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Heiko Billing,
Anja Sander,
Caner Süsal,
Jörg Ovens, Reinhard Feneberg,
Britta Höcker,
Karel Vondrak,
Ryszard Grenda,
Stybjorn Friman,
David V Milford,
Mihai Lucan,
Gerhard Opelz,
Burkhard Tönshoff
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ABSTRACT: Biomarker-based post-transplant immune monitoring for the prediction of impending graft rejection requires validation in specific patient populations. Serum of 28 pediatric renal transplant recipients within the framework of a well-controlled prospective randomized trial was analyzed pre- and post-transplant for soluble CD30 (sCD30), a biomarker reflecting mainly T-cell reactivity, and anti-human leukocyte antigen (anti-HLA) antibody reactivity, a biomarker for B-cell activation. A sCD30 concentration ≥40.3 U/ml on day 14 was able to discriminate between patients with or without biopsy-proven acute rejection (BPAR) with a sensitivity of 100% and a specificity of 76%. Six of seven patients (86%) with BPAR showed a sCD30 above this cut-off, whereas only 3/21 patients (14%) without BPAR had a sCD30 above this cut-off (P = 0.004). For pre- and post-transplant anti-HLA class II reactivities by enzyme-linked immunosorbent assay, a cut-off value of 140 optical density was able to discriminate rejecters from nonrejecters with a sensitivity of 86% or 71% and a specificity of 81% or 90%, respectively. Withdrawal of steroids was associated with a approximately twofold higher serum sCD30 compared to controls, but did not affect anti-HLA reactivities. An increased post-transplant sCD30 serum concentration and positive pre- and post-transplant anti-HLA class II reactivities are informative biomarkers for impending BPAR in pediatric renal transplant recipients. (TWIST, Clinical Trial No: FG-506-02-43).
Transplant International 12/2012; · 2.92 Impact Factor
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Britta Höcker,
Helmut Fickenscher,
Henri-Jacques Delecluse,
Stephan Böhm,
Uta Küsters,
Paul Schnitzler,
Martin Pohl,
Ulrike John,
Markus J Kemper,
Henry Fehrenbach,
Marianne Wigger,
Martin Holder,
Monika Schröder,
Heiko Billing,
Alexander Fichtner, Reinhard Feneberg,
Anja Sander,
Sabine Köpf-Shakib,
Caner Süsal,
Burkhard Tönshoff
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ABSTRACT: Background. The epidemiology and morbidity of Epstein-Barr virus (EBV) infection in pediatric renal transplant recipients have been characterized insufficiently.Methods. In a prospective, multicenter study among 106 pediatric kidney allograft recipients, aged 11.4±5.9 years, we investigated the epidemiology of EBV infection, the relationship between EBV load, EBV serology and EBV-related morbidity (PTLD or symptomatic EBV infection defined as flu-like symptoms or infectious mononucleosis).Results. EBV primary infection occurred in 27 of 43 (63%) seronegative, and reactivation/reinfection in 28 of 63 (44%) seropositive patients. There was no association between the degree or duration of EBV load and EBV-related morbidity: The vast majority (17 of 18 (94%) patients) with a high, persistent EBV load remained PTLD-free throughout a follow-up of 5.0±1.3 years, while 2 of 3 (66%) patients with EBV-related PTLD exhibited only a low EBV load beforehand. Eight of 18 (44%) patients with a high, persistent EBV load remained asymptomatic during a follow-up of 5.3±2.9 years. Multivariate analysis identified the EBV high-risk (D+/R-) serostatus (OR 7.07, P<.05), the presence of HLA-DR7 (OR 5.65, P<.05), and the intensity of the immunosuppressive therapy, (OR 1.53, P<.01) as independent risk factors for the development of a symptomatic EBV infection.Conclusions. Presence of EBV high-risk seroconstellation, HLA-DR7, and intensity of immunosuppressive therapy are significant risk factors for a symptomatic EBV infection, while there is no close association between the degree or duration of EBV load and EBV-related morbidity.
