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For three decades, the international Banff classification has been the gold standard for kidney allograft rejection diagnosis, but this system has become complex over time with the integration of multimodal data and rules, leading to misclassifications that can have deleterious therapeutic consequences for patients. To improve diagnosis, we developed a decision-support system, based on an algorithm covering all classification rules and diagnostic scenarios, that automatically assigns kidney allograft diagnoses. We then tested its ability to reclassify rejection diagnoses for adult and pediatric kidney transplant recipients in three international multicentric cohorts and two large prospective clinical trials, including 4,409 biopsies from 3,054 patients (62.05% male and 37.95% female) followed in 20 transplant referral centers in Europe and North America. In the adult kidney transplant population, the Banff Automation System reclassified 83 out of 279 (29.75%) antibody-mediated rejection cases and 57 out of 105 (54.29%) T cell-mediated rejection cases, whereas 237 out of 3,239 (7.32%) biopsies diagnosed as non-rejection by pathologists were reclassified as rejection. In the pediatric population, the reclassification rates were 8 out of 26 (30.77%) for antibody-mediated rejection and 12 out of 39 (30.77%) for T cell-mediated rejection. Finally, we found that reclassification of the initial diagnoses by the Banff Automation System was associated with an improved risk stratification of long-term allograft outcomes. This study demonstrates the potential of an automated histological classification to improve transplant patient care by correcting diagnostic errors and standardizing allograft rejection diagnoses. ClinicalTrials.gov registration: NCT05306795 . A decision-support system that automates the Banff classification system for diagnosis of kidney allograft rejection leads to reclassification and correction of pathologists’ diagnoses and improves risk stratification of allograft outcomes.

Congenital nephrotic syndrome (CNS) is a heterogeneous group of disorders characterized by nephrotic-range proteinuria, hypoalbuminaemia and oedema, which manifest in utero or during the first 3 months of life. The main cause of CNS is genetic defects in podocytes; however, it can also be caused, in rare cases, by congenital infections or maternal allo-immune disease. Management of CNS is very challenging because patients are prone to severe complications, such as haemodynamic compromise, infections, thromboses, impaired growth and kidney failure. In this consensus statement, experts from the European Reference Network for Kidney Diseases (ERKNet) and the European Society for Paediatric Nephrology (ESPN) summarize the current evidence and present recommendations for the management of CNS, including the use of renin–angiotensin system inhibitors, diuretics, anticoagulation and infection prophylaxis. Therapeutic management should be adapted to the clinical severity of the condition with the aim of maintaining intravascular euvolaemia and adequate nutrition, while preventing complications and preserving central and peripheral vessels. We do not recommend performing routine early nephrectomies but suggest that they are considered in patients with severe complications despite optimal conservative treatment, and before transplantation in patients with persisting nephrotic syndrome and/or a WT1-dominant pathogenic variant.Here, experts from the European Reference Network for Kidney Diseases and the European Society for Paediatric Nephrology present recommendations for the management of congenital nephrotic syndrome, including the use of renin–angiotensin system inhibitors, diuretics, anticoagulation and infection prophylaxis.

Background Rare diseases affect approximately 400 million people worldwide. Many of them suffer from delayed diagnosis. Among them, NPHP1 -related renal ciliopathies need to be diagnosed as early as possible as potential treatments have been recently investigated with promising results. Our objective was to develop a supervised machine learning pipeline for the detection of NPHP1 ciliopathy patients from a large number of nephrology patients using electronic health records (EHRs). Methods and results We designed a pipeline combining a phenotyping module re-using unstructured EHR data, a semantic similarity module to address the phenotype dependence, a feature selection step to deal with high dimensionality, an undersampling step to address the class imbalance, and a classification step with multiple train-test split for the small number of rare cases. The pipeline was applied to thirty NPHP1 patients and 7231 controls and achieved good performances (sensitivity 86% with specificity 90%). A qualitative review of the EHRs of 40 misclassified controls showed that 25% had phenotypes belonging to the ciliopathy spectrum, which demonstrates the ability of our system to detect patients with similar conditions. Conclusions Our pipeline reached very encouraging performance scores for pre-diagnosing ciliopathy patients. The identified patients could then undergo genetic testing. The same data-driven approach can be adapted to other rare diseases facing underdiagnosis challenges.

