BackgroundX-linked hypophosphatemic rickets (XLH) is associated with uninhibited FGF23 activity, which leads to phosphaturia, hypophosphatemia and depressed active vitamin D (1,25OH2D) levels. Conventional treatment with phosphate supplements and vitamin D analogs may lead to hypercalciuria (HC), nephrocalcinosis (NC) and hyperparathyroidism. We investigated the effects of burosumab treatment, an anti-FGF23 monoclonal antibody recently approved for XLH, on these complications.MethodsThis retrospective study included children with XLH who were treated with burosumab for at least one year at one of three referral centers. Clinical and biochemical potential treatment outcomes were regularly followed, including multiple urine calcium measurements and NC severity score (0 = no NC, 3 = worse NC).ResultsTwenty-six (13 male) children aged 7.6 ± 3.9 years were followed for 27.5 ± 9.6 months. Mean serum phosphate levels rapidly increased from 2.67 ± 0.61 at baseline to 3.57 ± 0.53 mg/dL after 3 months (p < 0.001) and remained stable thereafter. Concomitant decreases were observed in phosphaturia, serum alkaline phosphatase and parathyroid hormone. HC (U-Ca/Cr > 0.2 mg/mg) was detected in 2/26 (7.7%) patients before burosumab initiation, resolved in one and persisted, albeit improved, in the second. Two patients were newly diagnosed with HC, 15 and 3 months after therapy, which persisted in one of them despite dose reduction attempts. Seven patients had NC at baseline (mean score: 1.8 ± 0.34), but none showed deterioration or developed new NC.ConclusionIn children with XLH treated with burosumab, HC was an infrequent side effect and preexisting NC did not worsen.

OBJECTIVE:To evaluate the risk for urinary tract infection (UTI) in infants with isolated hydronephrosis (IH). STUDY DESIGN:A retrospective, population-based study including all infants insured by Clalit Health Services and followed from birth to age 2 years in 3 regions of central Israel. Infants were divided into 3 groups based on electronic medical record diagnoses by age 6 months: (1) control: no urological diagnosis; (2) IH; and (3) complicated urological diagnosis (CUD): any additional nephrological/urological diagnosis with/without HN. The primary outcome was a diagnosis of UTI in the first 2 years of life. RESULTS:The cohort included 340 619 infants (52% male): 333 920 controls, 4369 with IH, and 2331 with CUD. Infants with IH were associated with a greater risk for UTI than control patients (17% vs 4%, P < .001). UTI risk for a male infant with IH was greater than for a female infant in the control group (12.6% vs 6.5%, P < .001). In a multivariable logistic regression analysis, both IH (OR 7.04; 95% CI 6.46-7.66) and CUD (OR 14.9; 95% CI 13.6-16.4) were independently associated with UTI. CONCLUSION:Infants with IH are at a greater risk for UTI in the first 2 years of life, supporting the recommendation for a high index of suspicion for UTI in this population.

Background:C3 Glomerulopathy (C3G) is a complement-mediated disease, with predominant C3 deposits, where pathogenic genetic variants in complement system components and circulating autoantibodies result in loss of control of the alternative pathway, have been described. A high incidence of disease recurrence including graft failure has been reported after kidney transplantation (KTx). Currently treatment modalities for preventing and treating post KTx C3G recurrence (plasma exchange, rituximab and eculizumab) in adults have yielded inconsistent results. Data on post KTx C3G recurrence in childhood-onset C3G is still unknown. Methods:A comprehensive case study of patients diagnosed with C3G as children or adolescents, who underwent KTx between the years 2015-2023. Data collected included complement workup, treatment modalities, and outcomes. Results:19 patients with C3G were identified during the study period. Five patients developed ESRD and received a kidney transplant. C3G recurrence was diagnosed post KTx in 100% of patients. Graft function improved in 3 of these patients (two with anti-factor H antibodies) after eculizumab treatment, one patient reached graft failure 9 months after transplantation despite eculizumab, recieved a second successful transplantation with pre-emptive eculizumab treatment and one patient showed histologic signs of disease recurrence without clinical signs. Conclusions:C3G recurrence after KTx in patients diagnosed as children or adolescents may be higher than previously described. Treatment with eculizumab is beneficial in some patients. New treatments are needed for improving post-transplant outcome in patients with C3G.

