Single-center outcome analysis of 46 fetuses with megacystis after intrauterine vesico-amniotic shunting with the Somatex®intrauterine shunt.

OBJECTIVES: To assess the spectrum of underlying pathologies, the intrauterine course and postnatal outcome of 46 fetuses with megacystis that underwent intrauterine vesico-amniotic shunting (VAS) with the Somatex® shunt in a single center. METHODS: Retrospective analysis of 46 fetuses with megacystis that underwent VAS either up to 14 + 0 weeks (early VAS), between 14 + 1 and 17 + 0 weeks (intermediate VAS) or after 17 + 0 weeks of gestation (late VAS) in a single tertiary referral center. Intrauterine course, underlying pathology and postnatal outcome were assessed and correlated with the underlying pathology and gestational age at first VAS. RESULTS: 46 fetuses underwent VAS, 41 (89%) were male and 5 (11%) were female. 28 (61%) fetuses had isolated and 18 (39%) had complex megacystis with either aneuploidy (n = 1), anorectal malformations (n = 6), cloacal malformations (n = 3), congenital anomalies overlapping with VACTER association (n = 6) or Megacystis-Microcolon Intestinal-Hypoperistalsis Syndrome (MMIHS) (n = 2). The sonographic 'keyhole sign' significantly predicted isolated megacystis (p < 0.001). 7 pregnancies were terminated, 4 babies died in the neonatal period, 1 baby died at the age of 2.5 months and 34 (74%) infants survived until last follow-up. After exclusion of the terminated pregnancies, intention-to-treat survival rate was 87%. Mean follow-up period was 24 months (range 1-72). The underlying pathology was highly variable and included posterior urethral valve (46%), hypoplastic or atretic urethra (35%), MMIHS or prune belly syndrome (10%) and primary vesico-ureteral reflux (2%). In 7% no pathology could be detected postnatally. No sonographic marker was identified to predict the underlying pathology prenatally. 14 fetuses underwent early, 24 intermediate and 8 late VAS. In the early VAS subgroup, amnion infusion prior to VAS was significantly less often necessary (7%), shunt complications were significantly less common (29%) and immediate kidney replacement therapy postnatally became less often necessary (0%). In contrast, preterm delivery ≤ 32 + 0 weeks was more common (30%) and survival rate was lower (70%) after early VAS compared to intermediate or late VAS. Overall, 90% of liveborn babies had sufficient kidney function without need for kidney replacement therapy until last follow-up, and 95% had sufficient pulmonary function without need for mechanical respiratory support. 18% of babies with complex megacystis suffered from additional health restrictions due to their major concomitant malformations. CONCLUSIONS: Our data suggest that VAS is feasible from the first trimester onward. Early intervention has the potential to preserve neonatal kidney function in the majority of cases and enables neonatal survival in up to 87% of cases. Despite successful fetal intervention, parents should be aware of the potential of mid- or long-term kidney failure and of additional health impairments due to concomitant extra-renal anomalies that cannot be excluded at time of intervention.

The effect of mycophenolate mofetil on podocytes in nephrotoxic serum nephritis.

Mycophenolate mofetil (MMF) is applied in proteinuric kidney diseases, but the exact mechanism of its effect on podocytes is still unknown. Our previous in vitro experiments suggested that MMF can ameliorate podocyte damage via restoration of the Ca2+-actin cytoskeleton axis. The goal of this study was to characterize podocyte biology during MMF treatment in nephrotoxic serum (NTS) nephritis (NTN). NTN was induced in three-week old wild-type mice. On day 3, half of the mice were treated with MMF (100 mg/kgBW/d p.o.) for one week. On day 10, we performed proteomic analysis of glomeruli as well as super-resolution imaging of the slit diaphragm. For multiphoton imaging of Ca2+ concentration ([Ca2+]i), the experimental design was repeated in mice expressing podocyte-specific Ca2+ sensor. MMF ameliorated the proteinuria and crescent formation induced by NTS. We identified significant changes in the abundance of proteins involved in Ca2+ signaling and actin cytoskeleton regulation, which was further confirmed by direct [Ca2+]i imaging in podocytes showing decreased Ca2+ levels after MMF treatment. This was associated with a tendency to restoration of podocyte foot process structure. Here, we provide evidence that MPA has a substantial direct effect on podocytes. MMF contributes to improvement of [Ca2+]i and amelioration of the disorganized actin cytoskeleton in podocytes. These data extend the knowledge of direct effects of immunosuppressants on podocytes that may contribute to a more effective treatment of proteinuric glomerulopathies with the least possible side effects.

