Illness-related parental stress and quality of life in children with kidney diseases.

BACKGROUND: This cross-sectional study investigated quality of life (QoL) and illness-related parental stress in children with kidney diseases by (1) comparing mean levels of these two variables between several kidney disease categories; (2) exploring correlations between QoL and parental stress; and (3) describing which disease category reports lowest QoL and highest parental stress. METHODS: We included 295 patients with a kidney disease (0-18 years) and their parents, followed at 6 reference centers for pediatric nephrology. Children's QoL was assessed by the PedsQL™ 4.0 Generic Core Scales, and illness-related stress by the Pediatric Inventory for Parents. All patients were divided into 5 kidney disease categories according to the multidisciplinary care program criteria prescribed by the Belgian authorities: (1) structural kidney diseases, (2) tubulopathies and metabolic diseases, (3) nephrotic syndrome, (4) acquired diseases with proteinuria and hypertension, and (5) kidney transplantation. RESULTS: Child self-reports showed no differences in QoL between kidney disease categories, in contrast to parent proxy reports. Parents of transplant patients reported lower QoL in their child and more parental stress compared with the 4 non-transplant categories. QoL and parental stress were negatively correlated. Lowest QoL and highest parental stress scores were mainly found in transplant patients. CONCLUSIONS: This study showed lower QoL and higher parental stress in pediatric transplant patients compared with non-transplants, based on parent reports. Higher parental stress is associated with worse QoL in the child. These results highlight the importance of multidisciplinary care for children with kidney diseases, with special attention to transplant patients and their parents. A higher resolution version of the Graphical abstract is available as Supplementary information.

The long-acting C5 inhibitor, ravulizumab, is efficacious and safe in pediatric patients with atypical hemolytic uremic syndrome previously treated with eculizumab.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare, complement-mediated disease associated with poor outcomes if untreated. Ravulizumab, a long-acting C5 inhibitor developed through minimal, targeted modifications to eculizumab was recently approved for the treatment of aHUS. Here, we report outcomes from a pediatric patient cohort from the ravulizumab clinical trial (NCT03131219) who were switched from chronic eculizumab to ravulizumab treatment. METHODS: Ten patients received a loading dose of ravulizumab on Day 1, followed by maintenance doses administered initially on Day 15, and then, every 4-8 weeks thereafter, depending on body weight. All patients completed the initial evaluation period of 26 weeks and entered the extension period. RESULTS: No patients required dialysis at any point throughout the study. The median estimated glomerular filtration rate values remained stable during the trial: 99.8 mL/min/1.73m2 at baseline, 93.5 mL/min/1.73m2 at 26 weeks, and 104 mL/min/1.73m2 at 52 weeks. At last available follow-up, all patients were in the same chronic kidney disease stage as recorded at baseline. Hematologic variables (platelets, lactate dehydrogenase, and hemoglobin) also remained stable throughout the initial evaluation period and up to the last available follow-up. All patients experienced adverse events; the most common were upper respiratory tract infection (40%) and oropharyngeal pain (30%). There were no meningococcal infections reported, no deaths occurred, and no patients discontinued during the study. CONCLUSIONS: Overall, treatment with ravulizumab in pediatric patients with aHUS who were previously treated with eculizumab resulted in stable kidney and hematologic parameters, with no unexpected safety concerns when administered every 4-8 weeks. TRIAL REGISTRATION: Trial identifiers: Trial ID: ALXN1210-aHUS-312 Clinical trials.gov : NCT03131219 EudraCT number: 2016-002499-29 Graphical abstract.

Improve in-depth immunological risk assessment to optimize genetic-compatibility and clinical outcomes in child and adolescent recipients of parental donor kidney transplants: protocol for the INCEPTION study.

