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Background Short stature is a frequent complication after pediatric kidney transplantation (KT). Whether the type of transplantation and prior treatment with recombinant human growth hormone (GH) affects post-transplant growth, is unclear. Methods Body height, leg length, sitting height, and sitting height index (as a measure of body proportions) were prospectively investigated in 148 prepubertal patients enrolled in the CKD Growth and Development study with a median follow-up of 5.0 years. We used linear mixed-effects models to identify predictors for body dimensions. Results Pre-transplant Z scores for height (− 2.18), sitting height (− 1.37), and leg length (− 2.30) were reduced, and sitting height index (1.59) was increased compared to healthy children, indicating disproportionate short stature. Catch-up growth in children aged less than 4 years was mainly due to stimulated trunk length, and in older children to improved leg length, resulting in normalization of body height and proportions before puberty in the majority of patients. Use of GH in the pre-transplant period, congenital CKD, birth parameters, parental height, time after KT, steroid exposure, and transplant function were significantly associated with growth outcome. Although, unadjusted growth data suggested superior post-transplant growth after (pre-emptive) living donor KT, this was no longer true after adjusting for the abovementioned confounders. Conclusions Catch-up growth after KT is mainly due to stimulated trunk growth in young children (

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 PRO‐TECT 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.

Distal renal tubular acidosis is a rare renal tubular disorder characterized by hyperchloremic metabolic acidosis and impaired urinary acidification. Mutations in three genes (ATP6V0A4, ATP6V1B1 and SLC4A1) constitute a monogenic causation in 58-70% of familial cases of distal renal tubular acidosis. Recently, mutations in FOXI1 have been identified as an additional cause. Therefore, we hypothesized that further monogenic causes of distal renal tubular acidosis remain to be discovered. Panel sequencing and/or whole exome sequencing was performed in a cohort of 17 families with 19 affected individuals with pediatric onset distal renal tubular acidosis. A causative mutation was detected in one of the three "classical" known distal renal tubular acidosis genes in 10 of 17 families. The seven unsolved families were then subjected to candidate whole exome sequencing analysis. Potential disease causing mutations in three genes were detected: ATP6V1C2, which encodes another kidney specific subunit of the V-type proton ATPase (1 family); WDR72 (2 families), previously implicated in V-ATPase trafficking in cells; and SLC4A2 (1 family), a paralog of the known distal renal tubular acidosis gene SLC4A1. Two of these mutations were assessed for deleteriousness through functional studies. Yeast growth assays for ATP6V1C2 revealed loss-of-function for the patient mutation, strongly supporting ATP6V1C2 as a novel distal renal tubular acidosis gene. Thus, we provided a molecular diagnosis in a known distal renal tubular acidosis gene in 10 of 17 families (59%) with this disease, identified mutations in ATP6V1C2 as a novel human candidate gene, and provided further evidence for phenotypic expansion in WDR72 mutations from amelogenesis imperfecta to distal renal tubular acidosis.

Background Mycophenolate mofetil (MMF) plays an increasingly important role in the treatment of children with nephrotic syndrome, especially in steroid sparing protocols. Recent publications show the relationship of exposure to its active moiety mycophenolic acid (MPA) and clinical efficacy. Performance of full-time pharmacokinetic (PK) profiles, however, is inconvenient and laborious. Established limited sampling strategies (LSS) to estimate the area under the concentration (AUC) versus time curve of MPA (MPA-AUC) in pediatric renal transplant recipients cannot be easily transferred to children suffering from nephrotic syndrome, mainly because of the lack of concomitant immunosuppressive therapy. We therefore aimed for the generation and validation of a LSS to estimate MPA exposure to facilitate therapeutic drug monitoring in children with nephrotic syndrome. Methods We performed 27 complete PK profiles in 23 children in remission [mean age (±SD):12.3 ± 4.26 years] to generate and validate an LSS. Sampling time points were before administration (C0) and 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours after the administration of MMF. MPA was measured by enzyme multiplied immunoassay technique. There was no concomitant treatment with calcineurin inhibitors. Results Mean daily dose of MMF was 927 ± 209 mg/m of body surface area resulting in a mean MPA-AUC0-12 value of 59.2 ± 29.3 mg × h/L and a predose level of 3.03 ± 2.24 mg/L. Between-patient variability of dose-normalized MPA-AUC0-12 was high (coefficient of variation: 45.5%). Correlation of predose levels with the corresponding MPA-AUC0-12 was moderate (r = 0.59) in a subgroup of 18 patients (20 PK profiles, generation group). An algorithm based on 3 PK sampling time points during the first 2 hours after MMF dosing (estimated AUC0-12 = 8.7 + 4.63 × C0 + 1.90 × C1 + 1.52 × C2) was able to predict MPA-AUC with a low percentage prediction error (3.88%) and a good correlation of determination (r = 0.90). Validation of this algorithm in a randomized separate group of 6 patients (7 PK profiles, validation group) resulted in comparably good correlation (r = 0.95) and low percentage prediction error (5.57%). Conclusions An abbreviated profile within the first 2 hours after MMF dosing gives a good estimate of MPA exposure in children with nephrotic syndrome and hence has the potential to optimize MMF therapy.

Background Two interstitial microdeletions Xp11.22 including the CLCN5 and SHROOM4 genes were recently reported in a male individual affected with Dent disease, short stature, psychomotor delay and minor facial anomalies. Dent disease, characterized by a specific renal phenotype, is caused by truncating mutations of CLCN5 in the majority of affected cases. Case presentation Here, we present clinical and molecular findings in a male patient with clinical signs of Dent disease, developmental delay, short stature, microcephaly, and facial dysmorphism. Using molecular karyotyping we identified a hemizygous interstitial microdeletion Xp11.23p.11.22 of about 700 kb, which was inherited from his asymptomatic mother. Among the six deleted genes is CLCN5, which explains the renal phenotype in our patient. SHROOM4, which is partially deleted in this patient, is involved in neuronal development and was shown to be associated with X-linked intellectual disability. This is a candidate gene, the loss of which is thought to be associated with his further clinical manifestations. To rule out mutations in other genes related to intellectual disability, whole exome sequencing was performed. No other pathogenic variants that could explain the phenotypic features, were found. Conclusion We compared the clinical findings of the patient presented here with the reported case with an Xp11.22 microdeletion including CLCN5 and SHROOM4 and re-defined the phenotypic spectrum associated with this microdeletion. Electronic supplementary material The online version of this article (10.1186/s12920-018-0471-6) contains supplementary material, which is available to authorized users.