Clinical Infectious Diseases 10/2012; · 9.15 Impact Factor
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Britta Höcker,
Stephan Böhm,
Helmut Fickenscher,
Uta Küsters,
Paul Schnitzler,
Martin Pohl,
Ulrike John,
Markus J Kemper,
Henry Fehrenbach,
Marianne Wigger,
Martin Holder,
Monika Schröder, Reinhard Feneberg,
Sabine Köpf-Shakib,
Burkhard Tönshoff
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ABSTRACT: 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. (ClinicalTrials.gov number: NCT00963248).
Transplant International 04/2012; 25(7):723-31. · 2.92 Impact Factor
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ABSTRACT: Peritonitis is a common complication of chronic peritoneal dialysis (CPD) and can be associated with technique failure. Enterococcus is an uncommon peritoneal pathogen in children receiving CPD but represents a potential therapeutic challenge due to its innate resistance to cephalosporins and emerging resistance to glycopeptides.
The International Pediatric Peritonitis Registry is a global consortium of 47 paediatric dialysis centres designed to address validation of the International Society for Peritoneal Dialysis paediatric peritonitis treatment guidelines. Between 2001 and 2004, peritonitis episodes were assessed in 392 participating children receiving CPD.
Among the 392 patients, 340 episodes of culture-positive peritonitis were evaluated. Twenty of these episodes were due to Enterococcus species (5.9%). There were no clinical characteristics uniquely associated with enterococcal peritonitis at presentation. After 3 days of therapy, 75% of patients were pain free, 95% had decreased effluent cloudiness and 90% were afebrile. Only one patient required a catheter exchange, and all patients experienced full functional recovery. Despite broad in vitro resistance to cephalosporins and 21% resistance to glycopeptides, neither in vitro resistance pattern nor choice of empiric antibiotic regimen affected short- or long-term outcomes.
Enterococci are likely responsible for ∼6% of culture-positive peritonitis episodes in children receiving CPD. Although it was not possible to identify patients with enterococcal peritonitis based on presentation, clinical response was not associated with in vitro resistance patterns, and patients who initially received a cephalosporin-based empiric regimen until culture results are available are likely to respond quickly and have full functional recovery.
Nephrology Dialysis Transplantation 12/2010; 25(12):4048-54. · 3.40 Impact Factor
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ABSTRACT: Pharmacokinetic monitoring of CsA is unsatisfactory, because at comparable CsA blood concentrations, the frequency and severity of adverse effects vary considerably among patients. We have therefore recently developed a precise, reliable, and robust whole-blood pharmacodynamic assay that measures the suppression of CsA-target genes in T lymphocytes. Because of the different characteristics of CsA pharmacokinetics in children and the higher propensity for infectious complications, this assay requires validation in the pediatric patient population. We therefore quantified in a prospective study of 45 pediatric renal transplant recipients the residual expression of NFAT-regulated genes in lymphocytes by RT-PCR and correlated these findings with the frequency of recurrent infections in the maintenance period post-transplant. Patients with recurrent infections showed a significantly stronger inhibition of NFAT-regulated gene expression (18.2%) than patients without recurrent infections (31.7%; p = 0.012). This difference was specific, because various PK parameters of CsA and the concomitant immunosuppressive therapy were comparable between patients. Multivariate regression analysis showed that patient age and residual NFAT-regulated gene expression were the only independent determinants of recurrent infections. By ROC curve analysis, a cutoff value of 23% residual NFAT-regulated gene expression had the highest sensitivity (71.1%) and specificity (65.4%) for the discrimination of patients with and without recurrent infections. Pharmacodynamic monitoring of CsA by measurement of residual NFAT-regulated gene expression in T lymphocytes has the potential to identify over-immunosuppressed pediatric renal transplant recipients and is therefore a useful tool for the optimization of CsA therapy.