To determine the effect of non-reassuring fetal heart rate (NRFHR) patterns in labour on the postnatal renal function of neonates with a prenatal diagnosis of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). A retrospective cohort study was conducted in a single tertiary referral centre between 2012 and 2020. All cases with a prenatal diagnosis of CAKUT were extracted, and their fetal, maternal, obstetrical, and neonatal characteristics were analysed. Cases of multiple gestations, preterm delivery, small for gestational age, associated major malformations or genetic aberrations, and pre-labour acute obstetrical events were excluded from the analysis. The study group was comprised of patients who experienced NRFHR during labour. The control groups included (1) patients who had a trial of labour with a normal fetal heart rate pattern and (2) patients who delivered by elective Caesarean section (CS). The primary outcome was abnormal serum creatinine levels in the perinatal period. For statistical purposes, the CAKUT cases were classified into a low and high estimated risk for an abnormal postnatal renal outcome. A subgroup analysis of the results was performed accordingly. During the study period, 256 fetuses were diagnosed prenatally with CAKUT. Of them, 214 (83%) women underwent a trial of labour, and forty-two patients (17%) underwent an elective Caesarean Section. Of the patients who underwent a trial of labour, 21/214 (9.8%) experienced NRFHR during labour. No statistically significant between-group differences were found in maternal and fetal characteristics. NRFHR patterns were not associated with a deterioration in neonatal serum creatinine compared to those with normal fetal monitoring or those born by an elective CS. NRFHR patterns during labour and delivery did not impair neonatal renal function status in fetuses diagnosed prenatally with both low and high-risk CAKUT. Delivery can be managed according to standard obstetrical guidelines.

Introduction:Genetic etiologies are estimated to account for a large portion of chronic kidney diseases (CKD) in children. However, data are lacking regarding the true prevalence of monogenic etiologies stemming from an unselected population screen of children with advanced CKD. Methods:We conducted a national multicenter prospective study of all Israeli pediatric dialysis units to provide comprehensive "real-world" evidence for the genetic basis of childhood kidney failure in Israel. We performed exome sequencing and assessed the genetic diagnostic yield. Results:Between 2019 and 2022, we recruited approximately 88% (n = 79) of the children on dialysis from all 6 Israeli pediatric dialysis units. We identified genetic etiologies in 36 of 79 (45%) participants. The most common subgroup of diagnostic variants was in congenital anomalies of the kidney and urinary tract causing genes (e.g., EYA1, HNF1B, PAX2, COL4A1, and NFIA) which together explain 28% of all monogenic etiologies. This was followed by mutations in genes causing renal cystic ciliopathies (e.g., NPHP1, NPHP4, PKHD1, and BBS9), steroid-resistant nephrotic syndrome (e.g., LAGE3, NPHS1, NPHS2, LMX1B, and SMARCAL1) and tubulopathies (e.g., CTNS and AQP2). The genetic diagnostic yield was higher among Arabs compared to Jewish individuals (55% vs. 29%) and in children from consanguineous compared to nonconsanguineous families (63% vs. 29%). In 5 participants (14%) with genetic diagnoses, the molecular diagnosis did not correspond with the pre-exome diagnosis. Genetic diagnosis has a potential influence on clinical management in 27 of 36 participants (75%). Conclusion:Exome sequencing in an unbiased Israeli nationwide dialysis-treated kidney failure pediatric cohort resulted in a genetic diagnostic yield of 45% and can often affect clinical decision making.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause for chronic kidney disease below age 30 years. Many monogenic forms have been discovered due to comprehensive genetic testing like exome sequencing. However, disease-causing variants in known disease-associated genes only explain a proportion of cases. Here, we aim to unravel underlying molecular mechanisms of syndromic CAKUT in three unrelated multiplex families with presumed autosomal recessive inheritance. Exome sequencing in the index individuals revealed three different rare homozygous variants in FOXD2, encoding a transcription factor not previously implicated in CAKUT in humans: a frameshift in the Arabic and a missense variant each in the Turkish and the Israeli family with segregation patterns consistent with autosomal recessive inheritance. CRISPR/Cas9-derived Foxd2 knockout mice presented with a bilateral dilated kidney pelvis accompanied by atrophy of the kidney papilla and mandibular, ophthalmologic, and behavioral anomalies, recapitulating the human phenotype. In a complementary approach to study pathomechanisms of FOXD2-dysfunction-mediated developmental kidney defects, we generated CRISPR/Cas9-mediated knockout of Foxd2 in ureteric bud-induced mouse metanephric mesenchyme cells. Transcriptomic analyses revealed enrichment of numerous differentially expressed genes important for kidney/urogenital development, including Pax2 and Wnt4 as well as gene expression changes indicating a shift toward a stromal cell identity. Histology of Foxd2 knockout mouse kidneys confirmed increased fibrosis. Further, genome-wide association studies suggest that FOXD2 could play a role for maintenance of podocyte integrity during adulthood. Thus, our studies help in genetic diagnostics of monogenic CAKUT and in understanding of monogenic and multifactorial kidney diseases.

