26 results on '"Ahlenstiel‐Grunow, T."'
Search Results
2. Impact of Everolimus and Low-Dose Cyclosporin on Cytomegalovirus Replication and Disease in Pediatric Renal Transplantation
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Höcker, B., Zencke, S., Pape, L., Krupka, K., Köster, L., Fichtner, A., Dello Strologo, L., Guzzo, I., Topaloglu, R., Kranz, B., König, J., Bald, M., Webb, N.J.A., Noyan, A., Dursun, H., Marks, S., Ozcakar, Z.B., Thiel, F., Billing, H., Pohl, M., Fehrenbach, H., Schnitzler, P., Bruckner, T., Ahlenstiel-Grunow, T., and Tönshoff, B.
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- 2016
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3. BK Polyomavirus-Specific Cellular Immune Responses Are Age-Dependent and Strongly Correlate With Phases of Virus Replication
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Schmidt, T., Adam, C., Hirsch, H.H., Janssen, M.W.W., Wolf, M., Dirks, J., Kardas, P., Ahlenstiel-Grunow, T., Pape, L., Rohrer, T., Fliser, D., Sester, M., and Sester, U.
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- 2014
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4. A multi-center interventional study to assess pharmacokinetics, effectiveness, and tolerability of prolonged-release tacrolimus after pediatric kidney transplantation: study protocol for a prospective, open-label, randomized, two-phase, two-sequence, single dose, crossover, phase III b trial.
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Karaterzi S, Tönshoff B, Ahlenstiel-Grunow T, Baghai M, Beck B, Büscher A, Eifler L, Giese T, Lezius S, Müller C, Oh J, Zapf A, Weber LT, and Pape L
- Abstract
Background: Tacrolimus, a calcineurin inhibitor (CNI), is currently the first-line immunosuppressive agent in kidney transplantation. The therapeutic index of tacrolimus is narrow due to due to the substantial impact of minor variations in drug concentration or exposure on clinical outcomes (i.e., nephrotoxicity), and it has a highly variable intra- and inter-individual bioavailability. Non-adherence to immunosuppressants is associated with rejection after kidney transplantation, which is the main cause of long-term graft loss. Once-daily formulations have been shown to significantly improve adherence compared to twice-daily dosing. Envarsus
® , the once-daily prolonged-release formulation of tacrolimus, offers the same therapeutic efficacy as the conventional twice-daily immediate-release tacrolimus formulation (Prograf® ) with improved bioavailability, a more consistent pharmacokinetic profile, and a reduced peak to trough, which may reduce CNI-related toxicity. Envarsus® has been approved as an immunosuppressive therapy in adults following kidney or liver transplantation but has not yet been approved in children. The objective of this study is to evaluate the pharmacokinetic profile, efficacy, and tolerability of Envarsus® in children and adolescents aged ≥ 8 and ≤ 18 years to assess its potential role as an additional option for immunosuppressive therapy in children after kidney transplantation., Methods/design: The study is designed as a randomized, prospective crossover trial. Each patient undergoes two treatment sequences: sequence 1 includes 4 weeks of Envarsus® and sequence 2 includes 4 weeks of Prograf® . Patients are randomized to either group A (sequence 1, followed by sequence 2) or group B (sequence 2, followed by sequence 1). The primary objective is to assess equivalency between total exposure (of tacrolimus area under the curve concentration (AUC0-24)), immediate-release tacrolimus (Prograf® ) therapy, and prolonged-release tacrolimus (Envarsus® ) using a daily dose conversion factor of 0.7 for prolonged- versus immediate-release tacrolimus. Secondary objectives are the assessment of pharmacodynamics, pharmacogenetics, adherence, gut microbiome analyses, adverse events (including tacrolimus toxicity and biopsy-proven rejections), biopsy-proven rejections, difference in estimated glomerular filtration rate (eGFR), and occurrence of donor-specific antibodies (DSAs)., Discussion: This study will test the hypothesis that once-daily prolonged-release tacrolimus (Envarsus® ) is bioequivalent to twice-daily intermediate-release tacrolimus after pediatric kidney transplantation and may reduce toxicity and facilitate medication adherence. This novel concept may optimize immunosuppressive therapy for more stable graft function and increased graft survival by avoiding T-cell mediated and/or antibody-mediated rejection due to improved adherence. In addition, the study will provide data on the pharmacodynamics and pharmacogenetics of prolonged-release tacrolimus in children and adolescents., Clinical Trial Registration: EUDRA-CT 2019-003710-13 and ClinicalTrial.gov, identifier NCT06057545., Competing Interests: LP, JO, and LW received honoraria as speakers from Chiesi Germany GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The study is an Investigator-initiated Trial and the University Hospital of Essen is the sponsor. The authors declare that this study received funding from Chiesi Germany GmbH. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Karaterzi, Tönshoff, Ahlenstiel-Grunow, Baghai, Beck, Büscher, Eifler, Giese, Lezius, Müller, Oh, Zapf, Weber and Pape.)- Published
- 2024
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5. Correction to: Novel ways to monitor immunosuppression in pediatric kidney transplant recipients-underlying concepts and emerging data.
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Ahlenstiel-Grunow T and Pape L
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- 2021
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6. Novel ways to monitor immunosuppression in pediatric kidney transplant recipients-underlying concepts and emerging data.
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Ahlenstiel-Grunow T and Pape L
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After pediatric kidney transplantation, immunosuppressive therapy is given to avoid acute and chronic rejections. However, the immunosuppression causes an increased risk of severe viral complications and bacterial infections and is associated with serious side effects. It is therefore crucial to achieve the optimal individual balance between over- and under-immunosuppression and thereby avoid unnecessary exposure to immunosuppressive drugs. In routine use, steering of immunosuppressants is performed primarily by monitoring of trough levels that mirror pharmacokinetics (although not, however, pharmacodynamics). Other diagnostic and prognostic markers to assess the individual intensity of immunosuppression are missing. Potential methods to determine immune function and grade of immunosuppression, such as analysis of the torque teno virus (TTV) load, QuantiFERON Monitor®, and ImmuKnow® as well as virus-specific T cells (Tvis), are currently being evaluated. In some studies TTV load, QuantiFERON Monitor® and ImmuKnow® were associated with the risk for post-transplant rejections and infections, but randomized controlled trials after pediatric kidney transplantation are not available. Post-transplant monitoring of Tvis levels seem to be promising because Tvis control virus replication and have been shown to correlate with virus-specific as well as general cellular immune defense, which represents the individual's susceptibility to infections. Additional Tvis-monitoring provides an innovative opportunity to personalize the antiviral management and the dosing of the immunosuppressive therapy after pediatric kidney transplantation to avoid unnecessary therapeutic interventions and identify over-immunosuppression., (© 2021. The Author(s).)