Background Recombinant human growth hormone (rhGH) is frequently used for treatment of short stature in children with chronic kidney disease (CKD) prior to kidney transplantation (KT). To what extent this influences growth and transplant function after KT is yet unknown. Methods Post-transplant growth (height, sitting height, leg length) and clinical parameters of 146 CKD patients undergoing KT before the age of 8 years, from two German pediatric nephrology centers, were prospectively investigated with a mean follow-up of 5.56 years. Outcome in patients with (rhGH group) and without (non-prior rhGH group) prior rhGH treatment was assessed by the use of linear mixed-effects models. Results Patients in the rhGH group spent longer time on dialysis and less frequently underwent living related KT compared to the non-prior rhGH group but showed similar height z-scores at the time of KT. After KT, steroid exposure was lower and increments in anthropometric z-scores were significantly higher in the rhGH group compared to those in the non-prior rhGH group, although 18% of patients in the latter group were started on rhGH after KT. Non-prior rhGH treatment was associated with a faster decline in transplant function, lower hemoglobin, and higher C-reactive protein levels (CRP). After adjustment for these confounders, growth outcome did statistically differ for sitting height z-scores only. Conclusions Treatment with rhGH prior to KT was associated with superior growth outcome in prepubertal kidney transplant recipients, which was related to better transplant function, lower CRP, less anemia, lower steroid exposure, and earlier maturation after KT. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information

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). Supplementary Information The online version contains supplementary material available at 10.1007/s00467-021-05135-3.

Background and objectives Although renin-angiotensin-aldosterone system inhibition (RAASi) is a cornerstone in the treatment of children with CKD, it is sometimes discontinued when kidney function declines. We studied the reasons of RAASi discontinuation and associations between RAASi discontinuation and important risk markers of CKD progression and on eGFR decline in the Cardiovascular Comorbidity in Children with CKD study. Design, setting, participants, & measurements In this study, 69 children with CKD(67% male, mean age 13.7 years, mean eGFR 27 ml/min per 1.73 m2) who discontinued RAASi during prospective follow-upwere included. Initial change in BP, albuminuria, and potassium after discontinuation were assessed (median time 6 months). Rate of eGFR decline (eGFR slope) during amedian of 1.9 years before and 1.2 years after discontinuation were estimated using linear mixed effects modeling. Results Physician-reported reasons for RAASi discontinuation were increase in serum creatinine, hyperkalemia, and symptomatic hypotension. After discontinuation of RAASi, BP and albuminuria increased, whereas potassium decreased. eGFR declinedmore rapidly after discontinuation of RAASi (-3.9ml/min per 1.73m2 per year; 95%confidence interval, -5.1 to -2.6) compared with the slope during RAASi treatment (-1.5 ml/min per 1.73 m2 per year; 95% confidence interval, -2.4 to -0.6; P=0.005). In contrast, no change in eGFR slope was observed in a matched control cohort of patients in whom RAASi was continued. Conclusions Discontinuation of RAASi in children with CKD is associated with an acceleration of kidney function decline, even in advanced CKD. © 2020 by the American Society of Nephrology., EO0802 National Institute for Health Research, NIHR Bundesministerium für Bildung und Forschung, BMBF: 01EO0802, Support for the 4C Study was received from the European Renal Association-European Dialysis and Transplant Association Research Programme, the Kuratorium für Heimdialyse Foundation for Preventive Medicine and the German Federal Ministry of Education andResearch(referencenumber:01EO0802).Dr.Schaefer,Dr.Wühl, Dr. Bacchetta, Mr. Azukaitis, Dr. Melk, and Dr. Shroff are members of the European Reference Network for Rare Kidney Diseases (ERKNet). Dr. Shroff is supported by a National Institute for Health Research Career Development Fellowship., Support for the 4C Study was received from the European Renal Association-European Dialysis and Transplant Association Research Programme, the Kuratorium f?r Heimdialyse Foundation for Preventive Medicine and the German Federal Ministry of Education and Research (referencenumber: 01EO0802). Dr. Schaefer, Dr. W?hl, Dr. Bacchetta, Mr. Azukaitis, Dr. Melk, and Dr. Shroff are members of the European Reference Network for Rare Kidney Diseases (ERKNet). Dr. Shroff is supported by a National Institute for Health Research Career Development Fellowship.

Children presenting with proliferative lupus nephritis (LN) are treated with intensified immunosuppressive protocols. Data on renal outcome and treatment toxicity is scare. Twelve-month renal outcome and comorbidity were assessed in 79 predominantly Caucasian children with proliferative LN reported to the Lupus Nephritis Registry of the German Society of Paediatric Nephrology diagnosed between 1997 and 2015. At the time of diagnosis, median age was 13.7 (interquartile range 11.8–15.8) years; 86% showed WHO histology class IV, nephrotic range proteinuria was noted in 55%, and median estimated glomerular filtration rate amounted to 75 ml/min/1.73 m2. At 12 months, the percentage of patients with complete and partial remission was 38% and 41%, respectively. Six percent of patients were non-responders and 15% presented with renal flare. Nephrotic range proteinuria at the time of diagnosis was associated with inferior renal outcome (odds ratio 5.34, 95% confidence interval 1.26–22.62, p = 0.02), whereas all other variables including mode of immune-suppressive treatment (e.g., induction treatment with cyclophosphamide (IVCYC) versus mycophenolate mofetil (MMF)) were not significant correlates. Complications were reported in 80% of patients including glucocorticoid toxicity in 42% (Cushingoid appearance, striae distensae, cataract, or osteonecrosis), leukopenia in 37%, infection in 23%, and menstrual disorder in 20%. Growth impairment, more pronounced in boys than girls, was noted in 78% of patients. In this cohort of juvenile proliferative LN, renal outcome at 12 months was good irrespectively if patients received induction treatment with MMF or IVCYC, but glucocorticoid toxicity was very high underscoring the need for corticoid sparing protocols.

WOS: 000412042200025, PubMed ID: 28566477, We investigated the value of genetic, histopathologic, and early treatment response information in prognosing long-term renal outcome in children with primary steroid-resistant nephrotic syndrome. From the PodoNet Registry, we obtained longitudinal clinical information for 1354 patients (disease onset at >3 months and, E-Rare (German Ministry of Education and Research); Polish Ministry of Science and Education grant [N402631840]; German Research FoundationGerman Research Foundation (DFG) [Scha 477/11-1]; Scientific and Technological Research Council of TurkeyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [108S417]; European Union (EU) Seventh Framework Programme (EURenOmics) grant [2012-305608], The PodoNet project has been made possible by support received from E-Rare (German Ministry of Education and Research), European Union (EU) Seventh Framework Programme (EURenOmics) grant 2012-305608, Polish Ministry of Science and Education grant N402631840, German Research Foundation grant Scha 477/11-1, and Scientific and Technological Research Council of Turkey grant 108S417.