BACKGROUND: Parental donor kidney transplantation is the most common treatment option for children and adolescents with kidney failure. Emerging data from observational studies have reported improved short- and medium-term allograft outcomes in recipients of paternal compared to maternal donors. The INCEPTION study aims to identify potential differences in immunological compatibility between maternal and paternal donor kidneys and ascertain how this affects kidney allograft outcomes in children and adolescents with kidney failure. METHODS: This longitudinal observational study will recruit kidney transplant recipients aged ≤18 years who have received a parental donor kidney transplant across 4 countries (Australia, New Zealand, United Kingdom and the Netherlands) between 1990 and 2020. High resolution human leukocyte antigen (HLA) typing of both recipients and corresponding parental donors will be undertaken, to provide an in-depth assessment of immunological compatibility. The primary outcome is a composite of de novo donor-specific anti-HLA antibody (DSA), biopsy-proven acute rejection or allograft loss up to 60-months post-transplantation. Secondary outcomes are de novo DSA, biopsy-proven acute rejection, acute or chronic antibody mediated rejection or Chronic Allograft Damage Index (CADI) score of > 1 on allograft biopsy post-transplant, allograft function, proteinuria and allograft loss. Using principal component analysis and Cox proportional hazards regression modelling, we will determine the associations between defined sets of immunological and clinical parameters that may identify risk stratification for the primary and secondary outcome measures among young people accepting a parental donor kidney for transplantation. This study design will allow us to specifically investigate the relative importance of accepting a maternal compared to paternal donor, for families deciding on the best option for donation. DISCUSSION: The INCEPTION study findings will explore potentially differential immunological risks of maternal and paternal donor kidneys for transplantation among children and adolescents. Our study will provide the evidence base underpinning the selection of parental donor in order to achieve the best projected long-term kidney transplant and overall health outcomes for children and adolescents, a recognized vulnerable population. TRIAL REGISTRATION: The INCEPTION study has been registered with the Australian New Zealand Clinical Trials Registry, with the trial registration number of ACTRN12620000911998 (14th September 2020).

Patients with primary hyperoxaluria type 2 have significant morbidity and require careful follow-up.

Primary hyperoxaluria type 2 is a rare inherited disorder of glyoxylate metabolism causing nephrocalcinosis, renal stone formation and ultimately kidney failure. Previously, primary hyperoxaluria type 2 was considered to have a more favorable prognosis than primary hyperoxaluria type 1, but earlier reports are limited by low patient numbers and short follow up periods. Here we report on the clinical, genetic, and biochemical findings from the largest cohort of patients with primary hyperoxaluria type 2, obtained by a retrospective record review of genetically confirmed cases in the OxalEurope registry, a dataset containing 101 patients from eleven countries. Median follow up was 12.4 years. Median ages at first symptom and diagnosis for index cases were 3.2 years and 8.0 years, respectively. Urolithiasis was the most common presenting feature (82.8% of patients). Genetic analysis revealed 18 novel mutations in the GRHPR gene. Of 238 spot-urine analyses, 23 (9.7%) were within the normal range for oxalate as compared to less than 4% of 24-hour urine collections. Median intra-individual variation of 24-hour oxalate excretion was substantial (34.1%). At time of review, 12 patients were lost to follow-up; 45 of the remaining 89 patients experienced chronic kidney disease stage 2 or greater and 22 patients had reached stage 5. Median renal survival was 43.3 years, including 15 kidney transplantations in 11 patients (1 combined with liver transplantation). Renal outcome did not correlate with genotype, biochemical parameters or initially present nephrocalcinosis. Thus, primary hyperoxaluria type 2 is a disease with significant morbidity. Accurate diagnosis by 24-hour urine analysis and genetic testing are required with careful follow-up.

Outcomes of kidney transplantations in children weighing 15 kilograms or less: a retrospective cohort study.

Kidney transplantation (KT) is often delayed in small children because of fear of postoperative complications. We report early- and long-term outcomes in children transplanted at ≤15 kg in the two largest Belgian pediatric transplant centers. Outcomes before (period 1) and since the introduction of basiliximab and mycophenolate-mofetil in 2000 (period 2) were compared. Seventy-two KTs were realized between 1978 and 2016: 38 in period 1 and 34 in period 2. Organs came from deceased donors in 48 (67%) cases. Surgical complications occurred in 25 KTs (35%) with no significant difference between the two periods. At least one acute rejection (AR) occurred in 24 (33%) KTs with significantly less patients experiencing AR during period 2: 53% and 12% in period 1 and, period 2 respectively (P < 0.001). Graft survival free of AR improved significantly in period 2 compared with period 1: 97% vs. 50% at 1 year; 87% vs. 50% at 10 years post-KT (P = 0.003). Graft survival tended to increase over time (period 1: 74% and 63% at 1 and 5 years; period 2: 94% and 86% at 1 and 5 years; P = 0.07), as well as patient survival. Kidney transplantation in children ≤15 kg remains a challenging procedure with 35% of surgical complications. However, outcomes improved and are nowadays excellent in terms of prevention of AR, patient and graft survival.