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- 2021
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7. Virus-specific T cells in pediatric renal transplantation.
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Ahlenstiel-Grunow T and Pape L
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- Antiviral Agents therapeutic use, Child, Herpesvirus 4, Human, Humans, Prospective Studies, T-Lymphocytes, BK Virus, Epstein-Barr Virus Infections, Kidney Transplantation adverse effects, Polyomavirus Infections
- Abstract
After pediatric kidney transplantation, immunosuppressive therapy causes an increased risk of severe viral complications, especially from cytomegalovirus (CMV), BK polyomavirus (BKPyV) or Epstein-Barr virus (EBV), and less frequent from adenovirus (ADV). However, suitable predictive markers for the individual outcome of viral infections are missing and the therapeutic management remains a challenge to the success of pediatric kidney transplantation. Virus-specific T cells are known for controlling viral replication and there is growing evidence that virus-specific T cells may serve as a prognostic marker to identify patients at risk for viral complications. This review provides an overview of the usability of virus-specific T cells for improving diagnostic and therapeutic management of viral infections with reference to the necessity of antiviral prophylaxis, timing of pre-emptive therapy, and dosing of immunosuppressive medication after pediatric kidney transplantation. Several studies demonstrated that high levels of virus-specific T cells are associated with decrease of virus load and favorable outcome, whereas lack of virus-specific T cells coincided with virus-induced complications. Accordingly, the additional monitoring of virus-specific T cells aims to personalize the management of antiviral therapy, identify overimmunosuppression, and avoid unnecessary therapeutic interventions. Prospective randomized trials in pediatric kidney recipients comparing standard antiviral and immunosuppressive regimens with T cell-guided therapeutic interventions are needed, before monitoring of virus-specific T cells is implemented in the routine care of pediatric kidney graft recipients.
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- 2021
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8. Steering Transplant Immunosuppression by Measuring Virus-Specific T Cell Levels: The Randomized, Controlled IVIST Trial.
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Ahlenstiel-Grunow T, Liu X, Schild R, Oh J, Taylan C, Weber LT, Staude H, Verboom M, Schröder C, Sabau R, Großhennig A, and Pape L
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- Adolescent, CD4 Lymphocyte Count, Child, Child, Preschool, Drug Administration Schedule, Drug Monitoring, Female, Graft Rejection blood, Graft Rejection diagnosis, Humans, Infant, Kidney Failure, Chronic blood, Kidney Failure, Chronic etiology, Male, Cyclosporine administration & dosage, Everolimus administration & dosage, Graft Rejection prevention & control, Immunosuppressive Agents administration & dosage, Kidney Failure, Chronic surgery, Kidney Transplantation
- Abstract
Background: Pharmacokinetic monitoring is insufficient to estimate the intensity of immunosuppression after transplantation. Virus-specific T cells correlate with both virus-specific and general cellular immune defense. Additional steering of immunosuppressive therapy by virus-specific T cell levels might optimize dosing of immunosuppressants., Methods: In a multicenter, randomized, controlled trial, we randomized 64 pediatric kidney recipients to a control group with trough-level monitoring of immunosuppressants or to an intervention group with additional steering of immunosuppressive therapy by levels of virus-specific T cells (quantified by cytokine flow cytometry). Both groups received immunosuppression with cyclosporin A and everolimus in the same target range of trough levels. Primary end point was eGFR 2 years after transplantation., Results: In the primary analysis, we detected no difference in eGFR for the intervention and control groups 2 years after transplantation, although baseline eGFR 1 month after transplantation was lower in the intervention group versus the control group. Compared with controls, patients in the intervention group received significantly lower daily doses of everolimus and nonsignificantly lower doses of cyclosporin A, resulting in significantly lower trough levels of everolimus (3.5 versus 4.5 µ g/L, P <0.001) and cyclosporin A (47.4 versus 64.1 µ g/L, P <0.001). Only 20% of patients in the intervention group versus 47% in the control group received glucocorticoids 2 years after transplantation ( P =0.04). The groups had similar numbers of donor-specific antibodies and serious adverse events., Conclusions: Steering immunosuppressive therapy by virus-specific T cell levels in addition to pharmacokinetic monitoring seems safe, results in a similar eGFR, and personalizes immunosuppressive therapy by lowering exposure to immunosuppressive drugs, likely resulting in lower drug costs., Clinical Trial Registry Name and Registration Number: IVIST trial, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2009-012436-32 and ISRCTN89806912., (Copyright © 2021 by the American Society of Nephrology.)
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- 2021
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9. BK Polyomavirus-specific T Cells as a Diagnostic and Prognostic Marker for BK Polyomavirus Infections After Pediatric Kidney Transplantation.
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Ahlenstiel-Grunow T, Sester M, Sester U, Hirsch HH, and Pape L
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- Adolescent, Age Factors, BK Virus growth & development, Cell Separation, Child, Child, Preschool, Disease Progression, Female, Flow Cytometry, Host-Pathogen Interactions, Humans, Immunocompromised Host, Immunosuppressive Agents adverse effects, Infant, Infant, Newborn, Lymphocyte Count, Male, Opportunistic Infections diagnosis, Opportunistic Infections virology, Polyomavirus Infections diagnosis, Polyomavirus Infections virology, Predictive Value of Tests, Prospective Studies, T-Lymphocytes virology, Time Factors, Treatment Outcome, Tumor Virus Infections diagnosis, Tumor Virus Infections virology, Virus Replication, BK Virus immunology, Kidney Transplantation adverse effects, Opportunistic Infections immunology, Polyomavirus Infections immunology, T-Lymphocytes immunology, Tumor Virus Infections immunology
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Background: After kidney transplantation, uncontrolled BK polyomavirus (BKPyV) replication causes kidney graft failure through BKPyV-associated nephropathy (BKPyVAN), but markers predicting outcome are missing. BKPyV-specific T cells may serve as a predictive marker to identify patients at risk of persistent DNAemia and BKPyVAN., Methods: Out of a total of 114 pediatric kidney recipients transplanted between 2008 and 2018, 36 children with posttransplant BKPyV-DNAemia were identified. In a prospective noninterventional study, BKPyV-specific CD4 and CD8 T cells were measured in 32 of 36 viremic pediatric kidney recipients using intracellular cytokine staining and flow cytometry. The course of the BKPyV replication was monitored with regard to duration of BKPyV-DNAemia and need of therapeutic intervention and diagnosis of proven BKPyVAN., Results: Levels of BKPyV-specific T cells negatively correlated with subsequent duration of BKPyV-DNAemia. Patients with BKPyV-specific CD4 T cells ≥0.5 cells/µL and/or BKPyV-specific CD8 T cells ≥0.1 cells/µL had transient, self-limiting DNAemia (PPV 1.0, NPV 0.86). BKPyV-specific CD4 and CD8 T cells below these thresholds were found in children with persistent BKPyV-DNAemia and biopsy-proven BKPyVAN with need for therapeutic intervention. After reducing immunosuppressive therapy, levels of BKPyV-specific CD4 T cells increased while plasma BKPyV-DNAemia declined., Conclusions: This study found that BKPyV-specific T cell levels may help to distinguish patients with transient, self-limiting BKPyV-DNAemia from those with persisting BKPyV-DNAemia and biopsy-proven BKPyVAN, who would benefit from individualized therapeutic interventions such as reduced immunosuppression. Thereby the risk for rejection because of unnecessary reduction of immunosuppression in case of self-limiting BKPyV-DNAemia can be minimized.