Corrected Proof Children with Alport syndrome develop renal failure early in life. Since the safety and efficacy of preemptive nephroprotective therapy are uncertain we conducted a randomized, placebo-controlled, double-blind trial in 14 German sites of pediatric patients with ramipril for three to six years plus six months follow-up to determine these parameters. Pretreated children and those whose parents refused randomization became an open-arm control, which were compared to prospective real-world data from untreated children. The co-primary endpoints were safety (adverse drug reactions) and efficacy (time to progression). Out of 66 oligosymptomatic children, 22 were randomized and 44 joined the open-arm comparison. Ramipril therapy showed no safety issues (total of 216.4 patient-years on ramipril; adverse event rate-ratio 1.00; 95% confidence interval 0.66-1.53). Although not significant, our results cautiously showed that ramipril therapy was effective: in the randomized arm, Ramipril decreased the risk of disease progression by almost half (hazard ratio 0.51 (0.12–2.20)), diminished the slope of albuminuria progression and the decline in glomerular filtration. In adjusted analysis, indications of efficacy were supported by prospective data from participants treated open label compared with untreated children, in whom ramipril again seemed to reduce progression by almost half (0.53 (0.22-1.29)). Incorporating these results into the randomized data by Bayesian evidence synthesis resulted in a more precise estimate of the hazard-ratio of 0.52 (0.19-1.39). Thus, our study shows the safety of early initiation of therapy and supports the hope to slow renal failure by many years, emphasizing the value of preemptive therapy. Hence, screening programs for glomerular hematuria in children and young adults could benefit from inclusion of genetic testing for Alport-related gene-variants.

Children with chronic kidney disease are frequently born small for gestational age (SGA) and prone to disproportionately short stature. It is unclear how SGA affects growth after kidney transplantation (KTx). Linear growth (height, sitting height, and leg length) was prospectively investigated in a cohort of 322 pediatric KTx recipients, with a mean follow-up of 4.9 years. Sitting height index (ratio of sitting height to total body height) was used to assess body proportions. Predictors of growth outcome in KTx patients with (n = 94) and without (n = 228) an SGA history were evaluated by the use of linear mixed-effects models. Mean z-scores for all linear body dimensions were lower in SGA compared with non-SGA patients (p

This study correlates the clinical presentation of Henoch–Schonlein purpura nephritis (HSPN) with findings on initial renal biopsy. Data from 202 pediatric patients enrolled in the HSPN registry of the German Society of Pediatric Nephrology reported by 26 centers between 2008 and 2014 were analyzed. All biopsy reports were re-evaluated for the presence of cellular crescents or chronic pathological lesions (fibrous crescents, glomerular sclerosis, tubular atrophy >5%, and interstitial fibrosis >5%). Patients with HSPN with cellular glomerular crescents were biopsied earlier after onset of nephritis (median 24 vs 36 days, p = 0.04) than those without, whereas patients with chronic lesions were biopsied later (57 vs 19 days, p < 0.001) and were older (10.3 vs 8.6 years, p = 0.01) than those without. Patients biopsied more than 30 days after the onset of HSPN had significantly more chronic lesions (52 vs 22%, p < 0.001), lower eGFR (88 vs 102 ml/min/1.73m2, p = 0.01), but lower proteinuria (2.3 vs 4.5 g/g, p

Die Leitlinie der Gesellschaft fur Padiatrische Nephrologie gibt evidenzbasierte Empfehlungen zu Diagnostik bzw. Differenzialdiagnose des idiopathischen nephrotischen Syndroms und zur Therapie des steroidsensiblen nephrotischen Syndroms (SSNS) im Kindesalter. Kinder mit einem SSNS zeigen in den allermeisten Fallen uber viele Jahre eine Steroidsensibilitat und haben auch bei haufigen Rezidiven eine prinzipiell gute Prognose. Erstmanifestation und Rezidive der Erkrankung sollten gemas den bestehenden Therapieempfehlungen mit einer standardisierten Glukokortikoid (Steroid)-Therapie behandelt werden. Bei 80–90 % der Patienten kommt es im Verlauf zu Rezidiven. Diese konnen selten („infrequent relapser“, bei ca. 30 %) oder haufig auftreten („frequent relapser“ oder steroidabhangig, bei ca. 30–50 %) oder von einer spateren Steroidresistenz gefolgt sein (bis zu 15 %). Bei haufigen Rezidiven besteht mit zunehmender Therapiedauer die Gefahr der Steroidtoxizitat. Als steroidsparende Medikamente stehen Cyclosporin A, Tacrolimus, Mycophenolatmofetil, Cyclophosphamid, Levamisol und Rituximab zur Verfugung; sie sollten nur bei Patienten zum Einsatz kommen, die steroidassoziierte Nebenwirkungen entwickelt haben. Patienten mit haufigen Rezidiven, steroidabhangigem („steroid-dependent nephrotic syndrome“, SDNS) oder -resistentem NS sollten wegen der Indikationsstellung fur steroidsparende bzw. remissionserhaltende Therapien und zu deren Uberwachung von spezialisierten kindernephrologischen Zentren betreut werden. Die Gefahr teils schwerwiegender Nebenwirkungen sowie von Komplikationen im Verlauf erfordert eine oft jahrelange konsequente Betreuung mit differenzierter immunsuppressiver und supportiver Therapie, um Dauerschaden zu vermeiden.

