardiovascular risk after late steroid withdrawal: 2-year results of a prospective, randomised trial in paediatric renal transplantation

BACKGROUND Long-term corticosteroid treatment impairs growth and increases cardiovascular risk factors. Hence, steroid withdrawal constitutes a major topic in paediatric renal transplantation and maintenance immunosuppression. METHODS The lack of data from randomised controlled trials caused us to conduct the first prospective, randomised, multicentre study on late steroid withdrawal among paediatric kidney allograft recipients treated with standard-dose cyclosporine microemulsion (CsA) and mycophenolate mofetil (MMF) for 2 years. Forty-two low- or regular-immunologic risk patients were randomly assigned, >or=1 year post-transplant, to continue taking or to withdraw steroids over 3 months. RESULTS Two years after steroid withdrawal, they showed a longitudinal growth superior to controls [mean height standard deviation score (SDS) gain, 0.6 +/- 0.1 SDS versus -0.2 +/- 0.1 SDS (P < 0.001)]. The prevalence of the metabolic syndrome declined significantly (P < 0.05), 2 years after steroid withdrawal, from 39% (9/23) to 6% (1/16). Steroid-free patients had less frequent arterial hypertension (50% versus 93% (P < 0.05)) and required fewer antihypertensive drugs [0.6 +/- 0.2 versus 1.5 +/- 0.3 (P < 0.05 versus control)]. Additionally, they had a significantly improved carbohydrate and lipid metabolism with fewer hypercholesterolaemia and hypertriglyceridaemia (P < 0.05 versus control). Patient and graft survival amounted to 100%. Allograft function remained stable 2 years after steroid withdrawal. The incidence of acute rejections was similar in the steroid-withdrawal group (1/23, 4%) and controls (2/19, 11%). CONCLUSION Late steroid withdrawal in selected CsA- and MMF-treated paediatric kidney transplant recipients improves growth, mitigates cardiovascular risk factors and reduces the prevalence of the metabolic syndrome, at no increased risk of acute rejection or unstable graft function.

Treatment strategies in pediatric solid organ transplant recipients with calcineurin inhibitor-induced nephrotoxicity.

Abstract:  Although short‐term kidney allograft survival has improved significantly since the introduction of the calcineurin inhibitors (CNI) cyclosporine A (CsA) and tacrolimus, long‐term transplant survival remains a major concern, chronic allograft nephropathy (CAN) being the principal reason for graft loss after the first post‐transplant year. This is particularly major for pediatric renal transplant recipients because of their higher life expectancy compared with adults. The mechanisms leading to CAN are multiple, including acute and chronic alloimmune responses and nephrotoxicity of CNIs. CNI‐induced nephrotoxicity is also a long‐term concern in other pediatric solid organ transplant recipients, such as liver and heart. Prevention of allograft nephropathy requires a balance of maintaining adequate immunosuppression, while avoiding the toxic effects of CNIs. Regimens that are based on mycophenolate mofetil (MMF) alone or in combination with newer agents may allow for reduced reliance on CNIs and thus may represent an effective treatment paradigm for long‐term maintenance of a renal allograft. From the available data it appears that the currently safest treatment strategy in pediatric renal and heart transplant recipients with CNI toxicity is an MMF‐based therapy with low‐dose CNIs ± low‐dose steroids, while in pediatric liver transplant recipients, CNI‐free MMF‐based immunosuppressive therapy with or without steroids appears feasible in a significant subset of patients. In renal transplant recipients, the benefit of a CNI‐free MMF/steroid therapy on renal function is gained at the cost of increased rejection in a subset of patients, although the relative importance of rejection vs. overall renal function requires further clinical investigation. The introduction of mammalian target of rapamycin (mTOR) inhibitors provides an opportunity for unique CNI‐sparing regimens that combine two antiproliferative agents (MMF and TOR inhibitors). It is possible that a sirolimus‐based CNI‐free immunosuppressive regimen in terms of renal transplant survival is superior to CNI minimization, where the detrimental effects of CNIs on allograft function and structure are still operative, albeit to a lesser degree. Substitution of CNIs by mTOR inhibitors is therefore promising, but requires validation in long‐term studies in large cohorts.