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- 2020
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10. The role of protocol biopsies after pediatric kidney transplantation.
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Kanzelmeyer NK, Lerch C, Ahlenstiel-Grunow T, Bräsen JH, Haffner D, and Pape L
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- Adolescent, Biopsy statistics & numerical data, Child, Child, Preschool, Clinical Protocols, Female, Glomerular Filtration Rate physiology, Graft Rejection pathology, Humans, Kidney pathology, Kidney Transplantation methods, Male, Pediatrics methods, Pediatrics statistics & numerical data, Biopsy methods, Kidney Transplantation adverse effects
- Abstract
Data on protocol biopsies (PBs) after pediatric kidney transplantation are rare.We evaluated 6-month post-transplantation renal function in 86 children after PB as observational study. Patients were divided into 3 groups:Glomerular filtration rate (GFR) and delta GFR were determined.PBs 6 months post-kidney transplantation did not influence the clinical course in stable pediatric patients and are therefore of questionable value. Decreased kidney function may however be stabilized by therapeutic intervention according to results of PB.
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- 2020
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11. Oxalobacter formigenes treatment combined with intensive dialysis lowers plasma oxalate and halts disease progression in a patient with severe infantile oxalosis.
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Pape L, Ahlenstiel-Grunow T, Birtel J, Krohne TU, and Hoppe B
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- Calcium Oxalate blood, Disease Progression, Female, Humans, Hyperoxaluria etiology, Infant, Kidney Transplantation, Liver Transplantation, Renal Insufficiency, Chronic diagnosis, Hyperoxaluria therapy, Oxalobacter formigenes metabolism, Renal Dialysis methods, Renal Insufficiency, Chronic complications
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Background: Infantile oxalosis, the most devastating form of primary hyperoxaluria type 1 (PH1), often leads to end-stage renal disease (ESRD) during the first weeks to months of life., Case-Diagnosis: Here, we report the outcome of the therapeutic use of Oxalobacter formigenes (Oxabact OC5; OxThera AB, Stockholm, Sweden) in a female infant with PH1 who exhibited severely elevated plasma oxalate (Pox) levels, pronounced nephrocalcinosis, anuretic end-stage renal disease, and retinal oxalate deposits. Following the diagnosis of PH1 at an age of 8 weeks, a combined regimen of daily peritoneal dialysis, daily pyridoxine treatment and hemodialysis (3 times a week) was unable to reduce the pronounced hyperoxalemia. After the addition of Oxalobacter formigenes therapy to the otherwise unchanged treatment regimen, Pox levels first stabilized and subsequently declined from 130 μmol/L to around 80 μmol/L. Nephrocalcinosis and retinal deposits stabilized. Oxalobacter formigenes treatment was well-tolerated and no related adverse events were observed. The patient showed nearly age-appropriate growth and development and received successful combined liver-kidney transplantation at the age of two years., Conclusions: Treatment with O. formigenes combined with intensive dialysis led to reduction of Pox, stabilization of systemic oxalosis, and improvement in the clinical disease course. O. formigenes treatment may be an option for reduction of oxalosis in infantile patients with insufficient response to conservative treatments until combined liver-kidney transplantation can be performed.
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- 2020
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12. Immunosuppression, BK polyomavirus infections, and BK polyomavirus-specific T cells after pediatric kidney transplantation.
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Ahlenstiel-Grunow T and Pape L
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- Adolescent, BK Virus isolation & purification, Child, Child, Preschool, Cyclosporine therapeutic use, Drug Therapy, Combination, Female, Humans, Immunosuppression Therapy adverse effects, Immunosuppressive Agents therapeutic use, Infant, Longitudinal Studies, Male, Polyomavirus Infections etiology, Retrospective Studies, Tacrolimus therapeutic use, Transplant Recipients, Viremia diagnosis, Viremia etiology, Immunosuppression Therapy methods, Kidney Transplantation adverse effects, Polyomavirus Infections diagnosis
- Abstract
Background: After kidney transplantation, immunosuppressive therapy increases risk of BK polyomavirus-associated nephropathy (BKPyVAN). Outcomes of BKPyV viremia are various and prognostic markers are missing. The impact of different immunosuppressive regimens on BKPyV infections is currently under discussion., Methods: We analyzed immunosuppressive therapy and BKPyV-specific cellular immunity to distinguish patients at risk of BKPyVAN from those with self-limiting viremia for purposes of risk-stratified BKPyV management. In a retrospective analysis, 46 pediatric kidney recipients with BKPyV viremia were analyzed with regard to duration of BKPyV viremia and immunosuppressive therapy; in addition, in 37/46 patients, BKPyV-specific CD4 and CD8 T cells were measured., Results: Nine patients showed persistent BKPyV viremia and BKPyVAN, and required therapeutic intervention, while 37 patients had asymptomatic, self-limiting viremia. At onset of viremia, 78% of patients with persistent viremia and BKPyVAN were treated with tacrolimus, whereas tacrolimus therapy was significantly less frequent in patients with self-limiting viremia (14%). The majority of patients with transient, self-limiting viremia received cyclosporine A (81%) and/or mTOR inhibitors (81%). Patients with persistent BKPyV viremia and BKPyVAN showed lack of BKPyV-specific CD4 and CD8 T cells (6/6), whereas the majority of patients with self-limiting viremia (27/31) had detectable BKPyV-specific CD4 and/or CD8 T cells ≥ 0.5 cells/μl (p < 0.001)., Conclusions: These results indicate that tacrolimus enhances risk of BKPyVAN with need of therapeutic intervention, whereas under cyclosporine A and mTOR inhibitors, the majority of pediatric kidney recipients showed self-limiting viremia. In patients at risk of BKPyV infections, combination of cyclosporine A and mTOR inhibitor may be advantageous.
