Search

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.

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.

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 analyse the validity of membrane-bound SIGLEC1 (CD169) as a sensitive biomarker for monitoring disease activity in pediatric systemic lupus erythematosus (SLE). Methods 27 children and adolescents with SLE were followed for a mean of 13.5 months. During consecutive routine visits SLEDAI-2k, C3, C4 and ds-DNA values were determined. Additionally, expression of SIGLEC1 on monocytes was determined by flow cytometry. The amount of PE-labelled CD169 mAb bound per monocyte was analyzed using QuantiBRITE™ PE tubes. Associations between biomarkers and the clinical course were investigated by regression analysis. Results In general, SIGLEC1 expression is high on SLE-derived monocytes (mean 6 359 (SD 6 056) molecules/monocyte, cut-off 2 500 molecules/monocyte), all patients with newly diagnosed SLE exhibit elevated expression (mean 13366 (SD 7 750) molecules/monocyte). Changes (Δ) in SIGLEC1 levels during the clinical course is the only biomarker that significantly correlates with the change in SLEDAI-2k (betaST = 0.28, p = 0.001). At follow-up visit, a clinically important worsening was experienced by 47.6% of patients with a Δ SIGLEC1 > 2 151 molecules/cell (OR 5.31) and 72.4% with a Δ SIGLEC1 > 756 molecules/cell (OR 8.90). Conversely, 36.4% of patients with a Δ SIGLEC1 Conclusions SIGLEC1 expression on monocytes is a sensitive biomarker for adjusting disease activity in childhood SLE and represents a promising and easily applicable tool for disease monitoring.

© 2022 International Society of NephrologyIntroduction: 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.

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.

Aim Children and adolescents with end-stage renal disease face a high morbidity and mortality. Palliative care provides a multidisciplinary approach to reduce disease burden and improve quality of life. This study evaluated concepts and current structures of palliative care from the perspective of a multidisciplinary paediatric nephrology team including physicians, nurses and psychosocial health professionals. Methods Evaluation was done by an online survey sent to the members of the German Society of Nephrology and to the nurse managers of German paediatric dialysis centres between April 9, 2018 and May 31, 2018. Results Out of the 52 respondents, 54% were physicians, 21% nurses and 25% psychosocial health professionals. The quality of actual palliative care service was rated as moderate (3.3 on a scale from one to six). Specialised palliative care teams (54%) and the caring paediatric nephrologist (50%) were considered as primarily responsible for palliative care. Two thirds wished for training in palliative care. In only 15% of the respondents' centres, palliative care specialisation existed. Conclusion Palliative care structures in paediatric nephrology were not sufficient in the view of the multidisciplinary healthcare team. Therefore, efforts should be taken to integrate palliative care into the routine treatment of children and adolescents with chronic kidney diseases.

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. German Society for Pediatric Nephrology (GPN); ESCAPE Network; European Society for Paediatric Nephrology (ESPN); German PKD foundation; Koeln Fortune program; GEROK program of the Medical Faculty of University of Cologne; Marga and Walter Boll-Foundation; German Federal Ministry of Research and Education (BMBF)Federal Ministry of Education & Research (BMBF) [01GM1515, 01GM1903]; working group CAKUT of the ESPN; working group Inherited Kidney Diseases of the ESPN We thank the German Society for Pediatric Nephrology (GPN) and the ESCAPE Network for their support. We thank Mr Mathias Burgmaier (Aachen) and Mr Samuel Kilian (Heidelberg) for support in conducting statistical analysis. ML was supported by grants of the GPN, the European Society for Paediatric Nephrology (ESPN), the German PKD foundation, the Koeln Fortune program, the GEROK program of the Medical Faculty of University of Cologne, and the Marga and Walter Boll-Foundation. FS, CB, and ML are supported by the German Federal Ministry of Research and Education (BMBF grant 01GM1515 and 01GM1903). KB was supported by the Koeln Fortune program and the GEROK program of the Medical Faculty of University of Cologne, as well as the Marga and Walter Boll-Foundation. This work was generated within the European Reference Network for Rare Kidney Disorders (ERKNet). The work was supported by the working groups CAKUT and Inherited Kidney Diseases of the ESPN.

Context Children with nephropathic cystinosis (NC) show persistent hypophosphatemia, due to Fanconi syndrome, as well as mineral and bone disorders related to chronic kidney disease (CKD); however, systematic analyses are lacking. Objective To compare biochemical parameters of bone and mineral metabolism between children with NC and controls across all stages of CKD. Design Cross-sectional multicenter study. Setting Hospital clinics. Patients Forty-nine children with NC, 80 CKD controls of the same age and CKD stage. Main outcome measures Fibroblast growth factor 23 (FGF23), soluble Klotho, bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase 5b (TRAP5b), sclerostin, osteoprotegerin (OPG), biochemical parameters related to mineral metabolism, and skeletal comorbidity. Results Despite Fanconi syndrome medication, NC patients showed an 11-fold increased risk of short stature, bone deformities, and/or requirement for skeletal surgery compared with CKD controls. This was associated with a higher frequency of risk factors such as hypophosphatemia, hypocalcemia, low parathyroid hormone (PTH), metabolic acidosis, and a specific CKD stage-dependent pattern of bone marker alterations. Pretransplant NC patients in mild to moderate CKD showed a delayed increase or lacked an increase in FGF23 and sclerostin, and increased BAP, TRAP5b, and OPG concentrations compared with CKD controls. Post-transplant, BAP and OPG returned to normal, TRAP5b further increased, whereas FGF23 and PTH were less elevated compared with CKD controls and associated with higher serum phosphate. Conclusions Patients with NC show more severe skeletal comorbidity associated with distinct CKD stage-dependent alterations of bone metabolism than CKD controls, suggesting impaired mineralization and increased bone resorption, which is only partially normalized after renal transplantation.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of end-stage renal disease in children and adolescents. The diversity of the malformations summarized by CAKUT is high and there are numerous associated syndromes. The genetic background of these malformations remains unknown in the majority of cases. The aim of this study was to evaluate factors associated with the development of chronic kidney disease (CKD) and underlying genetic aberrations in children and adolescents with CAKUT. For this purpose, data from patients with CAKUT presented at the pediatric nephrology outpatient clinic were analyzed in a cross-sectional single-center study. Among the 405 patients, the commonest findings related to CAKUT were renal hypoplasia/dysplasia (65%), followed by hydronephrosis (43%). Forty-four percent of the patients were suffering from CKD, 6% were ranked as end-stage renal disease. In the univariate analysis, male gender and premature birth were associated with higher CKD stages (p = 0.004 resp. p < 0.001). Children with an abnormal prenatal ultrasound had more often a glomerular filtration rate of

