Peter Hoyer - Academia.edu (original) (raw)
Papers by Peter Hoyer
Zeitschrift Fur Gastroenterologie, Aug 1, 2021
Deutsches Arzteblatt International, Sep 16, 2011
Background: Urinary incontinence (bedwetting, enuresis) is the commonest urinary symptom in child... more Background: Urinary incontinence (bedwetting, enuresis) is the commonest urinary symptom in children and adolescents and can lead to major distress for the affected children and their parents. Physiological and non-physiological types of urinary incontinence are sometimes hard to tell apart in this age group. Methods: This article is based on selected literature retrieved by a PubMed search and on an interdisciplinary expert consensus. Results and conclusion: Nocturnal enuresis has a variety of causes. The main causative factors in monosymptomatic enuresis nocturna (MEN) are an impaired ability to wake up when the bladder is full, due to impaired or absent perception of fullness during sleep, and an imbalance between bladder capacity and nocturnal urine production. On the other hand, non-monosymptomatic enuresis nocturna (non-MEN) is usually traceable to bladder dysfunction, which is also the main cause of diurnal incontinence. A basic battery of non-invasive diagnostic tests usually suffices to determine which type of incontinence is present. Further and more specific testing is indicated if an organic cause is suspected or if the treatment fails. The mainstay of treatment is urotherapy (all non-surgical and non-pharmacological therapeutic modalities). Some patients, however, will need supportive medication in addition. Urinary incontinence has different causes in children and adults and must therefore be diagnosed and treated differently as well. All physicians who treat the affected children (not just pediatri cians and family doctors, but also pediatric nephrologists, urologists, pediatric surgeons, and child psychiatrists) must be aware of the specific features of urinary incontinence in childhood.
Scientific Reports, Dec 10, 2021
Allograft-specific regulatory T cells (T reg cells) are crucial for long-term graft acceptance af... more Allograft-specific regulatory T cells (T reg cells) are crucial for long-term graft acceptance after transplantation. Although adoptive T reg cell transfer has been proposed, major challenges include graft-specificity and stability. Thus, there is an unmet need for the direct induction of graft-specific T reg cells. We hypothesized a synergism of the immunotolerogenic effects of rapamycin (mTOR inhibition) and plerixafor (CXCR4 antagonist) for T reg cell induction. Thus, we performed fully-mismatched heart transplantations and found combination treatment to result in prolonged allograft survival. Moreover, fibrosis and myocyte lesions were reduced. Although less CD3 + T cell infiltrated, higher T reg cell numbers were observed. Noteworthy, this was accompanied by a plerixafor-dependent plasmacytoid dendritic cells-(pDCs)-mobilization. Furthermore, in vivo pDC-depletion abrogated the plerixaformediated T reg cell number increase and reduced allograft survival. Our pharmacological approach allowed to increase T reg cell numbers due to pDC-mediated immune regulation. Therefore pDCs can be an attractive immunotherapeutic target in addition to plerixafor treatment. Antigen APC Antigen-presenting cell cDCs Conventional dendritic cells CXCR4 C-X-C chemokine receptor type 4 FACS Fluorescence-activated cell sorting FoxP3 Forkhead box P3
Pediatric Nephrology, Jun 6, 2021
Idiopathic nephrotic syndrome is the most frequent glomerular disease in children in most parts o... more Idiopathic nephrotic syndrome is the most frequent glomerular disease in children in most parts of the world. Children with steroid-sensitive nephrotic syndrome (SSNS) generally have a good prognosis regarding the maintenance of normal kidney function even in the case of frequent relapses. The course of SSNS is often complicated by a high rate of relapses and the associated side effects of repeated glucocorticoid (steroid) therapy. The following recommendations for the treatment of SSNS are based on the comprehensive consideration of published evidence by a working group of the German Society for Pediatric Nephrology (GPN) based on the systematic Cochrane reviews on SSNS and the guidelines of the KDIGO working group (Kidney Disease -Improving Global Outcomes).
Cell discovery, Jan 31, 2023
Joint statement for assessing and managing high blood pressure in children and adolescents: Chapter 2. How to manage high blood pressure in children and adolescents
Frontiers in Pediatrics
The joint statement is a synergistic action between HyperChildNET and the European Academy of Ped... more The joint statement is a synergistic action between HyperChildNET and the European Academy of Pediatrics about the diagnosis and management of hypertension in youth, based on the European Society of Hypertension Guidelines published in 2016 with the aim to improve its implementation. Arterial hypertension is not only the most important risk factor for cardiovascular morbidity and mortality, but also the most important modifiable risk factor. Early hypertension-mediated organ damage may already occur in childhood. The duration of existing hypertension plays an important role in risk assessment, and structural and functional organ changes may still be reversible or postponed with timely treatment. Therefore, appropriate therapy should be initiated in children as soon as the diagnosis of arterial hypertension has been confirmed and the risk factors for hypertension-mediated organ damage have been thoroughly evaluated. Lifestyle measures should be recommended in all hypertensive childre...