WOS: 000414516700002, PubMed ID: 28873129, IMPORTANCE Conventional methods to diagnose and monitor chronic kidney disease (CKD) in children, such as creatinine level and cystatin C-derived estimated glomerular filtration rate (eGFR) and assessment of proteinuria in spot or timed urine samples, are of limited value in identifying patients at risk of progressive kidney function loss. Serum soluble urokinase receptor (suPAR) levels strongly predict incident CKD stage 3 in adults. OBJECTIVE To determine whether elevated suPAR levels are associated with renal disease progression in children with CKD. DESIGN, SETTING, AND PARTICIPANTS Post hoc analysis of 2 prospectively followed up pediatric CKD cohorts, ie, the ESCAPE Trial (1999-2007) and the 4C Study (2010-2016), with serum suPAR level measured at enrollment and longitudinal eGFR measured prospectively. In the 2 trials, a total of 898 children were observed at 30 (ESCAPE Trial; n = 256) and 55 (4C Study; n = 642) tertiary care hospitals in 13 European countries. Renal diagnoses included congenital anomalies of the kidneys and urinary tract (n = 637 [70.9%]), tubulointerstitial nephropathies (n = 92 [10.2%]), glomerulopathies (n = 69 [7.7%]), postischemic CKD (n = 42 [4.7%]), and other CKD (n = 58 [6.5%]). Total follow-up duration was up to 7.9 years, and median follow-up was 3.1 years. Analyses were conducted from October 2016 to December 2016. EXPOSURES Serum suPAR level was measured at enrollment, and eGFR was measured every 2 months in the ESCAPE Trial and every 6 months in the 4C Study. The primary end point of CKD progression was a composite of 50% eGFR loss, eGFR less than 10 mL/min/1.73m(2), or initiation of renal replacement therapy. MAIN OUTCOMES AND MEASURES The primary end point in this studywas renal survival, defined as a composite of 50% loss of GFR that persisted for at least 1 month, the start of renal replacement therapy, or an eGFR less than 10 mL/min/1.73m(2). RESULTS Of the 898 included children, 560 (62.4%) were male, and the mean (SD) patient age at enrollment was 11.9 (3.5) years. The mean (SD) eGFR was 34 (16) mL/min/1.73m2. The 5-year end point-free renal survival was 64.5%(95% CI, 57.4-71.7) in children with suPAR levels in the lowest quartile compared with 35.9%(95% CI, 28.7-43.0) in those in the highest quartile (P < .001). By multivariable analysis, the risk of attaining the end point was higher in children with glomerulopathies and increased with age, blood pressure, proteinuria, and lower eGFR at baseline. In patients with baseline eGFR greater than 40 mL/min/1.73m(2), higher log-transformed suPAR levels were associated with a higher risk of CKD progression after adjustment for traditional risk factors (hazard ratio, 5.12; 95% CI, 1.56-16.7; P =.007). CONCLUSIONS AND RELEVANCE Patients with high suPAR levels were more likely to have progression of their kidney disease. Further studies should determine whether suPAR levels can identify children at risk for future CKD., European Community Seventh Framework ProgrammeEuropean Union (EU)European Community (EC) [2012-305608]; Boehringer Ingelheim StiftungBoehringer Ingelheim; European Commission Fifth Framework ProgrammeEuropean Union (EU) [QLRT-2001-00908]; Kuratorium fur Dialyse und Nierentransplantation Neu-Isenburg (KfH); Baxter Extramural Grant Program; European Renal Association-European Dialysis and Transplant Association Research Programme; KfH Foundation for Preventive Medicine; German Federal Ministry of Education and ResearchFederal Ministry of Education & Research (BMBF) [01E00802]; National Institute of Diabetes and Digestive and Kidney DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01DK101350, R01DK100307], Dr Schaefer received support for this study from grant agreement 2012-305608 (EURenOmics) from the European Community Seventh Framework Programme (FP7/2007-2013). The ESCAPE Trial was supported by grants from the Boehringer Ingelheim Stiftung, the European Commission Fifth Framework Programme (grant QLRT-2001-00908), the Kuratorium fur Dialyse und Nierentransplantation Neu-Isenburg (KfH), and the Baxter Extramural Grant Program. Support for the 4C Study was received from the European Renal Association-European Dialysis and Transplant Association Research Programme, the KfH Foundation for Preventive Medicine, and the German Federal Ministry of Education and Research (grant 01E00802). Drs Wei, Sever, and Reiser were supported by grant R01DK101350 from the National Institute of Diabetes and Digestive and Kidney Diseases. Dr Trachtman was supported by grant R01DK100307 from the National Institute of Diabetes and Digestive and Kidney Diseases.

Soluble urokinase-type plasminogen activator receptor (suPAR) could be a causative factor in idiopathic focal segmental glomerulosclerosis (FSGS). It is currently unknown to what extent suPAR levels could be affected by treatment with immunosuppressive drugs such as cyclosporin A (CsA) and mycophenolate mofetil (MMF). Treatment with CsA, but not MMF, is accompanied by nephrotoxicity, and since suPAR levels correlate with glomerular filtration rate (GFR), treatment with these drugs could indirectly modulate suPAR levels by their effect on renal function.We measured suPAR levels in a recent prospective multicenter crossover trial comparing the efficacy of MMF and CsA in pediatric patients with minimal change disease (MCD) and frequently relapsing steroid-sensitive nephrotic syndrome (FR-SSNS). All patients had biopsy-proven MCD and normal renal function; they were treated with each drug for 1 year in a crossover study design. Serum suPAR levels were measured before and after 1 year of therapy with MMF (n = 40) and CsA (n = 35).The suPAR levels decreased after 1 year of treatment with MMF (p 0.05). Conversely, suPAR levels increased after 1 year of treatment with CsA in the same patients (p = 0.01). These changes in suPAR levels were not correlated to the estimated glomerular filtration rate (eGFR) or changes in the GFR.Data from this prospective randomized trial suggest that treatment with MMF and CsA is associated with different effects on suPAR levels in children with MCD and that these are independent of their effects on GFR.

Background The attainment of normal growth and maturation remains a major challenge in the management of children and adolescents requiring renal replacement therapy (RRT).

Background. Lowe syndrome (LS) and Dent-2 disease (DD2) are disorders associated with mutations in the OCRL gene and characterized by progressive chronic kidney disease (CKD). Here, we aimed to investigate the long-term renal outcome and identify potential determinants of CKD and its progression in children with these tubulopathies. Methods. Retrospective analyses were conducted of clinical and genetic data in a cohort of 106 boys (LS: 88 and DD2: 18). For genotype-phenotype analysis, we grouped mutations according to their type and localization. To investigate progression of CKD we used survival analysis by Kaplan-Meier method using stage 3 CKD as the end-point. Results. Median estimated glomerular filtration rate (eGFR) was lower in the LS group compared with DD2 (58.8 versus 87.4 mL/min/1.73 m2, P < 0.01). CKD stage II-V was found in 82% of patients, of these 58% and 28% had moderate-to-severe CKD in LS and DD2, respectively. Three patients (3%), all with LS, developed stage 5 of CKD. Survival analysis showed that LS was also associated with a faster CKD progression than DD2 (P < 0.01). On multivariate analysis, eGFR was dependent only on age (b0.46, P < 0.001). Localization, but not type of mutations, tended to correlate with eGFR. There was also no significant association between presence of nephrocalcinosis, hypercalciuria, proteinuria and number of adverse clinical events and CKD. Conclusions. CKD is commonly found in children with OCRL mutations. CKD progression was strongly related to the underlying diagnosis but did not associate with clinical parameters, such as nephrocalcinosis or proteinuria.

Background. 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. Methods. 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). Results. 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. Conclusion. 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.