Background Kidney trans plantation is associated with secondary complications, including the risk of developing posttransplant cytopenias. This study aimed to evaluate the characteristics, identify predictors, and assess the management and consequences of cytopenias in the pediatric kidney transplant population. Methods This is a single-center retrospective analysis of 89 pediatric kidney transplant recipients. Possible factors preceding cytopenias were compared with the goal of recognizing predictors for posttransplant cytopenias. Posttransplant neutropenias were analyzed for the total study period and separately for the period beyond 6 months posttransplant (late neutropenias), to rule out confounding influences of induction and initial intensive therapy. Results Sixty patients (67%) developed at least one episode of posttransplant cytopenia. All episodes of posttransplant thrombocytopenias were mild or moderate. Posttransplant infections and graft rejection were found to be significant predictors for thrombocytopenia (HR 6.06, 95% CI 1.6–22.9, and HR 5.82, 95% CI 1.27–26.6, respectively). A total of 30% of posttransplant neutropenias were severe (ANC ≤ 500). Pretransplant dialysis and posttransplant infections were significant predictors for late neutropenias (HR 11.2, 95% CI 1.45–86.4, and HR 3.32, 95% CI 1.46–7.57, respectively). Graft rejection occurred in 10% of patients with cytopenia, all following neutropenia, within 3 months from cytopenia appearance. In all such cases, mycophenolate mofetil dosing had been held or reduced prior to rejection. Conclusions Posttransplant infections are substantial contributors to developing posttransplant cytopenias. Preemptive transplantation appears to reduce risk of late neutropenia, the accompanying reduction in immunosuppressive therapy, and the ensuing risk of graft rejection. An alternative response to neutropenia, possibly using granulocyte colony stimulating factor, may diminish graft rejection. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information

To assess the long-term efficacy of burosumab for pediatric patients with X-linked hypophosphatemia, focusing on linear growth. This multi-center retrospective study included 35 pediatric patients who began treatment with burosumab between January 2018 and January 2021. We collected clinical data, anthropometric measurements, laboratory results, and Rickets Severity Score (RSS), from 2 years prior to treatment initiation and up to 4 years after. Burosumab was initiated at a mean age of 7.5 ± 4.4 years (range 0.6–15.9), with a mean initial dose of 0.8 ± 0.3 mg/kg, which was subsequently increased to 1.1 ± 0.4 mg/kg. The patients were followed for 2.9 ± 1.4 years (range 1–4) after initiating burosumab. Serum phosphorus levels increased from 2.7 ± 0.8 mg/dl at burosumab initiation to 3.4 ± 0.6 mg/dl after 3 months and remained stable (p < 0.001). Total reabsorption of phosphorus increased from 82.0 ± 6.8 to 90.1 ± 5.3