Pediatric Surgery International, 1997
In a 3-year-old boy an abdominal mass was palpated by chance, which consisted of cystic and solid... more In a 3-year-old boy an abdominal mass was palpated by chance, which consisted of cystic and solid structures and was shown on ultrasound scan and computed tomography to be located retroperitoneally. Intraoperatively, the cystic tumor contained clear, yellowish fluid and had a stalk leading to the interspinal space between L2 and L3. However, no signs of dysraphism, were found. Neuropathologic examination surprisingly showed non-neoplastic ectopic neural tissue, which has never been recorded at this extraspinal site before. Key words Extraspinal • Retroperitoneal ectopic neural tissue • Retroperitoneal tumor Fig. 1 Ultrasound scan demonstrating close relation between cystic tumor and renal pelvis Fig. 2 CT scan showing extension of tumor with displacement of surrounding viscera
British Journal of Clinical Pharmacology, 2003
To assess the single-dose pharmacokinetics and tolerability of pegylated interferona 2b (PEG-Intr... more To assess the single-dose pharmacokinetics and tolerability of pegylated interferona 2b (PEG-Intron) in young and elderly healthy subjects. Methods In this parallel-design study, a single 1 m g kg -1 PEG-Intron dose was given subcutaneously to 24 subjects in the age groups 20-45, 65-69, 70-74 and 75-80 years ( n = 6/group). Blood sampling and tolerability assessments were performed up to 168 h postdose. The pharmacokinetic parameters were similar in all age groups. The elderly to young subject ratios for C max were 91.1, 79.5, and 107% for the 65-69 years, 70-74 years and 75-80 years groups, respectively. The corresponding values for AUC(0-• ) and CL/F were 111, 102 and 108%, and 82.5, 95.8 and 86.4%, respectively. Mean differences from the 20 to 45 years group and the 65-69 years, 70-74 years and 75-80 years groups for PEG-Intron V d/F were 108, 128 and 104%, respectively. None of these differences was statistically significant based on ANOVA . Results from a Dunnett's test (as post hoc assessment) confirmed that the pharmacokinetic parameters of Group II, Group III or Group IV were not different from those of Group I. Almost all (23/24; 96%) subjects reported typical interferona side-effects (flu-like symptoms, headache). One elderly patient had a myocardial infarction 12 h postdose, but recovered fully. Conclusions There are no pharmacokinetic reasons for initial dose adjustment of PEG-Intron based on age.
Steroid-Resistant Nephrotic Syndrome Associated with Kimura’s Disease
American Journal of Nephrology, 2002
Kimura’s disease is a chronic inflammatory disease characterized by tumor-like lesions in the sof... more Kimura’s disease is a chronic inflammatory disease characterized by tumor-like lesions in the soft tissue and lymph nodes of head and neck area or parotid gland. It has a high frequency of an association with nephrotic syndrome. Reported cases of nephrotic syndrome and Kimura’s disease were mostly from adult patients with only 5 children mentioned. This study reports the case of a 15-year-old-boy who manifested with steroid-resistant nephrotic syndrome for 4 years. Pathological examination of the kidney revealed mild mesangial proliferation. Subsequently, he developed a soft-tissue mass in the parotid gland area. Histopathological investigation of the mass revealed eosinophilic infiltration together with plasma cells and mast cells which is a main characteristic of Kimura’s disease. The patient, however, continued to have nephrotic-range proteinuria after removing the subcutaneous mass.
Kidney360, Mar 31, 2022
Our previous protocols for 3D super-resolution kidney imaging have not been optimized to be compa... more Our previous protocols for 3D super-resolution kidney imaging have not been optimized to be compatible with paraffin-embedded samples. *This study overcomes these limitations, allowing 3D super-resolved imaging in FFPE kidney blocks. *This advancement opens up for 3D super-resolution kidney imaging of biobank material and in clinical settings.
Scientific Reports, Jul 19, 2022
Podocytes are highly specialized cells playing a key role in the filtration function of the kidne... more Podocytes are highly specialized cells playing a key role in the filtration function of the kidney. A damaged podocyte ultrastructure is associated with a reorganization of the actin cytoskeleton and accompanied with a loss of adhesion to the glomerular basement membrane leading to proteinuria in many forms of glomerular diseases, e.g. nephrotic syndrome. If the first-line therapy with glucocorticoids fails, alternative immunosuppressive agents are used, which are known to have the potential to stabilize the actin cytoskeleton. A new option for preventing relapses in steroid dependent nephrotic syndrome is the monoclonal antibody rituximab, which, in addition to its B-cell depleting effect, is assumed to have direct effects on podocytes. We here provide data on the non-immunological off-target effects of the immunosuppressant rituximab on podocyte structure and dynamics in an in vitro puromycin aminonucleoside model of podocyte injury. A conditionally immortalized human podocyte cell line was used. Differentiated podocytes were treated with puromycin aminonucleoside and rituximab. Our studies focussed on analyzing the structure of the actin cytoskeleton, cellular adhesion and apoptosis using immunofluorescence staining and protein biochemistry methods. Treatment with rituximab resulted in a stabilization of podocyte actin stress fibers in the puromycin aminonucleoside model, leading to an improvement in cell adhesion. A lower apoptosis rate was observed after parallel treatment with puromycin aminonucleoside and rituximab visualized by reduced nuclear fragmentation. Consistent with this data, Westernblot analyses demonstrated that rituximab directly affects the caspase pathways by inhibiting the activation of Caspases-8,-9 and-3, suggesting that rituximab may inhibit apoptosis. In conclusion, our results indicate an important role of the immunosuppressant rituximab in terms of stability and morphogenesis of podocytes, involving apoptosis pathways. This could help to improve therapeutical concepts for patients with proteinuria mediated by diseased podocytes. The renal filtration barrier consists of fenestrated endothelial cells, the glomerular basement membrane (GBM) and podocytes 1,2. This complex structure ensures the selective ultrafiltration of plasma. Podocytes are terminally differentiated visceral glomerular epithelial cells forming the final barrier to urinary protein loss by means of foot processes and interposed slit diaphragms 3. To maintain an intact glomerular filter, the foot processes are linked to the GBM via α3/β1 integrins and dystroglycans and contain an actin-based cytoskeleton together with actin-associated proteins such as synaptopodin 4. All these components are essential to prevent the development of proteinuria, defined as the leakage of protein from the blood to the urinary compartment, which occurs in many forms of glomerular diseases. Injury of podocytes leads to fusion of filtration slits, apical displacement or disruption of the slit diaphragm and foot process effacement which is based on rearrangements of the actin cytoskeleton of the involved foot processes 5. If these structural changes in podocyte morphology occur early, they are fully reversible and the foot processes reorganize within minutes due to their high dynamics. In contrast, persistence of podocyte injury as e.g. found in steroid resistant nephrotic syndrome (NS) can cause podocyte detachment from the GBM and cell death associated with development of proteinuria and with permanent deterioration of the glomerular filter 6 .