In patients on conventional hemodialysis (HD), morbidity is high and quality of life is poor. Intensified HD programs have been developed to help overcome these shortcomings, , but very few pediatric dialysis centers have reported the implementation of such a HD program.An online survey was sent to all 221 pediatric dialysis centers which participate in the International Pediatric Dialysis Network (IPDN). The aim of the survey was to assess the attitude of pediatric nephrologists towards intensified HD, the penetrance of intensified HD into their clinical practice and barriers to implementation.Of the 221 pediatric dialysis centers sent the survey, respondents from 61% (134) replied. Among these respondents, 69% acknowledged being aware of the evidence in support of the use of intensified HD, independent of whether intensified HD was offered at their own center, and 50% associated the use of daily nocturnal HD with the best overall patient outcome. In contrast, only 2% of respondents were in favor of conventional HD. Overall, 38% of the respondents stated that at their center intensified HD is prescribed to a subgroup of patients, most commonly in the form of short daily HD sessions. The most important barriers to expansion of intensified HD programs were lack of adequate funding (66%) and shortage of staff (63%), whereas lack of expertise and of motivation were reported infrequently as obstacles (21 and 14%, respectively).Intensified HD is considered by many pediatric nephrologists to be the dialysis modality most likely associated with the best patient outcome. The limited use of this treatment approach highlights the importance of defining and successfully addressing the barriers to implementation.

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.

