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Context: The pathophysiology of cystinosis-associated metabolic bone disease is complex., Objective: We hypothesized a disturbed interaction between osteoblasts and osteoclasts., Methods: This binational cross-sectional multicenter study included 103 patients with cystinosis (61% children) with chronic kidney disease (CKD) stages 1 to 5D/T at hospital clinics. Ten key bone markers were evaluated., Results: Skeletal complications occurred in two-thirds of the patients, with adults having a 5-fold increased risk compared with children. Patients with CKD stages 1 to 3 showed reduced z-scores for serum phosphate and calcium and suppressed fibroblast growth factor 23 (FGF23) and parathyroid hormone levels, in conjunction with elevated bone-specific alkaline phosphatase levels. Serum phosphate was associated with estimated glomerular filtration rate, combined phosphate and active vitamin D treatment, and native vitamin D supplementation, while serum calcium was associated with age and dosage of active vitamin D. Sclerostin was generally elevated in children, and associated with age, FGF23 levels, and treatment with active vitamin D and growth hormone. The osteoclast marker tartrate-resistant acid phosphatase 5b was increased, and associated with age and treatment with active vitamin D. The ratio of soluble ligand of receptor activator of nuclear factor-κB (sRANKL) and osteoprotegerin (OPG), a surrogate for the regulation of osteoclastogenesis by osteoblasts, was decreased and associated with phosphate and 1,25(OH)2D3 levels. These changes were only partly corrected after transplantation., Conclusion: Bone health in cystinosis deteriorates with age, which is associated with increased osteoclast activity despite counter-regulation of osteoblasts via OPG/RANKL, which in conjunction with elevated sclerostin levels and persistent rickets/osteomalacia, may promote progressive bone loss., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Background: Therapeutic apheresis (TA) are promising treatment option for neuroimmunological disorders. In paediatrics, the available data is limited, particularly for the use of IA. The aim of this study was to analyse the use of PE and IA in children and adolescents, with emphasis on outcome and neurological course after treatment as well as the safety of the two modalities., Methods: Clinical data from paediatric patients with neuroimmunological disorders treated with TA in two German university children's hospitals between 2015 and 2022 were retrospectively analysed., Results: In total, 39 patients underwent 322 sessions of TA, of which 184 were IA and 138 PE. The most common diagnosis was autoimmune encephalitis in 39 % (n = 15) of the patients. Other indications were central nervous system inflammatory demyelinating disorders in 21 % (n = 8), Guillain-Barré syndrome in 18 % (n = 7), Myelin Oligodendrocyte Glycopeptide-antibody associated syndromes in 8 % (n = 3), Myasthenia gravis in 5 % (n = 2) and other neurological disorders in 10 % (n = 4). Overall, there was an improvement in 76 % of patients (81 % with IA, 70 % with PE; p = 0.41) immediately after treatment and an improvement in 88 % of patients (90 % with IA, 85 % with PE; p = 0.63) one month after treatment. Complications occurred in 13 % of all sessions (13 % with IA and 13 % with PE; p = 1). Most complications were considered as moderate., Conclusion: Both, IA and PE, are effective treatment options in the therapy of neuroimmunological disorders in children and adolescents, with no major differences in terms of efficiency or safety., Competing Interests: Declaration of competing interest None of the authors has any conflicts of interest to declare in association with this manuscript., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We present a case of lamotrigine-triggered DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome with acute kidney injury stage 3. A 17-year-old girl with known epilepsy treated with lamotrigine presented with acute kidney injury as well as skin eruption, fever, and apathy. Extended diagnostics, considering infectious and autoimmune diseases, remained unremarkable. Lamotrigine blood levels were within the target range. Kidney biopsy showed acute interstitial nephritis with tubular necrosis. Methylprednisolone pulse therapy led to an improvement in kidney function; skin eruption and neurological symptoms resolved. During the hospital stay, the girl admitted to inconsistent and variable intake of lamotrigine, occasionally resulting in notable overdosing. This report demonstrates that acute kidney injury in lamotrigine-induced DRESS syndrome is an acute interstitial nephritis with tubular necrosis, an aspect that has not been deeply characterized so far. Additionally, we aim to elevate awareness towards non-adherence as cause of disease, especially among the adolescent population., (© 2024. The Author(s).)