Pediatric Transplantation 11/2010; 14(7):844-51. · 1.48 Impact Factor
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ABSTRACT: Ethical concerns and disadvantages of newborn screening (NBS) for cystic fibrosis (CF) related to genetic testing have raised controversies and impeded implementation of CF NBS in some countries. In the present study, we used a prospective and sequential immunoreactive trypsinogene (IRT)/pancreatitis-associated protein (PAP) strategy, with IRT as first and PAP as second tier, and validated this biochemical approach against the widely used IRT/DNA protocol in a population-based NBS study in southwest Germany.
Prospective quantitation of PAP and genetic analysis for the presence of four mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene most prevalent in southwest Germany (F508del, R553X, G551D, G542X) were performed in all newborns with IRT > 99.0th percentile. NBS was rated positive when either PAP was ≥1.0 ng/mL and/or at least one CFTR mutation was detected. In addition, IRT > 99.9th percentile was also considered a positive rating. Positive rating led to referral to a CF centre for testing of sweat Cl(-) concentration.
Out of 73,759 newborns tested, 98 (0.13%) were positive with IRT/PAP and 56 (0.08%) with IRT/DNA. After sweat testing of 135 CF NBS-positive infants, 13 were diagnosed with CF. Detection rates were similar for both IRT/PAP and IRT/DNA. One of the 13 diagnosed CF newborns had a PAP concentration <1.0 ng/mL.
Sequential measurement of IRT/PAP provides good sensitivity and specificity and allows reliable and cost-effective CF NBS which circumvents the necessity of genetic testing with its inherent ethical problems.
Journal of Inherited Metabolic Disease 10/2010; 33(Suppl 2):S263-71. · 3.58 Impact Factor
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ABSTRACT: Imexon [AOP99.0001 (4-imino-1,3-diazobicyclo[3. 1. 0]-hexan-2-one)] belongs to a novel class of promising anticancer agents that induce tumor apoptosis through oxidative stress. Clinical experience since the late 1960s has provided initial evidence for a clinical antitumor activity. Our open-label, multicenter phase I clinical trial was designed to further investigate the adverse event (AEs) profile and pharmacokinetics of AOP99.0001 in pretreated myeloma patients and collect initial data on the potential clinical efficacy in this indication. Thirty-six patients with relapsed or refractory myeloma, who had been pretreated with at least two lines of therapy earlier, were included. Imexon was applied intravenously on 5 consecutive days for 2 weeks (d1-5 and d8-12) for a 3-week cycle. The plasma half-life of AOP99.0001 and its active metabolite AOP99.0002 was found to be approximately 1.2 and 2.6 h, respectively. The mean duration of treatment with Imexon was 6.8 weeks in a dose range between 50 and 1000 mg/m without reaching dose-limiting toxicity. Drug-related AEs occurring with a frequency of greater than 10% were fatigue, nausea, constipation, headache, asthenia, anemia, thrombocytopenia, leukopenia and creatinine increase. A total of nine severe adverse events occurred in three patients. No mortality was encountered when patients were on treatment with Imexon. Preliminary antimyeloma efficacy of AOP99.0001 was observed with 1 minimal response, 12 (36%) stable disease responses, and all other evaluable patients had progressive disease. Remarkably, the patient with minimal response also experienced a complete clinical resolution of myeloma-associated polyneuropathy. Overall, Imexon was safe and well tolerated in the dose range investigated. Imexon showed minor clinical activity as a single agent in heavily pretreated myeloma patients. On account of its unique mechanism of action, favorable toxicity profile, initial clinical evidence for antimyeloma activity, and its known synergistic activity in combination with approved agents for myeloma treatment, AOP99.0001 is recommended for future clinical studies in combination regimens in multiple myeloma.