PubMedID: 31010601 Rationale & Objective: Arteriovenous fistulas (AVFs) have been recommended as the preferred vascular access for pediatric patients on maintenance hemodialysis (HD), but data comparing AVFs with other access types are scant. We studied vascular access choice, placement, complications, and outcomes in children. Study Design: Prospective observational cohort study. Setting & Participants: 552 children and adolescents from 27 countries on maintenance HD followed up prospectively by the International Pediatric HD Network (IPHN) Registry between 2012 and 2017. Predictor: Type of vascular access: AVF, central venous catheter (CVC), or arteriovenous graft. Outcome: Infectious and noninfectious vascular access complication rates, dialysis performance, biochemical and hematologic parameters, and clinical outcomes. Analytical Approach: Univariate and multivariable linear mixed models, generalized linear mixed models, and proportional hazards models; cumulative incidence functions. Results: During 314 cumulative patient-years, 628 CVCs, 225 AVFs, and 17 arteriovenous grafts were placed. One-third of the children with an AVF required a temporary CVC until fistula maturation. Vascular access choice was associated with age and expectations for early transplantation. There was a 3-fold higher living related transplantation rate and lower median time to transplantation of 14 (IQR, 6-23) versus 20 (IQR, 14-36) months with CVCs compared with AVFs. Higher blood flow rates and Kt/Vurea were achieved with AVFs than with CVCs. Infectious complications were reported only with CVCs (1.3/1,000 catheter-days) and required vascular access replacement in 47%. CVC dysfunction rates were 2.5/1,000 catheter-days compared to 1.2/1,000 fistula-days. CVCs required 82% more revisions and almost 3-fold more vascular access replacements to a different site than AVFs (P < 0.001). Limitations: Clinical rather than population-based data. Conclusions: CVCs are the predominant vascular access choice in children receiving HD within the IPHN. Age-related anatomical limitations and expected early living related transplantation were associated with CVC use. CVCs were associated with poorer dialysis efficacy, higher complication rates, and more frequent need for vascular access replacement. Such findings call for a re-evaluation of pediatric CVC use and practices. © 2019 National Kidney Foundation, Inc. Baxter International Iran University of Medical Sciences Uniwersytet Jagiellonski Collegium Medicum Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Seoul National University United Arab Emirates University All-India Institute of Medical Sciences Great Ormond Street Hospital Charity National Rosacea Society Children's Hospital of Philadelphia Ankara University of Minnesota City, University of London: Gdansk We acknowledge the financial support of Baxter Health Care and Fresenius Medical Care. They were not involved in study design; collection, analysis, or interpretation of data; writing the report; or the decision to submit the report for publication. We thank Mr Rouven Behnisch for support in conducting statistical analyses. The following Principal Investigators are current contributors to the IPHN Registry. Argentina: P.A. Coccia (Hospital Italiano de Buenos Aires), A. Suarez (Hospital de Ninos Sor. Maria Ludovica La Plata), L. Alconcher (Hospital Interzonal General, Bahia Blanca); Canada: E. Harvey (Hospital for Sick Children, Toronto), C. White (BC Children's Hospital, Vancouver); Chile: F. Cano (Hospital Luis Calvo Mackenna, Santiago), M.A. Contreras (Roberto del Rio Hospital, Santiago); China: H. Xu (Children's Hospital of Fudan University, Shanghai); Colombia: J.J. Vanegas (Instituto del Rinon, Medellin), L.M. Higuita (Baxter Servicio al Cliente Colombia, Medellin); Czech Republic: K. Vondrak (University Hospital Motol, Prague); Finland: J. Lauronen (Hospital for Children and Adolescents, Helsinki); France: B. Ranchin (Hôpital Femme Mcre Enfant, Lyon), T. Ulinski (Armand Trousseau Hospital, Paris), S. Krid (Hopital Necker_Enfants Malades, Paris), M. Fischbach (Children's Dialysis Center, Strasbourg), Ch. Samaille (Hospital Jeanne de Frandre, Lille), M. Fila (Pediatric Nephrology Unit, Montpellier); Germany: D. Muller (Charité Virchow-Klinikum, Berlin), S. Habbig (University Hospital, Cologne), R. Büscher (Children's Hospital Essen), C.P. Schmitt (Center for Pediatrics and Adolescent Medicine, Heidelberg); G. Klaus (KfH Kidney Center, Marburg), H. Billing (Children's University Hospital, Tübingen); Greece: C. Stafanidis (A&P Kyriakou Children’s Hospital, Athens); Hungary: A.J. Szabo (Semmelweis University, Budapest); India: A. Bagga (All India Institute of Medical Sciences, New Delhi), B. Basu (NRS Medical College & Hospital, Kolkata), S. Sethi (The Medicity, Gurgaon); Iran: N. Hooman (Iran University of Medical Sciences, Tehran); Italy: E. Verrina (G. Gaslini Institute, Genova), S. Testa (Fondazione Ospedale Maggiore Policlinico, Milano), E. Vidal (Pediatric Nephrology, Dialysis and Transplant Unit, Padova), G. Leozappa (Department of Nefrologia-Urologia, Rome); Israel: D. Landau (Soroka Medical Center, Beer-Sheva); Korea: I.S. Ha (Seoul National University Children's Hospital, Seoul); Macedonia: E. Sahpazova (Pediatric Clinic, Skopje); Malaysia: Y.N. Lim (Kuala Lumpur Hospital, Kuala Lumpur); New Zealand: W. Wong (Starship Children's Hospital, Auckland); Nicaragua: Y. Silva (Hospital Infantil de Nicaragua, Managua); Oman: M. Al Ryami (Royal Hospital, Muscat); Peru: R. Loza Munarriz (Cayetano Heredia Hospital, Lima); Philippines: Z. Antonio (National Kidney and Transplant Institute, Quezon City); Poland: A.M. Zurowska, D. Borzych-Duzalka (Medical University, Gdansk); D. Drozdz (Jagiellonian University Medical College), S. Prokurat (Children's Memorial Health Institute, Warsaw), M. Szczepanska (Dialysis Division for Children, Zabrze); Saudi Arabia: J. Kari (King Abdul Aziz University Hospital, Jeddah); Serbia: D. Kruscic (University Children’s Hospital, Belgrade); Singapore: H.K. Yap (Shaw-NKF-NUH Children's Kidney Center); Spain: G. Ariceta (University Hospital Materno-Infantil Vall d'Hebron, Barcelona); Sweden: L. Swartz (Barnkliniken, Lund); Turkey: A. Bayazit (Cukrova University, Adana), A.S. Bakkaloglu (Hacettepe University, Ankara); S. Bakkaloglu (Gazi University, Ankara), I. Bilge (Department of Pediatric Nephrology, Çapa-Istanbul; Tepecik Children and Research Hospital, Izmir), S. Mir (Ege University Faculty of Medicine, Izmir-Bornova); United Arab Emirates: G. Kumar (Sheikh Khalifa Medical City, Abu Dhabi), L. Eid (Dubai Hospital, Dubai); E. Simkova (Al Jalila Hospital, Dubai); United Kingdom: R. Shroff (Great Ormond Street Hospital, London), C. Ried (Evelina Hospital, London); Uruguay: J. Grünberg (SE.N.NI.AD, Montevideo); United States: H. Patel (Children's Hospital, Columbus), B.A. Warady (Children's Mercy Hospital, Kansas City), M. Rheault (University of Minnesota, Amplatz Children's Hospital, Minneapolis), M. Pradhan (The Children's Hospital of Philadelphia, Philadelphia), J. Flynn (Seattle Children's Hospital, Seattle), C. Wong (Lucile Packard Children’s Hospital, Palo Alto).

Background: In Germany, practice patterns of conservative renal care (CRC), dialysis withdrawal (DW), and concomitant palliative care in patients who choose these options are unknown. Method: A survey was designed including 13 structured and one open questions on the management and frequency of CRC and DW, local palliative care structure, and fundamentals of the decision-making process, and addressed to the head physicians of all renal centers (n = 193) of a non-profit renal care provider (KfH – Kuratorium für Dialyse und Nierentransplantation, Neu-Isenburg, Germany). Results: Response rate was 62.2% (n = 122 centers) comprising 14,197 prevalent dialysis patients and 159,652 renal outpatients. Two-thirds of the respondents were men (85% in the age group between 45 and 64 years). Mean time of experience in renal medicine was 22.2 years in men, 20.8 years in women. 94% of all centers provided CRC with a different frequency and proportion of patients (mean 8.4% of the center population, median 5%, range 0–50%). Mean proportion of DW was 2.85% per year (median 2%, range 1–15%). Physicians and center features were not significantly associated with utilization of CRC or DW. Palliative care management varied including local palliative teams, support by general physicians, or by the renal team itself. Hospice care was only established in patients undergoing CRC. Fundamentals of the decision-making process were the desire of the patient (90% in CRC, 67% in DW). Patients undergoing CRC changed their opinion towards treatment modality “frequently” in 18% of the cases, “occasionally” in 73%. Physicians’ decisions were mostly driven by presumed fatal prognosis and poor physical or mental conditions of the individual patient. Different barriers to provide palliative care for the renal population like lack of education in palliative medicine, shortness of staff, lack of financial resources, and local palliative care structures were reported. Conclusion: Compared to international numbers, in Germany, proportion of CRC and DW reported by non-profit renal centers is in the lower range. Center practice of palliative care management varies and is driven by availability of local palliative care resources and presumably by attitudes of the renal teams. Quality of palliative care and the decision-making process need further evaluation.

