Acute kidney injury in lamotrigine-induced DRESS syndrome.

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.

Chest configuration in children and adolescents with infantile nephropathic cystinosis compared with other chronic kidney disease entities and its clinical determinants.

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.

Biallelic known and novel DCDC2 variants in cholestatic liver disease: Phenotype-genotype observations in four children.

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.

Do We Need Palliative Care in Pediatric Nephrology? Patients' and Caregivers' Disease Experience.

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.

Refining Kidney Survival in 383 Genetically Characterized Patients With Nephronophthisis.

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.

SARS-CoV2 mRNA Vaccine-Specific B-, T- and Humoral Responses in Adolescents After Kidney Transplantation.

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.

Phenotypic Variability in Siblings With Autosomal Recessive Polycystic Kidney Disease.

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.

Safety of Therapeutic Apheresis in Children and Adolescents.

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.

Working Towards a Treat-to-Target Protocol in Juvenile Proliferative Lupus Nephritis - A Survey of Pediatric Rheumatologists and Nephrologists in Germany and Austria.

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.

Modified Zipper Method, a Promising Treatment Option in Severe Pediatric Immune-Mediated Neurologic Disorders.

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.

Body growth, upper arm fat area, and clinical parameters in children with nephropathic cystinosis compared with other pediatric chronic kidney disease entities.

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.

Refining genotype-phenotype correlations in 304 patients with autosomal recessive polycystic kidney disease and PKHD1 gene variants.

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.

Complement activation in children with Streptococcus pneumoniae associated hemolytic uremic syndrome.

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.

SIGLEC1 (CD169) is a sensitive biomarker for the deterioration of the clinical course in childhood systemic lupus erythematosus.

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 < -2 818 molecules/cell (OR 4.16, percentiles as cut-off criteria) and 50.0% of patients with a Δ SIGLEC1 < -1 370 molecules/cell (OR 3.55, application of Youden index) showed clinical improvement. SIGLEC1 expression correlates inversely with the amount of therapeutically applied hydroxychloroquine (p < 0.001). 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.

Factors Associated With the Development of Chronic Kidney Disease in Children With Congenital Anomalies of the Kidney and Urinary Tract.

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 <30 ml/min/1.73 m2 (p = 0.004). Patients with urinary tract infections as first symptom whereas had significant lower CKD stages (p = 0,006). In the multivariate analysis, premature birth (p = 0.033) and urinary tract infection as the first symptom (p = 0.043) were significantly associated with CKD stage ≥ II. Among the 16% of the children who have undergone genetic analyses the most frequent genetic aberration was a mutation in HNF1ß-gene. These results can be used for the care of patients with CAKUT subject to factors associated with developing CKD.

Bone and Mineral Metabolism in Children with Nephropathic Cystinosis Compared with other CKD Entities.

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.

Conservative Care, Dialysis Withdrawal, and Palliative Care: Results from a Survey of a Non-Profit Dialysis Provider in Germany.

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.

Vascular Access Choice, Complications, and Outcomes in Children on Maintenance Hemodialysis: Findings From the International Pediatric Hemodialysis Network (IPHN) Registry.

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.

Treatment and long-term outcome in primary distal renal tubular acidosis.

BACKGROUND: Primary distal renal tubular acidosis (dRTA) is a rare disorder, and we aimed to gather data on treatment and long-term outcome. METHODS: We contacted paediatric and adult nephrologists through European professional organizations. Responding clinicians entered demographic, biochemical, genetic and clinical data in an online form. RESULTS: Adequate data were collected on 340 patients (29 countries, female 52%). Mutation testing had been performed on 206 patients (61%); pathogenic mutations were identified in 170 patients (83%). The median (range) presentation age was 0.5 (0-54) years and age at last follow-up was 11.0 (0-70.0) years. Adult height was slightly below average with a mean (SD score) of -0.57 (±1.16). There was an increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (35%) and adults (82%). Nephrocalcinosis was reported in 88%. Nephrolithiasis was more common with SLC4A1 mutations (42% versus 21%). Thirty-six percent had hearing loss, particularly in ATP6V1B1 (88%). The median (interquartile range) prescribed dose of alkali (mEq/kg/day) was 1.9 (1.2-3.3). Adequate metabolic control (normal plasma bicarbonate and normocalciuria) was achieved in 158 patients (51%), more commonly in countries with higher gross domestic product (67% versus 23%), and was associated with higher height and estimated glomerular filtration rate. CONCLUSION: Long-term follow-up from this large dRTA cohort shows an overall favourable outcome with normal adult height for most and no patient with CKD Stage 5. However, 82% of adult patients have CKD Stages 2-4. Importance of adequate metabolic control was highlighted by better growth and renal function but was achieved in only half of patients.

HNF1B nephropathy has a slow-progressive phenotype in childhood-with the exception of very early onset cases: results of the German Multicenter HNF1B Childhood Registry.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 < 2 years. Hyperuricemia (37%) was a frequent finding at young age (median 1 year), whereas hypomagnesemia (24%), elevated liver enzymes (21%), and hyperglycemia (8%) showed an increased incidence in the teenaged child. Genetic analysis revealed no genotype-phenotype correlations but a significant parent-of-origin effect with a preponderance of 81% of maternal inheritance in dominant cases. CONCLUSIONS: In most children, HNF1B nephropathy has a non-progressive course of cyst development and a slow-progressive course of kidney function. A subgroup of patients developed ESRD at very young age < 2 years requiring special medical attention. The parent-of-origin effect suggests an influence of epigenetic modifiers in HNF1B disease.