Frontiers in Pediatrics
In West Africa, kidney diseases are frequently seen, but diagnostic and therapeutic options are p... more In West Africa, kidney diseases are frequently seen, but diagnostic and therapeutic options are poor due to limited access to specialized facilities. To unravel the etiology and develop clinical guidelines, we collected clinical data and results of kidney biopsies in 121 pediatric and mostly young adult patients with edema and proteinuria in The Gambia. Workup included clinical examination, urine and serum analysis, and kidney biopsy findings. Selected cases were treated with steroids.ResultsThe median age was 14.9 years (range 1.8–52.0) at presentation. The most frequent underlying histologies were post-infectious glomerulonephritis (PIGN) in 38%, focal-segmental glomerulosclerosis (FSGS) in 30%, minimal change nephrotic syndrome (MCNS) in 15%, and membranous glomerulonephritis (MGN) in 10% of cases. Patients with PIGN were significantly younger and had less proteinuria and higher serum albumin levels than the other three. Infected scabies was seen more often in cases with PIGN. Cl...
Frontiers in Endocrinology, 2020
Background: Hashimoto's thyroiditis is frequently associated with other autoimmune diseases and m... more Background: Hashimoto's thyroiditis is frequently associated with other autoimmune diseases and may include renal involvement. Case description: A 17-year-old female with previously diagnosed Hashimoto's thyroiditis and vitiligo was admitted to a pediatric intensive care unit with hypokalemic paralysis and acidosis, after having suffered from recurrent muscular weakness for approximately one year. A few days later she developed central pontine myelinolysis. After initial stabilization she was also diagnosed with distal renal tubular acidosis (dRTA) and tubular proteinuria which can occur in Sjögren's syndrome. Extended screening for autoimmune diseases additionally revealed celiac disease. Treatment with Prednisone and substitution of potassium quickly lead to the resolution of proteinuria and dRTA, but unilateral paralysis of the sixth nerve as a result of central pontine myelinolysis was irreversible. Conclusions: This is the rare case of polyautoimmunity including autoimmune thyroiditis, Sjögren's syndrome, vitiligo and celiac disease in an adolescent with few disease-specific symptoms. The diagnoses were made via a complicating nephritis causing dRTA and proteinuria. Delay in diagnosis lead to permanent neurological damage. This case highlights the need for pediatricians to be aware of rare accompanying diseases and their complications in "common" pediatric autoimmune diseases like Hashimoto's thyroiditis and celiac disease.
Clinical Genetics, Oct 25, 2020
Early initiation of therapy in patients with Alport syndrome (AS) slows down renal failure by man... more Early initiation of therapy in patients with Alport syndrome (AS) slows down renal failure by many years. Genotype-phenotype correlations propose that the location and character of the individual's variant correlate with the renal outcome and any extra renal manifestations. In-depth clinical and genetic data of 60/62 children who participated in the EARLY PROTECT Alport trial were analyzed. Genetic variants were interpreted according to current guidelines and criteria. Genetically solved patients with X-linked inheritance were then classified according to the severity of their COL4A5 variant into less-severe, intermediate, and severe groups and disease progress was compared. Almost 90% of patients were found to carry (likely) pathogenic variants and classified as genetically solved cases. Patients in the less-severe group demonstrated a borderline significant difference in disease progress compared to those in the severe group (p = 0.05). While having only limited power according to its sample size, an obvious strength is the precise clinical and genetic data of this well ascertained cohort. As in published data differences in clinical progress were shown between patients with COL4A5 less-severe and severe variants. Therefore, clinical and segregational data are important for variant (re)classification. Genetic testing should be mandatory allowing early diagnosis and therapy of AS.
