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Background Primary hyperoxalurias (PHs) constitute rare disorders resulting in abnormal glyoxalate metabolism. PH-associated phenotypes range from progressive nephrocalcinosis and/or recurrent urolithiasis to early kidney failure. Methods A retrospective study was conducted for patients with confirmed PH diagnoses from three tertiary centers in Saudi Arabia. Detailed clinical molecular diagnosis was performed for 25 affected individuals. Whole exome sequencing (WES)–based molecular diagnosis was performed for all affected individuals. Results The male:female ratio was 52% male (n = 13) and 48% female (n = 12), and consanguinity was present in 88%. Nephrolithiasis and/or nephrocalcinosis were present in all patients. Kidney stones were present in 72%, nephrocalcinosis in 60%, hematuria in 32%, proteinuria in 16%, abdominal pain in 36%, developmental delay in 8%, and chronic kidney disease stage 5 (CKD stage 5) was observed in 28% of the patients. The most common PH disorder was type I caused by variants in the AGXT gene, accounting for 56%. The GRHPR gene variants were identified in 4 patients, 16% of the total cases. Seven patients did not reveal any associated variants. Missense variants were the most commonly observed variants (48%), followed by frame-shift duplication variants (28%). Conclusions Characterization of the genetic and clinical aspects of PH in this unique population provides direction for improved patient management and further research. Graphical abstract

Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical and genetic heterogeneity. Applied to one of the worldwide largest cohorts of patients with NPH, genetic analysis encompassing targeted and whole exome sequencing identified disease-causing variants in 600 patients from 496 families with a detection rate of 71%. Of 788 pathogenic variants, 40 known ciliopathy genes were identified. However, the majority of patients (53%) bore biallelic pathogenic variants in NPHP1. NPH-causing gene alterations affected all ciliary modules defined by structural and/or functional subdomains. Seventy six percent of these patients had progressed to kidney failure, of which 18% had an infantile form (under five years) and harbored variants affecting the Inversin compartment or intraflagellar transport complex A. Forty eight percent of patients showed a juvenile (5-15 years) and 34% a late-onset disease (over 15 years), the latter mostly carrying variants belonging to the Transition Zone module. Furthermore, while more than 85% of patients with an infantile form presented with extra-kidney manifestations, it only concerned half of juvenile and late onset cases. Eye involvement represented a predominant feature, followed by cerebellar hypoplasia and other brain abnormalities, liver and skeletal defects. The phenotypic variability was in a large part associated with mutation types, genes and corresponding ciliary modules with hypomorphic variants in ciliary genes playing a role in early steps of ciliogenesis associated with juvenile-to-late onset NPH forms. Thus, our data confirm a considerable proportion of late-onset NPH suggesting an underdiagnosis in adult chronic kidney disease.

Introduction: Infantile oxalosis is the most severe form of primary hyperoxaluria type 1 (PH1), with onset of end-stage kidney disease (ESKD) during infancy. We aimed to analyze the outcome of these patients as our current understanding is limited owing to a paucity of reports. Methods: A retrospective registry study was conducted using data from the OxalEurope registry. All PH1 patients with ESKD onset at age

Primary hyperoxaluria type 1 (PH1) is a rare, progressive, genetic disease with limited treatment options. We report the efficacy and safety of lumasiran, an RNA interference therapeutic, in infants and young children with PH1.This single-arm, open-label, phase 3 study evaluated lumasiran in patients aged6 years with PH1 and an estimated glomerular filtration rate45 mL/min/1.73 mAll patients (N = 18) completed the 6-month primary analysis period. Median age at consent was 50.1 months. Least-squares mean percent reduction in spot UOx:Cr was 72.0%. At month 6, 50% of patients (9/18) achieved spot UOx:Cr ≤1.5× upper limit of normal. Least-squares mean percent reduction in plasma oxalate was 31.7%. The most common treatment-related adverse events were transient, mild, injection-site reactions.Lumasiran showed rapid, sustained reduction in spot UOx:Cr and plasma oxalate and acceptable safety in patients aged6 years with PH1, establishing RNA interference therapies as safe, effective treatment options for infants and young children.

Introduction: In primary hyperoxaluria type 1 (PH1), oxalate overproduction frequently causes kidney stones, nephrocalcinosis, and kidney failure. As PH1 is caused by a congenital liver enzyme defect, combined liver–kidney transplantation (CLKT) has been recommended in patients with kidney failure. Nevertheless, systematic analyses on long-term transplantation outcomes are scarce. The merits of a sequential over combined procedure regarding kidney graft survival remain unclear as is the place of isolated kidney transplantation (KT) for patients with vitamin B6-responsive genotypes.Methods: We used the OxalEurope registry for retrospective analyses of patients with PH1 who underwent transplantation. Analyses of crude Kaplan–Meier survival curves and adjusted relative hazards from the Cox proportional hazards model were performed.Results: A total of 267 patients with PH1 underwent transplantation between 1978 and 2019. Data of 244 patients (159 CLKTs, 48 isolated KTs, 37 sequential liver–KTs [SLKTs]) were eligible for comparative analyses. Comparing CLKTs with isolated KTs, adjusted mortality was similar in patients with B6-unresponsive genotypes but lower after isolated KT in patients with B6-responsive genotypes (adjusted hazard ratio 0.07, 95% CI: 0.01–0.75, P = 0.028). CLKT yielded higher adjusted event-free survival and death-censored kidney graft survival in patients with B6-unresponsive genotypes (P = 0.025, P < 0.001) but not in patients with B6-responsive genotypes (P = 0.145, P = 0.421). Outcomes for 159 combined procedures versus 37 sequential procedures were comparable. There were 12 patients who underwent pre-emptive liver transplantation (PLT) with poor outcomes.Conclusion: The CLKT or SLKT remains the preferred transplantation modality in patients with PH1 with B6-unresponsive genotypes, but isolated KT could be an alternative approach in patients with B6-responsive genotypes.