Introduction: The choice and timing of kidney replacement therapy (KRT) is influenced by clinical factors, laboratory features, feasibility issues, family preferences, and clinicians' attitudes. We analyzed the factors associated with KRT modality and timing in a multicenter, multinational prospective pediatric cohort study., Methods: A total of 695 pediatric patients with chronic kidney disease (CKD) enrolled into the Cardiovascular Comorbidity in Children with CKD (4C) study at age 6 to 17 years with estimated glomerular filtration rate (eGFR) of 10 to 60 ml/min per 1.73 m 2 were investigated. Competing risk regression was performed to identify factors associated with initiation of dialysis or preemptive transplantation (Tx), including primary renal diagnosis, demographics, anthropometrics, and laboratory parameters., Results: During the 8-year observation period, 342 patients (49%) started KRT. Of these, 200 patients started dialysis, whereas 142 patients underwent preemptive Tx. A lower eGFR at enrolment (Hazard ratio [HR]: 0.76 [95% confidence interval: 0.74-0.78]), a steeper eGFR slope (HR: 0.90 [0.85-0.95], and a higher systolic blood pressure SD score (SDS) (HR: 2.07 [1.49-2.87]) increased the likelihood of KRT initiation. Patients with glomerulopathies were more likely to start dialysis than children with congenital anomalies of the kidneys and urinary tracts (CAKUT) (HR: 3.81 [2.52-5.76]). Lower body mass index (BMI) SDS (HR: 0.73 [0.6-0.89]) and lower hemoglobin (HR: 0.8 [0.72-0.9]) were associated with higher likelihood of dialysis. A significant center effect was observed, accounting for 6.8% (dialysis) to 8.7% (preemptive Tx) of explained variation., Conclusion: The timing and choice of KRT in pediatric patients is influenced by the rate of kidney function loss, the underlying kidney disease, nutritional status, blood pressure, anemia and center-specific factors., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Introduction: Hepatocyte nuclear factor 1-beta ( HNF1B ) gene variants or the chromosome 17q12 deletion (17q12del) represent the most common monogenic cause of developmental kidney disease. Although neurodevelopmental disorders have been associated with the 17q12del, specific genotype-phenotype associations with respect to kidney function evolution have not yet been fully defined. Here, we aimed to determine whether 17q12del or specific HNF1B variants were associated with kidney survival in a large patient population with HNF1B disease., Methods: This was a retrospective observational study involving 521 patients with HNF1B disease from 14 countries using the European Reference Network for rare kidney diseases with detailed information on the HNF1B genotype ( HNF1B variants or the 17q12del). Median follow-up time was 11 years with 6 visits per patient. The primary end point was progression to chronic kidney disease (CKD) stage 3 (estimated glomerular filtration rate [eGFR] < 60 ml/min per 1.73 m 2 ). Secondary end points were the development of hypomagnesemia or extrarenal disorders, including hyperuricemia and hyperglycemia., Results: Progression toward CKD stage 3 was significantly delayed in patients with the 17q12del compared to patients with HNF1B variants (hazard ratio [HR]: 0.29, 95% confidence interval [CI]: 0.19-0.44, P  < 0.001). Progression toward CKD stage 3 was also significantly delayed when HNF1B variants involved the HNF1B Pit-1, Oct-1, and Unc-86 homeodomain (POU h ) DNA-binding and transactivation domains rather than the POU-specific domain (POU s ) DNA-binding domain (HR: 0.15 [95% CI: 0.06-0.37), P  < 0.001 and HR: 0.25 (95% CI: 0.11-0.57), P  = 0.001, respectively). Finally, the 17q12del was positively associated with hypomagnesemia and negatively associated with hyperuricemia, but not with hyperglycemia., Conclusion: Patients with the 17q12del display a significantly better kidney survival than patients with other HNF1B variants; and for the latter, variants in the POU s DNA-binding domain lead to the poorest kidney survival. These are clinically relevant HNF1B kidney genotype-phenotype correlations