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- 2020
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13. Diagnostics, treatment, and immune response in BK polyomavirus infection after pediatric kidney transplantation.
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Ahlenstiel-Grunow T and Pape L
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- Allografts immunology, Allografts virology, Antiviral Agents therapeutic use, BK Virus isolation & purification, Child, DNA, Viral isolation & purification, Fluoroquinolones therapeutic use, Graft Rejection immunology, Graft Rejection prevention & control, Graft Rejection virology, Humans, Immunosuppression Therapy adverse effects, Immunosuppressive Agents administration & dosage, Immunosuppressive Agents adverse effects, Kidney immunology, Kidney virology, Polyomavirus Infections immunology, Polyomavirus Infections therapy, Polyomavirus Infections virology, Prognosis, Randomized Controlled Trials as Topic, TOR Serine-Threonine Kinases antagonists & inhibitors, Treatment Outcome, Tumor Virus Infections immunology, Tumor Virus Infections therapy, Tumor Virus Infections virology, Virus Replication immunology, BK Virus immunology, Graft Rejection diagnosis, Kidney Transplantation adverse effects, Polyomavirus Infections diagnosis, T-Lymphocytes immunology, Tumor Virus Infections diagnosis
- Abstract
After pediatric kidney transplantation BK polyomavirus (BKPyV) infections are associated with an increased risk of graft loss by BKPyV-associated nephropathy (BkPyVAN). However, suitable prognostic markers for the individual outcome of BKPyV infections are missing and the management of therapeutic interventions remains a challenge to the success of pediatric kidney transplantation. This review gives an overview on current diagnostic and therapeutic strategies in the field of BKPyV infections after pediatric kidney transplantation. Methods determining the individual immune response to BKPyV are described and their usability is discussed. There is growing evidence that BKPyV-specific T cells (BKPyV-Tvis) may serve as prognostic markers in order to steer immunosuppressive therapy in pediatric kidney recipients with BKPyV viremia in future. Prospective randomized trials in viremic kidney recipients comparing Tvis-steered therapeutic intervention with standard reduction of immunosuppression are needed before implementation of BKPyV-Tvis monitoring in routine care of BKPyV infections.
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- 2020
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14. Cytokine Profiles in Children After Pediatric Kidney Transplantation With Acute Cellular Compared to Chronic Antibody-mediated Rejection and Stable Patients: A Pilot Study.
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Borsum N, Verboom M, Ahlenstiel-Grunow T, and Pape L
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Different patterns of plasma cytokines can be expected in the case of chronic active-antibody-mediated (cAMR) and acute cellular rejection (AR) after kidney transplantation (KTx)., Methods: IL-2, 4, 6, 10, 17A, tumor necrosis factor alpha, and interferon gamma were measured in 51 pediatric KTx recipients at time of renal biopsy (17 AR, 14 cAMR, 20 normal). Patients were divided into a training (n = 30) and a validation (n = 21) set., Results: IL-6 was significantly higher in AR patients and significantly lower in the case of cAMR. In children with s-creatinine increase, IL-6 values were significantly different between AR and cAMR. IL-10 levels showed similar tendencies. For IL-2, 4, 17A, tumor necrosis factor alpha, and interferon gamma, no differences were found. In the independent validation cohort, the receiver operating characteristic area under the curve for IL-6 was 0.79 and 0.70 for AR and cAMR. In children with AR, an IL-6 <1141 fg/ml, and in those with cAMR, an IL-6 >721 fg/ml was associated with a specificity of 86%/76%, a sensitivity of 71%/80%, a positive predictive value of 56%/45%, and a negative predictive value of 92%/94%., Conclusions: In this pilot study, the plasma IL-6 level is a promising biomarker to identify pediatric kidney transplant recipients free from AR and cAMR and might help to distinguish between both entities, whereas there is only a nonsignificant trend toward the usability of IL-10. Validation in larger cohorts in combination with other biomarkers are warranted., (Copyright © 2019 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)
- Published
- 2019
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15. Correction to: Rabbit anti-human thymocyte immunoglobulin for the rescue treatment of chronic antibody-mediated rejection after pediatric kidney transplantation.
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Cihan Y, Kanzelmeyer N, Drube J, Kreuzer M, Lerch C, Hennies I, Froede K, Verboom M, Ahlenstiel-Grunow T, and Pape L
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The article "Rabbit anti-human thymocyte immunoglobulin for the rescue treatment of chronic antibody-mediated rejection after pediatric kidney transplantation", written by Yasemen Cihan, Nele Kanzelmeyer, Jens Drube, Martin Kreuzer, Christian Lerch, Imke Hennies, Kerstin Froede, Murielle Verboom.
- Published
- 2018
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16. Impaired Microcirculation in Children After Kidney Transplantation: Everolimus Versus Mycophenolate Based Immunosuppression Regimen.
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Ruben S, Kreuzer M, Büscher A, Büscher R, Thumfart J, Querfeld U, Staude H, Ahlenstiel-Grunow T, Melk A, Fischer DC, Leifheit-Nestler M, Pape L, and Haffner D
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- Adolescent, Case-Control Studies, Child, Child, Preschool, Cross-Sectional Studies, Endothelium physiopathology, Everolimus pharmacology, Everolimus therapeutic use, Fibroblast Growth Factor-23, Humans, Immunosuppressive Agents therapeutic use, Mycophenolic Acid pharmacology, Mycophenolic Acid therapeutic use, Vascular Diseases diagnosis, Immunosuppressive Agents pharmacology, Kidney Transplantation adverse effects, Microcirculation drug effects
- Abstract
Background/aims: Whether the immunosuppressive regimen is associated with micro- and macro-vascular status in pediatric kidney transplant recipients (KTx) is unknown., Methods: We performed a cross-sectional, case-control study in 44 pediatric KTx patients on either everolimus (EVR) plus calcineurin inhibitor or standard treatment, i.e. mycophenolate mofetil plus calcineurin inhibitor. Measurement of carotid intima-media thickness (cIMT) via ultrasound, central pulse wave velocity (PWV) by a cuff-based oscillometric technique, and skin microvascular blood flow during local heating via laser-Doppler-fluximetry (LDF) served as marker of subclinical vascular disease. Serum concentrations of angiopoietin-1 and -2, fibroblast-growth factor 23 (FGF23) and soluble klotho were measured., Results: EVR-treated patients exhibited a similar degree of hypertension, increased cIMT, elevated pro-inflammatory angiopoietin-2, and diminished endothelial survival factor angiopoietin-1 compared to healthy children but presented with a twofold more reduced skin micro-vascular function compared to standard treatment (each p< 0.001). By contrast, PWV and soluble klotho levels were normal in both groups., Conclusion: Endothelial dysfunction seems more frequent in KTx patients on EVR-based immunosuppressive regimen compared to standard immunosuppression., (© 2018 The Author(s). Published by S. Karger AG, Basel.)
