Martin Pohl

University of Freiburg, Freiburg, Baden-Württemberg, Germany

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Publications (13)84.23 Total impact

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    ABSTRACT: Previous studies have found that pediatric solid organ transplant recipients suffer from adenotonsillar hyperplasia. However, as this condition is also common in normal children, it remains unclear whether the incidence is truly increased. The aim of this study was to compare the incidences of surgery on the adenoids and tonsils of normal children with those receiving renal transplants and to define risk factors in the transplant population. Data on 49 consecutive children from a single renal transplant unit were compared to data from a large governmental survey of healthy German children (KiGGS). For analysis of 'survival without operation', controls were matched for gender, region and immigration status (n = 8,650), as well as for age to compare incidence rates (n = 637). The age-matched solid organ transplant recipients had a higher incidence of adenoidectomies [2.3-fold, [95 % confidence interval (CI) for relative risk 1.6-3.3) and a higher incidence of tonsillectomies/tonsillotomies (3.5-fold, 95 % CI 2.1-5.7). The normal peak of adenoidectomies was delayed by 2 years in the pre-school group, and transplanted teenagers showed an extra peak for both operations. Boys and those transplanted at a younger age were significantly more likely to need adenoidectomies. Ciclosporin levels, Epstein-Barr virus and cytomegalovirus infections did not influence the incidence of operations. Children receiving renal transplants are at markedly increased risk of adenotonsillar hyperplasia requiring surgery, especially males and young recipients.
    Pediatric Nephrology 03/2014; · 2.94 Impact Factor
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    ABSTRACT: An emerging number of clinically and genetically heterogeneous diseases now collectively termed ciliopathies have been connected to the dysfunction of primary cilia. We describe an 8-year-old girl with a complex phenotype that did not clearly match any familiar syndrome. Hypotonia, facial dysmorphism and retardation were noted shortly after birth. Other features included short stature, mild skeletal anomalies, strabism, deafness, subdural hygroma, hepatosplenomegaly and end-stage renal failure. Renal biopsy revealed tubular atrophy, interstitial fibrosis and segmental glomerulosclerosis. After exclusion of a chromosomal abnormality by array-comparative genomic hybridization (CGH), we performed next-generation sequencing (NGS) using a customized panel that targeted 131 genes known or hypothesized to cause ciliopathies. We identified the novel homozygous WDR19 mutation c.1483G > C (p.Gly495Arg) that affects an evolutionarily highly conserved residue in the intraflagellar transport protein IFT144, is absent from databases and is predicted to be pathogenic by all bioinformatic sources used. Mutations in WDR19 encoding the intraflagellar transport component IFT144 have recently been described in single families with the clinically overlapping skeletal ciliopathies Jeune and Sensenbrenner syndromes, combined or isolated nephronophthisis (NPHP) and retinitis pigmentosa (RP) (Senior-Loken syndrome). Our patient emphasizes the usefulness and efficiency of a comprehensive NGS panel approach in patients with unclassified ciliopathies. It further suggests that WDR19 mutations can cause a broad spectrum of ciliopathies that extends to Jeune and Sensenbrenner syndromes, RP and renal NPHP-like phenotypes.
    Pediatric Nephrology 02/2014; · 2.94 Impact Factor
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    ABSTRACT: Nephronophthisis is an autosomal recessive cystic kidney disease that leads to renal failure in childhood or adolescence. Most NPHP gene products form molecular networks. Here we identify ANKS6 as a new NPHP family member that connects NEK8 (NPHP9) to INVS (NPHP2) and NPHP3. We show that ANKS6 localizes to the proximal cilium and confirm its role in renal development through knockdown experiments in zebrafish and Xenopus laevis. We also identify six families with ANKS6 mutations affected by nephronophthisis, including severe cardiovascular abnormalities, liver fibrosis and situs inversus. The oxygen sensor HIF1AN hydroxylates ANKS6 and INVS and alters the composition of the ANKS6-INVS-NPHP3 module. Knockdown of Hif1an in Xenopus results in a phenotype that resembles loss of other NPHP proteins. Network analyses uncovered additional putative NPHP proteins and placed ANKS6 at the center of this NPHP module, explaining the overlapping disease manifestation caused by mutation in ANKS6, NEK8, INVS or NPHP3.