that inform genetic counseling., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Introduction: Fluid and salt overload in patients on dialysis result in high blood pressure (BP), left ventricular hypertrophy (LVH) and hemodynamic instability, resulting in cardiovascular morbidity., Methods: Analysis of 910 pediatric patients on maintenance hemodialysis/hemodiafiltration (HD/HDF), prospectively followed-up with 2758 observations recorded every 6-months in the International Pediatric Hemodialysis Network (IPHN)., Results: Uncontrolled hypertension was present in 55% of observations, with 27% of patients exhibiting persistently elevated predialysis BP. Systolic and diastolic age- and height-standardized BP (BP-SDS) were independently associated with the number of antihypertensive medications (odds ratio [OR] = 1.47, 95% confidence interval 1.39-1.56, 1.36 [1.23-1.36]) and interdialytic weight gain (IDWG; 1.19 [1.14-1.22], 1.09 [1.06-1.11]; all  P  < 0.0001). IDWG was related to urine output (OR = 0.27 [0.23-0.32]) and dialysate sodium (dNa; 1.06 [1.01-1.10]; all P  < 0.0001). The prevalence of masked hypertension was 24%, and HD versus HDF use was an independent risk factor of elevated age- and height-standardized mean arterial pressure (MAP-SDS) (OR = 2.28 [1.18-4.41], P  = 0.01). Of the 1135 echocardiograms, 51% demonstrated LVH. Modifiable risk factors included predialysis systolic BP-SDS (OR = 1.06 [1.04-1.09], P  < 0.0001), blood hemoglobin (0.97 [0.95-0.99], P = 0.004), HD versus HDF modality (1.09 [1.02-1.18], P  = 0.01), and IDWG (1.02 [1.02-1.03], P  = 0.04). In addition, HD modality increased the risk of LVH progression (OR = 1.23 [1.03-1.48], P = 0.02). Intradialytic hypotension (IDH) was prevalent in patients progressing to LVH and independently associated with predialysis BP-SDS below 25th percentile, lower number of antihypertensives, HD versus HDF modality, ultrafiltration (UF) rate, and urine output, but not with dNa., Conclusion: Uncontrolled hypertension and LVH are common in pediatric HD, despite intense pharmacologic therapy. The outcome may improve with use of HDF, and superior anemia and IDWG control; the latter via lowering dNa, without increasing the risk of IDH., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Background: Infantile nephropathic cystinosis (INC) is a systemic lysosomal storage disease causing intracellular cystine accumulation, resulting in renal Fanconi syndrome, progressive kidney disease (CKD), rickets, malnutrition, and myopathy. An INC-specific disproportionately diminished trunk length compared to leg length poses questions regarding the functionality of the trunk., Methods: Thus, we prospectively investigated thoracic dimensions and proportions, as well as their clinical determinants in 44 pediatric patients with INC with CKD stages 1-5 and 97 age-matched patients with CKD of other etiology between the ages of 2-17 years. A total of 92 and 221 annual measurements of patients with INC and CKD, respectively, were performed, and associations between anthropometric and clinical parameters were assessed using linear mixed-effects models., Results: Patients with INC exhibited altered chest dimensions that were distinct from CKD controls, characterized by markedly increased chest depth to height and chest depth to chest width ratio z-scores (> 1.0), while those of patients with CKD were only mildly affected (z-score within ± 1.0). Ratio z-scores differed significantly between both patient groups from 2-6 years of age onward. The degree of chest disproportion in INC patients was significantly associated with both the degree of CKD and tubular dysfunction (e.g., low serum phosphate and bicarbonate) across three different age groups (2-6, 7-12, and 13-17 years)., Conclusion: Our data show an INC-specific alteration in thoracic shape from early childhood onward, which is distinct from CKD of other etiologies, suggesting early childhood subclinical changes of the musculoskeletal unit of the thoracic cage, which are associated with kidney function. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s).)