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- 2018
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17. Rabbit anti-human thymocyte immunoglobulin for the rescue treatment of chronic antibody-mediated rejection after pediatric kidney transplantation.
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Cihan Y, Kanzelmeyer N, Drube J, Kreuzer M, Lerch C, Hennies I, Froede K, Verboom M, Ahlenstiel-Grunow T, and Pape L
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- Adolescent, Animals, Bortezomib therapeutic use, Child, Preschool, Chronic Disease, Female, Glomerular Filtration Rate, Graft Rejection immunology, Graft Survival, Humans, Immunoglobulins, Intravenous therapeutic use, Kidney immunology, Kidney pathology, Kidney surgery, Male, Prednisolone therapeutic use, Rabbits, Retrospective Studies, Rituximab therapeutic use, Treatment Outcome, Antilymphocyte Serum therapeutic use, Graft Rejection drug therapy, Immunosuppressive Agents therapeutic use, Kidney Transplantation adverse effects
- Abstract
Background: Chronic antibody-mediated rejection (cAMR) is the leading cause of late kidney graft loss, but current therapies are often ineffective. Rabbit anti-human thymocyte immunoglobulin (rATG) may be helpful, but its use is virtually undocumented., Methods: Data were analyzed retrospectively from nine pediatric kidney transplant patients with cAMR were treated with rATG (1.5 mg/kg × 5 days) at our center after non-response to pulsed prednisolone, intravenous immunoglobulin, rituximab, and increased immunosuppressive intensity (including switching to belatacept in some cases), with or without bortezomib., Results: The median time from diagnosis to cAMR was 179 days. rATG was started 5-741 days after diagnosis. Median estimated glomerular filtration rate (eGFR) increased from 40 mL/min/1.73 m
2 when rATG was started to 62 mL/min/1.73 m2 9 months later (p = 0.039). Four patients showed substantially higher eGFR after 9 months and 2 patients showed a small improvement; eGFR continued to decline in 3 patients after starting rATG. No grafts were lost during follow-up. At last follow-up, donor-specific antibodies (DSAs) were no longer detectable in 4 out of 8 patients for whom data were available, median fluorescence intensity had decreased substantially in 1 out of 8 patients; anti-HLA DQ DSAs persisted in 2 out of 8 patients. No adverse events with a suspected relation to rATG, including allergic reactions, leukocytopenia or infections, were observed in any of the patients., Conclusions: In this small series of patients, rATG appears a promising treatment for unresponsive cAMR. Further evaluation, including earlier introduction of rATG, is warranted.- Published
- 2017
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18. Intermediate Follow-up of Pediatric Patients With Hemolytic Uremic Syndrome During the 2011 Outbreak Caused by E. coli O104:H4.
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Loos S, Aulbert W, Hoppe B, Ahlenstiel-Grunow T, Kranz B, Wahl C, Staude H, Humberg A, Benz K, Krause M, Pohl M, Liebau MC, Schild R, Lemke J, Beringer O, Müller D, Härtel C, Wigger M, Vester U, Konrad M, Haffner D, Pape L, Oh J, and Kemper MJ
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- Adolescent, Antibodies, Monoclonal, Humanized therapeutic use, Child, Child, Preschool, Escherichia coli Infections drug therapy, Escherichia coli Infections epidemiology, Female, Follow-Up Studies, Germany epidemiology, Glomerular Filtration Rate, Hemolytic-Uremic Syndrome microbiology, Humans, Hypertension epidemiology, Hypertension etiology, Kidney Transplantation, Male, Medical Records, Prognosis, Proteinuria epidemiology, Proteinuria etiology, Renal Dialysis, Renal Insufficiency, Chronic complications, Renal Insufficiency, Chronic epidemiology, Renal Insufficiency, Chronic etiology, Retrospective Studies, Young Adult, Disease Outbreaks, Escherichia coli Infections complications, Escherichia coli Infections microbiology, Escherichia coli O104 isolation & purification, Hemolytic-Uremic Syndrome complications, Hemolytic-Uremic Syndrome epidemiology
- Abstract
Background.: In 2011 Escherichia coli O104:H4 caused an outbreak with >800 cases of hemolytic uremic syndrome (HUS) in Germany, including 90 children. Data on the intermediate outcome in children after HUS due to E. coli O104:H4 have been lacking., Methods.: Follow-up data were gathered retrospectively from the medical records of patients who had been included in the German Pediatric HUS Registry during the 2011 outbreak., Results.: Seventy-two of the 89 (81%) patients were included after a median follow-up of 3.0 (0.9-4.7) years. Hypertension and proteinuria were present in 19% and 28% of these patients, respectively. Of 4 patients with chronic kidney disease (CKD) > stage 2 at short-term follow-up, 1 had a normalized estimated glomerular filtration rate, and 3 (4%) had persistent CKD > stage 2. In 1 of these patients, CKD improved from stage 4 to 3; 1 who had CKD stage 5 at presentation received kidney transplantation; and 1 patient required further hemodialysis during follow-up. One patient (1.4%) still had major neurological symptoms at the latest follow-up. Dialysis during the acute phase (P = .01), dialysis duration (P = .01), and the duration of oligo-/anuria (P = .005) were associated with the development of renal sequelae. Patients treated with eculizumab (n = 11) and/or plasmapheresis (n = 13) during the acute phase of HUS had comparable outcomes., Conclusions.: The overall outcome of pediatric patients after HUS due to E. coli O104:H4 was equivalent to previous reports on HUS due to other types of Shiga toxin-producing E. coli (STEC). Regular follow-up visits in patients are recommended after STEC-HUS., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
- Published
- 2017
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19. Belatacept after kidney transplantation in adolescents: a retrospective study.