Aims Intensified hemodialysis (HD) programs have been developed to overcome the shortcomings of conventional HD. However, there are no data on the implementation of intensified HD programs into routine care. Therefore, we investigated the attitude of nephrologists towards intensified HD, its penetrance into clinical practice, and barriers to implementation. Materials and methods We performed an online survey within the German Society of Nephrology on the beliefs and attitudes towards intensified HD. Results 44% of the respondents believe that there is sufficient evidence in favor of intensified HD independent of whether the respondent offers intensified HD or not. Before expanding intensified HD, adequate funding (81%) and more staff (60%) are needed. 44% of the respondents offer intensified HD to their patients. The offer of intensified HD is made to the patients mainly if the patient is not adequately treated with conventional HD (50%); only 19% offer it routinely to all patients with CKD stage 4, in preparation for renal replacement therapy. 33% of the respondents offer short daily HD, 70% nocturnal intermittent, and 4% daily nocturnal. In 30% of the respondent centers, intensified dialysis is performed at home. Conclusion Nearly one-half of the respondents already offer intensified HD. Inappropriate funding of intensified HD programs represents the most important barrier for further implementation. .

HNF1B gene mutations are an important cause of bilateral (cystic) dysplasia in children, complicated by chronic renal insufficiency. The clinical variability, the absence of genotype-phenotype correlations, and limited long-term data render counseling of affected families difficult. Longitudinal data of 62 children probands with genetically proven HNF1B nephropathy was obtained in a multicenter approach. Genetic family cascade screening was performed in 30/62 cases. Eighty-seven percent of patients had bilateral dysplasia, 74% visible bilateral, and 16% unilateral renal cysts at the end of observation. Cyst development was non-progressive in 72% with a mean glomerular filtration rate (GFR) loss of − 0.33 ml/min/1.73m2 per year (± 8.9). In patients with an increase in cyst number, the annual GFR reduction was − 2.8 ml/min/1.73m2 (± 13.2), in the total cohort − 1.0 ml/min/1.73m2 (±10.3). A subset of HNF1B patients differs from this group and develops end stage renal disease (ESRD) at very early ages

Membranoproliferative glomerulonephritis (MPGN) is a rare cause of glomerulopathy in children. Recently, a new classification based on immunohistological features has been established. Infections and anomalies in complement-regulating genes, leading to alternative complement pathway activation, are suspected to trigger the disease. Nevertheless, little is known about optimal treatment and outcome in children with immune-complex-MPGN (IC-MPGN) and C3-glomerulopathy (C3G). The method used is retrospective analysis of clinical, histological, and genetic characteristics of 14 pediatric patients with MPGN in two medical centers. Mean age of the patients was 10.6 ± 4.5 years. Patients were grouped into C3G (n = 6) and IC-MPGN (n = 8). One patient showed a likely pathogenic variant in the CFHR5 gene. All 10 patients had risk polymorphisms in complement-regulating genes. Most patients were treated with ACE inhibition, steroids, and mycophenolate mofetil. Three patients with C3G received eculizumab. Median follow-up was 2.3 years. After 1 year of disease, three patients (two C3G, one IC-MPGN) reached complete, five patients partial (three IC-MPGN, two C3G), and five patients no remission (four IC-MPGN, one C3G). One patient progressed to end-stage renal disease (ESRD) 6 years after disease onset. IC-MPGN and C3G are rare disorders in children. Most patients have signs of complement activation associated with risk polymorphisms or likely pathogenic variants in complement-regulating genes. Steroids and mycophenolate mofetil seem to be effective and for some patients, eculizumab might be a treatment option. Outcome is heterogeneous and precise differentiation between IC-MPGN and C3G is still pending.

Introduction SIGLEC1 (sialic acid-binding Ig-like lectin 1, CD169) is a monocytic adhesion molecule induced by interferon – α. In adult systemic lupus erythematosus (SLE), SIGLEC1 correlates cross-sectionally and longitudinally with disease activity. The aim of this work was to examine whether SIGLEC1 also reflects the disease activity in paediatric SLE. Methods Over a period of 29 months the disease activity was clinically evaluated using SLEDAI (SLE-Disease Activity Index-2000). In 28 consecutive paediatric SLE patients (mean age 16 years, range 3–38 years, 86% female, 14% male), the number of SIGLEC1 molecules per CD14 +on blood monocyte was quantified using flow cytometry. At the same time, the level of anti-ds DNA-antibody titer (ELISA) and the concentration of complement factors C3 and C4 (nephelometry) were determined. The association between SIGLEC1, C3, C4 and ds DNA-antibody with SLEDAI was estimated using a mixed linear model to model the repeated measurement of parameters within a patient. The cut-off for the change in SIGLEC1 between two consecutive visits to predict minimal clinical improvement or worsening in SLEDAI was chosen on the maximum Youden Index. Results The density of SIGLEC1 molecules on the surface of monocytes based on two visits, correlated with the SLEDAI (128 determinations, betaST 0.22, p 1120 molecules/monocyte between two visits show a higher probability (OR=7.0, p 2902 SIGLEC1 molecules/monocyte have a higher chance (OR=6.3, p=0.004) to have a clinical improvement (SLEDAI more/equal 2 points). Conclusion This prospective cohort study showed for the first time the significant relationship between the routinely measured interferon biomarker SIGLEC1 and the disease activity in paediatric SLE patients. Thus, SIGLEC1 represents a potential marker for activity monitoring in this disease.