N 6 -threonyl-carbamoylation of adenosine 37 of ANN-type tRNAs (t 6 A) is a universal modification essential for translational accuracy and efficiency. The t 6 A pathway uses two sequentially acting enzymes, YRDC and OSGEP, the latter being a subunit of the multiprotein KEOPS complex. We recently identified mutations in genes encoding four out of the five KEOPS subunits in children with Galloway-Mowat syndrome (GAMOS), a clinically heterogeneous autosomal recessive disease characterized by early-onset steroid-resistant nephrotic syndrome and microcephaly. Here we show that mutations in YRDC cause an extremely severe form of GAMOS whereas mutations in GON7 , encoding the fifth KEOPS subunit, lead to a milder form of the disease. The crystal structure of the GON7/LAGE3/OSGEP subcomplex shows that the intrinsically disordered GON7 protein becomes partially structured upon binding to LAGE3. The structure and cellular characterization of GON7 suggest its involvement in the cellular stability and quaternary arrangement of the KEOPS complex. The biosynthesis of N 6 -threonylcarbamoylated adenosine 37 in tRNA (t 6 A) involves the YRDC enzyme and the KEOPS complex. Here, the authors report mutations in YRDC and the KEOPS component GON7 in Galloway-Mowat syndrome and determine the crystal structure of a GON7-containg subcomplex that suggests a role in KEOPS complex stability.

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) defined by the triad of hemolytic anemia, thrombocytopenia, and acute kidney injury. Microthrombi develop in the glomerular capillaries secondary to endothelial damage and exert shear stress on red blood cells, consume platelets, and contribute to renal dysfunction and failure. Per current understanding of pathophysiology, HUS is classified into infectious, secondary, and atypical disease. The most common etiology is infectious sequelae of Shiga toxin-producing (STEC); other causative organisms include shigella and salmonella. Secondary HUS arises from cancer, chemotherapy, solid organ and hematopoietic stem cell transplant, pregnancy, or autoimmune disorders. Primary atypical hemolytic-uremic syndrome (aHUS) is associated with genetic mutations in complement and complement regulatory proteins. Under physiologic conditions, complement regulators keep the alternative complement system continuously active at low levels. In times of inflammation, mutations in complement-related proteins lead to uncontrolled complement activity. The hyperactive inflammatory state leads to glomerular endothelial damage, activation of the coagulation cascade, and TMA findings. Atypical hemolytic-uremic syndrome is a rare disorder with a prevalence of 2.21 to 9.4 per million people aged 20 years or younger; children between the ages of 0 and 4 are most affected. Multidisciplinary health care is necessary for timely management of its extra-renal manifestations. These include vascular disease of the heart, brain, and skin, pulmonary hypertension and hemorrhage, and pregnancy complications. Adequate screening is required to monitor for sequelae. First-line treatment is the monoclonal antibody eculizumab, but several organ systems may require specialized interventions and coordination of care with sub-specialists.

Levamisole is effectively used in steroid-dependent nephrotic syndrome and the more frequent side effects reported are cytopenia and liver enzymes alterations. Several studies have demonstrated that this drug can induce high titers of circulating perinuclear antineutrophil cytoplasmic autoantibodies (ANCA) and vasculitis, most of them occurring in the case of prolonged use. A four-year-old boy that was affected with steroid-dependent nephrotic syndrome was treated with Levamisole as a steroid-sparing agent at a dose of 2 mg/kg/48 h. After initiation of the treatment, the number of relapses drastically decreased, enabling a significant reduction in the cumulative steroid dose. Levamisole was well tolerated, and was therefore administered for several years. At the age of 15, he was also diagnosed with celiac disease. After nine years of continuous Levamisole treatment, he presented with a high fever, hand and foot joint arthritis, and increased levels of total and direct bilirubin. Since the symptoms started two days after the injection of the second dose of the COVID-19 vaccine, it was initially concluded that these manifestations were rare vaccination side effects. Therefore, he did not receive any specific treatments, and Levamisole was continued at the same dose. After an initial improvement, two months later, the patient presented with the same symptoms. Suspecting Levamisole-induced vasculitis, an ANCA titer was measured and this returned positive. Clinical manifestations and double positivity for both myeloperoxidase (MPO) and anti-proteinase 3 (PR3) antibodies argued against the fact that that these findings were secondary to vaccination, cocaine abuse, or celiac disease. Assuming that we were facing a rare drug reaction, Levamisole was promptly interrupted. This resulted in a rapid remission of fever and arthritis improvement, and a decrease in ANCA titers. By reporting this case, we want to raise awareness among clinicians regarding a rare complication of treatment with Levamisole that is often misdiagnosed due to the fact that the current literature lacks univocal guidelines regarding the precise timing of ANCA titrations and the duration of the treatment.