Anti-cancer drugs 08/2010; 21(7):708-15. · 2.23 Impact Factor
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Jerome C Lane,
Bradley A Warady, Reinhard Feneberg,
Nancy L Majkowski,
Alan R Watson,
Michel Fischbach,
Hee Gyung Kang,
Klaus E Bonzel,
Eva Simkova,
Constantinos J Stefanidis,
Günter Klaus,
Steven R Alexander,
Mesiha Ekim,
Ilmay Bilge,
Franz Schaefer
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ABSTRACT: The International Pediatric Peritonitis Registry (IPPR) was established to collect prospective data regarding peritoneal dialysis (PD)-associated peritonitis in children. In this report, we present the IPPR results that pertain to relapsing peritonitis (RP).
This was an online, prospective entry into the IPPR of data that pertain to peritonitis cases by participating centers.
Of 490 episodes of nonfungal peritonitis, 52 (11%) were followed by a relapse. There was no significant difference between RP and non-RP in distribution of causative organisms and antibiotic sensitivities. Initial empiric therapy-ceftazidime with either first-generation cephalosporin or glycopeptide (vancomycin or teicoplanin)-was not associated with relapse. Switching to monotherapy with a first-generation cephalosporin on the basis of culture results was associated with higher relapse rate (23%) than other final antibiotic therapies (0 to 9%). Culture-negative RP was less likely to have a satisfactory early treatment response than non-RP (82 versus 98%). Young age, single-cuff catheter, downward-pointing exit site, and chronic systemic antibiotic prophylaxis were additional independent risk factors for RP in the multivariate analysis. Compared with non-RP, RP was associated with a lower rate of full functional recovery (73 versus 91%), higher ultrafiltration problems (14 versus 2%), and higher rate of permanent PD discontinuation (17 versus 7%).
This is the largest multicenter, prospective study to date to examine RP in children. In addition, this is the first report in the literature to examine specifically the relationship of postempiric antibiotic treatment regimens to the subsequent risk for relapse.
Clinical Journal of the American Society of Nephrology 06/2010; 5(6):1041-6. · 5.23 Impact Factor
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Britta Höcker,
Lutz T Weber, Reinhard Feneberg,
Jens Drube,
Ulrike John,
Henry Fehrenbach,
Martin Pohl,
Miriam Zimmering,
Stefan Fründ,
Günter Klaus,
Elke Wühl,
Burkhard Tönshoff
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ABSTRACT: 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.
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.
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%).
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.
Nephrology Dialysis Transplantation 09/2009; 25(2):617-24. · 3.40 Impact Factor
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Britta Höcker,
Lutz T Weber, Reinhard Feneberg,
Jens Drube,
Ulrike John,
Henry Fehrenbach,
Martin Pohl,
Miriam Zimmering,
Stefan Fründ,
Günter Klaus,
Elke Wühl,
Burkhard Tönshoff
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ABSTRACT: : 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.
: 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.
: 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.
: 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.
Transplantation 03/2009; 87(6):934-41. · 4.00 Impact Factor
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Aleksandra Zurowska, Reinhard Feneberg,
Bradley A Warady,
Miriam Zimmering,
Maria Monteverde,
Sara Testa,
Salim Calyskan,
Dorota Drozdz,
Isidro Salusky,
Markus J Kemper,
Mesiha Ekim,
Enrico Verrina,
Joachim Misselwitz,
Franz Schaefer
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ABSTRACT: The proportion of gram-negative causative organisms in peritoneal dialysis-associated peritonitis is increasing. Little published information for this complication exists in children. The objective of this study is to evaluate the clinical presentation, early and late response to treatment, and identification of factors influencing the outcome of gram-negative peritonitis (GNP) in children.
Case series.
104 children (aged 7.9 +/- 5.9 years) with 121 GNP episodes reported to the International Pediatric Peritonitis Registry from October 2001 through December 2004.
Patient, clinical, bacteriological, and treatment features.
Initial response to empirical treatment was assessed after approximately 72 hours of therapy. Final outcome was judged according to the occurrence of death, technique failure, relapse, need for catheter exchange, and a composite end point defining full functional recovery.