OBJECTIVE: To identify prenatal, perinatal, and postnatal risk factors for dialysis within the first year of life in children with autosomal recessive polycystic kidney disease (ARPKD) as a basis for parental counseling after prenatal and perinatal diagnosis. STUDY DESIGN: A dataset comprising 385 patients from the ARegPKD international registry study was analyzed for potential risk markers for dialysis during the first year of life. RESULTS: Thirty-six out of 385 children (9.4%) commenced dialysis in the first year of life. According to multivariable Cox regression analysis, the presence of oligohydramnios or anhydramnios, prenatal kidney enlargement, a low Apgar score, and the need for postnatal breathing support were independently associated with an increased hazard ratio for requiring dialysis within the first year of life. The increased risk associated with Apgar score and perinatal assisted breathing was time-dependent and vanished after 5 and 8 months of life, respectively. The predicted probabilities for early dialysis varied from 1.5% (95% CI, 0.5%-4.1%) for patients with ARPKD with no prenatal sonographic abnormalities to 32.3% (95% CI, 22.2%-44.5%) in cases of documented oligohydramnios or anhydramnios, renal cysts, and enlarged kidneys. CONCLUSIONS: This study, which identified risk factors associated with onset of dialysis in ARPKD in the first year of life, may be helpful in prenatal parental counseling in cases of suspected ARPKD. ispartof: JOURNAL OF PEDIATRICS vol:199 pages:22-+ ispartof: location:United States status: published

Background/Aims: Whether the immunosuppressive regimen is associated with micro- and macro-vascular status in pediatric kidney transplant recipients (KTx) is unknown. Methods: We performed a cross-sectional, case-control study in 44 pediatric KTx patients on either everolimus (EVR) plus calcineurin inhibitor or standard treatment, i.e. mycophenolate mofetil plus calcineurin inhibitor. Measurement of carotid intima-media thickness (cIMT) via ultrasound, central pulse wave velocity (PWV) by a cuff-based oscillometric technique, and skin microvascular blood flow during local heating via laser-Doppler-fluximetry (LDF) served as marker of subclinical vascular disease. Serum concentrations of angiopoietin-1 and -2, fibroblast-growth factor 23 (FGF23) and soluble klotho were measured. Results: EVR-treated patients exhibited a similar degree of hypertension, increased cIMT, elevated pro-inflammatory angiopoietin-2, and diminished endothelial survival factor angiopoietin-1 compared to healthy children but presented with a twofold more reduced skin micro-vascular function compared to standard treatment (each p< 0.001). By contrast, PWV and soluble klotho levels were normal in both groups. Conclusion: Endothelial dysfunction seems more frequent in KTx patients on EVR-based immunosuppressive regimen compared to standard immunosuppression.

Claudin-16 protein (CLDN16) is a component of tight junctions (TJ) with a restrictive distribution so far demonstrated mainly in the kidney. Here, we demonstrate the expression of CLDN16 also in the tooth germ and show that claudin-16 gene (CLDN16) mutations result in amelogenesis imperfecta (AI) in the 5 studied patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). To investigate the role of CLDN16 in tooth formation, we studied a murine model of FHHNC and showed that CLDN16 deficiency led to altered secretory ameloblast TJ structure, lowering of extracellular pH in the forming enamel matrix, and abnormal enamel matrix protein processing, resulting in an enamel phenotype closely resembling human AI. This study unravels an association of FHHNC owing to CLDN16 mutations with AI, which is directly related to the loss of function of CLDN16 during amelogenesis. Overall, this study indicates for the first time the importance of a TJ protein in tooth formation and underlines the need to establish a specific dental follow-up for these patients.

Peritoneal dialysis (PD) or conventional hemodialysis (HD) are considered to be equally efficient dialysis methods in children and adolescents. The aim of our study was to analyze whether an intensified, nocturnal HD program (NHD) is superior to PD in an adolescent cohort.Thirteen patients were prospectively enrolled in a NHD program. We measured uremia-associated parameters, parameters for nutrition, medication and blood pressure and analyzed the data. These data were compared to those of 13 PD controls, matched for gender, age and weight at the beginning the respective dialysis program and after 6 months of treatment.Serum phosphate levels decreased significantly in the NHD group and remained unchanged in the PD group. Arterial blood pressure in the NHD was significantly lower despite the reduction of antihypertensive treatment, whereas blood pressure levels remained unchanged in the PD controls. Preexisting left ventricular hypertrophy resolved and albumin levels improved with NHD. Dietary restrictions could be lifted for those on NHD, whereas they remained in place for the patients on PD treatment. Residual diuresis remained unchanged after 6 months of either NHD or PD. NHD patients experienced fewer days of hospitalization than the PD controls.Based on our results, NHD results in significantly improved parameters of uremia and nutrition. If individually and logistically possible, NHD should be the treatment modality of preference for older children and adolescents.

Paediatric palliative care is no longer restricted to patients with cancer and has been extended to patients with other chronic conditions, such as cystic fibrosis or neuromuscular disorders. This review focused on the current state of palliative care for children and adolescents with chronic kidney disease (CKD). We assessed the literature on CKD published up to August 2017. All the papers, except one from 1996, were published this century. This review discusses the role that palliative care plays in the process of decision-making and explores the possibilities of implementing palliative care into the routine therapy of affected patients and providing support for their families. Offering early palliative care as an integral part of the kidney, supportive care provided by the nephrology care team is both necessary and feasible for patients with CKD. As a minimum, a specialised palliative care team should be involved in patients with multiple comorbidities, in conservative treatment scenarios and in acute life-threatening complications. Further studies and guidelines are required to improve the care of patients with CKD and their families. CONCLUSION Supportive palliative care should be implemented into the routine care of patients with life-limiting kidney disease.