Introduction Lupus nephritis (LN) is a severe manifestation of pediatric systemic lupus erythematosus (pSLE). This study aims to describe the epidemiology, clinical, biological, histological features and prognosis of pediatric LN in the Afro-descendant (AD) population of the French Overseas Departments of America. Methods We conducted a retrospective and longitudinal multicenter study of pediatric LN patients from January 2000 to June 2024. Patients were identified from multiple sources including pediatricians’ registries, pathologist’s registries for kidney biopsies, national registry for rare diseases and referral centers. Data were collected from medical records. Diagnostic criteria for pSLE kidney impairment were based on international classifications. Results Twenty-seven patients with pediatric LN were included. The mean age at diagnosis was 11.3 years (range: 6–17) and mean follow-up duration was 7.5 years (range: 0.3–27). Kidney involvement (75% of ISN/RPS class III/IV) was present at pSLE diagnosis in 55% of patients. Kidney flares occurred more frequently in patients under 12 years of age at diagnosis, with an average of 1.7 flares per patient ( p  = 0.03). The mean number of background therapy per patient during follow up was 2.5 (1–5) with a majority ( n  = 15, 55%) receiving glucocorticoids and mycophenolate mofetil as first line. Six patients (22%) had an eGFR below 60 ml/min/1.73m 2 at the last follow-up (2 patients on dialysis, 2 had kidney transplants). Conclusion This study represents the largest cohort of pediatric LN in AD population. Younger patients exhibited more frequent kidney flares, particularly within the first two years of diagnosis. Overall outcomes in pediatric LN showed a higher rate of dialysis and kidney failure than in Caucasian series. Clinical trial number Not applicable. Key messages 1. Largest cohort of pediatric patients with lupus nephritis of Afro-Caribbean origin. 2. More kidney flares correlated with younger age at onset. 3. At the last follow-up (mean 7.5 years), one quarter had chronic kidney disease 3–5 (GFR<60 ml/min/1.73m2). 4. Influenced by neighboring low-income countries, our patients had worse kidney outcomes than Caucasians.

Background Distal renal tubular acidosis (dRTA) is a rare disease characterized by hyperchloremic metabolic acidosis affecting growth, bone and kidney health. Methods The aim of B22CS study was to evaluate long-term safety and efficacy (anthropometric/pubertal, tubular damages/kidney function, bone biomarkers, compliance assessments) of Sibnayal ® , a prolonged-release alkalinizing formulation with twice daily dosing, in children and adults with dRTA. All patients were previously included in the pivotal B21CS study, so were already receiving Sibnayal ® when included in B22CS open-label follow-up study. Results A total of 30 patients with primary dRTA (mean age:10.6 ± 6.0 years) entered this long-term study (average of 6 years). At inclusion, most patients had adequate metabolic control, normal kidney function and height. Sibnayal ® was well tolerated over the study duration.The most frequent adverse event was hypovitaminosis D (13 patients). Causality to treatment was reported for only 4% of all TEAEs (6 patients) and were mostly gastrointestinal. All adverse events resolved without treatment discontinuation. Sibnayal ® allowed a sustained control of metabolic acidosis as plasma bicarbonate level was 22.0 ± 3.2 mmol/L at baseline versus 22.6 ± 2.5 mmol/L at the End of Follow-up (EoF), p = NS. From baseline to EoF, mean Z-score height significantly increased (-0.6 ± 1.0 to -0.3 ± 1.0, p  = 0.03), without significant change in weight and body mass index. Kidney function remained stable from baseline to EoF: estimated glomerular filtration rate = 105 ± 17 and 104 ± 20 mL/min/1.73m 2 , respectively, p = NS. Urinary ratios: Calcium/Creatinine (UCa/UCr), Citrate/Creatinine (UCi/UCr), Calcium/Citrate (UCa/UCi) were not significantly different between baseline and EoF (p = NS). Mean lumbar bone mineral density Z-score significantly increased from baseline (-1.1 ± 1.0) to EoF (-0.8 ± 1.0), p  = 0.005, with significant improvement between baseline and EoF in pre- and post-pubertal patients ( p  = 0.035 and p  < 0.001, respectively), whilst it was maintained in pubertal patients (p = NS). Conclusion Long-term data support the good safety and efficacy profile of Sibnayal ® in the treatment of dRTA with adequate control of metabolic acidosis, stable kidney function and significant positive long-term clinical outcomes.