(Val-)Ganciclovir prophylaxis reduces Epstein-Barr virus primary infection in pediatric renal transplantation

Epstein‐Barr virus (EBV) primary infection constitutes a serious risk for pediatric transplant recipients, particularly as regards the development of EBV‐related post‐transplant lymphoproliferative disease (PTLD). Currently, there is no established prophylactic regimen. We investigated the association between chemoprophylaxis with valganciclovir (VGCV) or ganciclovir (GCV) and the incidence of EBV viremia in EBV‐naïve pediatric renal transplant recipients (R−) who had received a graft from an EBV‐positive donor (D+) and are therefore at high risk of EBV primary infection. In a prospective, multicenter trial (n = 114), we compared a cohort on chemoprophylaxis (n = 20) with a similar control cohort without chemoprophylaxis (n = 8). Over the 1‐year study period, antiviral prophylaxis with VGCV/GCV was associated with a significantly decreased incidence of EBV primary infection: 9/20 patients (45%) in the prophylaxis group experienced an EBV primary infection compared to 8/8 controls (100%) (P < 0.0001). Chemoprophylaxis was associated with a significantly lower EBV viral load (P < 0.001). Type or intensity of immunosuppressive therapy did not influence the occurrence of EBV primary infection or the level/persistence of EBV viral load. Chemoprophylaxis with VGCV/GCV is associated with a reduced incidence of EBV viremia in high‐risk pediatric kidney allograft recipients in the first year post‐transplant.

Prospective, randomized trial on late steroid withdrawal in pediatric renal transplant recipients under cyclosporine microemulsion and mycophenolate mofetil.

Background. Many transplant centers practice late steroid withdrawal after pediatric renal transplantation, but evidence-based data on the overall risk-to-benefit ratio in this patient population are lacking. Methods. We therefore conducted the first prospective, randomized, open-label multicenter study to validate this strategy: 42 low-immunologic risk pediatric kidney allograft recipients, aged 10.3±4.3 years, on cyclosporine microemulsion, mycophenolate mofetil, and corticosteroids were randomly assigned, more than or equal to 1-year posttransplant, to continue steroids or to withdraw over 3 months. This report contains the 1-year results. Results. In response to steroid withdrawal, patients experienced a significant catch-up growth with a mean standardized height gain of 0.3±0.1 standard deviation score (SDS) per year (P<0.05 vs. control), whereas mean height SDS in the control group did not change (0.0±0.1 SDS). Standardized body mass index declined significantly by 0.68±0.23 SDS after steroid withdrawal, but rose significantly by 0.26±0.34 SDS in the control group. Patients off steroids had less frequent arterial hypertension (50% vs. 87.5% (P<0.05) and significantly lower serum cholesterol (by 21%) and triglyceride values (by 36%) than control patients. Patient and graft survival were 100%. The incidence of acute rejection episodes in the steroid-withdrawal group was 1 of 23 (4%) compared with 1 of 19 (5%) in controls. Transplant function remained stable in both groups. Conclusion. Late steroid withdrawal in low-immunologic risk European pediatric kidney transplant recipients on cyclosporine microemulsion and mycophenolate mofetil is not associated with an increased rate of acute rejection episodes, enables catch-up growth and ameliorates cardiovascular risk factors.

Efficacy and safety of basiliximab in pediatric renal transplant patients receiving cyclosporine, mycophenolate mofetil, and steroids