44% of episodes of GNP occurred in children younger than 5 years. Causative organisms included Pseudomonas species, 21%; Klebsiella species, 18%; Escherichia coli, 17%; and Acinetobacter species, 12%. Thirty-two percent of organisms classified as gram-negative were not identified further. Clinical manifestations were severe and uniform for all causative gram-negative agents. A substantial proportion (20%) of organisms were resistant to ceftazidime, with resulting suboptimal response to empirical therapy. By day 3 of initial empiric treatment, 85% of children with GNP had improved clinically (39%, complete resolution; 46%, improvement in symptoms), 10% showed poor response, and 5% had worsening of symptoms. Multivariate analysis identified severe abdominal pain, use of a single-cuff catheter, and intermittent (versus continuous) intraperitoneal ceftazidime administration as independent predictors of worse initial response to treatment. Full functional recovery was achieved in 86% of episodes. Nineteen patients (16%) required catheter removal, 11 (9%) experienced a relapse, 7 (6%) discontinued peritoneal dialysis therapy permanently, and 3 died. Lack of clinical improvement after 72 hours of therapy (odds ratio, 5.39; P < 0.01) and the presence of an exit-site infection (odds ratio, 7.69; P = 0.01) independently increased the risk of an incomplete functional recovery.
The study was not designed to assess absolute incidence figures or risk factors for the development of GNP in children.
GNP is a significant complication of long-term peritoneal dialysis therapy in children, and a substantial proportion of affected children are at risk of permanent sequelae. Because results of empiric treatment with ceftazidime are suboptimal in the setting of this infection, alternative antimicrobial agents should be reconsidered.
American Journal of Kidney Diseases 03/2008; 51(3):455-62. · 5.43 Impact Factor
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Bradley A Warady, Reinhard Feneberg,
Enrico Verrina,
Joseph T Flynn,
Dirk E Müller-Wiefel,
Nesrin Besbas,
Aleksandra Zurowska,
Nejat Aksu,
Michel Fischbach,
Ernesto Sojo,
Osman Donmez,
Lale Sever,
Aydan Sirin,
Steven R Alexander,
Franz Schaefer
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ABSTRACT: In children who are on chronic peritoneal dialysis, peritonitis is the primary complication compromising technique survival, and the optimal therapy of peritonitis remains uncertain. An Internet-based International Pediatric Peritonitis Registry was established in 47 pediatric centers from 14 countries to evaluate the efficacy and safety of largely opinion-based peritonitis treatment guidelines in which empiric antibiotic therapy was stratified by disease severity. Among a total of 491 episodes of nonfungal peritonitis entered into the registry, Gram-positive organisms were cultured in 44%, Gram-negative organisms were cultured in 25%, and cultures remained negative in 31% of the episodes. In vitro evaluation revealed 69% sensitivity of Gram-positive organisms to a first-generation cephalosporin and 80% sensitivity of Gram-negative organisms to a third-generation cephalosporin. Neither the risk factors assumed by the guidelines nor the choice of empiric therapy was predictive of either the early treatment response or the final functional outcome of the peritonitis episodes. Overall, 89% of cases achieved full functional recovery, a portion after relapsing peritonitis (9%). These data serve as the basis for new evidence-based guidelines. Modification of empiric therapy to include aminoglycosides should be considered.