Frontiers in Pediatrics
Background: The calcineurin inhibitor (CNI) tacrolimus (TAC) is a cornerstone agent in immunosupp... more Background: The calcineurin inhibitor (CNI) tacrolimus (TAC) is a cornerstone agent in immunosuppressive therapy in pediatric liver transplantation (LTX). Adverse effects limit the use of CNI. In adults, calculating the individual TAC metabolism rate allows to estimate the transplant recipient's risk for therapy-associated complications.Methods: A retrospective, descriptive data analysis was performed in children who had undergone LTX in 2009–2017 and had received TAC twice daily in the first year after LTX. A weight-adjusted concentration/dose ratio (C/D ratio) was calculated [TAC trough level/(daily TAC dose/body weight)] every 3 months after LTX to estimate the average individual TAC metabolism rate. Depending on the C/D ratio, all patients were divided into two groups: fast metabolizers (FM) and slow metabolizers (SM). Clinical and laboratory parameters were analyzed as risk factors in both groups.Results: A total of 78 children (w 34, m 44, median age at LTX 2.4; 0.4–17.0 y...
Pediatric Nephrology, 2017
Background In 2010, INF2 mutations were associated with autosomal-dominant focal segmental glomer... more Background In 2010, INF2 mutations were associated with autosomal-dominant focal segmental glomerulosclerosis (FSGS), clinically presenting with moderate proteinuria in adolescence. However, in the meantime, cases with more severe clinical courses have been described, including progression to end-stage renal disease (ESRD) during childhood. INF2 mutations in patients with isolated FSGS are clustered in exons 2 to 4, encoding the diaphanous inhibitory domain, involved in the regulation of the podocyte actin cytoskeleton. Methods We report a family with 14 affected individuals (autosomal-dominant mode of inheritance), most of whom presented with nephrotic-range proteinuria, hypertension, and progressive renal failure. Four members received a kidney transplant without disease recurrence. Two patients underwent renal biopsy with the result of minimal-change glomerulopathy and IgA nephropathy respectively. We performed mutational analysis of ACTN4, CD2AP, COQ6, INF2, LAMB2, NPHS1, NPHS2, PLCE1, TRPC6, and WT1 in the index patient by next-generation sequencing. Additionally, in 6 affected and 2 unaffected family members target diagnostics were performed. Results We identified a novel heterozygous mutation c.490G>C (p.(Ala164Pro) in exon 3 of the INF2 gene in the index patient and 6 additionally examined affected family members. In silico analysis predicted it as Bprobably damaging^. Additionally, three patients and 2 unaffected relatives harbored a novel heterozygous variant in ACTN4 (c.1149C>G, p.(Ile383Met)) with uncertain pathogenicity. Conclusion Mutations in INF2 are associated with familial proteinuric diseases-irrespective of the presence of FSGS and in the case of rapid disease progression. Therefore, mutational analysis should be considered in patients with renal histology other than FSGS and severe renal phenotype.
Extracellular vesicles (EVs) from several body fluids, including urine, appear as promising bioma... more Extracellular vesicles (EVs) from several body fluids, including urine, appear as promising biomarkers. Within the last decade, numerous groups have compared the efficacy of EV preparation protocols. Frequently, the efficacy of EV preparation methods is judged by the recovery of particles as estimated by conventional nanoparticle tracking analysis (NTA) or other particle quantification devices. Here, at the example of different urinary EV (uEV) preparation methods, we determined the particle yield in obtained samples with conventional NTA, analyzed their EV content by imaging flow cytometry (IFCM) and quantified the intensity of TSG101 and the contaminant protein uromodulin (UMOD) in Western blots. Our results demonstrate a correlation among CD9-positive objects detected by IFCM and TSG101 Western blot intensities, while particle numbers as determined by NTA correlated with the amount of UMOD.Consequently, our results question the reliability of conventional NTA analyses for identif...
Author response for "Precise variant interpretation, phenotype ascertainment and genotype‐phenotype correlation of children in the EARLY PRO‐TECT Alport trial
GMS Zeitschrift für medizinische Ausbildung, 2013
Since 1986 medical students at the University Children's Hospital Essen are trained as peers ... more Since 1986 medical students at the University Children's Hospital Essen are trained as peers in a two week intensive course in order to teach basic paediatric examination techniques to younger students. Student peers are employed by the University for one year. Emphasis of the peer teaching program is laid on the mediation of affective and sensomotorical skills e.g. get into contact with parents and children, as well as manual paediatric examination techniques. The aim of this study is to analyse whether student peers are able to impart specific paediatric examination skills as good as an experienced senior paediatric lecturer. 123 students were randomly assigned to a group with either a senior lecturer or a student peer teacher. Following one-hour teaching-sessions in small groups students had to demonstrate the learned skills in a 10 minute modified OSCE. In comparison to a control group consisting of 23 students who never examined a child before, both groups achieved a signif...
Background Podocytes are highly specialized cells playing a key role in the filtration function o... more Background Podocytes are highly specialized cells playing a key role in the filtration function of the kidney. A damaged podocyte ultrastructure is associated with a reorganization of the actin cytoskeleton and accompanied with a loss of adhesion to the glomerular basement membrane leading to proteinuria in many forms of glomerular diseases, e.g. nephrotic syndrome. If the first-line therapy with glucocorticoids fails, alternative immunosuppressive agents are used, which are known to have the potential to stabilize the actin cytoskeleton. A new option for preventing relapses in steroid dependent nephrotic syndrome is the monoclonal antibody rituximab, which, in addition to its B-cell depleting effect, is assumed to have direct effects on podocytes.Objectives We here provide data on the non-immunological off-target effects of the immunosuppressant rituximab on podocyte structure and dynamics in an in vitro puromycin aminonucleoside model of podocyte injury.Methods A conditionally imm...