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Lerch C, Kanzelmeyer NK, Ahlenstiel-Grunow T, Froede K, Kreuzer M, Drube J, Verboom M, and Pape L
- Subjects
- Adolescent, Female, Humans, Male, Retrospective Studies, Treatment Outcome, Abatacept administration & dosage, Immunosuppressive Agents administration & dosage, Kidney Transplantation, Medication Adherence
- Abstract
Regardless of recipient age at kidney transplantation (KTx), patients are at greatest risk for graft loss in adolescence, partly due to nonadherence to an oral immunosuppressive regimen. Belatacept, a non-nephrotoxic, first-in-class immunosuppressant that inhibits costimulation of T cells requires intravenous application only every 4 weeks, potentially leading to better adherence. However, it is only approved for use in adults. We report here the findings of the first study of belatacept in adolescents, comprising all patients in our department switched to belatacept post-KTx. Six patients (median age 15.5 years) were switched after a median of 7.5 months (range 23 days to 12 years), treatment range 3-28 months (cumulative 83 months): Three patients switched early (<3 months after KTx) had increased estimated glomerular filtration rate (GFR); one patient switched 12 years post-KTx has stable GFR; two patients were switched following rapid decline of and with markedly impaired GFR, changing slope in one patient. One patient had one acute rejection. In addition of two patients who received belatacept for other conditions, the only relevant adverse event was neutropenia (after a cumulative 109 months). Belatacept as primary immunosuppression is an option in Epstein-Barr virus-seropositive nonadherent adolescents if administered sufficiently early before deterioration of graft function., (© 2017 Steunstichting ESOT.)
- Published
- 2017
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20. Switching from immediate- to extended-release cysteamine in nephropathic cystinosis patients: a retrospective real-life single-center study.
- Author
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Ahlenstiel-Grunow T, Kanzelmeyer NK, Froede K, Kreuzer M, Drube J, Lerch C, and Pape L
- Subjects
- Adolescent, Child, Child, Preschool, Cohort Studies, Cysteamine adverse effects, Cystine blood, Cystinosis etiology, Delayed-Action Preparations, Drug Compounding, Female, Glomerular Filtration Rate, Humans, Infant, Leukocytes metabolism, Male, Renal Agents adverse effects, Retrospective Studies, Treatment Outcome, Cysteamine administration & dosage, Cysteamine therapeutic use, Cystinosis drug therapy, Renal Agents administration & dosage, Renal Agents therapeutic use
- Abstract
Background: Nephropathic cystinosis is a rare lysosomal storage disease which is characterized by the accumulation of free cystine in lysosomes and subsequent intracellular crystal formation of cystine throughout the body. If not treated with cysteamine, a cystine-depleting agent, end-stage renal disease will develop early, followed by multiple organ failure as the disease progresses. The established cysteamine formulation requires a strict dosing regimen at 6-h intervals. An extended release (ER) twice-daily formulation has recently been developed. The aim of our study was to evaluate the implementation and outcomes of this option in routine care., Methods: All pediatric cystinosis patients' records in Hannover Medical School were screened, and data on cysteamine therapy, tolerability, dosing, estimated glomerular filtration rates (eGFR), white blood cell cystine levels, and proton pump inhibitor (PPI) use were extracted for the period January 2014 to January 2016., Results: The median age of the 12 patients enrolled in the study was 12.5 (range 1-18) years. At the end of the study period ten of these patients received ER-cysteamine. There were no additional side effects. Halitosis/bad breath was often subjectively judged as improved or eliminated, and PPI use could be stopped in one of three patients. The main reasons for switching to the ER formulation were difficult night-time administration and uncontrolled disease. Mean eGFR values remained stable with a median of 67 ml/min/1.73 m
2 before and after the transition. White blood cell (WBC) cystine values remained low after the switch (1 nmol/mg protein before and after transition; p = 0.64)., Conclusions: In this single-center cohort, the switch from IR- to ER-cysteamine was safe and effective over the short term and provided advantages in terms of frequency of administration and less halitosis/bad breath. The long-term benefit of this option needs to be evaluated in future studies.- Published
- 2017
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21. Pubertal Development in Pediatric Kidney Transplant Patients Receiving Mammalian Target of Rapamycin Inhibitors or Conventional Immunosuppression.
- Author
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Förster J, Ahlenstiel-Grunow T, Zapf A, Mynarek M, and Pape L
- Subjects
- Adolescent, Androstenedione blood, Child, Child, Preschool, Female, Glomerular Filtration Rate, Humans, Infant, Male, Retrospective Studies, Testosterone blood, Immunosuppression Therapy, Kidney Transplantation, Puberty physiology, TOR Serine-Threonine Kinases antagonists & inhibitors
- Abstract
Background: Data regarding the onset of puberty in children receiving mammalian target of rapamycin (mTOR) inhibitors are limited., Methods: Kidney transplant patients aged <14 years were analyzed retrospectively to a maximum age of 18 years, with a minimal observation period of 1 year. Immunosuppression comprised (1) standard CNI-based regimen or (2) low-exposure mTOR inhibitor with reduced-exposure CNI, initiated either de novo or in the maintenance phase., Results: Of 108 children analyzed, 67 received an mTOR inhibitor (56 everolimus, 11 sirolimus) and 41 did not. The age at which girls reached Tanner stage P2 was similar with mTOR inhibitor therapy (median 11.6 years) or without (median 11.1 years) (P = 0.262), as was age at stage B2 (median 11.6 vs. 11.2 years; P = 0.753). In boys, both the age of attaining Tanner stage P2 (median 12.9 vs. 13.0 years; P = 0.796) and Tanner stage G2 (median 13.1 vs. 12.9 years; P = 0.344) were also similar with or without an mTOR inhibitor. Age at menarche in girls, and age at spermarche in boys, did not differ between the 2 groups., Conclusions: In this retrospective analysis, sexual maturation ages and reproductive hormone levels were comparable in adolescent kidney transplant patients receiving low-exposure mTOR inhibitors and reduced CNI therapy or conventional CNI-based immunosuppression.
- Published
- 2016
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22. Systemic complement activation and complement gene analysis in enterohaemorrhagic Escherichia coli-associated paediatric haemolytic uraemic syndrome.