    Nature Genetics 06/2013; · 35.21 Impact Factor
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    ABSTRACT: BACKGROUND: Posttransplantation lymphoproliferative disease (PTLD) is an often Epstein-Barr virus (EBV)-associated mainly malignant complication after transplantation. We present data on EBV-specific T cells in children treated with rituximab with or without chemotherapy on the pediatric PTLD Pilot 2005 protocol. METHODS: Peripheral blood mononuclear cells were isolated from 16 pediatric patients with PTLD, 4 transplanted children with EBV reactivation, and 18 healthy controls. EBV-specific T cells were quantified by flow cytometric detection of intracellular interferon-γ after stimulation with autologous EBV-transformed lymphoblastoid cell lines and correlated with EBV load in peripheral blood. RESULTS: At diagnosis, PTLD patients had similar numbers of EBV-specific CD4 and CD8 T cells as healthy EBV-positive controls. EBV-specific T cells tended to be lower in early PTLD compared with late PTLD. During treatment with rituximab, CD4 and/or CD8 EBV-specific T cells increased in most patients, possibly reflecting restored immunocompetence due to a reduction of immunosuppression as well as antigenic stimulation by cross-presentation of EBV antigen from destroyed B cells. However, this increase did not predict response to rituximab or chemotherapy. EBV load and circulating B cells became undetectable in most patients during rituximab therapy. B-cell recovery after treatment was accompanied by redetection of EBV in peripheral blood, which was controlled by T-cell responses in 11 of 11 evaluable cases. CONCLUSIONS: In pediatric PTLD patients, pretreatment EBV-specific T-cell numbers are in the range of healthy controls. These cells increased on reduction of immunosuppression and treatment with rituximab. Recurrence of EBV viremia during complete remission is matched by strong T-cell responses.
    Transplantation 12/2012; · 3.78 Impact Factor
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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; · 9.37 Impact Factor
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    ABSTRACT: Identification of mutations in the HOGA1 gene as the cause of autosomal recessive primary hyperoxaluria (PH) type III has revitalized research in the field of PH and related stone disease. In contrast to the well-characterized entities of PH type I and type II, the pathophysiology and prevalence of type III is largely unknown. In this study, we analyzed a large cohort of subjects previously tested negative for type I/II by complete HOGA1 sequencing. Seven distinct mutations, among them four novel, were found in 15 patients. In patients of non-consanguineous European descent the previously reported c.700+5G>T splice-site mutation was predominant and represents a potential founder mutation, while in consanguineous families private homozygous mutations were identified throughout the gene. Furthermore, we identified a family where a homozygous mutation in HOGA1 (p.P190L) segregated in two siblings with an additional AGXT mutation (p.D201E). The two girls exhibiting triallelic inheritance presented a more severe phenotype than their only mildly affected p.P190L homozygous father. In silico analysis of five mutations reveals that HOGA1 deficiency is causing type III, yet reduced HOGA1 expression or aberrant subcellular protein targeting is unlikely to be the responsible pathomechanism. Our results strongly suggest HOGA1 as a major cause of PH, indicate a greater genetic heterogeneity of hyperoxaluria, and point to a favorable outcome of type III in the context of PH despite incomplete or absent biochemical remission. Multiallelic inheritance could have implications for genetic testing strategies and might represent an unrecognized mechanism for phenotype variability in PH.European Journal of Human Genetics advance online publication, 11 July 2012; doi:10.1038/ejhg.2012.139.
    European journal of human genetics: EJHG 07/2012; · 3.56 Impact Factor
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    ABSTRACT: In May and June 2011 the largest known outbreak of hemolytic uremic syndrome (HUS) occurred in northern Germany. Because, quite unusually, a large number of adults was affected and the causative Escherichia coli strain, serotype O104:H4, showed an atypical virulence factor pattern, it was speculated that this outbreak was associated with an aggressive course and an unfavorable prognosis also in children. Retrospective analysis of medical records of 90 children and comparison to previous outbreak and sporadic case series. Median age was unusually high (11.5 years) compared with that in historical series. Only 1 patient (1.1%) died in the acute phase. Most patients (67/90 [74%]) received supportive care only. Renal replacement therapy was required in 64 of 90 (71%) of the children. Neurological complications, mainly seizures and altered mental stage, were present in 23 of 90 (26%) patients. Ten patients received plasmapheresis, 6 eculizumab, and 7 a combination of both. After a median follow-up of 4 months, renal function normalized in 85 of 90 (94%) patients, whereas 3 patients had chronic kidney disease stage 3 or 4, and 1 patient (1.1%) still requires dialysis. Complete neurological recovery occurred in 18 of 23 patients. Mild to moderate and major residual neurological changes were present in 3 patients and 1 patient, respectively, although all patients were still improving. E. coli O104:H4 caused the largest HUS outbreak in children reported in detail to date and most patients received supportive treatment only. Initial morbidity, as well as short-term outcome, due to this pathogen, is comparable to previous pediatric series of Shiga toxin-producing E. coli HUS.