Neonatal sclerosing cholangitis (NSC) is associated with progressing biliary fibrosis that often requires liver transplantation in childhood. Several recent studies have identified variants in DCDC2, encoding doublecortin domain-containing protein 2 (DCDC2), expressed in primary cilia, that accompany syndromic disease and NSC. We report four patients with hepatobiliary disease associated with two novel homozygous or compound heterozygous variants in DCDC2. Three patients with protein-truncating variants in DCDC2, expressing no DCDC2, presented with the originally described severe hepatic phenotype in infancy. One patient with a novel homozygous DCDC2 missense variant shows a markedly milder phenotype only manifest in childhood and with retained DCDC2 expression. Concomitant nephronophthisis is present in three patients and learning disability in two. This report widens the phenotypic spectrum of DCDC2-associated hepatobiliary disease. Testing for DCDC2 expression and DCDC2 variants should be included in the evaluation of cholangiopathy of unknown aetiology in childhood as well as in infancy., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Chronic life-limiting illnesses such as chronic kidney disease (CKD) require integral support to the families concerned in addition to medical care. Palliative care is an option to facilitate families to address future concerns, such as procedures for acute life-threatening complications, or to relieve physical and psychosocial suffering. The exact needs of patients or parents have not yet been investigated. To assess needs in supportive palliative care, we conducted a monocentric qualitative interview study. We included patients 14 to 24 years old as well as parents of younger children (below 14 years) with CKD ≥ stage 3. In total, fifteen interviews were conducted. Data were analyzed with a deductive and descriptive approach using qualitative content analysis as described by Mayring. Sociodemographic data and basic information of disease were collected using questionnaires. In contrast to caregivers, adolescents and young adults do not express worries about their own mortality or reduced life expectancy. Rather, they report about their limitations to everyday life associated with the disease, especially in the areas of school and work. They wish to live a normal life. Caregivers are concerned about the future and the disease trajectory. They also describe difficulties in balancing the management of the disease with other responsibilities such as work and healthy siblings' needs. Patients and caregivers appear to need a chance to talk about their everyday struggles and disease-related fears and concerns. Talking about their concerns and needs may help deal with their emotions and facilitate acceptance of their situation characterized by a life-limiting disease. Our study confirms the need for psychosocial support in pediatric nephrology to address the needs of the affected families. This can be offered by pediatric palliative care teams.

Protection of adult kidney transplant recipients against SARS-CoV2 was shown to be strongly impaired owing to low reactogenicity of available vaccines. So far, data on vaccination outcomes in adolescents are scarce due to later vaccination approval for this age group. We therefore comprehensively analyzed vaccination-specific humoral-, T- and B-cell responses in kidney transplanted adolescents aged 12-18 years in comparison to healthy controls 6 weeks after standard two-dose BNT162b2 ("Comirnaty"; Pfizer/BioNTech) vaccination. Importantly, 90% (18/20) of transplanted adolescents showed IgG seroconversion with 75% (15/20) developing neutralizing titers. Still, both features were significantly diminished in magnitude compared to controls. Correspondingly, spike-specific B cells were quantitatively reduced and enriched for non-isotype-class-switched IgD + 27 + memory cells in patients. Whereas spike specific CD4 + T cell frequencies were similar in both groups, cytokine production and memory differentiation were significantly impaired in transplant recipients. Although our data identify limitations in all arms of vaccine-specific immunity, the majority of our adolescent patients showed robust humoral responses despite antimetabolite-based treatment being associated with poor vaccination outcomes in adults., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sattler, Thumfart, Tóth, Schrezenmeier, Proß, Stahl, Siegle, He, Thole, Ludwig, Straub-Hohenbleicher, Friedersdorff, Jahrsdörfer, Schrezenmeier, Bufler and Kotsch.)