Children on dialysis as well as renal transplanted children report severely impaired health-related quality of life.

OBJECTIVES: To assess health-related quality of life (HRQoL) across three renal replacement therapy modalities (preemptive transplant, non-preemptive transplant, and dialysis) in comparison with the healthy norm and other chronic health conditions, and to explore related patient factors. STUDY DESIGN: All prevalent end-stage renal disease (ESRD) patients aged 8-18 years who spent at least 6 months on their current treatment modality in the Netherlands, Belgium, and part of Germany were approached to complete the Pediatric Quality of Life Inventory 4.0 (PedsQL™) questionnaire. We determined the differences between groups on PedsQL™ mean scores, the proportion of children with an impaired HRQoL (≥ 1 SD lower than the healthy norm), the proportion of problems on individual items of the PedsQL™, and the effect of time on current treatment. Linear regression models were used to explore determinants of HRQoL. RESULTS: 192 out of 278 patients (20% preemptive transplant, 58% non-preemptive transplant, 22% dialysis) filled in the PedsQL™ (response rate 69%). Independent of treatment modality, patients had significantly lower mean scores and consequently higher proportions of impaired HRQoL on almost all domains compared to the healthy norm and other chronic health conditions. Patients with a preemptive transplant only reported higher scores on physical health compared to the other treatment modalities. Having comorbidities was the most important determinant associated with lower HRQoL scores. CONCLUSION: Dialysis and renal transplantation both have a severe impact on the HRQoL of children with ESRD. Physicians should be aware of this continuous burden. Furthermore, to develop tailored interventions for children with ESRD, qualitative studies are needed to gain more insight in the determinants of HRQoL in the different treatment modalities.

Early-onset of ADCK4 glomerulopathy with renal failure: a case report.

BACKGROUND: We present a rare early presentation of a ADCK4-related glomerulopathy. This case is of interest as potentially treatable if genetic results are timely obtained. CASE PRESENTATION: We report the case of a 5-year-old boy who was identified with significant proteinuria by a urinary routine screening program for school children. Physical examination revealed dysplastic ears and abnormal folded pinna. Albumin level was 41 g/L (39-53 g/L), and urine proteins/creatinine ratio was 2.6 g/g. Renal ultrasound showed enlarged kidneys and perimedullary hyperechogenicity. Treatment by angiotensin-converting-enzyme inhibitor was not beneficial. Renal biopsy showed signs of focal segmental glomerulosclerosis. After 4 years of follow-up, he developed a clinical nephrotic syndrome and no response to prednisone and other immunosuppressive agents was obtained. Within 6 months, he was in end-stage-renal-failure (ESRF) and hemodialysis was started. He was transplanted at 10 years with his mother's kidney. Genes known to be responsible in steroid-resistant nephrotic syndromes were tested. Our patient is compound heterozygous for two mutations in the aarF domain-containing-kinase 4 (ADCK4) gene. ADCK4 gene is one of the genes involved in coenzyme Q10 (CoQ10) biosynthesis, is located in chromosome 19q13.2 and expressed in podocytes. ADCK4 mutations show a largely renal-limited phenotype. The nephropathy usually presents during adolescence, fast evolves towards ESRF, and may be treatable by CoQ10 supplementation if started early in the disease. Our patient presented nephrotic range proteinuria at 5 years, and he reached ESRF at 10 years. CONCLUSION: ADCK4-related glomerulopathy is an important novel and potentially treatable cause of isolated nephropathy not only in adolescents, but also in children in their first decade of life. Discovery of important proteinuria in an asymptomatic child should prompt early genetic investigations.

Infants Requiring Maintenance Dialysis: Outcomes of Hemodialysis and Peritoneal Dialysis.