The Wilms' tumor suppressor gene 1 (WT1) encodes a transcription factor involved in kidney and gonadal development. WT1 is also a key regulator of podocyte functions and mutations have been found in a small percentage of children with isolated or syndromal steroid-resistant nephrotic syndrome. It is commonly assumed that the nephrotic syndrome (NS) in patients with WT1 mutations is unresponsive to therapy and characterized by rapid progression to end-stage renal disease. We report long-term observations in 3 children with focal-segmental glomerulosclerosis associated with WT1 mutations and NS (2 cases) or nephrotic range proteinuria (1 case). All patients showed a favorable response to an intensified therapy consisting of cyclosporin A (CyA) in combination with induction therapy with intravenous and oral prednisone. Treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers was added to the regimen at various times. As shown both by the short-term response and during long-term follow-up, this treatment resulted in clinical remission of the NS and/or significant reduction of proteinuria, while normal renal function could be maintained over many years. Thus, glomerular diseases in selected patients with mutations in genes regulating renal development and podocyte function may respond to combination therapy with CyA and corticosteroids.

Die Pravention und fruhzeitige Diagnose der arteriellen Hypertonie bereits im Kindesalter werden zunehmend wichtiger. Die Medikamente, die fur die Therapie im Kindes- und Jugendalter zur Verfugung stehen, werden im vorliegenden Beitrag hinsichtlich Wirkungsmechanismus, Nebenwirkungen und Dosierungen erortert. Zur Behandlung geeignet sind ACE-Hemmer, Angiotensin-1-Rezeptor-Antagonisten, β-Blocker, Diuretika und Kalziumantagonisten. Bei der Auswahl antihypertensiver Medikamente sollten bestehende Komorbiditaten berucksichtigt werden.

Background. The rate of complete remission after induction therapy for steroid-resistant nephrotic syndrome (SRNS) due to either focal segmental glomerulosclerosis (FSGS) or minimal change nephrotic syndrome (MCNS) has been reported to be

Nephrin belongs to a family of highly conserved proteins with a well characterized function as modulators of cell adhesion and guidance, and nephrin may have a role in metabolic pathways linked to podocyte and pancreatic β–cell survival. However, this role is incompletely characterized. In this study, we developed floxed nephrin mice for pancreatic β-cell–specific deletion of nephrin, which had no effect on islet size and glycemia. Nephrin deficiency, however, resulted in glucose intolerance in vivo and impaired glucose–stimulated insulin release ex vivo. Glucose intolerance was also observed in eight patients with nephrin mutations compared with three patients with other genetic forms of nephrotic syndrome or nine healthy controls. In vitro experiments were conducted to investigate if nephrin affects autocrine signaling through insulin receptor A (IRA) and B (IRB), which are both expressed in human podocytes and pancreatic islets. Coimmunoprecipitation of nephrin and IRB but not IRA was observed and required IR phosphorylation. Nephrin per se was sufficient to induce phosphorylation of p70S6K in an phosphatidylinositol 3-kinase–dependent but IR/Src-independent manner, which was not augmented by exogenous insulin. These results suggest a role for nephrin as an independent modulator of podocyte and pancreatic β–cell nutrient sensing in the fasting state and the potential of nephrin as a drug target in diabetes.

Background and objectives Poor linear growth is a frequent complication of CKD. This study evaluated the effect of kidney transplantation on age-related growth of linear body segments in pediatric renal transplant recipients who were enrolled from May 1998 until August 2013 in the CKD Growth and Development observational cohort study. Design, setting, participants, & measurements Linear growth (height, sitting height, arm and leg lengths) was prospectively investigated during 1639 annual visits in a cohort of 389 pediatric renal transplant recipients ages 2–18 years with a median follow-up of 3.4 years (interquartile range, 1.9–5.9 years). Linear mixed-effects models were used to assess age- related changes and predictors of linear body segments. Results During early childhood, patients showed lower mean SD scores (SDS) for height (−1.7) and a markedly elevated sitting height index (ratio of sitting height to total body height) compared with healthy children (1.6 SDS), indicating disproportionate stunting (each P

This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with cyclosporin microemulsion (CyA) in pediatric renal recipients. A 6-month, randomized, prospective, open, parallel group study with an open extension phase was conducted in 18 centers from nine European countries. In total, 196 pediatric patients (

WT1 mutations cause a wide spectrum of renal and extrarenal manifestations. Here we evaluated disease prevalence, phenotype spectrum, and genotype–phenotype correlations of 61 patients with WT1 -related steroid-resistant nephrotic syndrome relative to 700 WT1 -negative patients, all with steroid-resistant nephrotic syndrome. WT1 patients more frequently presented with chronic kidney disease and hypertension at diagnosis and exhibited more rapid disease progression. Focal segmental glomerulosclerosis was equally prevalent in both cohorts, but diffuse mesangial sclerosis was largely specific for WT1 disease and was present in 34% of cases. Sex reversal and/or urogenital abnormalities (52%), Wilms tumor (38%), and gonadoblastoma (5%) were almost exclusive to WT1 disease. Missense substitutions affecting DNA-binding residues were associated with diffuse mesangial sclerosis (74%), early steroid-resistant nephrotic syndrome onset, and rapid progression to ESRD. Truncating mutations conferred the highest Wilms tumor risk (78%) but typically late-onset steroid-resistant nephrotic syndrome. Intronic (KTS) mutations were most likely to present as isolated steroid-resistant nephrotic syndrome (37%) with a median onset at an age of 4.5 years, focal segmental glomerulosclerosis on biopsy, and slow progression (median ESRD age 13.6 years). Thus, there is a wide range of expressivity, solid genotype–phenotype associations, and a high risk and significance of extrarenal complications in WT1 -associated nephropathy. We suggest that all children with steroid-resistant nephrotic syndrome undergo WT1 gene screening.

Cyclosporine (CyA) has made a great impact on 1-year allograft survival, however, after years, renal function deteriorates, possibly due to chronic toxicity. Recently, Mycophenolate mofetil (MMF) was introduced as a non-nephrotoxic immunosuppressant that might be effective in chronical transplant arteriolopathy. We therefore started MMF at a dose of 600 mg/m2 b. i. d. in 18 pediatric renal transplant recipients (10.8 +/- 3.9 (SD) years of age at transplantation, 11/18 with a history of rejections) with biopsy-proven chronic arteriolopathy and other signs of CyA toxicity at a mean follow up time of 6.2 +/- 2.7 (range 2.3-11.8) years after transplantation. One month prior to conversion, mean serum creatinine was 171 +/- 96 micromol/l, lower than at the time of conversion (188 +/- 100 micromol/l, P = 0.003, paired t-test). At last follow-up (median 13.7 months, range 5.0 to 25.0 months) after conversion, mean serum creatinine decreased significantly to 127 +/- 69 micromol/l (P = 0,0003, paired t-test). The CyA dosage was reduced from a mean of 150 +/- 39 mg/ m2 per day to 59 +/- 13 mg/m2 per day in 7 patients, and CyA was discontinued in 11 patients after a median period of nine months (range 1-18 months). After a median period of 21 days, a pharmacokinetic profile was performed in all patients. The mean MMF dose was 1117 +/- 319 mg/m2 per day (range 675-1774 mg/m2 per day). The mean Mycophenolic acid (MPA) trough concentration was 4.0 +/- 2.0 microg/ml, range 1.4-7.9 microg/ml. Mean 12 h MPA AUC was 70.6 +/- 28.1 (range 31.9-127) microg x h/ml. Except for one patient with diarrhea associated with a high AUC, and for one patient with a steroid-sensitive rejection episode after 566 days, no other patient experienced side effects or a rejection episode. Prednisolone was left unaltered at 2-4 mg/m2 per day. We conclude that MMF allows safe reduction of CyA with markedly better graft function, suggesting that chronical CyA-toxicity partially accounts for deteriorating allograft function.