Introduction: Nephronophthisis (NPH) comprises a group of rare disorders accounting for up to 10% of end-stage kidney disease (ESKD) in children. Prediction of kidney prognosis poses a major challenge. We assessed differences in kidney survival, impact of variant type, and the association of clinical characteristics with declining kidney function., Methods: Data was obtained from 3 independent sources, namely the network for early onset cystic kidney diseases clinical registry ( n = 105), an online survey sent out to the European Reference Network for Rare Kidney Diseases ( n = 60), and a literature search ( n = 218)., Results: A total of 383 individuals were available for analysis: 116 NPHP1 , 101 NPHP3 , 81 NPHP4 and 85 NPHP11/TMEM67 patients. Kidney survival differed between the 4 cohorts with a highly variable median age at onset of ESKD as follows: NPHP3, 4.0 years (interquartile range 0.3-12.0); NPHP1 , 13.5 years (interquartile range 10.5-16.5); NPHP4, 16.0 years (interquartile range 11.0-25.0); and NPHP11/TMEM67, 19.0 years (interquartile range 8.7-28.0). Kidney survival was significantly associated with the underlying variant type for NPHP1 , NPHP3 , and NPHP4 . Multivariate analysis for the NPHP1 cohort revealed growth retardation (hazard ratio 3.5) and angiotensin-converting enzyme inhibitor (ACEI) treatment (hazard ratio 2.8) as 2 independent factors associated with an earlier onset of ESKD, whereas arterial hypertension was linked to an accelerated glomerular filtration rate (GFR) decline., Conclusion: The presented data will enable clinicians to better estimate kidney prognosis of distinct patients with NPH and thereby allow personalized counseling., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Introduction: Autosomal recessive polycystic kidney disease (ARPKD) is a rare monogenic disorder characterized by early onset fibrocystic hepatorenal changes. Previous reports have documented pronounced phenotypic variability even among siblings in terms of patient survival. The underlying causes for this clinical variability are incompletely understood., Methods: We present the longitudinal clinical courses of 35 sibling pairs included in the ARPKD registry study ARegPKD, encompassing data on primary manifestation, prenatal and perinatal findings, genetic testing, and family history, including kidney function, liver involvement, and radiological findings., Results: We identified 70 siblings from 35 families with a median age of 0.7 (interquartile range 0.1-6.0) years at initial diagnosis and a median follow-up time of 3.5 (0.2-6.2) years. Data on PKHD1 variants were available for 37 patients from 21 families. There were 8 patients from 7 families who required kidney replacement therapy (KRT) during follow-up. For 44 patients from 26 families, antihypertensive therapy was documented. Furthermore, 37 patients from 24 families had signs of portal hypertension with 9 patients from 6 families having substantial hepatic complications. Interestingly, pronounced variability in the clinical course of functional kidney disease was documented in only 3 sibling pairs. In 17 of 20 families of our cohort of neonatal survivors, siblings had only minor differences of kidney function at a comparable age., Conclusion: In patients surviving the neonatal period, our longitudinal follow-up of 70 ARPKD siblings from 35 families revealed comparable clinical courses of kidney and liver diseases in most families. The data suggest a strong impact of the underlying genotype., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Objective: To introduce and evaluate a modified version of the "zipper method"-a treatment strategy alternating intravenous immunoglobulin (IVIG) and plasma exchange (PLEX) first reported for 9 pediatric cases of Guillain-Barré syndrome in 2018-for treatment of severe immune-mediated neurologic disorders in children., Methods: The modified zipper method comprised longer intervals between PLEX-IVIG cycles (48   hours instead of 24   hours), more cycles (7-10 instead of 5), a consistent plasma volume exchange (instead of the original multistep approach), and variable infusion times for IVIGs (4-8   hours). The modified zipper method was applied as an individual treatment approach once standard therapy failed. The follow-up ranged from 6 months to 2 years. Cases were analyzed retrospectively. Disease severity was mainly quantified by the Guillain-Barré syndrome disability score., Results: Four children (9-15 years) with (1) Miller-Fisher syndrome, (2) Bickerstaff brainstem encephalitis, (3) common Guillain-Barré syndrome, and (4) severe acute disseminated encephalomyelitis were treated by the modified zipper method. Results for duration of mechanical ventilation (median of 12 days, interquartile range [IQR] 8-16), hospital stay (median of 23 days, IQR 22-24), and time to unaided walking (median of 22 days, IQR 21-37) outperformed previous studies with IVIG/PLEX alone or IVIG + PLEX combinations unlike the zipper method., Conclusion: The modified zipper method is associated with a low mortality, a short mechanical ventilation time, a short hospital stay, and an excellent outcome in children with severe Guillain-Barré syndrome or acute disseminated encephalomyelitis. Our regimen is streamlined for applicability. Results emphasize its robust effectiveness as an option for therapy escalation in severe neuroimmunologic diseases. Now, multicenter trials are needed to evaluate this novel treatment strategy.