[Prevalence of SARS-CoV-2 in children from a cohort of 2192 patients]. / Prävalenz von SARS-CoV-2 bei Kindern in einer Kohorte von 2192 Patienten.

BACKGROUND: As of 18 June 2020 a total of 187,764 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were reported in Germany and of these 6.9% were under the age of 19 years. There were initial indications that children are often asymptomatic and show a milder clinical course. OBJECTIVE: The aim of this study was to gain information on the prevalence of SARS-CoV­2 infections in a pediatric cohort. MATERIAL AND METHODS: Between 13 March and 18 June 2020 all children from whom a smear for SARS-CoV­2 was taken either to rule out an infection or as a suspected case were included. Data were collected on standardized patient record sheets. The analysis of data was anonymized and retrospective. RESULTS: During the given period 2192 children were investigated and 37 patients tested positive (1.7%) for SARS-CoV­2. Of these 36/37 were suspected cases and 28/37 were symptomatic. The leading symptoms were dry cough, runny nose and fever and three children had to be hospitalized. None showed a difficult course of the disease. Among those tested 505 were patients at risk due to an underlying chronic disease, 3 of whom (0.6%) were tested positive with an asymptomatic or mild course. CONCLUSION: We can confirm the first data showing that children and adolescents often have an asymptomatic or mild clinical course of infection or disease. We found no evidence of a high grey area of SARS-CoV­2 infections in this regional pediatric cohort.

[Health care of refugees in 2015 - Evaluation of an ambulance for refugees in a Cologne emergency accommodation (Cologne Model)]. / Gesundheitliche Versorgung von Geflüchteten in 2015 ­ Evaluation einer Ambulanz für Geflüchtete in einer Kölner Notunterkunft (Kölner Modell).

Access to medical care is a core element in the care of refugees and asylum seekers, and should therefore be guaranteed in a barrier-free way. In practice, there are usually numerous access barriers and the first contact with the German Health Care System takes place in form of a statutory examination to exclude infectious diseases. In addition to the introduction of health insurance cards for refugees, an offer of medical consultation for several hours a week in the municipal emergency accommodations provides an opportunity for low threshold access to primary care and a bridging function to the integration into the regular health care system. This offer is independent of the obligatory initial examination according to § 62 Asylum Law (AsylG) 1. The evaluation of the first year of such a health care center is presented.

Extrarenal Manifestations in Shigatoxin-associated Haemolytic Uremic Syndrome.

BACKGROUND: Shigatoxin-associated haemolytic uremic syndrome (STEC-HUS) is the most frequent cause of acute kidney injury in children worldwide. Extrarenal manifestations are the main determinants for both, short- and long-term prognosis of patients with STEC-HUS. PATIENTS: 46 patients treated over the last 10 years for STEC-HUS in a single center. METHODS: This retrospective study analysed the incidence and outcome of extrarenal manifestations in our cohort of children with STEC-HUS. Risk factors for extrarenal involvement and adverse outcome were assessed by detailed chart review. RESULTS: Eleven extrarenal manifestations occurred in 9/46 patients comprising 8 neurological, 2 gastro-intestinal, and 1 cardiovascular complication. One patient died from cerebral bleeding. Liver transplantation was required in a girl 18 months after HUS due to secondary sclerosing cholangitis. PATIENTS with extrarenal manifestations were significantly younger and presented with higher leucocyte counts and higher alanine aminotransferase levels at admission. Renal replacement therapy was necessary for a longer period than in patients without extrarenal complications. CONCLUSION: Extrarenal manifestations occurred in about 20% of our patients with STEC-HUS. The identification of risk-factors will help to provide a better management of these patients which might also include novel treatment strategies like complement inhibition.