Zeitschrift Fur Gastroenterologie, Aug 1, 2021
Deutsches Arzteblatt International, Sep 16, 2011
Background: Urinary incontinence (bedwetting, enuresis) is the commonest urinary symptom in child... more Background: Urinary incontinence (bedwetting, enuresis) is the commonest urinary symptom in children and adolescents and can lead to major distress for the affected children and their parents. Physiological and non-physiological types of urinary incontinence are sometimes hard to tell apart in this age group. Methods: This article is based on selected literature retrieved by a PubMed search and on an interdisciplinary expert consensus. Results and conclusion: Nocturnal enuresis has a variety of causes. The main causative factors in monosymptomatic enuresis nocturna (MEN) are an impaired ability to wake up when the bladder is full, due to impaired or absent perception of fullness during sleep, and an imbalance between bladder capacity and nocturnal urine production. On the other hand, non-monosymptomatic enuresis nocturna (non-MEN) is usually traceable to bladder dysfunction, which is also the main cause of diurnal incontinence. A basic battery of non-invasive diagnostic tests usually suffices to determine which type of incontinence is present. Further and more specific testing is indicated if an organic cause is suspected or if the treatment fails. The mainstay of treatment is urotherapy (all non-surgical and non-pharmacological therapeutic modalities). Some patients, however, will need supportive medication in addition. Urinary incontinence has different causes in children and adults and must therefore be diagnosed and treated differently as well. All physicians who treat the affected children (not just pediatri cians and family doctors, but also pediatric nephrologists, urologists, pediatric surgeons, and child psychiatrists) must be aware of the specific features of urinary incontinence in childhood.
Scientific Reports, Dec 10, 2021
Allograft-specific regulatory T cells (T reg cells) are crucial for long-term graft acceptance af... more Allograft-specific regulatory T cells (T reg cells) are crucial for long-term graft acceptance after transplantation. Although adoptive T reg cell transfer has been proposed, major challenges include graft-specificity and stability. Thus, there is an unmet need for the direct induction of graft-specific T reg cells. We hypothesized a synergism of the immunotolerogenic effects of rapamycin (mTOR inhibition) and plerixafor (CXCR4 antagonist) for T reg cell induction. Thus, we performed fully-mismatched heart transplantations and found combination treatment to result in prolonged allograft survival. Moreover, fibrosis and myocyte lesions were reduced. Although less CD3 + T cell infiltrated, higher T reg cell numbers were observed. Noteworthy, this was accompanied by a plerixafor-dependent plasmacytoid dendritic cells-(pDCs)-mobilization. Furthermore, in vivo pDC-depletion abrogated the plerixaformediated T reg cell number increase and reduced allograft survival. Our pharmacological approach allowed to increase T reg cell numbers due to pDC-mediated immune regulation. Therefore pDCs can be an attractive immunotherapeutic target in addition to plerixafor treatment. Antigen APC Antigen-presenting cell cDCs Conventional dendritic cells CXCR4 C-X-C chemokine receptor type 4 FACS Fluorescence-activated cell sorting FoxP3 Forkhead box P3
Pediatric Nephrology, Jun 6, 2021
Idiopathic nephrotic syndrome is the most frequent glomerular disease in children in most parts o... more Idiopathic nephrotic syndrome is the most frequent glomerular disease in children in most parts of the world. Children with steroid-sensitive nephrotic syndrome (SSNS) generally have a good prognosis regarding the maintenance of normal kidney function even in the case of frequent relapses. The course of SSNS is often complicated by a high rate of relapses and the associated side effects of repeated glucocorticoid (steroid) therapy. The following recommendations for the treatment of SSNS are based on the comprehensive consideration of published evidence by a working group of the German Society for Pediatric Nephrology (GPN) based on the systematic Cochrane reviews on SSNS and the guidelines of the KDIGO working group (Kidney Disease -Improving Global Outcomes).
Cell discovery, Jan 31, 2023
Joint statement for assessing and managing high blood pressure in children and adolescents: Chapter 2. How to manage high blood pressure in children and adolescents
Frontiers in Pediatrics
The joint statement is a synergistic action between HyperChildNET and the European Academy of Ped... more The joint statement is a synergistic action between HyperChildNET and the European Academy of Pediatrics about the diagnosis and management of hypertension in youth, based on the European Society of Hypertension Guidelines published in 2016 with the aim to improve its implementation. Arterial hypertension is not only the most important risk factor for cardiovascular morbidity and mortality, but also the most important modifiable risk factor. Early hypertension-mediated organ damage may already occur in childhood. The duration of existing hypertension plays an important role in risk assessment, and structural and functional organ changes may still be reversible or postponed with timely treatment. Therefore, appropriate therapy should be initiated in children as soon as the diagnosis of arterial hypertension has been confirmed and the risk factors for hypertension-mediated organ damage have been thoroughly evaluated. Lifestyle measures should be recommended in all hypertensive childre...