Background: To describe treatment practices for juvenile proliferative lupus nephritis (LN) class III and IV of pediatric rheumatologists and nephrologists in Germany and Austria in preparation for a treat-to-target treatment protocol in LN., Methods: Survey study by members of the Society for Pediatric and Adolescent Rheumatology (GKJR) and the German Society for Pediatric Nephrology (GPN) on diagnostics and (concomitant) therapy of LN., Results: Fifty-eight physicians completed the survey. Overall, there was a considerable heterogeneity regarding the suggested diagnostics and management of juvenile proliferative LN. Increased urinary protein excretion, either assessed by 24 h urine collection or spot urine (protein-creatinine ratio), and reduced estimated glomerular filtration rate were specified as important parameters for indication of kidney biopsy to diagnose proliferative LN and monitoring of therapy. Corticosteroids were generally proposed for induction and maintenance therapy, most often in conjunction with either mycophenolate mofetil (MMF) or cyclophosphamide (CP) as steroid-sparing immunosuppressants. MMF was clearly preferred over CP for induction therapy of LN class III, whereas CP and MMF were equally proposed for LN class IV. MMF was most often recommended for maintenance therapy in conjunction with oral corticosteroids and continued for at least 3 years and 1 year, respectively, after remission. Hydroxychloroquine was widely accepted as a concomitant measure followed by renin-angiotensin system inhibitors in cases of arterial hypertension and/or proteinuria., Conclusion: The majority of pediatric rheumatologists and nephrologists in Germany and Austria propose the use of corticosteroids, most often in combination with either MMF or CP, for treatment of proliferative LN in children. The considerable heterogeneity of responses supports the need for a treat-to-target protocol for juvenile proliferative LN between pediatric rheumatologists and nephrologists., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Vollbach, Schuetz, Hedrich, Speth, Mönkemöller, Brunner, Neudorf, Rietschel, Hospach, Kallinich, Hinze, Wagner, Tönshoff, Weber, Latta, Thumfart, Bald, Wiemann, Zappel, Tenbrock and Haffner.)

Background: Therapeutic apheresis (TA) is based on the principles of either removing dissolved pathogenic substances (e.g., antibodies) from the blood plasma or replacing plasma factors. It expands the therapeutic scope for a variety of diseases. Safety analysis in the pediatric field are scant. The aim of this analysis was to analyze specific complications of TA modalities - plasma exchange (PE) and immunoadsorption (IA) - in children and adolescents., Methods: Children and adolescents ( n = 298) who had received TA from 2008 to 2018 in five pediatric nephrology centers were analyzed retrospectively. In total, 4.004 treatments (2.287 PE and 1.717 IA) were evaluated., Results: Indications for TA were mainly nephrological and neurological diseases. The three main indications were antibody-mediated graft rejection (13.4%), hemolytic uremic syndrome mainly with neurological involvement (12.8%), and AB0-incompatible transplantation (11.7%). Complications developed in 440 of the 4004 sessions (11%), of which one third were non-specific (nausea, headache). IA was better tolerated than PE. Complications were reported in 9.5% ( n = 163) of the IA versus 12.1% (277) of the PE sessions ( p < 0.001). When considering different types of complications, significantly more non-specific/non-allergic events ( p = 0.02) and allergic reactions occurred in PE sessions ( p < 0.001). More complications occurred with PE, when using fresh frozen plasma (16.2%; n = 145) in comparison to human albumin (14.5%; n = 115) ( p < 0.001)., Conclusions: Therapeutic apheresis in childhood and adolescence is a safe treatment procedure. IA showed a lower complication rate than PE. Therefore, IA may be preferably provided if the underlying disease pathomechanisms do not require PE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Taylan, Schaaf, Dorn, Schmitt, Loos, Kanzelmeyer, Pape, Müller, Weber and Thumfart.)