Background Assisted home dialysis (AHD) is an option to combine the benefits of home dialysis therapy with the needs of dialysis patients who are unable to perform self-treatment at home. While this method is growing in many countries worldwide, no data so far are reported for Germany. Methods A survey was designed to identify the barriers to the implementation of AHD with the focus on attitudes and beliefs concerning AHD. The survey was sent to all 2060 members of the Germany Society of Nephrology. Results The response rate was 14% of nephrologists (n = 286), representing 24% of all German centres. AHD was regarded as a highly meaningful option (>90% of all responding nephrologists). Fifty-five percent of the centres practice AHD (preferred peritoneal dialysis). The number of treated patients on AHD was small (77% of the centres treat no more than 10 patients). The nephrologists in centres that performed AHD were of older age and the number of dialysis patients treated in these centres was greater. AHD was offered in 57% of centres at chronic kidney disease Stage 4. Inadequate conventional dialysis and patient’s request were reasons for choosing AHD. Barriers for offering AHD were lack of reimbursement, shortage of staff, lack of expertise and lack of team motivation. Conclusions In the view of German nephrologists, AHD is a meaningful method to provide home dialysis care. Inadequate funding and a lack of qualified staff were identified as severe barriers to implementation of AHD. To overcome these barriers and to achieve a higher penetration of AHD, dedicated actions have to be considered. Further studies are needed to prove the AHD concept with regard to outcome effects and cost efficacy.

Preemptive renal transplantation is the method of choice for end stage renal disease in childhood and adolescence. However, without preemptive transplantation, waiting time for kidney transplantation might exceed several years. The poor quality of life and the extremely high morbidity and mortality rates of dialysis patients have led to the development of intensified hemodialysis programs in which the modes of dialysis (short daily, nocturnal intermittent or daily nocturnal) are different. Such programs have been shown to significantly improve several uremia-associated parameters, such as blood pressure, phosphate control, anemia and growth retardation, in both adult and pediatric (children and adolescents) patients and lead to a reduction in medications, including phosphate binders, erythropoietin and antihypertensive agents. Fluid limitations and dietary restrictions can also be lifted. With respect to psychosocial rehabilitation and quality of life, nocturnal intermittent dialysis programs provide a reasonable compromise of all forms of intensified programs. Experiences and practical approaches of our own in-center nocturnal intermittent hemodialysis program in the light of the recent publications are described in this review.

Case report We report on a male patient with Tuberous Sclerosis Complex (TSC), which was prenatally diagnosed. At the age of 3 months the patient developed acute renal failure with excessive hyperuricemia. Kidney function improved after rehydration and application of rasburicase, however without full recovery. Due to the inappropriate high levels of uric acid compared to kidney function, screening of hypoxanthine-guanine phosphoribosyltransferase (HPRT) related diseases was initiated. Mutation analysis revealed a deletion of exon 2 and 3 of the HPRT gene confirming the diagnosis of Lesch-Nyhan Disease (LND). After initiation of allopurinol therapy renal function further improved. In the following months the patient developed clinically a typical neurological phenotype of LND and TSC with seizures, severe dystonia and developmental delay. Conclusion Acute renal failure is a rare complication of HPRT related diseases. Combination of two inherited diseases may lead to a delayed diagnosis due to a mixed and maybe misleading phenotype.

Transition from child to adult-oriented care is widely regarded a challenging period for young people with kidney transplants and is associated with a high risk of graft failure. We analyzed the existing transition structures in Germany and Austria using a questionnaire and retrospective data of 119 patients transferred in 2011 to 2012. Most centers (73%) confirmed agreements on the transition procedure. Patients’ age at transfer was subject to regulation in 73% (18 years). Median age at transition was 18.3 years (16.5–36.7). Median serum creatinine increased from 123 to 132 μmol/L over the 12 month observation period before transfer (P = 0.002). A total of 25/119 patients showed increased creatinine ≥20% just before transfer. Biopsy proven rejection was found in 10/119 patients. Three patients lost their graft due to chronic graft nephropathy. Mean coefficient of variation (CoV%) of immunosuppression levels was 0.20 ± 0.1. Increased creatinine levels ≥20% just before transfer were less frequently seen in patients with CoV

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.

Das hamolytisch-uramische Syndrom (HUS) ist mit die haufigste Ursache des akuten Nierenversagens im Kindesalter. Es besteht aus der Trias Coombs-negative akute Hamolyse, Thrombozytopenie und akutem Nierenversagen. Das HUS stellt eine heterogene Gruppe mit unterschiedlicher Pathogenese und Verlaufsform dar. Histologisch ist allen Formen die thrombotische Mikroangiopathie (TMA) gemeinsam. Aus therapeutischer und prognostischer Sicht hat es sich in der Padiatrie bewahrt, das HUS in das klassische, diarrhoassoziierte HUS (D+ HUS) und das atypische, nicht diarrhoassoziierte HUS (D− HUS) einzuteilen. Dabei liegt im Kindesalter in uber 90% aller Falle ein D+ HUS vor. Obwohl in den letzten Jahren zahlreiche Ursachen des D− HUS identifiziert werden konnten, bleibt ein groser Teil der Falle pathogenetisch immer noch unklar. Wahrend das D+ HUS eine insgesamt gute Prognose hat, ist die des D− HUS eher ungunstig. Im vorliegenden Beitrag werden die verschiedenen Formen des HUS im Hinblick auf Atiologie, therapeutische Optionen und Prognose erlautert.

Die Ursachen der terminalen Niereninsuffizienz im Kindesalter unterscheiden sich deutlich von denen des Erwachsenenalters. Die Therapie der Wahl besteht in der Nierentransplantation. In Deutschland wurden im Jahre 2003 117 Kinder und Jugendliche nierentransplantiert. Spezifische Probleme bestehen in der Immunsuppression und den daraus resultierenden Komorbiditaten im Kindesalter. Der vorliegende Beitrag gibt eine Ubersicht uber die Moglichkeiten und Probleme der Vorbereitung, der Transplantation und des weiteren Verlaufs von Nierentransplantationen im Kindesalter.