BACKGROUND: The impact of different dialysis modalities on clinical outcomes has not been explored in young infants with chronic kidney failure. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: Data were extracted from the ESPN/ERA-EDTA Registry. This analysis included 1,063 infants 12 months or younger who initiated dialysis therapy in 1991 to 2013. FACTOR: Type of dialysis modality. OUTCOMES & MEASUREMENTS: Differences between infants treated with peritoneal dialysis (PD) or hemodialysis (HD) in patient survival, technique survival, and access to kidney transplantation were examined using Cox regression analysis while adjusting for age at dialysis therapy initiation, sex, underlying kidney disease, and country of residence. RESULTS: 917 infants initiated dialysis therapy on PD, and 146, on HD. Median age at dialysis therapy initiation was 4.5 (IQR, 0.7-7.9) months, and median body weight was 5.7 (IQR, 3.7-7.5) kg. Although the groups were homogeneous regarding age and sex, infants treated with PD more often had congenital anomalies of the kidney and urinary tract (CAKUT; 48% vs 27%), whereas those on HD therapy more frequently had metabolic disorders (12% vs 4%). Risk factors for death were younger age at dialysis therapy initiation (HR per each 1-month later initiation, 0.95; 95% CI, 0.90-0.97) and non-CAKUT cause of chronic kidney failure (HR, 1.49; 95% CI, 1.08-2.04). Mortality risk and likelihood of transplantation were equal in PD and HD patients, whereas HD patients had a higher risk for changing dialysis treatment (adjusted HR, 1.64; 95% CI, 1.17-2.31). LIMITATIONS: Inability to control for unmeasured confounders not included in the Registry database and missing data (ie, comorbid conditions). Low statistical power because of relatively small number of participants. CONCLUSIONS: Despite a widespread preconception that HD should be reserved for cases in which PD is not feasible, in Europe, we found 1 in 8 infants in need of maintenance dialysis to be initiated on HD therapy. Patient characteristics at dialysis therapy initiation, prospective survival, and time to transplantation were very similar for infants initiated on PD or HD therapy.

Children of non-Western origin with end-stage renal disease in the Netherlands, Belgium and a part of Germany have impaired health-related quality of life compared with Western children.

BACKGROUND: Many children with end-stage renal disease (ESRD) living in Western Europe are of non-Western European origin. They have unfavourable somatic outcomes compared with ESRD children of Western origin. In this study, we compared the Health-related Quality of Life (HRQoL) of both groups. METHODS: All children (5-18 years) with ESRD included in the RICH-Q project (Renal Insufficiency therapy in Children-Quality assessment and improvement) or their parents were asked to complete the generic version of the Paediatric Quality-of-Life Inventory 4.0 (PedsQL). RICH-Q comprises the Netherlands, Belgium and a part of Germany. Children were considered to be of non-Western origin if they or at least one parent was born outside Western-European countries. Impaired HRQoL for children with ESRD of Western or non-Western origin was defined as a PedsQL score less than fifth percentile for healthy Dutch children of Western or non-Western origin, respectively. RESULTS: Of the 259 eligible children, 230 agreed to participate. One hundred and seventy-four children responded (response rate 67%) and 55 (32%) were of non-Western origin. Overall, 31 (56%) of the ESRD children of non-Western origin, and 58 (49%) of Western origin had an impaired total HRQoL score. Total HRQoL scores of children with ESRD of Western origin and non-Western origin were comparable, but scores on emotional functioning and school functioning were lower in non-Western origin (P=0.004 and 0.01, respectively). The adjusted odds ratios (95% confidence interval) for ESRD children of non-Western origin to have impaired emotional functioning and school functioning, compared with Western origin, were 3.3(1.5-7.1) and 2.2(1.1-4.2), respectively. CONCLUSION: Children with ESRD of non-Western origin in three Western countries were found to be at risk for impaired HRQoL on emotional and school functioning. These children warrant special attention.

Ravulizumab in Atypical Hemolytic Uremic Syndrome: An Analysis of 2-Year Efficacy and Safety Outcomes in 2 Phase 3 Trials.