Children with infantile nephropathic cystinosis (INC), an inherited lysosomal storage disease resulting in cystine accumulation in all body cells, are prone to progressive chronic kidney disease (CKD), impaired growth and reduced weight gain; however, systematic anthropometric analyses are lacking. In this prospective multicenter study we investigated linear growth, body proportion, body mass index (BMI), upper arm fat area (UFA) and biochemical parameters in 43 pediatric INC patients with CKD stages 1 to 5 and 49 age-matched CKD controls, with 193 annual measurements. INC patients showed more impaired height than CKD controls (-1.8 vs -0.7 z-score; P < .001), despite adequate cysteamine therapy, treatment for Fanconi syndrome and more frequent use of growth hormone. Only the youngest INC patients shared the same body pattern with CKD controls characterized by preferential impairment of leg length and rather preserved trunk length. In late-prepuberty, body pattern changed only in INC patients due to improved leg growth and more impaired trunk length. Mean UFA z-score in INC patients was slightly reduced in early childhood and progressively decreased thereafter reaching -0.8 z-score in adolescence, while CKD controls showed a steady increase in standardized BMI and UFA especially during adolescent age. Menarche in female INC patients was significantly delayed compared to CKD controls. Our data indicate that with age and progression of disease, pediatric INC patients undergo unique changes of body growth and fat stores that are distinct from those with CKD stemming from other causes, suggesting other factors apart from CKD to contribute to this development. Pediatric patients with infantile nephropathic cystinosis display more severe impaired linear growth than other peer CKD patients, despite of cysteamine treatment, supplementation for Fanconi syndrome, and more frequent use of growth hormone, with a distinct change of body proportions and overall lower body fat., (© 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Autosomal recessive polycystic kidney disease (ARPKD) is a severe disease of early childhood that is clinically characterized by fibrocystic changes of the kidneys and the liver. The main cause of ARPKD are variants in the PKHD1 gene encoding the large transmembrane protein fibrocystin. The mechanisms underlying the observed clinical heterogeneity in ARPKD remain incompletely understood, partly due to the fact that genotype-phenotype correlations have been limited to the association of biallelic null variants in PKHD1 with the most severe phenotypes. In this observational study we analyzed a deep clinical dataset of 304 patients with ARPKD from two independent cohorts and identified novel genotype-phenotype correlations during childhood and adolescence. Biallelic null variants frequently show severe courses. Additionally, our data suggest that the affected region in PKHD1 is important in determining the phenotype. Patients with two missense variants affecting amino acids 709-1837 of fibrocystin or a missense variant in this region and a null variant less frequently developed chronic kidney failure, and patients with missense variants affecting amino acids 1838-2624 showed better hepatic outcome. Variants affecting amino acids 2625-4074 of fibrocystin were associated with poorer hepatic outcome. Thus, our data expand the understanding of genotype-phenotype correlations in pediatric ARPKD patients and can lay the foundation for more precise and personalized counselling and treatment approaches., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Hemolytic uremic syndrome caused by invasive pneumococcal disease (P-HUS) is rare in children and adolescents, but accompanied by high mortality in the acute phase and complicated by long-term renal sequelae. Abnormalities in the alternative complement pathway may additionally be contributing to the course of the disease but also to putative treatment options., Methods: Retrospective study to assess clinical course and laboratory data of the acute phase and outcome of children with P-HUS., Results: We report on seven children (median age 12 months, range 3-28 months) diagnosed with P-HUS. Primary organ manifestation was meningitis in four and pneumonia in three patients. All patients required dialysis which could be discontinued in five of them after a median of 25 days. In two patients, broad functional and genetic complement analysis was performed and revealed alternative pathway activation and risk haplotypes in both. Three patients were treated with the complement C5 inhibitor eculizumab. During a median follow-up time of 11.3 years, one patient died due to infectious complications after transplantation. Two patients showed no signs of renal sequelae., Conclusions: Although pathophysiology in P-HUS remains as yet incompletely understood, disordered complement regulation seems to provide a clue to additional insights for pathology, diagnosis, and even targeted treatment.