Summary During the past decade, health technology assessment bodies have faced new challenges in establishing the benefits of new drugs for individuals and health-care systems. A topic of increasing importance to the field of oncology is the so-called agnostic regulatory approval of targeted therapies for cancer (independent of tumour location and histology) granted on the basis of basket trials. Basket trials in oncology offer the advantage of simultaneously evaluating treatments for multiple tumours, even rare cancers, in a single clinical trial. To address the novel challenges introduced by these trials, an interdisciplinary panel was convened on behalf of the Transparency Committee of the French National Authority for Health to clarify an approach designed to guarantee a transparent, reproducible, and fair assessment of histology-agnostic treatments for reimbursement by the French National Health Insurance Fund. The requirements of this approach include the need for randomisation, clinically relevant endpoints, appropriate correction for multiple significance testing, characterisation of subgroup heterogeneity, and validation of underlying biomarker assays. A prospectively designated external control is encouraged when the implementation of a direct comparison is deemed infeasible. We also underline the importance of recording outcomes from basket trials in a registry for use as future external controls.

Resumen En la actualidad, la incidencia de las litiasis en los ninos se encuentra en constante aumento y presentan modificaciones morfoconstitucionales, en particular en los paises desarrollados. Su formacion es multifactorial y se relaciona con un desequilibrio entre promotores e inhibidores de la cristalizacion, que casi siempre se asocia a una sobresaturacion cristalina por defecto de diuresis. Las litiasis son en su mayoria secundarias a factores ambientales o infecciosos, en particular en ninos menores de 5 anos, con predominio masculino. Sin embargo, en alrededor del 10% de los casos, las causas son geneticas monogenicas. Estas enfermedades litiasicas hereditarias suelen ser enfermedades minoritarias, autosomicas recesivas, graves y tempranas, que pueden complicarse con una insuficiencia renal cronica. El desafio consiste en ser capaz de identificarlas entre todas las demas etiologias. Por lo tanto, resulta indispensable un estudio completo ante todo episodio inicial de litiasis en un nino, que incluya el analisis morfoconstitucional del calculo, la cristaluria y un estudio biologico de clarificacion. En funcion de los resultados, se pueden proponer exploraciones funcionales para orientar el diagnostico y guiar el estudio genetico, en particular en las litiasis oxalocalcicas. El estudio radiologico se limita, en los ninos, a la ecografia renal y de las vias urinarias asociada a una radiografia simple de abdomen si es necesario, lo que permite diagnosticar y seguir la evolucion de los calculos. Las etiologias son multiples. Las litiasis de oxalato de calcio son actualmente las mas numerosas y van en aumento, por delante de las litiasis de fosfato de calcio. La cistinuria constituye alrededor del 5% de las litiasis del nino. Las litiasis de acido urico siguen siendo muy poco frecuentes en comparacion con los adultos y pueden ser secundarias a causas geneticas. El tratamiento medico se basa en la hiperhidratacion sistematica asociada a medidas especificas en funcion de la etiologia. El tratamiento urologico puede mostrarse complejo. Los procedimientos de cirugia abierta deben limitarse al maximo, en favor de la litotricia extracorporea y las tecnicas endoscopicas segun el tamano del nino.

Resumen En el momento actual, la litiasis del nino presenta una incidencia en constante aumento y unas modificaciones morfoconstitucionales, en especial en los paises desarrollados. Su formacion es multifactorial, relacionada con un desequilibrio entre promotores e inhibidores de la cristalizacion, con mucha frecuencia asociada a una sobresaturacion cristalina por escasa diuresis. La mayoria de las litiasis son secundarias a factores ambientales o infecciosos, en especial en el nino menor de 5 anos, con un predominio masculino. Sin embargo, alrededor del 10% de ellas tienen relacion con causas geneticas monogenicas. Estas enfermedades litiasicas hereditarias suelen ser enfermedades autosomicas recesivas raras, graves, precoces y que pueden complicarse con una insuficiencia renal cronica. Todo el reto es identificarlas entre otras etiologias. Para ello, es indispensable un estudio completo ante un primer episodio litiasico en el nino, que comprende el analisis morfoconstitucional del calculo, la cristaluria y un estudio biologico de rutina. Segun los resultados, pueden solicitarse exploraciones funcionales para orientar el diagnostico y guiar el estudio genetico, en particular en las litiasis oxalocalcicas. En el nino, el estudio radiologico se limita a la ecografia renal y de las vias urinarias, asociada a una radiografia simple de abdomen si es necesario, lo cual permite diagnosticar y seguir la evolucion de los calculos. Las etiologias son multiples. La litiasis de oxalato calcico es actualmente la mas numerosa y va en aumento, por delante de las litiasis de fosfato de calcio. La cistinuria representa alrededor del 5% de las litiasis del nino. La litiasis de acido urico es muy rara en comparacion con los adultos y puede ser secundaria a causas geneticas. El tratamiento medico se basa en la hiperhidratacion sistematica asociada a medidas especificas segun la etiologia. El tratamiento urologico puede ser complejo. La cirugia abierta debe reducirse al minimo en provecho de la litotricia extracorporea y las tecnicas endoscopicas segun la corpulencia del nino.