The long-term prognosis of diarrhea-associated hemolytic uremic syndrome (D+ HUS) was evaluated in a cohort of 127 of 149 children who had survived the acute phase. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were estimated by serial (51)Cr-EDTA and (123)iodine-hippurate clearances. All children had acute renal failure during the initial phase and 74% of patients were dialyzed. During the 1st year, mean GFR and ERPF increased continuously until a plateau was reached. In the 2nd year after the diagnosis of HUS, GFR was below 80 and ERPF below 515 ml/min per 1. 73 m(2) in 16% and 47% of patients, respectively. At the end of a median follow-up of 5.0 (range 2.0-13.2) years, the proportion of children with renal sequelae such as proteinuria/=300 mg/l, hypertension, or a GFR80 ml/min per 1.73 m(2) was 23%. Anuria of more than 7 days' duration and hypertension during the acute phase were statistically significant risk factors for an unfavorable outcome. A reduced ERPF in the 2nd year was found in 93% of patients with sequelae. Mean filtration fraction (SD) in these patients was 0. 26 (+/-0.07) versus 0.19 (+/-0.05) in patients without sequelae (P0. 0001). These data suggest that loss of nephrons during the acute phase may implicate hyperfiltration in the residual functioning kidney mass leading to progressive renal disease. ERPF in the 2nd year after D+ HUS may serve as an excellent parameter to detect patients with a high risk of an unfavorable long-term outcome.

Recently, the reciprocal of cystatin C (Cys-C), a non-glycosylated 13-kilodalton protein that is produced by all investigated nucleated cells, was found to correlate closely with glomerular filtration rate (GFR). In order to determine the diagnostic validity in children for the detection of impaired GFR, venous blood samples from 381 children (aged 1.7-18 years) with various renal pathology referred for 51Cr-EDTA clearance investigations were obtained for measurement of Cys-C as well as beta2-microglobulin (beta2-MG) and serum creatinine. Two hundred and sixteen children with clearance values90 ml/min per 1.73 m2 constituted a control group, with a normal GFR. In the control group, Cys-C values were normally distributed with a mean of 0.94+/-0.27 mg/l and an upper reference limit (97.5th percentile) of 1.47 mg/l. In all children, there was a positive correlation between 51Cr-EDTA clearance and the reciprocal of Cys-C (r=0.64, P0.0001), beta2-MG (r=0.59, P0.0001), creatinine (r=0.55, P0.0001), and the height/creatinine ratio (r=0.73, P0.0001). Receiver-operating characteristics analysis showed that there were no significant differences between these three parameters for discriminating between patients with normal and reduced GFR, although there was a tendency towards the best diagnostic sensitivity of the GFR estimate according to the Schwartz formula. We conclude that for the detection of mildly impaired GFR, a full clearance study cannot be replaced by measurement of serum Cys-C or beta2-MG concentrations.

Ambulatory blood pressure (ABP) monitoring is increasingly used to evaluate the blood pressure of children and adolescents. The upper normal ABP values in the pediatric age group are still unknown, because reference values based on a sufficiently high number of healthy children have not yet been published. In this multicenter trial, we pooled ABP records of 1141 healthy children and adolescents with a body height between 115 and 185 cm. The study was carried out by seven centers according to a common protocol. The 50th percentile for 24-hour systolic ABP increased moderately with height, from 103 to 113 mm Hg in girls and from 105 to 120 mm Hg in boys. The 50th percentile for diastolic 24-hour means was 66 +/- 1 mm Hg, irrespective of height or gender. Diastolic daytime means were 73 +/- 1 mm Hg, which is remarkably high compared with reference values for casual blood pressure. The mean nocturnal systolic and diastolic ABP (midnight to 6 AM) was 13% +/- 6% and 23% +/- 9% lower compared with the daytime means (8 AM to 8 PM), respectively. This multicenter study provides well-based limits of normal ABP in mid-European children.

WOS: 000321044400026, PubMed ID: 23515051, Genetic screening paradigms for congenital and infantile nephrotic syndrome are well established; however, screening in adolescents has received only minor attention. To help rectify this, we analyzed an unselected adolescent cohort of the international PodoNet registry to develop a rational screening approach based on 227 patients with nonsyndromic steroid-resistant nephrotic syndrome aged 10-20 years. Of these, 21% had a positive family history. Autosomal dominant cases were screened for WT1, TRPC6, ACTN4, and INF2 mutations. All other patients had the NPHS2 gene screened, and WT1 was tested in sporadic cases. In addition, 40 sporadic cases had the entire coding region of INF2 tested. Of the autosomal recessive and the sporadic cases, 13 and 6%, respectively, were found to have podocin-associated nephrotic syndrome, and 56% of them were compound heterozygous for the nonneutral p.R229Q polymorphism. Four percent of the sporadic and 10% of the autosomal dominant cases had a mutation in WT1. Pathogenic INF2 mutations were found in 20% of the dominant but none of the sporadic cases. In a large cohort of adolescents including both familial and sporadic disease, NPHS2 mutations explained about 7% and WT1 4% of cases, whereas INF2 proved relevant only in autosomal dominant familial disease. Thus, screening of the entire coding sequence of NPHS2 and exons 8-9 of WT1 appears to be the most rational and cost-effective screening approach in sporadic juvenile steroid-resistant nephrotic syndrome., E-Rare (PodoNet project); EUEuropean Union (EU) [305608]; Polish Ministry of Science and EducationMinistry of Science and Higher Education, Poland [N402631840]; German Research FoundationGerman Research Foundation (DFG) [Scha 477/11-1]; Chilean FondecytComision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)CONICYT FONDECYT [11090045]; DAAD scholarshipDeutscher Akademischer Austausch Dienst (DAAD); Scientific and Technological Research Council of TurkeyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [108S417]; Hacettepe UniversityHacettepe University [06A101008], This work was financed by E-Rare (PodoNet project), the EU 7th Framework Programme (EURenOmics, grant 305608), the Polish Ministry of Science and Education grant N402631840, the German Research Foundation (Scha 477/11-1), and Chilean Fondecyt grant 11090045 (to MA). BSL was granted a DAAD scholarship. FO was supported by the Scientific and Technological Research Council of Turkey (grant 108S417) and by the Hacettepe University Infrastructure Project (grant 06A101008). We are grateful to Dr S Zietkiewicz from the Department of Molecular and Cellular Biology, Intercollegiate Faculty of Biotechnology at the University of Gdansk, Poland, for help with the in silico analyses.