Rationale & Objective: Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) caused by complement dysregulation. Ravulizumab is a C5i approved for the treatment of aHUS. This analysis assessed long-term outcomes of ravulizumab in adults and pediatric patients with aHUS. Study Design: This analysis reports 2-year data from 2 phase 3, single-arm studies. Setting & Participants: One study included C5i-naïve adults (NCT02949128), and the other included 2 cohorts of pediatric patients (C5i-naïve and those who switched to ravulizumab from eculizumab [pediatric switch patients]; NCT03131219). Exposure: Patients received intravenous ravulizumab every 4-8 weeks, with the dose depending on body weight. Outcomes: The primary endpoint in the studies of C5i-naïve patients was complete TMA response, which consisted of platelet count normalization, lactate dehydrogenase normalization, and ≥25% improvement in serum creatinine concentrations from baseline, at 2 consecutive assessments ≥4 weeks apart. Analytical Approach: All analyses used descriptive statistics. No formal statistical comparisons were performed. Results: In total, 86 and 92 patients were included in efficacy and safety analyses, respectively. Complete TMA response rates over 2 years were 61% and 90% in C5i-naïve adults and pediatric patients, respectively. The median increase in estimated glomerular filtration rate from baseline was maintained over 2 years in C5i-naïve adults (35 mL/min/1.73 m2) and pediatric patients (82.5 mL/min/1.73 m2). Most adverse events and serious adverse events occurred during the first 26 weeks. No meningococcal infections were reported. Improvement in the Functional Assessment of Chronic Illness Therapy - Fatigue score achieved by 26 weeks was maintained over 2 years. Limitations: Limitations were the small sample of pediatric switch patients and limited availability of genetic data. Conclusions: Long-term treatment with ravulizumab is well tolerated and associated with improved hematologic and renal parameters and quality of life in adults and pediatric patients with aHUS.

This research tested a drug called ravulizumab for the treatment of atypical hemolytic uremic syndrome (aHUS). aHUS is a rare disease that causes clots in tiny blood vessels. This can damage the kidneys and other organs. We analyzed data from 2 clinical trials in which children and adults with aHUS received ravulizumab through a tube placed in a vein (intravenous line). They received ravulizumab every 4-8 weeks depending on their weight. We found that treating patients for 2 years with ravulizumab was associated with improved blood health, kidney function, and quality of life and was well tolerated. These results support ravulizumab as a long-term treatment for people with aHUS.

Important differences in management policies for children with end-stage renal disease in the Netherlands and Belgium--report from the RICH-Q study.

BACKGROUND: The low prevalence of childhood end-stage renal disease and the small centre sizes have been a barrier for clinical studies and the development of evidence-based guidelines for chronic renal replacement therapy (cRRT) in children. Few data exist on the quality of care for these patients and the applicability of existing guidelines. The aim of this study is to quantify variation in treatment policies and actually delivered care in nine centres that deliver cRRT for children. METHODS: We surveyed treatment policies in all nine centres in the Netherlands and Belgium and compared them with the actually provided therapies and with recommendations from available guidelines. Data on treatment policies were gathered by questionnaires; actually provided care and outcomes were registered prospectively from 2007 to 2010. RESULTS: Data on policies and actual patient care were obtained from all nine centres. We found relevant differences between centres in treatment policies on various topics, e.g. estimated glomerular filtration rate threshold as an indication for initiation of cRRT, preferred initial mode of cRRT, peritoneal dialysis catheter care, haemodialysis frequency and vascular access. Discrepancies were seen between stated treatment policies and actual performed therapies. For the majority of policies, no evidence-based guidelines are available. CONCLUSIONS: Health care disparities exist due to large and unwanted variation in treatment policies between hospitals providing cRRT for children. Delivered care does not live up to stated policies, for which clear and internationally accepted guidelines are lacking.

Regulation of Th2 responses and allergic inflammation through bystander activation of CD8+ T lymphocytes in early life.

Th2-biased immune responses characterizing neonates may influence the later onset of allergic disease. The contribution of regulatory T cell populations in the prevention of Th2-driven pathologies in early life is poorly documented. We investigated the potential of CD8(+) T cells stimulated at birth with alloantigens to modulate the development of allergic airway inflammation. Newborn mice were immunized with semiallogeneic splenocytes or dendritic cells (DCs) and exposed at the adult stage to OVA aeroallergens. DC-immunized animals displayed a strong Th1 and Tc1/Tc2 alloantigen-specific response and were protected against the development of the allergic reaction with reduced airway hyperresponsiveness, mucus production, eosinophilia, allergen-specific IgE and IgG(1), and reduction of lung IL-4, IL-5, IL-10, and IL-13 mRNA levels. By contrast, splenocyte-immunized mice displayed a Th2 and a weak Tc2 alloantigen-specific response and were more sensitive to the development of the allergen-specific inflammation compared with mice unexposed at birth to alloantigens. DC-immunized animals displayed an important increase in the percentage of IFN-gamma-producing CD8(+)CD44(high), CD8(+)CD62L(high), and CD8(+)CD25(+) subsets. Adoptive transfers of CD8(+) T cells from semiallogeneic DC-immunized animals to adult beta(2)m-deficient animals prevented the development of allergic response, in particular IgE, IL-4, and IL-13 mRNA production in an IFN-gamma-dependent manner, whereas transfers of CD8(+) T cells from semiallogeneic splenocyte-immunized mice intensified the lung IL-4 and IL-10 mRNA level and the allergen-specific IgE. These findings demonstrated that neonatal induction of regulatory CD8(+) T cells was able to modulate key parameters of later allergic sensitization in a bystander manner, without recognition of MHC class I molecules.