Background: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an investigational RNA interference (RNAi) therapeutic agent, reduces hepatic oxalate production by targeting glycolate oxidase. Methods: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with PH1 who were 6 years of age or older to receive subcutaneous lumasiran or placebo for 6 months (with doses given at baseline and at months 1, 2, 3, and 6). The primary end point was the percent change in 24-hour urinary oxalate excretion from baseline to month 6 (mean percent change across months 3 through 6). Secondary end points included the percent change in the plasma oxalate level from baseline to month 6 (mean percent change across months 3 through 6) and the percentage of patients with 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6. Results: A total of 39 patients underwent randomization; 26 were assigned to the lumasiran group and 13 to the placebo group. The least-squares mean difference in the change in 24-hour urinary oxalate excretion (lumasiran minus placebo) was -53.5 percentage points (P

Primary hyperoxalurias are rare disease with autosomal recessive inheritance; they often lead to kidney failure and can lead to life-threatening conditions, especially in early onset forms. There are three types, responding to distinct enzyme deficits. Type 1 represents 85% of cases and results from an enzyme deficiency (alanine-glyoxylate aminotransferase) in the peroxisomes of the liver, causing hyperoxaluria leading to urolithiasis with or without nephrocalcinosis. As glomerular filtration decreases, a systemic overload appears and spares no organ. Treatment has hitherto been based on combined liver and kidney transplantation, with significant mortality and morbidity. The recent introduction of interfering RNA treatments opens up new perspectives. By blocking an enzymatic synthesis (glycolate oxidase or lacticodehydrogenase a) upstream of the deficit that causes the disease, oxaluria normalizes and the tolerance of the drug (administered by injection every 1 to 3 months) is good. This strategy will help prevent kidney failure in patients treated early and avoid liver transplantation in those who are diagnosed at an advanced stage of kidney failure.

Resume Des recommandations specifiques a la nephrologie ont ete redigees sous l’egide de l’Association internationale de nephrologie pediatrique en 2011. Ces recommandations preconisent une transition individualisee, debutant entre 12 et 14 ans, avec des informations sur la maladie et les traitements du patient adaptees a l’âge et au niveau intellectuel. Les recommandations insistent sur l’importance d’identifier un referent pediatre et un referent en service adulte, ainsi qu’une equipe paramedicale et de travailleurs sociaux ; elles insistent egalement sur l’importance d’associer les aidants (les familles et l’entourage proche, etc.), la necessite d’un dossier specifique de transition et d’une visite prealable du service adulte avant le transfert. L’International Pediatric Nephrology Association recommande que le transfert soit realise au « bon moment » de la vie du jeune et non a ses 18 ans ; ce « bon moment » etant defini par le moment ou le jeune se sent pret, en periode de stabilite aussi bien medicale que familiale, scolaire et sociale. Afin de fournir au jeune des competences d’autogestion (empowerment) appropriees de sa maladie et de sa vie, dans le cadre de la filiere maladies renales rares (ORKiD), nous avons elabore un programme avec questionnaire adapte a l’âge en nous inspirant de celui mis en place a Southampton au Royaume-Uni. Ce document presente les outils developpes par le groupe de travail de la filiere de soins ORKiD.

Primary hyperoxaluria (PH) is a group of diseases due to mutations in genes coding for enzymes involved in oxalate metabolism. Three types of PH are identified depending on the gene mutated. Type 1 is the most frequent with 80% of the cases, while PH2 and PH3 are rarer. The severity of renal involvement varies between the three types. Indeed, between 60% and 80% of PH1 but only 20% of PH2 patients will reach end‐stage kidney disease. In PH3 patients, dialysis is uncommon. Because oxalate clearance is impaired in CKD patients, oxalate can precipitate in various organs leading to systemic oxalosis. We report an uncommon presentation of bone oxalosis associated with hypercalcemia in a dialyzed patient. This report emphasizes the difficulties to diagnose primary hyperoxaluria and the challenge of treating dialyzed patients.

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disease caused by the functional defect of alanine-glyoxylate aminotransferase that results in the overproduction of oxalate. It can be devastating especially for kidneys, leading to end-stage renal disease (ESRD) during the first 2 to 3 decades of life in most patients. Consequently, many PH1 patients need kidney transplantation. However, because PH1 is caused by a liver enzyme deficiency, the only cure of the metabolic defect is liver transplantation. Thus, current transplant strategies to treat PH1 patients with ESRD include dual liver–kidney transplantation. However, the morbidity and mortality associated with liver transplantation make these strategies far from optimal. Fortunately, a therapeutic revolution is looming. Indeed, innovative drugs are being currently tested in clinical trials, and preliminary data show impressive efficacy to reduce the hepatic overproduction of oxalate. Hopefully, with these therapies, liver transplantation will no longer be necessary. However, some patients with progressing renal disease or those who will be diagnosed with PH1 at an advanced stage of chronic kidney disease will ultimately need kidney transplantation. Here we review the current knowledge on this subject and discuss the future of kidney transplant management in PH1 patients in the era of novel therapies.