Inosine monophosphate dehydrogenase activity in paediatrics: age-related regulation and response to mycophenolic acid.

PURPOSE: Since many drug targets and metabolizing enzymes are developmentally regulated, we investigated a potential comparable regulation of inosine 5'-monophosphate dehydrogenase (IMPDH) activity that has recently been advocated as a pharmacodynamic biomarker of mycophenolic acid (MPA) effects in the paediatric population. Since the field of pharmacodynamic monitoring of MPA is evolving, we also analyzed the response of IMPDH activity on MPA in children vs adolescents after renal transplantation. METHODS: We analyzed IMPDH activity in peripheral blood mononuclear cells (PBMCs) in 79 healthy children aged 2.0-17.9 years in comparison to 106 healthy adults. Pharmacokinetic/pharmacodynamic profiles of MPA and IMPDH over 6 or 12 h after mycophenolate mofetil dosing were performed in 17 paediatric renal transplant recipients. IMPDH activity was measured by HPLC and normalized to the adenosine monophosphate (AMP) content of the cells, MPA plasma concentrations were measured by HPLC. RESULTS: Inosine 5'-monophosphate dehydrogenase activity displayed a high inter-individual variability (coefficient of variation 40.2%) throughout the entire age range studied. Median IMPDH did not differ significantly in healthy pre-school children (82 [range, 42-184] µmol/s/mol AMP), school-age children (61 [30-153]), adolescents (83 [43-154]) and healthy adults (83 [26-215]). Similar to adults, IMPDH activity in children and adolescents was inversely correlated with MPA plasma concentration. CONCLUSIONS: In conclusion, our data do not show a pronounced developmental regulation of IMPDH activity in PBMCs in the paediatric population and there is a comparable inhibition of IMPDH activity by MPA in children and adolescents after renal transplantation.

Population pharmacokinetics of mycophenolic acid in pediatric renal transplant patients using parametric and nonparametric approaches.

Mycophenolic acid (MPA) is an immunosuppressive drug widely used in the prevention of acute rejection in pediatric renal transplant recipients and is characterized by a wide inter-individual variability in its pharmacokinetics. The aim of this study was to compare population pharmacokinetic modeling of MPA in pediatric renal transplant recipients given mycophenolate mofetil, the ester prodrug of MPA, using parametric and nonparametric population methods. The data from 34 pediatric renal transplants (73 full pharmacokinetic profiles obtained on day 21, months 3, 6 and 9 post-transplant) were analyzed using both the nonlinear mixed-effect modeling (NONMEM) and nonparametric adaptive grid (NPAG) approaches, based on a two-compartment model with first order lagged time absorption and first order elimination. The predictive performance of the two models was evaluated in a separate group of 32 patients. Higher mean population parameter values and ranges of individual pharmacokinetic parameters were obtained with NPAG, especially for the elimination constant ke: mean 1.16 h(-1) (0.26-4.33 h(-1)) and 0.78 h(-1) (0.66-1.15 h(-1)) with NPAG and NONMEM, respectively. With NPAG, the skewness and kurtosis values for ke (2.03 and 7.80, respectively) were far from the theoretical values expected for normal distributions. Such a non-normal distribution could explain the high value of shrinkage (35%) obtained for this parameter with the parametric NONMEM method. Bayesian forecasting of mycophenolic acid exposure using the NPAG population pharmacokinetic parameters as priors yielded a better predictive performance, with a significantly smaller bias than with the NONMEM model (-1.68% vs -9.53%, p<0.0001). In conclusion, in the present study, NPAG was found to be the most adequate population pharmacokinetic method to describe the pharmacokinetics of MPA in pediatric renal transplant recipients.

[Enuresis in childhood]. / Serie Kindersprechstunde, Teil 2: Enuresis. "Mein Kind ist Bettnässer"!