Pediatric Surgery International, 1997
In a 3-year-old boy an abdominal mass was palpated by chance, which consisted of cystic and solid... more In a 3-year-old boy an abdominal mass was palpated by chance, which consisted of cystic and solid structures and was shown on ultrasound scan and computed tomography to be located retroperitoneally. Intraoperatively, the cystic tumor contained clear, yellowish fluid and had a stalk leading to the interspinal space between L2 and L3. However, no signs of dysraphism, were found. Neuropathologic examination surprisingly showed non-neoplastic ectopic neural tissue, which has never been recorded at this extraspinal site before. Key words Extraspinal • Retroperitoneal ectopic neural tissue • Retroperitoneal tumor Fig. 1 Ultrasound scan demonstrating close relation between cystic tumor and renal pelvis Fig. 2 CT scan showing extension of tumor with displacement of surrounding viscera
British Journal of Clinical Pharmacology, 2003
To assess the single-dose pharmacokinetics and tolerability of pegylated interferona 2b (PEG-Intr... more To assess the single-dose pharmacokinetics and tolerability of pegylated interferona 2b (PEG-Intron) in young and elderly healthy subjects. Methods In this parallel-design study, a single 1 m g kg -1 PEG-Intron dose was given subcutaneously to 24 subjects in the age groups 20-45, 65-69, 70-74 and 75-80 years ( n = 6/group). Blood sampling and tolerability assessments were performed up to 168 h postdose. The pharmacokinetic parameters were similar in all age groups. The elderly to young subject ratios for C max were 91.1, 79.5, and 107% for the 65-69 years, 70-74 years and 75-80 years groups, respectively. The corresponding values for AUC(0-• ) and CL/F were 111, 102 and 108%, and 82.5, 95.8 and 86.4%, respectively. Mean differences from the 20 to 45 years group and the 65-69 years, 70-74 years and 75-80 years groups for PEG-Intron V d/F were 108, 128 and 104%, respectively. None of these differences was statistically significant based on ANOVA . Results from a Dunnett's test (as post hoc assessment) confirmed that the pharmacokinetic parameters of Group II, Group III or Group IV were not different from those of Group I. Almost all (23/24; 96%) subjects reported typical interferona side-effects (flu-like symptoms, headache). One elderly patient had a myocardial infarction 12 h postdose, but recovered fully. Conclusions There are no pharmacokinetic reasons for initial dose adjustment of PEG-Intron based on age.
Steroid-Resistant Nephrotic Syndrome Associated with Kimura’s Disease
American Journal of Nephrology, 2002
Kimura’s disease is a chronic inflammatory disease characterized by tumor-like lesions in the sof... more Kimura’s disease is a chronic inflammatory disease characterized by tumor-like lesions in the soft tissue and lymph nodes of head and neck area or parotid gland. It has a high frequency of an association with nephrotic syndrome. Reported cases of nephrotic syndrome and Kimura’s disease were mostly from adult patients with only 5 children mentioned. This study reports the case of a 15-year-old-boy who manifested with steroid-resistant nephrotic syndrome for 4 years. Pathological examination of the kidney revealed mild mesangial proliferation. Subsequently, he developed a soft-tissue mass in the parotid gland area. Histopathological investigation of the mass revealed eosinophilic infiltration together with plasma cells and mast cells which is a main characteristic of Kimura’s disease. The patient, however, continued to have nephrotic-range proteinuria after removing the subcutaneous mass.
Kidney360, Mar 31, 2022
Our previous protocols for 3D super-resolution kidney imaging have not been optimized to be compa... more Our previous protocols for 3D super-resolution kidney imaging have not been optimized to be compatible with paraffin-embedded samples. *This study overcomes these limitations, allowing 3D super-resolved imaging in FFPE kidney blocks. *This advancement opens up for 3D super-resolution kidney imaging of biobank material and in clinical settings.
Scientific Reports, Jul 19, 2022
Podocytes are highly specialized cells playing a key role in the filtration function of the kidne... more Podocytes are highly specialized cells playing a key role in the filtration function of the kidney. A damaged podocyte ultrastructure is associated with a reorganization of the actin cytoskeleton and accompanied with a loss of adhesion to the glomerular basement membrane leading to proteinuria in many forms of glomerular diseases, e.g. nephrotic syndrome. If the first-line therapy with glucocorticoids fails, alternative immunosuppressive agents are used, which are known to have the potential to stabilize the actin cytoskeleton. A new option for preventing relapses in steroid dependent nephrotic syndrome is the monoclonal antibody rituximab, which, in addition to its B-cell depleting effect, is assumed to have direct effects on podocytes. We here provide data on the non-immunological off-target effects of the immunosuppressant rituximab on podocyte structure and dynamics in an in vitro puromycin aminonucleoside model of podocyte injury. A conditionally immortalized human podocyte cell line was used. Differentiated podocytes were treated with puromycin aminonucleoside and rituximab. Our studies focussed on analyzing the structure of the actin cytoskeleton, cellular adhesion and apoptosis using immunofluorescence staining and protein biochemistry methods. Treatment with rituximab resulted in a stabilization of podocyte actin stress fibers in the puromycin aminonucleoside model, leading to an improvement in cell adhesion. A lower apoptosis rate was observed after parallel treatment with puromycin aminonucleoside and rituximab visualized by reduced nuclear fragmentation. Consistent with this data, Westernblot analyses demonstrated that rituximab directly affects the caspase pathways by inhibiting the activation of Caspases-8,-9 and-3, suggesting that rituximab may inhibit apoptosis. In conclusion, our results indicate an important role of the immunosuppressant rituximab in terms of stability and morphogenesis of podocytes, involving apoptosis pathways. This could help to improve therapeutical concepts for patients with proteinuria mediated by diseased podocytes. The renal filtration barrier consists of fenestrated endothelial cells, the glomerular basement membrane (GBM) and podocytes 1,2. This complex structure ensures the selective ultrafiltration of plasma. Podocytes are terminally differentiated visceral glomerular epithelial cells forming the final barrier to urinary protein loss by means of foot processes and interposed slit diaphragms 3. To maintain an intact glomerular filter, the foot processes are linked to the GBM via α3/β1 integrins and dystroglycans and contain an actin-based cytoskeleton together with actin-associated proteins such as synaptopodin 4. All these components are essential to prevent the development of proteinuria, defined as the leakage of protein from the blood to the urinary compartment, which occurs in many forms of glomerular diseases. Injury of podocytes leads to fusion of filtration slits, apical displacement or disruption of the slit diaphragm and foot process effacement which is based on rearrangements of the actin cytoskeleton of the involved foot processes 5. If these structural changes in podocyte morphology occur early, they are fully reversible and the foot processes reorganize within minutes due to their high dynamics. In contrast, persistence of podocyte injury as e.g. found in steroid resistant nephrotic syndrome (NS) can cause podocyte detachment from the GBM and cell death associated with development of proteinuria and with permanent deterioration of the glomerular filter 6 .