Trials in children with chronic kidney disease do not consistently report outcomes that are critically important to patients and caregivers. This can diminish the relevance and reliability of evidence for decision making, limiting the implementation of results into practice and policy. As part of the Standardized Outcomes in Nephrology—Children and Adolescents (SONG-Kids) initiative, we convened 2 consensus workshops in San Diego, California (7 patients, 24 caregivers, 43 health professionals) and Melbourne, Australia (7 patients, 23 caregivers, 49 health professionals). This report summarizes the discussions on the identification and implementation of the SONG-Kids core outcomes set. Four themes were identified; survival and life participation are common high priority goals, capturing the whole child and family, ensuring broad relevance across the patient journey, and requiring feasible and valid measures. Stakeholders supported the inclusion of mortality, infection, life participation, and kidney function as the core outcomes domains for children with chronic kidney disease.

Chronic kidney disease; Pediatric nephrology; Urology Malaltia renal crònica; Nefrologia pediàtrica; Urologia Enfermedad renal crónica; Nefrología pediátrica; Urología Nedosiran is an investigational RNA interference agent designed to inhibit expression of hepatic lactate dehydrogenase, the enzyme thought responsible for the terminal step of oxalate synthesis. Oxalate overproduction is the hallmark of all genetic subtypes of primary hyperoxaluria (PH). In this double-blind, placebo-controlled study, we randomly assigned (2:1) 35 participants with PH1 (n = 29) or PH2 (n = 6) with eGFR ≥30 mL/min/1.73 m2 to subcutaneous nedosiran or placebo once monthly for 6 months. The area under the curve (AUC) of percent reduction from baseline in 24-hour urinary oxalate (Uox) excretion (primary endpoint), between day 90–180, was significantly greater with nedosiran vs placebo (least squares mean [SE], +3507 [788] vs −1664 [1190], respectively; difference, 5172; 95% CI 2929–7414; P < 0.001). A greater proportion of participants receiving nedosiran vs placebo achieved normal or near-normal (

International audience; No abstract available

The prevalence of neurological involvement in patients with a deletion of or a variant in the HNF1B gene remains discussed. The aim of this study was to investigate the neuropsychological outcomes in a large cohort of children carrying either a HNF1B whole-gene deletion or a disease-associated variant, revealed by the presence of kidney anomalies. The neuropsychological development—based on school level—of 223 children included in this prospective cohort was studied. Data from 180 children were available for analysis. Patients mean age was 9.6 years, with 39.9% of girls. Among these patients, 119 carried a HNF1B deletion and 61 a disease-associated variant. In the school-aged population, 12.7 and 3.6% of patients carrying a HNF1B deletion and a disease-associated variant had special educational needs, respectively. Therefore, the presence of a HNF1B deletion increases the risk to present with a neuropsychiatric involvement when compared with the general population. On the other hand, almost 90% of patients carrying a HNF1B disease-associated variant or deletion have a normal schooling in a general educational environment. Even if these findings do not predict the risk of neuropsychiatric disease at adulthood, most patients diagnosed secondary to kidney anomalies do not show a neurological outcome severe enough to impede standard schooling at elementary school. These results should be taken into account in prenatal counseling.

International audience; BACKGROUND AND OBJECTIVES: In the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an RNA interference therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production. The objective of this first-in-human, randomized, placebo-controlled trial was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of lumasiran in healthy participants and patients with primary hyperoxaluria type 1. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This phase 1/2 study was conducted in two parts. In part A, healthy adults randomized 3:1 received a single subcutaneous dose of lumasiran or placebo in ascending dose groups (0.3-6 mg/kg). In part B, patients with primary hyperoxaluria type 1 randomized 3:1 received up to three doses of lumasiran or placebo in cohorts of 1 or 3 mg/kg monthly or 3 mg/kg quarterly. Patients initially assigned to placebo crossed over to lumasiran on day 85. The primary outcome was incidence of adverse events. Secondary outcomes included pharmacokinetic and pharmacodynamic parameters, including measures of oxalate in patients with primary hyperoxaluria type 1. Data were analyzed using descriptive statistics. RESULTS: Thirty-two healthy participants and 20 adult and pediatric patients with primary hyperoxaluria type 1 were enrolled. Lumasiran had an acceptable safety profile, with no serious adverse events or study discontinuations attributed to treatment. In part A, increases in mean plasma glycolate concentration, a measure of target engagement, were observed in healthy participants. In part B, patients with primary hyperoxaluria type 1 had a mean maximal reduction from baseline of 75% across dosing cohorts in 24-hour urinary oxalate excretion. All patients achieved urinary oxalate levels ≤1.5 times the upper limit of normal. CONCLUSIONS: Lumasiran had an acceptable safety profile and reduced urinary oxalate excretion in all patients with primary hyperoxaluria type 1 to near-normal levels. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Study of Lumasiran in Healthy Adults and Patients with Primary Hyperoxaluria Type 1, NCT02706886.