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Ahlenstiel-Grunow T, Hachmeister S, Bange FC, Wehling C, Kirschfink M, Bergmann C, and Pape L
- Subjects
- Adolescent, Antibodies, Monoclonal, Humanized therapeutic use, Biomarkers blood, Child, Child, Preschool, Complement Inactivating Agents therapeutic use, Complement System Proteins metabolism, Female, Hemolytic-Uremic Syndrome blood, Hemolytic-Uremic Syndrome drug therapy, Humans, Male, Transcriptome immunology, Complement Activation, Complement System Proteins genetics, Enterohemorrhagic Escherichia coli immunology, Hemolytic-Uremic Syndrome immunology
- Abstract
Background: In contrast to atypical haemolytic uraemic syndrome (aHUS), only single case reports and limited data have been published on systemic activation of the complement system and mutations in complement genes in paediatric enterohaemorrhagic Escherichia coli-induced HUS (EHEC-HUS)., Methods: Complement activation (CH50, APH50, C3d, sC5b-9) was analysed at four timepoints (Week 1, Week 2, Month 3 and Month 6 after primary diagnosis of HUS) in 25 children with EHEC-HUS. Seven patients received the complement C5 inhibitor eculizumab. Targeted next generation sequencing for a total of 89 genes involved in complement regulation and coagulation and haemostasis was performed in all patients., Results: Activity of classical (CH50) and alternative (APH50) complement pathways was normal or even elevated throughout the observation time, except for patients under eculizumab treatment. In contrast, the mean concentration of the soluble terminal complement complex (sC5b-9) was significantly elevated at the first timepoint (mean 498 ng/mL), dropping to normal values after 2 weeks. Initially elevated (42 mU/L) median C3d concentration reached normal levels from Week 2. Levels of sC5b-9 >320 ng/mL at the time of HUS diagnosis were associated with arterial hypertension, oedema and lower platelet counts, but not with the duration of dialysis. Genetic analysis revealed various changes that may have had a modifying impact on the clinical course., Conclusions: Complement activation at the acute phase of EHEC-HUS, indicated by increased levels of sC5b-9, predicts a poor outcome. Complement alterations appear to be more frequent in patients with EHEC-HUS than previously thought and are suspected to have a role in the severity of the disease., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)
- Published
- 2016
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23. Efficacy and Safety of an Everolimus- vs. a Mycophenolate Mofetil-Based Regimen in Pediatric Renal Transplant Recipients.
- Author
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Brunkhorst LC, Fichtner A, Höcker B, Burmeister G, Ahlenstiel-Grunow T, Krupka K, Bald M, Zapf A, Tönshoff B, and Pape L
- Subjects
- Adolescent, Anti-Inflammatory Agents, Non-Steroidal administration & dosage, Anti-Inflammatory Agents, Non-Steroidal adverse effects, Biomarkers, Child, Child, Preschool, Cohort Studies, Drug Therapy, Combination, Everolimus administration & dosage, Everolimus adverse effects, Female, Graft Rejection drug therapy, Graft Rejection immunology, Graft Survival drug effects, Graft Survival immunology, HLA Antigens immunology, Hospitalization, Humans, Immunosuppressive Agents administration & dosage, Immunosuppressive Agents adverse effects, Isoantibodies immunology, Kidney Function Tests, Male, Mycophenolic Acid administration & dosage, Mycophenolic Acid adverse effects, Mycophenolic Acid therapeutic use, Opportunistic Infections etiology, Retrospective Studies, Tissue Donors, Treatment Outcome, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Immunosuppressive Agents therapeutic use, Kidney Transplantation adverse effects, Mycophenolic Acid analogs & derivatives, Transplant Recipients
- Abstract
Introduction: Data on the efficacy and safety of everolimus in pediatric renal transplantation compared to other immunosuppressive regimens are scarce., Patients/methods: We therefore performed a multicenter, observational, matched cohort study over 4 years post-transplant in 35 patients on everolimus plus low-dose cyclosporine, who were matched (1:2) with a control group of 70 children receiving a standard-dose calcineurin-inhibitor- and mycophenolate mofetil-based regimen., Results: Corticosteroids were withdrawn in 83% in the everolimus vs. 39% in the control group (p<0.001). Patient and graft survival were comparable. The rate of biopsy-proven acute rejection episodes Banff score ≥ IA during the first year post-transplant was 6% in the everolimus vs. 13% in the control group (p = 0.23). The rate of de novo donor-specific HLA antibodies (11% in everolimus, 18% in controls) was comparable (p = 0.55). At 4 years post-transplant, mean eGFR in the everolimus group was 56±33 ml/min per 1.73 m² vs. 63±22 ml/min per 1.73 m² in the control group (p = 0.14). Everolimus therapy was associated with less BK polyomavirus replication (3% vs. 17% in controls; p = 0.04), but with a higher percentage of arterial hypertension and more hyperlipidemia (p<0.001)., Conclusion: In pediatric renal transplantation, an everolimus-based regimen with low-dose cyclosporine yields comparable four year results as a standard regimen, but with a different side effect profile.
- Published
- 2015
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24. Eculizumab in Typical Hemolytic Uremic Syndrome (HUS) With Neurological Involvement.
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Pape L, Hartmann H, Bange FC, Suerbaum S, Bueltmann E, and Ahlenstiel-Grunow T
- Subjects
- Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Child, Child, Preschool, Female, Humans, Infant, Male, Renal Dialysis, Antibodies, Monoclonal, Humanized therapeutic use, Central Nervous System Diseases drug therapy, Central Nervous System Diseases etiology, Escherichia coli Infections complications, Hemolytic-Uremic Syndrome complications, Shiga-Toxigenic Escherichia coli
- Abstract
In typical hemolytic uremic syndrome (HUS) approximately 25% of patients show central nervous system (CNS) involvement often leading to serious long-term disabilities. We used the C5-complement inhibitor Eculizumab as rescue therapy. From 2011 to 2014, 11 children (median age 22 months, range 11-175) with enterohemorrhagic Escherichia coli-positive HUS requiring dialysis who had seizures (11/11) and/or were in a stupor or coma (10/11) were treated with Eculizumab. Two patients enrolled on the Safety and Efficacy Study of Eculizumab in Shiga-Toxin Producing E coli Hemolytic-Uremic Syndrome (STEC-HUS) each received 6 doses of Eculizumab, 3 patients 2 doses, and 6 patients 1 dose. Laboratory diagnostics of blood samples and magnetic resonance imaging (MRI) were performed as per center practice. Data were analyzed retrospectively. Cranial MRI was abnormal in 8 of 10 patients with findings in the basal ganglia and/or white matter. A 2-year-old boy with severe cardiac involvement and status epilepticus needed repeated cardio-pulmonary resuscitation and extracorporeal membrane oxygenation. He died 8 days after start of Eculizumab treatment. Two patients with hemorrhagic colitis and repeated seizures required artificial ventilation for 6 and 16 days, respectively. At the time of discharge, 1 patient showed severe neurological impairment and 1 mild neurological impairment. The 8 surviving patients experienced no further seizures after the first dose of Eculizumab. Three patients showed mild neurological impairment at discharge, whilst the remaining 5 showed no impairment. The platelets normalized 4 days (median) after the first dose of Eculizumab (range 0-20 days). The mean duration of dialysis after the first dose of Eculizumab was 14.1 ± 6.1 days. In children with typical HUS and CNS involvement early use of Eculizumab appears to improve neurological outcome. In severe HUS cases which progress rapidly with multiple organ involvement, late treatment with Eculizumab seems to show less benefit. We speculate that prophylactic Eculizumab therapy before development of neurological symptoms could be advantageous.