In children with nocturnal bedwetting, the basic diagnostic evaluation to differentiate between monosymptomatic enuresis and organic or functional urinary incontinence is mandatory. When the diagnosis of monosymptomatic enuresis is set, a stepped therapeutic program is available, in which alarm/behavior therapy has a central role. Drug therapy of monosymptomatic enuresis in childhood is an established option and is reserved for certain indications.

Mycophenolate mofetil in pediatric renal transplantation.

Since mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), has been approved for maintenance immunosuppressive therapy also in children after renal transplantation it has become an important part of immunosuppressive protocols. By inhibiting inosine monophosphate dehydrogenase, the key enzyme in the de novo purine biosynthesis of proliferating T and B lymphocytes, MMF acts as a relatively specific inhibitor of human lymphocyte proliferation. MMF is more effective than azathioprine in combination with cyclosporin A (CsA) and corticosteroids and distinctly reduces the incidence of acute rejection episodes in the 1st year post-transplant in adults as well as in children. Beneficial effects on steroid-resistant rejection and chronic allograft dysfunction have been shown. In general, MMF is well tolerated. Major adverse events in pediatric renal transplant recipients include leukopenia, infections and gastrointestinal problems. Pharmacokinetic monitoring of MPA can help to optimise MMF therapy after renal transplantation, as associations between the risk of acute rejection episodes and MPA-AUC values and MPA predose levels have been demonstrated. The incidence of MMF-related side effects such as leukopenia and/or infections, however, is associated with pharmacokinetic parameters of free MPA. Reference data of relevant pharmacokinetic parameters are available. The possible steroid-sparing potential of MMF is an important issue in pediatric renal transplantation. Preliminary data demonstrate improved longitudinal growth, less cushingoid habitus and lower blood pressure after steroid-withdrawal in pediatric renal transplant recipients under MMF and CsA therapy.

Mycophenolate mofetil in pediatric renal transplantation without induction therapy: results after 12 months of treatment. German Pediatric Renal Transplantation Study Group.

BACKGROUND: Acute rejection episodes (ARE) of kidney transplants are considered as risk factor in the development of chronic rejection. In adult renal transplantation (RTx), ARE have been significantly reduced by mycophenolate mofetil (MMF) in combination with cyclosporin (CyA) and steroids (Pred). Reports of pediatric RTx on a maintenance immunosuppression with MMF are restricted to patients (P) after antibody induction therapy. METHODS: The efficacy and safety of MMF combined with CyA and Pred in pediatric RTx without induction therapy were evaluated in an open-labeled multicenter study. RESULTS: From 10/1996 to 6/1999, 65 pediatric P (MMF group) were followed for at least 6 months, 58 of 65 for 12 months. These P were compared with 54 retrospectively analyzed pediatric P who were transplanted between 1990 and 1996 and had received CyA, Pred, and azathioprine for immunosuppression (historic AZA group). Within the first 6 months after RTx, 18 of 65 (MMF group) and 32 of 54 (historic AZA group) P showed clinical signs of acute rejection (P<0.01). Thereafter only one further P in the MMF group developed a first ARE. Graft loss due to rejection occurred in one MMF- and seven AZA-treated P (P<0.05). The creatinine-clearance 3 and 6 months after RTx was higher in the MMF group. Major adverse events (MMF group) included infections of the urinary and the upper respiratory tract, diarrhea, and leukopenia. Cytomegalovirus-infection occurred in 13 P and 2 P developed cytomegalovirus disease. One P developed PTLD 10 months after RTx and recovered after the reduction of immunosuppression. CONCLUSIONS: The combination of MMF, CyA, and Pred reduced ARE in pediatric RTx without incurring major side effects.

Area under the plasma concentration-time curve for total, but not for free, mycophenolic acid increases in the stable phase after renal transplantation: a longitudinal study in pediatric patients. German Study Group on Mycophenolate Mofetil Therapy in Pediatric Renal Transplant Recipients.