Germline heterozygous missense mutations in the Wilms’ tumour suppressor gene 1 (WT1) cause Denys–Drash Syndrome (DDS), which is characterized by a progressive glomerulopathy (mainly diffuse mesangial sclerosis), genital abnormalities in genotypic males and a predisposition to Wilms’ tumour [1]. The protein exerts its function as a tissue-specific zinc finger transcription factor by binding to the promoter of its target genes and, thus, regulating their transcription. Loss of WT1 function through mutations results in the misregulation of these target genes and, subsequently, in developmental defects. The expression pattern of WT1 mRNA together with data obtained from WT1 deficient mice indicate that the function of the gene is not restricted to the urogenital system, but involves the development of other organs, such as spleen, adrenal glands, heart, mesothelium, spinal cord and brain [2–5]. We report a novel germline WT1 missense mutation in a genotypic male patient with DDS and cerebral atrophy.

Purpose: Desmopressin is widely used in primary nocturnal enuresis, bleeding disorders, central diabetes insipidus and diagnostic urine concentration testing. Hyponatremic hypervolemia leading to seizures has been reported as a rare but potentially life threatening side effect of desmopressin therapy. We sought to identify factors that predispose patients to hyponatremia and to find predictive factors associated with increased risk of water intoxication. Materials and Methods: We report 13 novel cases of desmopressin associated water intoxication and review the literature. A total of 93 instances of symptomatic hyponatremia during desmopressin treatment in children were identified. Specific data were reported in 58 of 93 cases. These 58 cases, in addition to our 13 novel cases, were further analyzed. Results: All children were treated with intranasal or intravenous desmopressin. No patient received oral desmopressin. Younger children are at greater risk for water intoxication than older children. The risk is particularly high at the beginning of desmopressin therapy. A total of 45 patients (63%) had prodromal symptoms, eg nausea, vomiting and headache. In 10 cases (14%) desmopressin was prescribed without an evident need. Conclusions: Based on this analysis, we conclude that the use of desmopressin should be cautiously considered, careful monitoring should be performed during the initiation of therapy, and particular care should be taken when treating young children and when prodromal symptoms such as nausea, vomiting and headaches occur.

Sarcoidosis is a systemic disease with multiorgan involvement. In children, renal impairment of sarcoidosis usually is caused by either hypercalcemia leading to nephrocalcinosis or interstitial nephritis with or without granulomata. We report the case of a 13-year-old boy presenting with severe arterial hypertension and acute renal failure caused by an isolated sarcoid granulomatous interstitial nephritis (GIN). Other known causes of GIN, eg, drug intake or fungal or mycobacterial infection, were excluded, and there was no evidence of extrarenal sarcoid involvement. Renal function improved initially with prednisone treatment. Blood pressure was controlled using ramipril, nifedipine, furosemide, dihydralazine, and metoprolol. Later, the patient showed signs of severe steroid toxicity and progressive renal failure. Monthly treatment with infliximab, a tumor necrosis factor-alpha antibody, was started, resulting in steady improvement in renal function and resolution of renal granulomata. In addition, antihypertensive medication could be reduced, and low-dose prednisone therapy was maintained. To our knowledge, this is the first report of successful treatment with infliximab of a patient with sarcoid GIN.

Objectives It is known that transition, as a shift of care, marks a vulnerable phase in the adolescents’ lives with an increased risk for non-adherence and allograft failure. Still, the transition process of adolescents and young adults living with a kidney transplant in Germany is not well defined. The present research aims to assess transition-relevant structures for this group of young people. Special attention is paid to the timing of the process. Setting In an observational study, we visited 21 departments of paediatric nephrology in Germany. Participants were doctors (n=19), nurses (n=14) and psychosocial staff (n=16) who were responsible for transition in the relevant centres. Structural elements were surveyed using a short questionnaire. The experiential viewpoint was collected by interviews which were transcribedverbatim before thematic analysis was performed. Results This study highlights that professionals working within paediatric nephrology in Germany are well aware of the importance of successful transition. Key elements of transitional care are well understood and mutually agreed on. Nonetheless, implementation within daily routine seems challenging, and the absence of written, structured procedures may hamper successful transition. Conclusions While professionals aim for an individual timing of transfer based on medical, social, emotional and structural aspects, rigid regulations on transfer age as given by the relevant health authorities add on to the challenge. Trial registration number ISRCTN Registry no 22988897; results (phase I) and pre-results (phase II).

There are nearly 70 000 dialysis patients in Germany (1). These patients need comprehensive interdisciplinary care. Their morbidity and mortality are elevated in comparison with the normal population, especially in younger and intermediate age groups (2). The life expectancy of patients with end-stage renal failure depends on the method used to compensate for the lack of renal function. Patients who have undergone renal transplantation (mortality 3.8 per 100 patient-years) live longer, on average, than dialysis patients on a transplant waiting list (mortality 6.3 per 100 patient-years) (3). Transplantation, however, is not an option for all patients. There are markedly fewer organ donors than potential recipients, and fewer than one-third of all dialysis patients are reported to EUROTRANSPLANT for placement on a waiting list (4). Improved dialysis methods therefore seems all the more important. In Germany, conventional hemodialysis is performed in a dialysis center—or, in rare cases, at home—for 4 to 5 hours, 3 or 4 days a week. This form of treatment often cannot adequately compensate for the sequelae of chronic renal failure, such as disordered calcium/phosphate metabolism, renal osteopathy, malnutrition, arterial hypertension, and uremic vasculopathy, even if the patient is simultaneously treated with dietary restrictions (potassium, phosphate), fluid restriction, and drugs (5– 7). The effects of chronic renal failure on the cardiovascular system, most prominently uremic cardiomyopathy and vasculopathy, are the main causes of high morbidity and mortality in dialysis patients (8, 9). These patients’ social life is often severely restricted. For many, normal participation at work or in school is all but impossible. Eknoyan et al. showed that modifying the technique of hemodialysis by, e.g., increasing blood flow or using high-flux filters does not lower mortality in hemodialysis patients (10). Other dialysis techniques, such as continuous, ambulatory peritoneal dialysis (CAPD), seem to lower mortality at the onset of dialysis treatment (11). It remains unclear from the available evidence whether hemodiafiltration also lowers mortality (12– 14).