Journal of the American Society of Nephrology 08/2007; 18(7):2172-9. · 9.66 Impact Factor
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ABSTRACT: The comparative sensitivity of EEG and magnetoencephalography (MEG) in the visual detection of focal epileptiform activity in simultaneous interictal sleep recordings were investigated. The authors examined 14 patients aged 3.5 to 17 years with localization-related epilepsy. Simultaneous 122-channel whole-head MEG and 33-channel EEG were recorded for 20 to 40 minutes during spontaneous sleep. The EEG and MEG data were separated and four blinded independent reviewers marked the presence and timing of epileptic discharges (ED) in the 28 data segments. EEG and MEG data were matched and spikes identified by at least three reviewers were classified in three categories according to the following criteria: type 1 MEG > EEG, type 2 EEG > MEG (type 1/2: difference of three or more raters), and type 3 EEG = MEG (three or more raters each). The presence of simultaneous sleep changes was visually determined for every single EEG-segment. Spikes with high spatiotemporal correlation were averaged and subjected to single dipole analysis of peak activity in EEG. Out of 4704 marked patterns, 1387 spikes fulfilled the above criteria. In fact, more spikes were unique to MEG (689) than to EEG (136) and to the combination of both modalities (562). ED were detected predominantly by MEG in eight patients and by EEG in two patients. The presence of vertex waves and spindles lead to a significantly higher number of spikes identified only in MEG. Averaging of type 1 spikes produced clear spike activity in EEG in 9 of 12 cases. On the contrary, only 2 of 10 type 2 spikes were visible in MEG after averaging. Dipoles of spikes visible in MEG showed a more tangential orientation compared with more radial dipoles of type 2 spikes. Spike characteristics, e.g., dipole orientation, are a key factor for a sole EEG representation. Exclusive MEG detection is more likely influenced by overlapping background activity in EEG. Because MEG is indifferent to radial activity, i.e., sleep changes, a higher ratio of spikes unique to MEG compared with EEG is detected in the case of overlapping sleep changes.
Journal of Clinical Neurophysiology 01/2007; 23(6):498-508. · 1.45 Impact Factor
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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.
Pediatric Transplantation 08/2006; 10(5):593-601. · 1.48 Impact Factor
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ABSTRACT: Symptomatic patent ductus arteriosus (sPDA) is a common problem in premature infants and can be treated effectively with intravenous indomethacin, leading to permanent ductal closure in 70% to 80% of infants. Infants who do not respond to pharmacologic closure of the duct ultimately have to undergo surgical or interventional closure of the PDA. Optimizing the pharmacologic treatment could offer an interesting approach to reduce the number of infants who need surgical closure of the duct.
We conducted a retrospective analysis in infants who were <33 weeks' gestation, had sPDA, and were treated with high-dose intravenous indomethacin. From 1993 to 2002, 129 infants with sPDA received indomethacin after diagnosis of sPDA was confirmed by echocardiography. Treatment was started in all infants with intravenous indomethacin (0.2 mg/kg given 5 times at 0 hours, 12 hours, 24 hours, 48 hours, and 72 hours). When the ductus was still open at 36 hours, indomethacin every 12 hours was continued and single doses increased up to 1 mg/kg until ductal closure was achieved.
In 68 (53%) of 129 infants who were treated with indomethacin, ductal closure occurred during intermediate-dose indomethacin therapy (up to 1.5 mg/kg total dose). In the 61 initial nonresponders, the continuation of indomethacin led to ductal closure in 59 infants. When infants who were treated with an intermediate dose were compared with the initial nonresponders, no differences in the incidences of renal or electrolyte abnormalities, gastrointestinal bleeding, intraventricular hemorrhage, or periventricular leukomalacia were found.
High-dose indomethacin after intermediate-dose therapy resulted in an overall closure rate of 98.5% (127 of 129). Although single indomethacin doses of up to 1 mg/kg were given, high-dose indomethacin was safe.
PEDIATRICS 12/2005; 116(6):1361-6. · 4.47 Impact Factor
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ABSTRACT: Recommendations for the management of peritoneal dialysis-associated peritonitis in children have recently been developed by an International Society for Peritoneal Dialysis (ISPD) expert committee. The International Pediatric Peritonitis Registry (IPPR) was established in October 2001 as a global consortium of 47 pediatric dialysis centers in order to assess the validity of these guidelines.
The IPPR is an internet-based registry collecting data on pediatric peritonitis episodes treated according to the ISPD guidelines. Data on 375 episodes have been collected as of July 2004. DATA ACQUISITION: Detailed data are obtained online on the diagnosis of peritonitis, antibiotic and adjunctive therapy, as well as on possible risk factors and treatment results.
Final data analysis of the IPPR will yield extensive information on the treatment and outcome of peritoneal dialysis-associated peritonitis in children.