Background Chronic kidney disease (CKD) is one of the main long-term prognosis factors in methylmalonic acidemia (MMA), a rare disease of propionate catabolism. Our objective was to precisely address the clinical and biological characteristics of long-term CKD in MMA adolescent and adult patients. Patients and methods In this retrospective study, we included MMA patients older than 13 years who had not received kidney and/or liver transplantation. We explored tubular functions, with special attention to proximal tubular function. We measured glomerular filtration rate (mGFR) by iohexol clearance and compared it to estimated glomerular filtration rate (eGFR) by Schwartz formula and CKD-EPI. Results Thirteen patients were included (M/F = 5/8). Median age was 24 years (13 to 32). Median mGFR was 57 mL/min/1.73 m 2 (23.3 to 105 mL/min/1.73 m 2 ). Ten out of 13 patients had mGFR below 90 mL/min/1.73 m 2 . No patient had significant glomerular proteinuria. No patient had complete Fanconi syndrome. Only one patient had biological signs suggestive of incomplete proximal tubulopathy. Four out of 13 patients had isolated potassium loss, related to a non-reabsorbable anion effect of urinary methylmalonate. Both Schwartz formula and CKD-EPI significantly overestimated GFR. Bias were respectively 16 ± 15 mL/min/1.73 m 2 and 37 ± 22 mL/min/1.73 m 2 . Conclusion CKD is a common complication of the MMA. Usual equations overestimate GFR. Therefore, mGFR should be performed to inform therapeutic decisions such as dialysis and/or transplantation. Mild evidence of proximal tubular dysfunction was found in only one patient, suggesting that other mechanisms are involved.

IntroductionThere is an unmet clinical need for the development of novel treatment strategies to improve the outcome of children with frequent relapsing or steroid-dependent nephrotic syndrome. Obinutuzumab (OBI) is a second-generation anti-CD20 monoclonal antibody that has demonstrated its superiority to rituximab (RTX) in vitro and in vivo. Our assumption is that a single infusion of low-dose OBI will induce longer B-cell depletion, longer sustained remission and reduce the frequency of relapses and the use of oral immunosuppressors compared with a single infusion of RTX.Methods and analysisWe conduct a double-blind, multicentre, randomised, parallel group in a 1:1 ratio controlled trial. In the experimental group, patients receive 1 infusion of OBI (300 mg/1.73 m2) and in the control group, the patients receive 1 infusion of RTX (375 mg/m2). The primary outcome of the study is the occurrence of the first relapse within 12 months following the initiation of treatment and secondary outcomes include the time to first relapse, the total number of relapses during the 24-month follow-up period, and any adverse events such as infusion-related complications, infectious complications, hypogammaglobulinaemia and neutropenia.Ethics and disseminationThe study has been approved by the ethics committee (Comité de Protection des Personnes) of Sud Méditerrannée 2 and authorised by the French drug regulatory agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé). Results of the primary study and the secondary aims will be disseminated through peer-reviewed publications.Trial registration numberNCT05786768.Eudract N°2022-003336-59.