To overcome the deleterious consequences of conventional dialysis, intensified dialysis programs have been developed and their feasibility and beneficial effects in children demonstrated. To investigate whether such a program can be further improved, we implemented hemodialfiltration within an established pediatric in-center, nocturnal hemodialysis program. After being started on conventional hemodialysis (HD), seven patients were switched to intermittent nocturnal hemodialysis (NHD) for 3 months, then to intermittent nocturnal online-hemodiafiltration (NHDF) for a further 3 months and finally back to NHD. Uremia-associated parameters, predialytic blood pressure, intradialytic events, protein catabolic rate and levels of albumin, vitamins and trace elements were investigated. Dialysis-related medication and dietary restrictions were also registered. Phosphate and intact parathyroid hormone levels were reduced after the switch from HD to NHD and NHDF. Dialysis dose (Kt/V) was increased in patients on NHD and NHDF; however, Kt/V was significantly higher with NHDF than NHD. Blood pressure was significantly reduced in patients on NHD and NHDF despite the reduction in antihypertensive medication; albumin levels were significantly higher on NHD and NHDF, indicating improved nutritional status; protein catabolic rate was also increased. Vitamins and trace elements remained unchanged. All dietary restrictions could be lifted in patients on NHD and NHDF. The introduction of a nocturnal dialysis program to an existing intensified HD program significantly improved the uremia-associated parameters, nutrition and hemodynamic stability of our seven patients. At least during our observational period, hemodiafiltration was able to further improve the existing HD program by increasing the Kt/v.

Item does not contain fulltext Familial hypomagnesemia is a rare human disorder caused by renal or intestinal magnesium (Mg(2+)) wasting, which may lead to symptoms of Mg(2+) depletion such as tetany, seizures, and cardiac arrhythmias. Our knowledge of the physiology of Mg(2+) (re)absorption, particularly the luminal uptake of Mg(2+) along the nephron, has benefitted from positional cloning approaches in families with Mg(2+) reabsorption disorders; however, basolateral Mg(2+) transport and its regulation are still poorly understood. Here, by using a candidate screening approach, we identified CNNM2 as a gene involved in renal Mg(2+) handling in patients of two unrelated families with unexplained dominant hypomagnesemia. In the kidney, CNNM2 was predominantly found along the basolateral membrane of distal tubular segments involved in Mg(2+) reabsorption. The basolateral localization of endogenous and recombinant CNNM2 was confirmed in epithelial kidney cell lines. Electrophysiological analysis showed that CNNM2 mediated Mg(2+)-sensitive Na(+) currents that were significantly diminished in mutant protein and were blocked by increased extracellular Mg(2+) concentrations. Our data support the findings of a recent genome-wide association study showing the CNNM2 locus to be associated with serum Mg(2+) concentrations. The mutations found in CNNM2, its observed sensitivity to extracellular Mg(2+), and its basolateral localization signify a critical role for CNNM2 in epithelial Mg(2+) transport.

Claudin-16 (CLDN16) is critical for renal paracellular epithelial transport of Ca2+and Mg2+in the thick ascending loop of Henle. To gain novel insights into the role of CLDN16 in renal Ca2+and Mg2+homeostasis and the pathological mechanisms underlying a human disease associated with CLDN16 dysfunction [familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), OMIM 248250], we generated a mouse model of CLDN16 deficiency. Similar to patients, CLDN16-deficient mice displayed hypercalciuria and hypomagnesemia. Contrary to FHHNC patients, nephrocalcinosis was absent in our model, indicating the existence of compensatory pathways in ion handling in this model. In line with the renal loss of Ca2+, compensatory mechanisms like parathyroid hormone and 1,25(OH)2D3were significantly elevated. Also, gene expression profiling revealed transcriptional upregulation of several Ca2+and Mg2+transport systems including Trpv5, Trpm6, and calbindin-D9k. Induced gene expression was also seen for the transcripts of two putative Mg2+transport proteins, Cnnm2 and Atp13a4. Moreover, urinary pH was significantly lower when compared with wild-type mice. Taken together, our findings demonstrate that loss of CLDN16 activity leads to specific alterations in Ca2+and Mg2+homeostasis and that CLDN16-deficient mice represent a useful model to further elucidate pathways involved in renal Ca2+and Mg2+handling.

In the kidney, ∼80% of the filtered phosphate (Pi) is reabsorbed along the proximal tubule. Changes in renal Pireabsorption are associated with modulation of the sodium-dependent Picotransporter type IIa (NaPi-IIa) and type IIc (NaPi-IIc) protein abundance in the brush-border membrane (BBM) of proximal tubule cells. NaPi-IIa is mainly regulated by dietary Piintake and parathyroid hormone (PTH). The purpose of the present study was to elucidate the effect of alteration in dietary magnesium (Mg2+) intake on renal Pihandling. Urinary Piexcretion and renal expression of NaPi-IIa and NaPi-IIc were analyzed in rats fed a normal (0.2%) or high-Mg2+(2.5%) diet. A high-Mg2+diet resulted in decreased renal Piexcretion and increased protein expression of NaPi-IIa and NaPi-IIc. Serum FGF-23 (fibroblast growth factor 23) levels were unchanged under a high-Mg2+diet. Serum PTH levels were slightly decreased under a high-Mg2+diet. To examine whether the observed changes in renal Pireabsorption are PTH dependent, expression of NaPi-IIa and NaPi-IIc was also analyzed in parathyroidectomized (PTX) rats fed a normal or high-Mg2+diet. In PTX rats, Mg2+had no significant effect on renal Piexcretion or NaPi-IIa protein expression. Mg2+increased NaPi-IIc protein expression in PTX rats. This experiment shows for the first time on the molecular level how Mg2+stimulates renal Pireabsorption. Under a high-Mg2+diet, NaPi-IIa expression is dependent on PTH levels, whereas NaPi-IIc expression seems to be independent of PTH levels.