Peritoneal dialysis international: journal of the International Society for Peritoneal Dialysis 03/2005; 25 Suppl 3:S130-4. · 2.10 Impact Factor
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ABSTRACT: Renal transplantation in children and adolescents is associated with various skeletal complications. The incidence of spontaneous fractures appears to be increased, but the reasons for this are not entirely clear. Our objective was therefore to evaluate macroscopic bone architecture, mass, and strength by peripheral quantitative computed tomography (pQCT), a method that is not influenced by size-related artifacts. In addition, we investigated the muscle-bone relationship in these patients because under physiologic conditions bone strength continually adapts to increasing mechanical loads, that is, muscle force.
In 55 patients (41 males) aged 15.8 +/- 4.1 years, we evaluated in a cross-sectional study 4.9 +/- 3.6 years after renal grafting bone mass, density, geometry, and strength of the radius, as well as forearm muscle size and strength, using pQCT at the proximal and distal radius, radiography of the second metacarpal shaft and hand dynamometry. Data were compared to a large cohort (N= 350) of healthy children.
Muscle mass and force were adequate for body size in pediatric renal transplant recipients. However, the radial bone was characterized by an inadequately thin cortex in relation to muscular force, as shown by a reduced height-adjusted cortical thickness both at the proximal (-0.83 +/- 1.12 SDS) and distal radius (-0.52 +/- 1.69 SDS), the metacarpal shaft (-0.54 +/- 1.35 SDS), and by a reduced relative cortical area (-0.90 +/- 1.13 SDS), while the mineralization of trabecular bone was unaltered. As a consequence of cortical thinning, the Strength-Strain Index that reflects the combined strength of trabecular and cortical bone was reduced in these patients.
While bone mineral density of the forearm is not decreased in pediatric renal transplant recipients, bone strength in relation to muscular force is reduced. This alteration may contribute to the increased propensity for fractures in these patients.
Kidney International 11/2004; 66(4):1694-706. · 6.61 Impact Factor
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ABSTRACT: The current focus of cyclosporin A (CsA) monitoring in adult transplantation for optimized immunosuppression is on the early portion of the CsA area under the concentration-time curve (AUC), particularly in the first 4 hours postdose, designated as AUC(0-4), and on the blood concentration 2 hours postdose (C2) as a highly predictive marker for AUC(0-4). Because data in pediatric patients are scarce, full-time (12 hours) and absorption profiles of CsA were analyzed in relation to CsA effectiveness in 61 pediatric renal transplant recipients aged 3.2 to 17.4 years on an immunosuppressive triple regimen with CsA, mycophenolate mofetil, and methylprednisolone. CsA dosing was based on body surface area and adjusted to CsA trough levels. Pharmacokinetic (PK) profiles were obtained 1 and 3 weeks (initial period) and 3 and 6 months posttransplant (stable period). Patients with an AUC(0-4) < 4400 microg x h/L at both PK sampling periods in the first 3 weeks posttransplant had an adjusted relative risk of 48.4% to suffer an acute rejection episode (ARE), whereas in patients with at least 1 AUC0-4 above this threshold, the adjusted relative risk for an ARE was only 13.1% (P < 0.02). The single PK parameters C0 or C2 did not discriminate between patients with and without acute rejection. The PK parameters C1.25 (r2 = 0.64) or C2 (r2 = 0.60) showed a stronger relationship to the absorption profile (AUC(0-4)) than C0 (r2 = 0.15). An abbreviated profile consisting of the PK variables C(0.5;2) or C(0;0.5;2) showed the closest correlation to the absorption profile (r2 = 0.89) and the lowest percentage prediction error. These data indicate that absorption profiling in pediatric renal transplant recipients has the potential to optimize immunosuppressive therapy with CsA.