Background In patients with primary hyperoxaluria (PH), endogenous oxalate overproduction increases urinary oxalate excretion, leading to compromised kidney function and often kidney failure. Highly elevated plasma oxalate (Pox) is associated with systemic oxalate deposition in patients with PH and severe chronic kidney disease (CKD). The relationship between Pox and estimated glomerular filtration rate (eGFR) in patients with preserved kidney function, however, is not well established. Our analysis aimed to investigate a potential correlation between these parameters in PH patients from three randomized, placebo-controlled trials (studies OC3-DB-01, OC3-DB-02, and OC5-DB-01). Methods Baseline data from patients with a PH diagnosis (type 1, 2, or 3) and eGFR > 40 mL/min/1.73 m2 were analyzed for a correlation between eGFR and Pox using Spearman’s rank and Pearson’s correlation coefficients. Data were analyzed by individual study and additionally were pooled for Studies OC3-DB-02 and OC5-DB-01 in which the same Pox assay was used. Results A total of 106 patients were analyzed. A statistically significant inverse Spearman’s correlation between eGFR and Pox was observed across all analyses; correlation coefficients were − 0.44 in study OC3-DB-01, − 0.55 in study OC3-DB-02, − 0.51 in study OC5-DB-01, and − 0.49 in the pooled studies (p Conclusions Baseline evaluations showed a moderate and statistically significant inverse correlation between eGFR and Pox in patients with PH already at early stages of CKD (stages 1–3b), demonstrating that a correlation is present before substantial loss in kidney function occurs. Graphical abstract

Primary hyperoxaluria (PH) is a family of ultra-rare autosomal recessive inherited disorders of hepatic glyoxylate metabolism characterized by oxalate overproduction. Nedosiran is an RNA interference agent that inhibits hepatic lactate dehydrogenase, the enzyme responsible for the common, final step of oxalate production in all three genetic subtypes of PH. Here, we assessed in a two-part, randomized, single-ascending-dose, phase 1 study (PHYOX1) the safety, pharmacokinetics, pharmacodynamics, and exposure-response of subcutaneous nedosiran in 25 healthy participants (Group A) and 18 patients with PH1 or PH2 (Group B). Group A received nedosiran (0.3, 1.5, 3.0, 6.0, then 12.0 mg/kg) or placebo, and Group B received open-label nedosiran (1.5, 3.0, or 6.0 mg/kg). No significant safety concerns were identified. Injection site reactions (four or more hours post dose) occurred in 13.3% of participants in Group A and 27.8% of participants in Group B. Mean maximum reduction in 24-hour urinary oxalate excretion from baseline to day 57 (end of study) across Group B dose cohorts was 55% (range: 22%-100%) after single-dose nedosiran, with 33% participants reaching normal 24-hour urinary oxalate excretion. Based on the available modeling and simulation data, a fixed monthly dose of nedosiran 160 mg (free acid; equivalent to 170 mg sodium salt) in adults was associated with the highest proportion of simulated individuals achieving normal or near-normal 24-hour urinary oxalate excretion and fewest fluctuations in urinary oxalate response. Thus, single-dose nedosiran demonstrated acceptable safety and evidence of a pharmacodynamic effect in both PH1 and PH2 subpopulations consistent with its mechanism of action.

Resume L’elimination des medicaments est essentiellement renale et hepatique, et 75 % des medicaments sont principalement elimines par les reins. La nephrotoxicite en pediatrie concerne surtout les medicaments, mais il est important de connaitre d’autres types de nephrotoxicite non medicamenteux, par ingestion accidentelle ou volontaire, ou par contact, avec des produits chimiques, des toxines environnementales, des drogues, des vegetaux ou des animaux. La nephrotoxicite peut etre aigue ou chronique, dose-dependante ou -independante, et peut atteindre tous les compartiments fonctionnels du rein, meme si la necrose tubulaire aigue est le mecanisme le plus frequemment observe. Chez l’enfant, les informations sont souvent extrapolees des observations faites chez l’adulte et parfois a partir de l’experimentation animale ; il importe donc de preciser les particularites de la nephrotoxicite en pediatrie, qui subissent des variations considerables entre la periode fœtale et l’adolescence. Nous proposons donc une mise au point sur la nephrotoxicite en pediatrie, avec des rappels de physiopathologie, le rappel des grandes situations de nephrotoxicite medicamenteuse, et enfin un expose des situations les plus frequentes de nephrotoxicite non medicamenteuse.