Disparities in dialysis treatment and outcomes for Dutch and Belgian children with immigrant parents.

BACKGROUND: In Belgium and the Netherlands, up to 40% of the children on dialysis are children with immigrant parents of non-Western European origin (non-Western). Concerns exist regarding whether these non-Western patients receive the same quality of care as children with parents of Western European origin (Western). We compared initial dialysis, post-initial treatment, and outcomes between non-Western and Western patients on dialysis. METHODS: All children <19 years old on chronic dialysis in the Netherlands and Belgium between September 2007 and May 2011 were included in the study. Non-Western patients were defined as children of whom one or both parents were born in non-Western countries. RESULTS: Seventy-nine of the 179 included patients (44%) were non-Western children. Compared to Western patients, non-Western patients more often were treated with hemodialysis (HD) instead of peritoneal dialysis (PD) as first dialysis mode (52 vs. 37%, p = 0.046). Before renal transplantation, non-Western patients were on dialysis for a median (range) of 30 (5-99) months, vs. 15 (0-66) months in Western patients (p = 0.007). Renal osteodystrophy was diagnosed in 34% of non-Western vs. 18% of Western patients (p = 0.028). The incidence rate ratio [95% confidence interval] for acute peritonitis was 2.44 [1.43-4.17] (p = 0.032) for non-Western compared to Western patients. CONCLUSIONS: There are important disparities between children on chronic dialysis with parents from Western European origin and those from non-Western European origin in the choice of modality, duration, and outcomes of dialysis therapy.

The Struggling Odyssey of Infantile Primary Hyperoxaluria.

Introduction: Oxalate overproduction in Primary Hyperoxaluria type I (PH1) leads to progressive renal failure and systemic oxalate deposition. In severe infantile forms of PH1 (IPH1), end-stage renal disease (ESRD) occurs in the first years of life. Usually, the management of these infantile forms is challenging and consists in an intensive dialysis regimen followed by a liver-kidney transplantation (combined or sequential). Methods: Medical records of all infants with IPH1 reaching ESRD within the first year of life, diagnosed and followed between 2005 and 2018 in two pediatric nephrology departments in Brussels and Paris, have been reviewed. Results: Seven patients were included. They reached ESRD at a median age of 3.5 (2-7) months. Dialysis was started at a median age of 4 (2-10 months). Peritoneal dialysis (PD) was the initial treatment for 6 patients and hemodialysis (HD) for one patient. Liver transplantation (LT) was performed in all patients and kidney transplantation (KT) in six of them. A sequential strategy has been chosen in 5 patients, a combined in one. The kidney transplanted as part of the combined strategy was lost. Median age at LT and KT was 25 (10-41) months and 32.5 (26-75) months, respectively. No death occurred in the series. At the end of a median follow-up of 3 years, mean eGFR was 64 ± 29 ml/min/1.73 m2. All patients presented retinal and bone lesions and five patients presented bones fractures. Conclusion: Despite encouraging survival figures, the morbidity in IPH1 patients remains extremely heavy and its management presents a huge challenge. Thanks to the newly developed RNA-interference drug, the future holds brighter prospects.

Case Report: Sustained Efficacy of Lumasiran at 18 Months in Primary Hyperoxaluria Type 1.

Background: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate, ultimately responsible for kidney stones, kidney failure and systemic oxalosis. Lumasiran, is a liver-directed RNA interference therapeutic agent. It has been shown to reduce hepatic oxalate production by targeting glycolate oxidase, and to dramatically reduce oxalate excretion. Care Report: We present the case of a teenager patient affected by PH1, who entered in the lumasiran compassionate use program. The patient had a rapid and sustained decrease in urinary oxalate/creatinine ratio, with a mean reduction after lumasiran administration of about 70%. During the 18 months long follow-up, urinary oxalate remained low, reaching nearly normal values. Plasma oxalate also decreased dramatically. Normal levels were reached immediately after the first dose and remained consistently low thereafter. During the same follow-up period, eGFR remained stable at about 60 ml/min/1.73 m2, but no new kidney stones were observed. Existing kidney stones did not increase in size. The patient did not suffer renal colic events and did not require further urological interventions. Conclusion: In our severely affected PH1 patient, lumasiran proved to be very effective in rapidly and consistently reducing plasma oxalate and urinary excretion to normal and near-normal levels, respectively. In the 18 months long follow-up post-lumasiran, the eGFR remained stable and the patient showed clinical improvements. As far as we know, this report covers the longest observation period after initiation of this novel RNAi therapy.