Objective This study aimed to determine the effect of nonreassuring fetal heart rate (NRFHR) patterns in labor on the postnatal renal function of neonates with a prenatal diagnosis of congenital anomalies of the kidney and urinary tract (CAKUT). Study Design A retrospective cohort study was conducted in a single tertiary referral center between 2012 and 2020. All cases with a prenatal diagnosis of CAKUT were extracted, and their fetal, maternal, obstetrical, and neonatal characteristics were analyzed. Cases of multiple gestations, preterm delivery, small for gestational age, major associated malformations or genetic aberrations, and prelabor acute obstetrical events were excluded from the analysis. The study group was comprised of patients who experienced NRFHR during labor. The control groups included (1) patients who had a trial of labor with a normal fetal heart rate pattern and (2) patients who delivered by elective cesarean section (CS). The primary outcome was abnormal serum creatinine levels in the perinatal period. For statistical purposes, the CAKUT cases were classified into a low and high estimated risk for an abnormal postnatal renal outcome. A subgroup analysis of the results was performed accordingly. Results Two hundred and fifty-six fetuses diagnosed prenatally with CAKUT comprised the study group. Among these, 214 women (83%) opted for a labor trial, while 42 (17%) chose elective CS. Within the labor trial group, 21/214 patients (9.8%) experienced NRFHR during labor. Analysis of maternal and fetal characteristics revealed no statistically significant disparities between the groups. NRFHR patterns were not associated with a deterioration in neonatal serum creatinine compared with those with normal fetal monitoring or those born by an elective CS. Conclusion NRFHR patterns during labor and delivery did not impair neonatal renal function status in fetuses diagnosed prenatally with low- and high-risk CAKUT. Delivery can be managed according to standard obstetrical guidelines. Key Points

To assess the accuracy of prenatal sonographic estimation of renal dysplasia and reduced renal function compared to objective postnatal renal scintigraphy. A retrospective cohort study was conducted in a single tertiary referral centre. Cases diagnosed prenatally with CAKUT, maintained follow-up in the pediatric nephrology institute, and underwent renal scintigraphy, comprised the study group. Prenatal ultrasounds were revised and classified for the risk for dysplasia and future renal function according to the renal parenchymal appearance (thickness, echogenicity, cysts). Cases that demonstrated intrauterine renal failure were excluded. The possibility for renal dysplasia was compared to postnatal renal scintigraphy results (mild and severe dysplasia). A total of 116 kidneys were evaluated (58 cases). The final diagnosis was ureteropelvic junction obstruction in 34 cases, vesicoureteral reflux in 9 cases, and other diagnoses such as posterior urethral valve, ureterocele, and ureterovesical junction obstruction in the remaining cases. Overall, 50 kidneys had dysplastic features on postnatal renal scintigraphy. The sensitivity, specificity, PPV, and NPV for prenatal classification of renal dysplasia were 76%, 84%, 70.5%, and 68.3%, respectively. Although postnatal renal scintigraphy is not performed routinely, the presented results shed light on the prenatal ability to predict renal dysplasia in CAKUT. Estimating renal parenchyma is subjective and operator-dependent, and the predictive value is currently suboptimal even in a tertiary referral centre. Creation of objective tools may improve the predictive ability of prenatal ultrasound to predict postnatal renal function.

RATIONALE & OBJECTIVE:Keratin-based hair-straightening treatment is a popular hair-styling method. The majority of keratin-based hair-straightening products in Israel contain glycolic acid derivatives, which are considered safe when used topically. Systemic absorption of these products is possible, and anecdotal reports have described kidney toxicity associated with their use. We report a series of cases of severe acute kidney injury (AKI) following use of hair-straightening treatment in Israel during the past several years.STUDY DESIGN:Case series.SETTING & PARTICIPANTS:We retrospectively identified 26 patients from 14 medical centers in Israel who experienced severe AKI and reported prior treatment with hair-straightening products in 2019-2022.FINDINGS:The 26 patients described had a median age of 28.5 (range, 14-58) years and experienced severe AKI following a hair-straightening procedure. The most common symptoms at presentation were nausea, vomiting, and abdominal pain. Scalp rash was noted in 10 (38%) patients. Two patients experienced a recurrent episode of AKI following a repeat hair-straightening treatment. Seven patients underwent kidney biopsies, which demonstrated intratubular calcium oxalate deposition in 6 and microcalcification in tubular cells in 1. In all biopsies, signs of acute tubular injury were present, and an interstitial infiltrate was noted in 4 cases. Three patients required temporary dialysis.LIMITATIONS:Retrospective uncontrolled study, small number of kidney biopsies.CONCLUSIONS:This series describes cases of AKI with prior exposure to hair-straightening treatments. Acute oxalate nephropathy was the dominant finding on kidney biopsies, which may be related to absorption of glycolic acid derivatives and their metabolism to oxalate. This case series suggests a potential underrecognized cause of AKI in the young healthy population. Further studies are needed to confirm this association and to assess the extent of this phenomenon as well as its pathogenesis.