Background Little data are available for infants who started renal replacement therapy before 6 months of age. Because of extra-renal comorbidities and uncertain outcomes, whether renal replacement therapy in neonates is justified remains debatable. Methods We performed a retrospective analysis of all patients who began chronic peritoneal dialysis below 6 months between 2007 and 2017 in two tertiary centres. Results are presented as median (min;max). Results Seventeen patients (10 boys) were included (8 prenatal diagnoses, 6 premies), with the following diagnoses: congenital anomalies of kidney and urinary tract (n = 9), oxalosis (n = 5), congenital nephrotic syndrome (n = 2) and renal vein thrombosis (n = 1). Five patients had associated comorbidities. At peritoneal dialysis initiation, age was 2.6 (0.1;5.9) months, height-standard deviation score (SDS) −1.3 (−5.7;1.6) and weight-SDS −1.4 (−3.6;0.6). Peritoneal dialysis duration was 12 (2;32) months, and at peritoneal dialysis discontinuation height-SDS was −1.0 (−4.3;0.7) weight-SDS −0.7 (−3.2;0.2), parathyroid hormone 123 (44;1540) ng/L, and hemoglobin 110 (73;174) g/L. During the first 6 months of peritoneal dialysis, the median time of hospitalisation stay was 69 (15;182) days. Ten patients presented a total of 27 peritonitis episodes. Reasons for peritoneal dialysis discontinuation were switch to hemodialysis (n = 6), transplantation (n = 6), recovery of renal function (n = 2) and death (n = 1). After a follow-up of 4.3 (1.7;10.3) years, 12 patients were transplanted, 2 patients were still on peritoneal dialysis, 2 patients were dialysis free with severe chronic kidney disease and 1 patient had died. Seven patients displayed neurodevelopmental delay, of whom five needed special schooling. Conclusion We confirm that most infants starting peritoneal dialysis before 6 months of age will be successfully transplanted and will have a favourable growth outcome. Their quality of life will be impacted by recurrent hospitalisations and neurodevelopmental delay is frequent.

Background and Aims Distal renal tubular acidosis (dRTA) is a rare disorder leading to impaired net acid excretion by the kidney inducing hyperchloremic metabolic acidosis and hypokalemia. The therapeutic effect of the standard of care is of short duration and requires multiple day and night administrations; it is also often accompanied by gastrointestinal discomfort and poor palatability impacting medication adherence. ADV7103, the first advanced therapy for dRTA, consists of a combination of prolonged-release potassium citrate and prolonged-release potassium bicarbonate granules providing round-the-clock alkali and potassium coverage with twice daily administration. Long-term adherence with ADV7103 is reported, along with acceptability of the product. Method B22CS is a multicentre, open-label long-term extension study, evaluating safety, tolerability, acceptability and efficacy of ADV7103 in adult and paediatric patients with dRTA. Adherence was assessed at each study visit up to 24 months, based on accountability of study drug retrieval, laboratory results, and interview of the patients in a diary and expressed as the proportion of patients that presented adherence lower than 50%, between 50% and 74%, between 75 and 90%, and higher than to 90%. Treatment acceptability as well as quality of life of the patients and their parents were assessed using a 100-mm visual analogue scales (VAS). Results Table 1 shows the evolution of compliance between Month 6 and Month 24. Overall, of the 29 patients remaining in the study after 24 months, 18 (62%) had adherence rates >90%, 5 (17%) had adherence rates of 75-90%, 6 (21%) had adherence rates of 50-74%, and there were no patients with adherence Compared to the alkalising treatments they had before the study, more than 80% of the patients perceived both the improvement of the formulation and of the number of daily doses at scores ≥ 75 mm. The overall improvement of quality of life reported by the patients was of 89 ± 19 mm and that reported by their parents was of 90 ± 14 mm after 24 months of treatment. Conclusion Adherence to treatment was maintained at a high level throughout the 24 months of the study confirming the good acceptance of ADV7103 therapy.

Objectives The one-compartment iohexol plasma clearance has been proposed as a reliable alternative to renal inulin clearance. However, this method’s performance depends on the formula used to calculate glomerular filtration rate (GFR). This study reports on performance comparisons between various mathematical formulas proposed for iohexol plasma clearance vs. inulin urinary clearance. Methods GFR was simultaneously determined by inulin and iohexol clearance in 144 participants (age: 10–84 years; glomerular filtration rate: 15–169 mL/min/1.73 m2). A retrospective cross-sectional study evaluated the performance of four formulas proposed to calculate plasma iohexol clearance (Brøchner–Mortensen, Fleming et al., Jødal–Brøchner–Mortensen, and Ng–Schwartz–Munoz). The performance of each formula was assessed using bias, precision (standard deviation of the bias), accuracy (percentage iohexol within 5, 10, and 15%), root mean square error, and concordance correlation coefficient vs. renal inulin clearance as reference. Results Regarding accuracy, there was no difference in root mean square error (RMSE), P5, P10, or P15 between the four formulas. The four concordance correlation coefficients (CCC) between the value from each formula and in-GFR were high and not significantly different. At in-GFR ≥90 mL/min/1.73 m2, Ng–Schwartz–Munoz formula performed slightly better than other formulas regarding median bias (−0.5; 95% CI [−3.0 to 2.0] and accuracy P15 (95.0; 95% CI [88.0–100.0]). Conclusions The studied formulas were found equivalent in terms of precision and accuracy, but the Ng–Schwartz–Munoz formula improved the accuracy at higher levels of in-GFR.