Hyperoxaluria: An early diagnosis will allow a timely combined renal and liver transplantations to avoid irreversible damages to all other organs.

A 4-month-old patient was admitted to the emergency room for vomiting, weight gain, food refusal and hypertension. Blood gases showed a metabolic acidosis with increased anion gap. Laboratory finding revealed severe renal failure (creatinine 8 mg/dL). Renal ultrasound showed an important hyperechogenicity of the parenchyma with loss of cortico-medullar differentiation suggesting a nephronophytosis. Genetic testing was negative. Urine oxalate levels were increased to 140 µmol/L. New genetic tests were positive for type I hyperoxaluria. The authors discuss the management of hyperoxaluria.

Case Report: Neonatal Unexplained HUS Treated With Complement Inhibitor Eculizumab.

Background: Hemolytic uremic syndrome (HUS) is rare in neonates. It is probably an under-recognized condition in the early postnatal period as it presents similarly to the most common perinatal asphyxia and to differentiate the two conditions is challenging. We describe the clinical presentation of a potential new subtype of neonatal HUS triggered by hypoxic-ischemic event. Our patient was successfully treated by a single dose of Eculizumab as early as at 9 days of life. Case Report: A 35-weeks infant was born with low hemoglobin and subsequently developed respiratory distress, hypotension, and acidosis. Blood transfusion was administered, acidosis corrected, neurological examination remained reassuring. Few hours later he developed renal failure, macroscopic hematuria, hemobilia, thrombocytopenia and coagulopathy refractory to platelet and fresh frozen plasma transfusions. No infection was found. Haptoglobin was non-measurable, and schistocytes present, complement factors C3, C4 and B were low, FBb increased. HUS was suspected. A single dose of Eculizumab™ was administered on day 9 of life. No genetic mutation of atypical HUS was found. He was discharged with improving renal function and developing cholestasis. Conclusion: In neonates with hemolytic anemia, thrombocytopenia, hematuria and renal failure, HUS should be suspected. In neonatal HUS Eculizumab should be considered as first-line therapy and discontinuation can be considered if no genetic mutation is found and clinical condition improves. In very young patients, cholestasis could appear as potential side effect of Eculizumab™.

Prospective Cohort Study Investigating the Safety and Efficacy of Ambulatory Treatment With Oral Cefuroxime-Axetil in Febrile Children With Urinary Tract Infection.

Aims: To assess the safety and efficacy of ambulatory oral cefuroxime-axetil treatment in children presenting with first febrile urinary tract infection (UTI) in terms of resolution of fever, antibiotics tolerance, bacterial resistance, and loss to ambulatory follow-up. Methods: Two-year prospective single-center evaluation of the local protocol of oral ambulatory treatment of children presenting first febrile urinary tract infection (UTI). Results: From October 2013 to October 2015, 82 children were treated ambulatory with oral cefuroxime-axetil. The median age was 8 months. When analyzing those 82 children treated orally, 51 (62%) completed oral treatment, 14 (17%) missed their scheduled follow-up visits (3 patients at day 2 and 11 patients at week 2), and 17 (21%) were switched to IV therapy for the following reasons: vomiting in 9, persistent fever in 5, antibiotic resistance in 2 and bacteremia in 1. Six children (8%) presented recurrent UTI after a median of 5 months of follow-up. Conclusions: This 2-year evaluation suggests that oral treatment with cefuroxime-axetil in febrile UTI is feasible but should be implemented with caution. Home-treated children require reevaluation during treatment since 21% of our cohort had to be temporarily switched to parenteral therapy and 17% did not attend scheduled follow-up visits during oral treatment.

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency.

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1Δ yeast strains, whereas expression of disease-associated variants did not. Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist. In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype. Together, these results indicate that SGPL1 mutations cause a syndromic form of SRNS.