A lifelong phenylalanine-restricted diet with supplementation of a phenylalanine-free amino acid formula is recommended in patients with phenylketonuria (PKU). The effect of a long-term PKU diet on renal function and blood pressure has not been investigated yet.We analyzed renal function in 67 patients with PKU, aged 15-43 years, by measuring glomerular filtration rate (GFR) and effective renal plasma flow by isotope clearance ((51)Cr-EDTA, (123)J-Hippuran), estimated GFR, blood retention parameters, urinary protein and electrolyte excretion. Renal ultrasound and 24 h ambulatory blood pressure monitoring were performed additionally. Patients were divided into three groups according to their: 1) current diet (CD), i.e., daily protein intake: ICD0.8 g/kg, IICD 0.8-1.04 g/kg, IIICD1.04 g/kg; 2) life-long diet time (LDT), i.e., cumulative years of life in which daily protein intake exceeded dietary recommendations: ILDT15 years, IILDT 15-19 years, IIILDT19 years.GFR was decreased in 19 % of the patients. With increasing protein intake, GFR decreased significantly (ICD 111 ml/min; IICD 105 ml/min; IIICD 99 ml/min. ILDT 112 ml/min; IILDT 103 ml/min; IIILDT 99 ml/min). Proteinuria was detected in 31 %, microalbuminuria in 7 %, and hypercalciuria in 23 % of the patients. 23 % of the patients had arterial hypertension, and 41 % revealed a nocturnal non-dipping status.In patients with PKU on a lifelong diet we could detect impaired renal function in 19 %, proteinuria in 31 %, and arterial hypertension in 23 %. Thus, chronic kidney disease may develop in PKU patients, and routine renal function tests should be performed during long-term follow-up.

Background. There is currently no established standard for maintenance therapy of steroid-resistant nephrotic syndrome (SRNS). We report the long-term clinical course, medication, pharmacokinetic data, and renal function of 23 children with primary, non-familial SRNS with focal segmental glomerulosclerosis (FSGS). Methods. To achieve initial remission, patients were treated with high-dose intravenous (i. v.) methylprednisolone and oral cyclosporin A (CsA). Maintenance therapy included transient alternate day oral prednisolone, CsA and angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers. In 18 patients, mycophenolate mofetil (MMF) (adjusted to achieve blood mycophenolic acid trough concentrations > 2 lg/mL) was sequentially added, and 16 patients were converted to MMF monotherapy. Results. During a mean follow-up time of 7.0 years (1.7–16.5 years; cumulative observation time 161 patientyears), sustained remission could be achieved in all patients. Five of 23 patients (21%) experienced 10 relapses; all responded to relapse therapy. Maintenance therapy could be permanently discontinued in seven patients (30%). After conversion from CsA to MMF, renal function improved significantly; the eGFR at last follow-up was 137 (range 106–198) mL/min 3 1.73 m 2 . The mean number of antihypertensive drugs decreased from 1.86 per patient after initial remission to 0.57 on MMF monotherapy (P < 0.002). Conclusions. The data of this uncontrolled retrospective study indicate that in children with SRNS/FSGS achieving initial remission, a sequential steroid-free therapy consisting of a combination of CsA and MMF followed by MMF alone (with the addition of ACE inhibitors and angiotensin receptor blockers), can provide sustained long-term remission, preservation of renal function and better control of blood pressure.

Casual office blood pressure (CBP) measurements are still standard in antihypertensive drug trials. In pediatric hypertensive trials, ethical considerations, very low disease prevalence and the marked impact of white-coat hypertension create the need for very sensitive and reproducible techniques of BP assessment. We hypothesized that ambulatory BP monitoring (ABPM) may identify treatment effects more sensitively than CBP and thereby reduce sample sizes required in pediatric antihypertensive trials.Standard deviations (SDs) were used to assess population variability of CBP and ABPM at baseline and after 6 months standardized antihypertensive treatment from a trial investigating the BP-lowering effect of ramipril in children with chronic kidney disease.In 157 hypertensive children, ramipril had a similar mean BP-lowering effect on clinic and ambulatory 24-h BP for systolic (-10 vs. -11 mmHg, P = NS) and diastolic values (-9 vs. -11 mmHg, P = NS). However, the SDs of the CBP responses were up to 39% larger than those of ABPM (SBP 15.5 vs. 9.4; DBP 13.8 vs. 8.8; both P0.0001). Using power analysis, we demonstrate that, depending on the magnitude of the expected antihypertensive effect and trial design, the utilization of ABPM in antihypertensive drug efficacy studies allows reduction of sample sizes by 57-75%. This reduction of cohort size with ABPM is substantially greater than previously observed for adults.The primary use of ABPM can substantially reduce the number of children put at potential risk in blinded antihypertensive drug trials by up to three quarters.

PubMedID: 19846849 BACKGROUND: Although inhibition of the renin-angiotensin system delays the progression of renal failure in adults with chronic kidney disease, the blood-pressure target for optimal renal protection is controversial. We assessed the long-term renoprotective effect of intensified blood-pressure control among children who were receiving a fixed high dose of an angiotensin-converting- enzyme (ACE) inhibitor. METHODS: After a 6-month run-in period, 385 children, 3 to 18 years of age, with chronic kidney disease (glomerular filtration rate of 15 to 80 ml per minute per 1.73 m2 of body-surface area) received ramipril at a dose of 6 mg per square meter of bodysurface area per day. Patients were randomly assigned to intensified blood-pressure control (with a target 24-hour mean arterial pressure below the 50th percentile) or conventional blood-pressure control (mean arterial pressure in the 50th to 95th percentile), achieved by the addition of antihypertensive therapy that does not target the renin-angiotensin system; patients were followed for 5 years. The primary end point was the time to a decline of 50% in the glomerular filtration rate or progression to end-stage renal disease. Secondary end points included changes in blood pressure, glomerular filtration rate, and urinary protein excretion. RESULTS: A total of 29.9% of the patients in the group that received intensified blood-pressure control reached the primary end point, as assessed by means of a Kaplan-Meier analysis, as compared with 41.7% in the group that received conventional blood-pressure control (hazard ratio, 0.65; confidence interval, 0.44 to 0.94; P = 0.02). The two groups did not differ significantly with respect to the type or incidence of adverse events or the cumulative rates of withdrawal from the study (28.0% vs. 26.5%). Proteinuria gradually rebounded during ongoing ACE inhibition after an initial 50% decrease, despite persistently good blood-pressure control. Achievement of blood-pressure targets and a decrease in proteinuria were significant independent predictors of delayed progression of renal disease. CONCLUSIONS: Intensified blood-pressure control, with target 24-hour blood-pressure levels in the low range of normal, confers a substantial benefit with respect to renal function among children with chronic kidney disease. Reappearance of proteinuria after initial successful pharmacologic blood-pressure control is common among children who are receiving long-term ACE inhibition. (ClinicalTrials.gov number, NCT00221845). Copyright © 2009 Massachusetts Medical Society.