Therapeutic Drug Monitoring 08/2004; 26(4):415-24. · 2.49 Impact Factor
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ABSTRACT: Hypertension and noninsulin-dependent diabetes mellitus are usually associated with marked glucose intolerance. Hypertensive and even nonhypertensive diabetic individuals display disturbances of the normal circadian blood pressure rhythm. However, little is known about circadian changes of the glucose uptake in muscle and fat cells, the major glucose utilizing tissues. Therefore, we investigated circadian rhythms of glucose uptake in primary muscle and fat cell cultures of hypertensive and type II diabetic rats and their respective control strains. 2-Deoxy-D-(1-3H)glucose uptake was measured over 48 h after synchronization of cells by means of medium change with and without addition of insulin, phloretine, and/or staurosporine. The circadian changes of glucose uptake were assessed by fitting cosine curves to the uptake values. Insulin stimulation of deoxyglucose uptake was only present in control animals, not in hypertensive and diabetic rats. Deoxyglucose uptake displayed a circadian rhythm in control animals, and was markedly disturbed in hypertensive and diabetic animals. Blocking of glucose transporters by phloretine abolished the circadian pattern of deoxyglucose uptake indicating a role of glucose transporters in its generation. Inhibition of kinases by staurosporine inhibited the insulin-stimulated deoxyglucose uptake, but did not dampen the circadian rhythmicity of basal deoxyglucose uptake. The generation of the circadian rhythm of glucose uptake in muscle and fat cell cultures is therefore probably insulin independent and independent of protein kinases. In summary, our results show for the first time: (a) a circadian rhythm of deoxyglucose uptake in glucose utilizing muscle and fat cells in vitro, (b) a disruption of this rhythm in cells of hypertensive and diabetic rats.
Chronobiology International 08/2004; 21(4-5):521-38. · 4.03 Impact Factor
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ABSTRACT: Kidney transplantation remains the most effective treatment for children with end-stage renal disease. We analysed data from the University of Heidelberg transplant programme to present our results on paediatric kidney transplantations over the past 35 years.
From 1967 to 2003, 354 paediatric kidney transplantations were performed at the University of Heidelberg. Data were obtained from the paediatric kidney transplantation records consisting of 291 (82%) cadaveric and 63 (18%) living donated transplants. Demographic data, family relationship of the living donors, surgical technique, immunosuppressive drugs, graft and patient survival rates were assessed.
The mean age of cadaveric and living donors was 32.0+/-17.1 and 37.6+/-7.5 years, respectively. The family relationship of the living donors included the mother in 65% of cases, the father in 31%, and other relatives in 4%. In the last 4 years, the respective mean cold ischaemia time was 1.6+/-0.5 h for living donated and 13.5+/-4.1 h for cadaveric donors. The mean age of children who received kidneys from cadaveric and living donors was 11.3+/-4.5 and 10.4+/-4.5 years, respectively, with a male to female ratio of 57 to 43%. Overall patient survival rates were 95% after 1 year and 89% after 5 years. The patient 5 and 10 year survival rates for living donor renal transplantations were 95 and 95%, respectively. Graft survival rates improved since 1990 compared with the period prior to 1990: 82.5 vs 56.7% graft survival at 1 year and 82.5 vs 50% after 5 years (P = 0.03). Comparing the operating technique in a subgroup of our patients that received the same immunosuppressive regimen, anastomoses with the aorta and vena cava (51%, n = 31) were associated with a graft survival of 86.6 and 83.3% after 1 and 5 years, whereas anastomoses with iliac vessels (49%, n = 30) were associated with a graft survival of 55.8 and 51.6% after 1 and 5 years, respectively (P = 0.01).
There has been a gradual improvement in our paediatric kidney transplantation results over time. Living donor paediatric kidney transplants have higher patient and better graft survival rates than cadaveric donor kidney transplants. Using the aorta and inferior vena cava for graft anastomosis, utilizing newer immunosuppressive drugs and implementing living kidney donation have positively affected the results of our paediatric kidney transplantations.
Nephrology Dialysis Transplantation 08/2004; 19 Suppl 4:iv69-74. · 3.40 Impact Factor