Frontiers in Pediatrics
In West Africa, kidney diseases are frequently seen, but diagnostic and therapeutic options are p... more In West Africa, kidney diseases are frequently seen, but diagnostic and therapeutic options are poor due to limited access to specialized facilities. To unravel the etiology and develop clinical guidelines, we collected clinical data and results of kidney biopsies in 121 pediatric and mostly young adult patients with edema and proteinuria in The Gambia. Workup included clinical examination, urine and serum analysis, and kidney biopsy findings. Selected cases were treated with steroids.ResultsThe median age was 14.9 years (range 1.8–52.0) at presentation. The most frequent underlying histologies were post-infectious glomerulonephritis (PIGN) in 38%, focal-segmental glomerulosclerosis (FSGS) in 30%, minimal change nephrotic syndrome (MCNS) in 15%, and membranous glomerulonephritis (MGN) in 10% of cases. Patients with PIGN were significantly younger and had less proteinuria and higher serum albumin levels than the other three. Infected scabies was seen more often in cases with PIGN. Cl...
Frontiers in Endocrinology, 2020
Background: Hashimoto's thyroiditis is frequently associated with other autoimmune diseases and m... more Background: Hashimoto's thyroiditis is frequently associated with other autoimmune diseases and may include renal involvement. Case description: A 17-year-old female with previously diagnosed Hashimoto's thyroiditis and vitiligo was admitted to a pediatric intensive care unit with hypokalemic paralysis and acidosis, after having suffered from recurrent muscular weakness for approximately one year. A few days later she developed central pontine myelinolysis. After initial stabilization she was also diagnosed with distal renal tubular acidosis (dRTA) and tubular proteinuria which can occur in Sjögren's syndrome. Extended screening for autoimmune diseases additionally revealed celiac disease. Treatment with Prednisone and substitution of potassium quickly lead to the resolution of proteinuria and dRTA, but unilateral paralysis of the sixth nerve as a result of central pontine myelinolysis was irreversible. Conclusions: This is the rare case of polyautoimmunity including autoimmune thyroiditis, Sjögren's syndrome, vitiligo and celiac disease in an adolescent with few disease-specific symptoms. The diagnoses were made via a complicating nephritis causing dRTA and proteinuria. Delay in diagnosis lead to permanent neurological damage. This case highlights the need for pediatricians to be aware of rare accompanying diseases and their complications in "common" pediatric autoimmune diseases like Hashimoto's thyroiditis and celiac disease.
Clinical Genetics, Oct 25, 2020
Early initiation of therapy in patients with Alport syndrome (AS) slows down renal failure by man... more Early initiation of therapy in patients with Alport syndrome (AS) slows down renal failure by many years. Genotype-phenotype correlations propose that the location and character of the individual's variant correlate with the renal outcome and any extra renal manifestations. In-depth clinical and genetic data of 60/62 children who participated in the EARLY PROTECT Alport trial were analyzed. Genetic variants were interpreted according to current guidelines and criteria. Genetically solved patients with X-linked inheritance were then classified according to the severity of their COL4A5 variant into less-severe, intermediate, and severe groups and disease progress was compared. Almost 90% of patients were found to carry (likely) pathogenic variants and classified as genetically solved cases. Patients in the less-severe group demonstrated a borderline significant difference in disease progress compared to those in the severe group (p = 0.05). While having only limited power according to its sample size, an obvious strength is the precise clinical and genetic data of this well ascertained cohort. As in published data differences in clinical progress were shown between patients with COL4A5 less-severe and severe variants. Therefore, clinical and segregational data are important for variant (re)classification. Genetic testing should be mandatory allowing early diagnosis and therapy of AS.