The clinical course of two children with mid-aortic syndrome and renal artery stenosis (RAS) who suffered from severe arterial hypertension is described. Hypertension was uncontrollable by antihypertensive medication and was managed by percutaneous transluminal renal angioplasty (PTRA) with stent implantation. The pediatric experience with PTRA is limited, and there are only few cases reported with additional stent implantation. Complications of these procedures are well known from experience with adult patients. However, since surgical revascularization may be technically difficult especially in small children, PTRA with or without stenting should be considered as a valuable treatment option in pediatric RAS.

Long-term treatment with cyclosporin A (CyA) of children with frequently relapsing steroid-sensitive nephrotic syndrome (SSNS) carries the risk of nephrotoxicity. We have analyzed renal function in 23 children with SSNS during CyA therapy. Repeated measurements of glomerular filtration rate (single-shot 51Cr-EDTA clearance) showed a decline from 131 +/- 21 ml/min per 1.73 m2 to 116 +/- 27 ml/min per 1.73 m2 at last follow-up. Similarly, effective renal plasma flow (simultaneous 123 I-hippurate clearance) was correlated with duration of CyA treatment, and showed a decline from 980 +/- 318 ml/min per 1.73 m2 to 724 +/- 242 ml/min per 1.73 m2. In a pilot study we investigated the effect of mycophenolate mofetil (MMF) in 7 children with a median age of 12.7 years [6 with minimal change nephrotic syndrome (MCNS), 1 with focal segmental glomerulosclerosis (FSGS)] with signs of nephrotoxicity because of long-term CyA therapy. Only 1 patient with SSNS showed a relapse during MMF therapy. In the patient with FSGS, MMF was started in addition to CyA, resulting in complete remission for a follow-up of 28 months. This preliminary study demonstrates that children with MCNS treated with CyA may be successfully converted to MMF without major side effects. In all cases, including FSGS, MMF had a beneficial effect on renal function. These data should be confirmed by a prospective randomized clinical trial.

Polymorphisms in the genes encoding the high-affinity IgE receptor, the interleukin 4 (IL4) receptor and IL13 can be associated with the development of asthma and allergy. Although several studies have described an association between atopy and idiopathic childhood nephrotic syndrome (NS), it is not clear whether this association is of a causal nature. Furthermore, it is not known whether these polymorphisms are associated with the clinical course of NS. A total of 84 children (52 male and 32 female; mean age 12.1 years) with NS were included in the present study. Of these, 78 could be classified as either atopic or non-atopic. Atopy was defined by elevated IgE levels (>100k-units/l) and/or a positive history of atopy (33 of 78 patients). DNA was extracted from blood collected in EDTA tubes, and polymorphisms at positions 50 and 551 of the IL4 receptor, position 110 of IL13 and position 181 of the high-affinity IgE receptor were investigated by sequence-specific PCR or direct sequencing. Although we noted a strong tendency towards a higher allele frequency of polymorphisms in children with atopy and NS compared with children with NS but without atopy (IL4 50, 30% compared with 18%; IL4 551, 39% compared with 31%; IL13 110, 45% compared with 33%; IgE 181, 12% compared with 13%), these differences did not reach statistical significance. There were no differences in the frequency of polymorphisms between the different clinical courses of NS (frequent relapsers, steroid-dependent or steroid-resistant NS). We conclude that polymorphisms in the IL4 receptor, the high-affinity IgE receptor and IL13 do not seem to predict the clinical course of NS, despite the fact that serum IgE elevations are more frequent in patients with NS than in normal control subjects. The investigated polymorphisms may contribute to the IgE switch in patients with NS.

Inhibition of the angiotensin-converting enzyme (ACE) exerts a renoprotective effect in adult patients with chronic kidney disease. We evaluated prospectively changes in blood pressure (BP), protein excretion and renal function after administration of the long-acting ACE inhibitor ramipril as monotherapy during 6 months in 14 moderately hypertensive children aged 5–18 years with various nephropathies. Four patients initially had a decreased glomerular filtration rate (GFR below 60 ml/min/1.73 m2). BP was evaluated by ambulatory 24-h monitoring. After 2 weeks of treatment by oral ramipril (1.5 mg/m2 once daily), mean values of systolic and diastolic 24-h ambulatory BP fell by more than 5 mmHg in nine patients. In eight patients the dose was doubled. At the end of the study systolic BP was below the 95th percentile in 9 and diastolic BP in 13 patients. The initially reduced nocturnal dip increased significantly. Of 11 patients with an increased albumin excretion (median 1.3 g/g creatinine), 6 responded to ramipril by a median reduction of 78% (range 24–83%), whilst in 5 albuminuria increased (median +19%). GFR was well preserved and no other adverse effects from the drug were noted. The study demonstrates that ramipril is an efficacious antihypertensive agent in children with renal hypertension. It is well tolerated, even in mild renal insufficiency. In addition, the drug has a persistent antiproteinuric action in about half of the patients contributing to conserve renal function.

Objective To establish a hospital-based nocturnal hemodialysis (NHD) program for children and adolescents. Study design Sixteen patients (age, 0.5 to 17 years) were prospectively included. Uremia-associated measures as well as amount and dosage of medication were enumerated. Quality of life also was evaluated. Results were compared with data of the same patients on conventional hemodialysis and with matched control subjects (conventional HD). Results NHD was well tolerated. Median Kt/V values increased. Predialytic mean arterial pressure, urea, phosphate, and parathyroid hormone levels decreased. There was an increase in protein catabolic rate. Dietary and fluid restrictions could be lifted. Amount and dosage of phosphate and potassium binders and antihypertensive medication could be reduced. Quality of life improved and days of absence from school decreased in all patients. Conclusions In addition to a better control of uremia-associated measures, NHD allows free dietary and fluid intake and improves patient well-being. Given the continuing shortage of donor organs for kidney transplantation and the high morbidity and mortality on conventional HD, intensified dialysis regimens are a much-needed therapeutic option.