Background. Basiliximab, a monoclonal CD25 antibody has proofed effective in reducing acute rejection episodes in adults in various immunosuppressive regimens. The effect of basiliximab in the pediatric population is controversial. Methods. In a 12-month, double-blind, placebo-controlled trial, renal transplant patients aged 1 to 18 years were randomized to basiliximab or placebo with cyclosporine microemulsion, mycophenolate mofetil, and corticosteroids. The intent-to-treat population comprised 192 patients (100 basiliximab and 92 placebo). Results. The primary efficacy endpoint, time to first biopsy-proven acute rejection episode, or treatment failure by month 6, occurred in 16.7% of basiliximab-treated patients and 21.7% of placebo-treated patients (Kaplan-Meier estimates; hazard ratio 0.72, two-sided 90% confidence interval 0.416–1.26, n.s.). The rate and severity of subclinical rejections in protocol biopsies performed at 6 months posttransplant was higher in the basiliximab group (25.0%) than in the placebo group (11.7%). Patient and death-censored graft survival at 12 months was 97% and 99%, respectively, in the basiliximab cohort, and 100% and 99% among placebo-treated patients (n.s.). Renal function was similar in both treatment groups, and there were no significant between-treatment differences in the incidence of adverse events or infections. Conclusions. Addition of basiliximab induction to a regimen of cyclosporine microemulsion, mycophenolate mofetil, and steroids resulted in a numerically lower but not significant incidence of biopsy-proven acute rejection versus placebo and excellent graft and patient survival at 1 year in pediatric renal transplant recipients. Whether this numerical difference is a true therapeutic benefit in view of the higher rate and severity of subclinical rejections in the basiliximab group in the protocol biopsy will be investigated in a long-term follow-up study.

Mycophenolate mofetil suspension in pediatric renal transplantation: three-year data from the tricontinental trial.

Abstract:  Mycophenolate mofetil (MMF) is widely used to prevent acute rejection in adult solid organ transplant recipients, but data in children and adolescents are scarce. This prospective, multicenter, open‐labeled, single‐arm study investigated the efficacy and safety of an MMF‐based immunosuppressive regimen in 100 pediatric renal transplant recipients over a 3‐yr period of time. Three age groups were formed (<6 yr, n = 33; 6 to <12 yr, n = 34; 12–18 yr, n = 33). Basic immunosuppression consisted of MMF (600 mg/m2 b.i.d), cyclosporin A microemulsion and corticosteroids. Seventy‐three percent of patients were given anti‐lymphocyte antibody induction therapy, of whom 74% received anti‐thymocyte globulin. Patient and graft survival 3 yr after transplantation amounted to 98 and 95%, respectively. Twenty‐five percent of all patients suffered a biopsy‐proven acute rejection episode in the first 6 month post‐transplant. Children undergoing induction therapy exhibited a numerically lower rejection rate (21 vs. 37%, p = 0.11). Three years after transplantation, the acute rejection rate added up to 30% (26% with induction therapy vs. 41% without induction therapy, p = 0.21). The number of patients with acute rejection was lowest in the youngest age group (18%), in comparison with 39% in the 6 to <12 yr and 33% in the 12–18 yr age group, respectively. For the entire patient population, the rate of patients who withdrew prematurely because of adverse events was low (12%). The present study shows that MMF therapy in pediatric renal transplant recipients leads to an excellent patient and graft survival 3 yr post‐transplant with an acceptable safety profile.

SRL-based immunosuppression vs. CNI minimization in pediatric renal transplant recipients with chronic CNI nephrotoxicity

Abstract:  Because calcineurin inhibitor (CNI)‐induced nephrotoxicity contributes significantly to late renal allograft loss, sirolimus (SRL)‐based, CNI‐free maintenance immunosuppression has been advocated, but data in the pediatric population are scarce. We therefore analyzed the efficacy and safety of an SRL‐based immunosuppressive regimen plus mycophenolate mofetil (MMF) and corticosteroids vs. CNI minimization (mean dose reduction by 39%) plus MMF and corticosteroids in 19 pediatric recipients with biopsy‐proven CNI‐induced nephrotoxicity in a single‐center case–control study. In the SRL group, we observed, one yr after study entry, an improvement of glomerular filtration rate (GFR) by 10.3 ± 3.0 mL/min/1.73 m2 (p < 0.05 vs. baseline) in seven of 10 patients and a stabilization in the remaining three, while in the CNI minimization group GFR improved by 17.7 ± 7.1 mL/min/1.73 m2 (p < 0.05) in six of nine recipients and stabilized in the remaining three. No patient in either group experienced an acute rejection episode. The main adverse event under SRL therapy was a transient hyperlipidemia in 70% of patients. In pediatric renal transplant recipients with declining graft function because of CNI‐induced nephrotoxicity, CNI withdrawal and switch to SRL‐based therapy or CNI minimization are associated with a comparable improvement of GFR after 12 months of observation.