International audience; INTRODUCTION: In nephropathic cystinosis (NC), adherence to cysteamine remains challenging; poor adherence is worsening the disease progression with a decline of kidney function and increase of extrarenal morbidities. Our objective was to describe adherence to cysteamine in NC patients, using electronic monitoring systems. METHODS: Patients with confirmed NC, aged \textgreater 4 years and receiving oral cysteamine (short acting or delayed release formulation as standard of care) from 3 French reference centers, were included. Adherence to treatment was primarily assessed as the percentage of days with a good adherence score, adherence score rating from 0 (poor) to 2 (good). A descriptive analysis was performed after 1-year follow-up. RESULTS: Seventeen patients (10 girls, median age: 13.9 (5.4-33.0) years) were included. Median age at diagnosis was 17.0 (3.0-76.9) months and age at start of cysteamine was 21.0 (15.5-116.3) months. Median daily dose of cysteamine was 1.05 (0.55-1.63) g/m(2)/day. Over the year, the median percentage of days with a good adherence score was 80 (1-99)% decreasing to 68 (1-99)% in patients \textgreater 11 years old. The median of average number of hours covered by treatment in a day was 22.5 (6.1-23.9) versus 14.9 (9.2-20.5) hours for delayed release versus short acting cysteamine. CONCLUSION: Our data are the first describing a rather good adherence to cysteamine, decreasing in adolescents and adults. We described a potential interest of the delayed release formulation. Our data highlight the need for a multidisciplinary approach including therapeutic education and individualized approaches in NC patients transitioning to adulthood. Graphical abstract.

Eplet incompatibility appears to be a better predictor of the de novo appearance of DSA post-Tx than HLA antigen matching in adults. We evaluated the HLA Matchmaker® software (version 2.1) in our pediatric cohort to predict the appearance of DSA post-Tx. We included 70 pediatric patients (26 girls, 10 living donors, mean age 11.2 ± 3.9 years) after a first R-Tx (January 2010-August 2016), without prior immunization, having complete HLA typing (A, B, C, DRB1 and DQB1) and DSA follow-up for at least one year. The mean of HLA and eplet incompatibilities was 4.7 ± 1.3 and 15.5 ± 6.1, respectively, with a correlation coefficient r2 between these two variables of 0.34 (P < .001). The eplet load was 12.8 ± 5.0 in living donors vs 15.9 ± 6.2 in deceased donors (P = NS), 12.6 ± 6.1 in preemptive R-Tx (n = 14) vs 16.3 ± 5.9 for non-preemptive R-Tx (P = .04). Seven patients (10%) developed DSA during the 3.5 ± 1.2 years post-Tx. The eplet load was 13.7 ± 5.5 for those who developed DSA vs 15.7 ± 6.1 for the others (P = NS). In our single-center series of pediatric R-Tx with good HLA matching and lower eplet load than previously published series, eplet incompatibilities do not predict the development of DSA. The question of the HLA matching requirement and the daily interest of the HLA Matchmaker® software to help select the grafts remain open.

Resume Objectif La polykystose renale recessive (PKR) est due a des mutations du gene PKHD1. L’objectif de l’etude est de caracteriser la variabilite phenotypique en fonction des differentes mutations de PKHD1. Methodes L’etude a ete realisee chez 308 patients atteints de PKR, diagnostiques dans notre laboratoire de genetique. Les medecins prescripteurs des analyses genetiques avaient fourni des donnees cliniques et biologiques minimales. Resultats Les patients ont ete divises en trois groupes genotypiques : le premier groupe (G1 ; n = 65) concernait les patients ayant deux mutations tronquantes, le second groupe (G2 ; n = 117) des patients avec une mutation tronquante et une mutation non tronquante, et le troisieme groupe (G3 ; n = 126) etait constitue des patients ayant deux mutations non tronquantes. Au total, 31 % des grossesses ont fait l’objet d’une interruption medicale de grossesse, 18 % des enfants sont decedes en periode neonatale, et 51 % des patients ont survecu apres la periode neonatale ; la proportion des patients ayant un phenotype severe (defini par une interruption medicale de grossesse ou un deces neonatal) etait significativement plus elevee dans le groupe G1 : 94 %, par rapport aux groupes G2 (47 %) et G3 (27 % ; p Conclusion La presence de deux mutations tronquantes du gene PKHD1 est associee a un phenotype perinatal et post-natal severe. Toutefois, la variabilite phenotypique des autres groupes genotypiques necessite une discussion au cas par cas lors du diagnostic antenatal.

El sindrome de Fanconi o de De Toni- Debre-Fanconi consiste en una insuficiencia tubular proximal que comporta una sintomatologia clinica comun mas o menos completa y que tiene numerosas etiologias primarias o adquiridas. El tubulo proximal es el principal punto de reabsorcion de agua y de muchos electrolitos, a traves de diversos mecanismos: reabsorcion activa o paracelular, transportadores especificos o endocitosis. Los signos clinicos y biologicos asocian principalmente, en funcion de la edad: poliuria-polidipsia, raquitismo u osteomalacia por fosfato-diabetes, retraso del crecimiento ponderoestatural multifactorial y acidosis por perdida de bicarbonato. La etiologia mas frecuente de las formas primarias es la cistinosis, una enfermedad lisosomica autosomica recesiva poco frecuente debida a numerosas mutaciones del gen CTNS que codifica la cistinosina. La compleja fisiopatologia va mas alla de la simple acumulacion de cistina en los tejidos: alteracion de las vias de senalizacion de endocitosis, autofagia y apoptosis celular. Los primeros signos clinicos aparecen hacia los 6 meses de edad, con un sindrome de Fanconi completo y grave. El diagnostico, que clasicamente se establece hacia la edad de 1 ano, constituye una urgencia terapeutica mediante la correccion de la tubulopatia proximal que causa el fallecimiento en la infancia y mediante el inicio temprano de la administracion de cisteamina por via oral, que condiciona el pronostico renal y extrarrenal a largo plazo. La afectacion corneal requiere la aplicacion de cisteamina por via topica varias veces al dia. En 30 anos, el perfil evolutivo de la enfermedad se ha transformado gracias a la cisteamina: retraso de la edad de la insuficiencia renal terminal y de las complicaciones extrarrenales (hipotiroidismo, diabetes, complicaciones neuromusculares); el 50% de los pacientes son ahora adultos, lo que comporta la creacion de consultas multidisciplinarias adaptadas a ellos que, hasta hace pocos anos, solo estaban formadas por nefropediatras.