    Clinical Infectious Diseases 06/2012; 55(6):753-9. · 9.37 Impact Factor
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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. · 3.16 Impact Factor
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    ABSTRACT: In patients with refractory steroid-sensitive nephrotic syndrome (SSNS), treatment with rituximab has shown encouraging results; however, long-term follow-up data are not available. We performed a retrospective analysis of 37 patients (25 boys) with steroid-dependent nephrotic syndrome who were treated with rituximab (375 mg/m(2) given weekly for one to four courses). Long-term follow-up data (>2 years, median 36, range 24-92.8 months) are available for 29 patients (12 boys). Twenty-six of 37 (70.3%) patients remained in remission after 12 months. Relapses occurred in 24 (64.8%) patients after a median of 9.6 (range 5.2-64.1) months. Time to first relapse was significantly shorter in patients receiving one or two compared to three or four initial infusions. In the 29 patients with long-term follow-up for >2 years, 12 (41%) patients remained in remission after the initial rituximab course for >24 months, 7 (24.1%) patients without further maintenance immunosuppression. Nineteen children received two to four repeated courses of rituximab increasing the total number of patients with long-term remission to 20 (69%), remission including 14 (48%) patients off immunosuppression. The proportion of patients with long-term remission was not related to the number of initial rituximab applications. No serious side effects were noted. Rituximab is an effective treatment option in the short- and long-term control of treatment refractory SSNS. Further controlled studies are needed to address optimal patient selection, dose and safety of rituximab infusions.
    Nephrology Dialysis Transplantation 11/2011; 27(5):1910-5. · 3.37 Impact Factor
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    ABSTRACT: BACKGROUND: Long-term corticosteroid treatment impairs growth and increases cardiovascular risk factors. Hence, steroid withdrawal constitutes a major topic in paediatric renal transplantation and maintenance immunosuppression. METHODS: The lack of data from randomised controlled trials caused us to conduct the first prospective, randomised, multicentre study on late steroid withdrawal among paediatric kidney allograft recipients treated with standard-dose cyclosporine microemulsion (CsA) and mycophenolate mofetil (MMF) for 2 years. Forty-two low- or regular-immunologic risk patients were randomly assigned, >or=1 year post-transplant, to continue taking or to withdraw steroids over 3 months. RESULTS: Two years after steroid withdrawal, they showed a longitudinal growth superior to controls [mean height standard deviation score (SDS) gain, 0.6 +/- 0.1 SDS versus -0.2 +/- 0.1 SDS (P < 0.001)]. The prevalence of the metabolic syndrome declined significantly (P < 0.05), 2 years after steroid withdrawal, from 39% (9/23) to 6% (1/16). Steroid-free patients had less frequent arterial hypertension (50% versus 93% (P < 0.05)) and required fewer antihypertensive drugs [0.6 +/- 0.2 versus 1.5 +/- 0.3 (P < 0.05 versus control)]. Additionally, they had a significantly improved carbohydrate and lipid metabolism with fewer hypercholesterolaemia and hypertriglyceridaemia (P < 0.05 versus control). Patient and graft survival amounted to 100%. Allograft function remained stable 2 years after steroid withdrawal. The incidence of acute rejections was similar in the steroid-withdrawal group (1/23, 4%) and controls (2/19, 11%). CONCLUSION: Late steroid withdrawal in selected CsA- and MMF-treated paediatric kidney transplant recipients improves growth, mitigates cardiovascular risk factors and reduces the prevalence of the metabolic syndrome, at no increased risk of acute rejection or unstable graft function.
    Nephrology Dialysis Transplantation 02/2010; · 3.37 Impact Factor
  • Klinische Padiatrie - KLIN PADIAT. 01/2010; 222(02).
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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. · 3.37 Impact Factor
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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. · 3.78 Impact Factor