Frontiers in Pediatrics
Background: The calcineurin inhibitor (CNI) tacrolimus (TAC) is a cornerstone agent in immunosupp... more Background: The calcineurin inhibitor (CNI) tacrolimus (TAC) is a cornerstone agent in immunosuppressive therapy in pediatric liver transplantation (LTX). Adverse effects limit the use of CNI. In adults, calculating the individual TAC metabolism rate allows to estimate the transplant recipient's risk for therapy-associated complications.Methods: A retrospective, descriptive data analysis was performed in children who had undergone LTX in 2009–2017 and had received TAC twice daily in the first year after LTX. A weight-adjusted concentration/dose ratio (C/D ratio) was calculated [TAC trough level/(daily TAC dose/body weight)] every 3 months after LTX to estimate the average individual TAC metabolism rate. Depending on the C/D ratio, all patients were divided into two groups: fast metabolizers (FM) and slow metabolizers (SM). Clinical and laboratory parameters were analyzed as risk factors in both groups.Results: A total of 78 children (w 34, m 44, median age at LTX 2.4; 0.4–17.0 y...
Pediatric Nephrology, 2017
Background In 2010, INF2 mutations were associated with autosomal-dominant focal segmental glomer... more Background In 2010, INF2 mutations were associated with autosomal-dominant focal segmental glomerulosclerosis (FSGS), clinically presenting with moderate proteinuria in adolescence. However, in the meantime, cases with more severe clinical courses have been described, including progression to end-stage renal disease (ESRD) during childhood. INF2 mutations in patients with isolated FSGS are clustered in exons 2 to 4, encoding the diaphanous inhibitory domain, involved in the regulation of the podocyte actin cytoskeleton. Methods We report a family with 14 affected individuals (autosomal-dominant mode of inheritance), most of whom presented with nephrotic-range proteinuria, hypertension, and progressive renal failure. Four members received a kidney transplant without disease recurrence. Two patients underwent renal biopsy with the result of minimal-change glomerulopathy and IgA nephropathy respectively. We performed mutational analysis of ACTN4, CD2AP, COQ6, INF2, LAMB2, NPHS1, NPHS2, PLCE1, TRPC6, and WT1 in the index patient by next-generation sequencing. Additionally, in 6 affected and 2 unaffected family members target diagnostics were performed. Results We identified a novel heterozygous mutation c.490G>C (p.(Ala164Pro) in exon 3 of the INF2 gene in the index patient and 6 additionally examined affected family members. In silico analysis predicted it as Bprobably damaging^. Additionally, three patients and 2 unaffected relatives harbored a novel heterozygous variant in ACTN4 (c.1149C>G, p.(Ile383Met)) with uncertain pathogenicity. Conclusion Mutations in INF2 are associated with familial proteinuric diseases-irrespective of the presence of FSGS and in the case of rapid disease progression. Therefore, mutational analysis should be considered in patients with renal histology other than FSGS and severe renal phenotype.
Extracellular vesicles (EVs) from several body fluids, including urine, appear as promising bioma... more Extracellular vesicles (EVs) from several body fluids, including urine, appear as promising biomarkers. Within the last decade, numerous groups have compared the efficacy of EV preparation protocols. Frequently, the efficacy of EV preparation methods is judged by the recovery of particles as estimated by conventional nanoparticle tracking analysis (NTA) or other particle quantification devices. Here, at the example of different urinary EV (uEV) preparation methods, we determined the particle yield in obtained samples with conventional NTA, analyzed their EV content by imaging flow cytometry (IFCM) and quantified the intensity of TSG101 and the contaminant protein uromodulin (UMOD) in Western blots. Our results demonstrate a correlation among CD9-positive objects detected by IFCM and TSG101 Western blot intensities, while particle numbers as determined by NTA correlated with the amount of UMOD.Consequently, our results question the reliability of conventional NTA analyses for identif...
Author response for "Precise variant interpretation, phenotype ascertainment and genotype‐phenotype correlation of children in the EARLY PRO‐TECT Alport trial
GMS Zeitschrift für medizinische Ausbildung, 2013
Since 1986 medical students at the University Children's Hospital Essen are trained as peers ... more Since 1986 medical students at the University Children's Hospital Essen are trained as peers in a two week intensive course in order to teach basic paediatric examination techniques to younger students. Student peers are employed by the University for one year. Emphasis of the peer teaching program is laid on the mediation of affective and sensomotorical skills e.g. get into contact with parents and children, as well as manual paediatric examination techniques. The aim of this study is to analyse whether student peers are able to impart specific paediatric examination skills as good as an experienced senior paediatric lecturer. 123 students were randomly assigned to a group with either a senior lecturer or a student peer teacher. Following one-hour teaching-sessions in small groups students had to demonstrate the learned skills in a 10 minute modified OSCE. In comparison to a control group consisting of 23 students who never examined a child before, both groups achieved a signif...
Background Podocytes are highly specialized cells playing a key role in the filtration function o... more Background Podocytes are highly specialized cells playing a key role in the filtration function of the kidney. A damaged podocyte ultrastructure is associated with a reorganization of the actin cytoskeleton and accompanied with a loss of adhesion to the glomerular basement membrane leading to proteinuria in many forms of glomerular diseases, e.g. nephrotic syndrome. If the first-line therapy with glucocorticoids fails, alternative immunosuppressive agents are used, which are known to have the potential to stabilize the actin cytoskeleton. A new option for preventing relapses in steroid dependent nephrotic syndrome is the monoclonal antibody rituximab, which, in addition to its B-cell depleting effect, is assumed to have direct effects on podocytes.Objectives We here provide data on the non-immunological off-target effects of the immunosuppressant rituximab on podocyte structure and dynamics in an in vitro puromycin aminonucleoside model of podocyte injury.Methods A conditionally imm...