Bone impairment appears to be a novel complication of nephropathic cystinosis despite cysteamine therapy. Its exact underlying pathophysiology is nevertheless unclear. The objective of this study was to evaluate bone status among patients included in the French Crystobs study. In addition to clinical data, bone status was evaluated using biomarkers (ALP, PTH, 25-D, 1-25D, FGF23), DXA (spine and total body), and high-resolution peripheral quantitative computed tomography (HR-pQCT) at the tibia and radius. Results were compared to age- and gender-matched healthy controls (1:2 basis) from the local reference cohorts. At a median age of 22.5 (10.2–34.6) years, 10 patients with nephropathic cystinosis were included (2 receiving conservative therapies, 2 undergoing hemodialysis, 6 with a past of renal transplantation); 7 out of 10 patients complained of a bone symptom (past of fracture, bone deformations, and/or bone pain). Biochemicals and spine DXA did not show any significant abnormalities. Using HR-pQCT, significant decreases in cortical parameters (e.g., cortical thickness 850 (520–1100) versus 1225 (480–1680) μm; p

In nephrology, some diseases begin specifically during childhood; however, they must be known by adult nephrologists so that to ensure continuity and homogeneity for their management. The aim of this review is therefore to propose a brief overview of the main pediatric diseases, for which a specific knowledge is warranted, and notably pediatric idiopathic nephrotic syndrome, cystinosis, primary hyperoxaluria and hereditaries tubulopathies.

Resume La trisomie 21 (T21) est frequemment associee a des malformations congenitales, habituellement cardiaques : les atteintes renales sont peu connues. L’objectif de notre travail est de presenter la diversite de ces anomalies. Les uropathies malformatives sont les plus frequemment rapportees, parmi lesquelles les pyelectasies, les mega-ureteres et les valves de l’uretre posterieur. Les anomalies renales sont principalement l’hypodysplasie, le rein en fer en cheval et l’ectopie renale. Des facteurs favorisant l’insuffisance renale aigue sont egalement decrits : anomalies bilaterales et atteintes dites « mineures » comme par exemple les microkystes glomerulaires, les dilatations tubulaires et les glomerules immatures. Les lesions histologiques observees ne sont pas specifiques mais surviennent plus precocement que dans la population generale. Deux particularites metaboliques sont a noter : la baisse de la clairance de l’acide urique et l’hypercalciurie par hyperabsorption passive du calcium. Ces anomalies peuvent evoluer vers l’insuffisance renale terminale, soulevant la problematique du choix de la meilleure prise en charge. Les anomalies renales de la T21 meritent d’etre connues afin de preserver le pronostic fonctionnel renal, en proposant un depistage systematique par echographie renale et des voies urinaires.

RESUME Les hyperoxaluries primitives sont transmises sur le mode autosomique recessif; il s’agit d’affections rares et souvent graves, engageant alors le pronostic renal et parfois le pronostic vital, notamment dans les formes a debut precoce. Le type 1, le plus frequent, resulte d’un deficit enzymatique (alanine-glyoxylate aminotransferase) dans les peroxysomes du foie, a l’origine d’une hyperoxalurie qui s’exprime initialement par des calculs avec ou sans nephrocalcinose. Au fur et a mesure que la filtration glomerulaire diminue, une surcharge systemique apparait et n’epargne aucun organe, mais l’essentiel du stockage de l’oxalate est osseux. Le diagnostic repose sur l’oxalurie, puis le genotypage, car la confirmation du type d’hyperoxalurie est indispensable a la prise en charge et permet le diagnostic prenatal. Le traitement conservateur (pyridoxine, hydratation, inhibiteurs de la cristallisation) est essentiel et doit etre precoce. Aucune methode de dialyse n’est suffisamment efficace pour compenser la production d’oxalate, de sorte que la transplantation hepatique et renale doit etre planifiee avant le stade d’insuffisance renale avancee, pour limiter les degâts de la thesaurismose. Dans un avenir proche, de nouvelles therapeutiques — notamment ARN interferant — pourront remplacer ou completer la transplantation d’organes. Les hyperoxaluries primitives de type 2 et 3 sont plus rares et ont un phenotype moins severe.

We report three pediatric cases of concomitant congenital Horner and Harlequin syndromes. This association suggests a lesion at the superior cervical ganglion or just inferior. Often, no underlying lesion is documented.