Mycophenolate mofetil, an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy in pediatric renal transplant recipients. However, little is known about the pharmacokinetics of MPA in this patient population in the stable transplant phase, and dosage guidelines are preliminary. The authors therefore compared the pharmacokinetics of MPA, free MPA, and the renal metabolite MPA glucuronide (MPAG) in the initial (sampling at 1 and 3 weeks) and stable phases (sampling at 3 and 6 months) posttransplant in 17 children (age, 12.0 +/- 0.77 years; range, 5.9 to 15.8 years), receiving the currently recommended dose of 600 mg MMF/m2 body surface area (BSA) twice a day. Plasma concentrations of MPA and MPAG were measured by reverse phase HPLC. Because MPA is extensively bound to serum albumin and only the free drug is presumed to be pharmacologically active, the authors also analyzed the MPA free fraction by HPLC after separation by ultrafiltration. The intraindividual variability of the area under the concentration-time curves (AUC0-12) of MPA throughout the 12-hour dosing interval was high in the immediate posttransplant period, but declined in the stable phase, whereas the interindividual variability remained unchanged. The median MPA-AUC0-12 values increased 2-fold from 32.4 (range, 13.9 to 57.0) mg x h/L at 3 weeks to 65.1 (range, 32.6 to 114) mg x h/L at 3 months after transplantation, whereas the median AUC0-12 values of free MPA did not significantly change over time. This discrepancy can be attributed to a 35% decline of the MPA free fraction from 1.4% in the initial phase posttransplant to 0.9% (p < 0.01) in the stable phase. In conclusion, pediatric renal transplant recipients given a fixed MMF dose exhibit a 2-fold increase of the AUC0-12 of total MPA in the stable phase posttransplant and a 35% decrease of the MPA free fraction, whereas the AUC0-12 of free MPA remains unchanged over time. Because the latter pharmacokinetic variable is theoretically best predictive of the clinical immunosuppressive efficacy of MMF, these findings may have consequences for the dosing recommendations of MMF in renal transplant recipients.

Pharmacokinetics of mycophenolic acid (MPA) and determinants of MPA free fraction in pediatric and adult renal transplant recipients. German Study group on Mycophenolate Mofetil Therapy in Pediatric Renal Transplant Recipients.

Dosage guidelines for mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), are still preliminary in children. This study compares the pharmacokinetics of MPA and its major metabolite MPA glucuronide (MPAG) in pediatric renal transplant recipients receiving 600 mg MMF/m2 body surface area twice a day to those of adults on the currently recommended oral dose of 1 g of MMF twice a day. Concentration-time profiles of 18 children (age, 10.7+/-0.72 yr; range, 5.9 to 15.3 yr) and 10 adults were investigated 1 and 3 wk after transplantation. Plasma concentrations of MPA and MPAG were measured by reverse-phase HPLC. Because MPA is extensively bound to serum albumin and only the free fraction is presumed to be pharmacologically active, the MPA free fraction was also analyzed by HPLC after separation through ultrafiltration. The areas under the concentration-time curves (AUC0-12) of total and free MPA throughout the 12-h dosing interval in children were, in general, comparable to the corresponding data in adult patients. The mean AUC0-12 of MPA and free MPA did not change significantly over the first 3 wk after transplantation, but there was substantial intra- and interindividual variation. MPAG-AUC0-12 values in children with primary renal transplant dysfunction were threefold higher than in those with functioning transplants. Renal impairment had no consistent effect on total MPA-AUC0-12 values, but the MPA free fraction in children (median, 1.65%; range, 0.40 to 13.8%) was significantly (r2=0.46) modulated by renal transplant function and serum albumin levels. In conclusion, concentration-time profiles of pediatric renal transplant recipients administered 600 mg MMF/m2 body surface area twice a day are comparable to those in adults on 1 g MMF twice a day in the first 3 wk after transplantation. Renal impairment and decreased serum albumin levels led to an increase in the free fraction of MPA and the free MPA-AUC0-12 values. Because the pharmacologic activity of MPA is a function of unbound drug concentration, these findings might be relevant for the pharmacodynamic effects of MPA.