BACKGROUND:Transition from pediatric to adult care services is a complex process, carrying medical, psychosocial and emotional issues. It is known that, during this period, patients may drop-out from follow-up, lose their adherence and suffer from psychosocial complications. This period is prone to rejection of the transplanted kidney. Managing this process correctly, can empower the young adult and make him a better and more compliant patient. The study aimed to create a new model for the Transition Clinic and analyze its impact on the transition process of young transplanted patients. METHODS:A new model of the Transition Clinic, included a multidisciplinary team - nephrologist, transplant coordinator, psychologist and social worker who built a "custom made" transition process for each patient according to his needs. The process ended with a gathering including a group of patients awaiting transfer, the transition clinic staff and staff from the hospitals that will follow-up these patients. During the study period patients answered quality questionnaires. RESULTS:A total of 32 patients have already participated in the new transition program. Participants reported that the process met their transition needs regarding informational, emotional and social issues. Most participants (59%) reported being "well-prepared", 29% reported being 'ready' and felt that the transition process helped them be more active and responsible for their medical care. The group gathering at the end of the process was a substantial component, allowing them to meet other transitioning young adults and soften the transition itself. CONCLUSIONS:Our model of Transition Clinic may be proposed for improving the transition process and optimizing the continuity of care, adherence and compliance to the medical treatment of kidney transplanted patients.

Histiocytoses are inflammatory myeloid neoplasms often driven by somatic activating mutations in mitogen-activated protein kinase (MAPK) cascade genes. H syndrome is an inflammatory genetic disorder caused by germ line loss-of-function mutations in SLC29A3, encoding the lysosomal equilibrative nucleoside transporter 3 (ENT3). Patients with H syndrome are predisposed to develop histiocytosis, yet the mechanism is unclear. Here, through phenotypic, molecular, and functional analysis of primary cells from a cohort of patients with H syndrome, we reveal the molecular pathway leading to histiocytosis and inflammation in this genetic disorder. We show that loss of function of ENT3 activates nucleoside-sensing toll-like receptors (TLR) and downstream MAPK signaling, inducing cytokine secretion and inflammation. Importantly, MEK inhibitor therapy led to resolution of histiocytosis and inflammation in a patient with H syndrome. These results demonstrate a yet-unrecognized link between a defect in a lysosomal transporter and pathological activation of MAPK signaling, establishing a novel pathway leading to histiocytosis and inflammation.

BACKGROUND:Differences in serologic response to COVID-19 infection or vaccination were reported in adult kidney transplant recipients (KTR) compared to non-immunocompromised patients. This study aims to compare the serologic response of naturally infected or vaccinated pediatric KTR to that of controls. METHODS:Thirty-eight KTR and 42 healthy children were included; aged ≤18 years, with a previously confirmed COVID-19 infection or post COVID-19 vaccination. Serological response was measured by anti-spike protein IgG antibody titers. Response post third vaccine was additionally assessed in KTR. RESULTS:Fourteen children in each group had previously confirmed infection. KTR were significantly older and developed a 2-fold higher antibody titer post-infection compared to controls [median (interquartile range [IQR]) age: 14.9 (7.8, 17.5) vs. 6.3 (4.5, 11.5) years, p = 0.02; median (IQR) titer: 1695 (982, 3520) vs. 716 (368, 976) AU/mL, p = 0.03]. Twenty-four KTR and 28 controls were vaccinated. Antibody titer was lower in KTR than in controls [median (IQR): 803 (206, 1744) vs. 8023 (3032, 30,052) AU/mL, p < 0.001]. Fourteen KTR received third vaccine. Antibody titer post booster in KTR reached similar levels to those of controls post two doses [median (IQR) 5923 (2295, 12,278) vs. 8023 (3034, 30,052) AU/mL, p = 0.37] and to KTR post natural infection [5282 AU/mL (2583, 13,257) p = 0.8]. CONCLUSION:Serologic response to COVID-19 infection was significantly higher in KTR than in controls. Antibody level in KTR was higher in response to infection vs. vaccination, contrary to reports in the general population. Response to vaccination in KTR reached levels comparable to controls only after third vaccine.