- Published
- 2015
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25. Clinical and molecular characterization of patients with heterozygous mutations in wilms tumor suppressor gene 1.
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Lehnhardt A, Karnatz C, Ahlenstiel-Grunow T, Benz K, Benz MR, Budde K, Büscher AK, Fehr T, Feldkötter M, Graf N, Höcker B, Jungraithmayr T, Klaus G, Koehler B, Konrad M, Kranz B, Montoya CR, Müller D, Neuhaus TJ, Oh J, Pape L, Pohl M, Royer-Pokora B, Querfeld U, Schneppenheim R, Staude H, Spartà G, Timmermann K, Wilkening F, Wygoda S, Bergmann C, and Kemper MJ
- Subjects
- Adolescent, Adult, Age of Onset, Austria, Child, Child, Preschool, Exons genetics, Female, Germany, Heterozygote, Humans, Infant, Introns genetics, Karyotype, Kidney Diseases pathology, Kidney Diseases therapy, Kidney Neoplasms diagnosis, Kidney Neoplasms genetics, Kidney Neoplasms surgery, Kidney Transplantation, Male, Mutation, Missense, Nephrectomy, Phenotype, Proteinuria diagnosis, Proteinuria drug therapy, Renal Dialysis, Retrospective Studies, Switzerland, Wilms Tumor diagnosis, Wilms Tumor genetics, Wilms Tumor surgery, Young Adult, Genes, Wilms Tumor, Kidney Diseases genetics, Proteinuria genetics, Urogenital Abnormalities genetics
- Abstract
Background and Objectives: The Wilms tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Genotype/phenotype correlations of WT1 mutations with renal function and proteinuria have been observed in world-wide cohorts with nephrotic syndrome or Wilms tumor (WT). This study analyzed mid-European patients with known constitutional heterozygous mutations in WT1, including patients without proteinuria or WT., Design, Setting, Participants & Measurements: Retrospective analysis of genotype, phenotype, and treatment of 53 patients with WT1 mutation from all pediatric nephrology centers in Germany, Austria, and Switzerland performed from 2010 to 2012., Results: Median age was 12.4 (interquartile range [IQR], 6-19) years. Forty-four of 53 (83%) patients had an exon mutation (36 missense, eight truncating), and nine of 53 (17%) had an intronic lysine-threonine-serine (KTS) splice site mutation. Fifty of 53 patients (94%) had proteinuria, which occurred at an earlier age in patients with missense mutations (0.6 [IQR, 0.1-1.5] years) than in those with truncating (9.7 [IQR, 5.7-11.9]; P<0.001) and splice site (4.0 [IQR, 2.6-6.6]; P=0.004) mutations. Thirteen of 50 (26%) were treated with steroids and remained irresponsive, while three of five partially responded to cyclosporine A. Seventy-three percent of all patients required RRT, those with missense mutations significantly earlier (at 1.1 [IQR, 0.01-9.3] years) than those with truncating mutations (16.5 [IQR, 16.5-16.8]; P<0.001) and splice site mutations (12.3 [IQR, 7.9-18.2]; P=0.002). Diffuse mesangial sclerosis was restricted to patients with missense mutations, while focal segmental sclerosis occurred in all groups. WT occurred only in patients with exon mutations (n=19). Fifty of 53 (94%) patients were karyotyped: Thirty-one (62%) had XY and 19 (38%) had XX chromosomes, and 96% of male karyotypes had urogenital malformations., Conclusions: Type and location of WT1 mutations have predictive value for the development of proteinuria, renal insufficiency, and WT. XY karyotype was more frequent and associated with urogenital malformations in most cases., (Copyright © 2015 by the American Society of Nephrology.)
- Published
- 2015
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26. A multicenter, randomized, open-labeled study to steer immunosuppressive and antiviral therapy by measurement of virus (CMV, ADV, HSV)-specific T cells in addition to determination of trough levels of immunosuppressants in pediatric kidney allograft recipients (IVIST01-trial): study protocol for a randomized controlled trial.
- Author
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Ahlenstiel-Grunow T, Koch A, Großhennig A, Frömke C, Sester M, Sester U, Schröder C, and Pape L
- Subjects
- Adenoviruses, Human immunology, Child, Cytomegalovirus immunology, Drug Monitoring, Humans, Immunosuppressive Agents blood, Sample Size, Simplexvirus immunology, Transplantation, Homologous, Antiviral Agents therapeutic use, Clinical Protocols, Immunosuppressive Agents therapeutic use, Kidney Transplantation, T-Lymphocytes immunology
- Abstract
Background: After kidney transplantation, immunosuppressive therapy causes impaired cellular immune defense leading to an increased risk of viral complications. Trough level monitoring of immunosuppressants is insufficient to estimate the individual intensity of immunosuppression. We have already shown that virus-specific T cells (Tvis) correlate with control of virus replication as well as with the intensity of immunosuppression. The multicentre IVIST01-trial should prove that additional steering of immunosuppressive and antiviral therapy by Tvis levels leads to better graft function by avoidance of over-immunosuppression (for example, viral infections) and drug toxicity (for example, nephrotoxicity)., Methods/design: The IVIST-trial starts 4 weeks after transplantation. Sixty-four pediatric kidney recipients are randomized either to a non-intervention group that is only treated conservatively or to an intervention group with additional monitoring by Tvis. The randomization is stratified by centre and cytomegalovirus (CMV) prophylaxis. In both groups the immunosuppressive medication (cyclosporine A and everolimus) is adopted in the same target range of trough levels. In the non-intervention group the immunosuppressive therapy (cyclosporine A and everolimus) is only steered by classical trough level monitoring and the antiviral therapy of a CMV infection is performed according to a standard protocol. In contrast, in the intervention group the dose of immunosuppressants is individually adopted according to Tvis levels as a direct measure of the intensity of immunosuppression in addition to classical trough level monitoring. In case of CMV infection or reactivation the antiviral management is based on the individual CMV-specific immune defense assessed by the CMV-Tvis level. Primary endpoint of the study is the glomerular filtration rate 2 years after transplantation; secondary endpoints are the number and severity of viral infections and the incidence of side effects of immunosuppressive and antiviral drugs., Discussion: This IVIST01-trial will answer the question whether the new concept of steering immunosuppressive and antiviral therapy by Tvis levels leads to better future graft function. In terms of an effect-related drug monitoring, the study design aims to realize a personalization of immunosuppressive and antiviral management after transplantation. Based on the IVIST01-trial, immunomonitoring by Tvis might be incorporated into routine care after kidney transplantation., Trial Registration: EudraCT No: 2009-012436-32, ISRCTN89806912 (17 June 2009).
- Published
- 2014
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