Risk factors for childhood chronic kidney disease: a population-based study.

BACKGROUND: The population-based prevalence and risk factors of childhood chronic kidney disease (CKD) are not well-defined. We ascertained childhood CKD epidemiology and perinatal risk factors, based on a large computerized medical record database that covers most of southern Israel's population. METHODS: Pre- and post-natal records of 79,374 eligible children (with at least one serum creatinine test) born during 2001-2015 were analyzed. "Ever-CKD" was defined as ≥ 2 estimated glomerular filtration rate (eGFR) values < 60 ml/min/1.73 m2 beyond age 2 years, more than 3 months apart. The last CKD status was determined on March 2019. RESULTS: Of 82 (0.1%) patients with ever-CKD, 35 (42.7%) had their first abnormal eGFR identified already at age 2 years. In multiple logistic regression analysis, congenital anomalies of kidney and urinary tract (CAKUT)-related diagnoses, glomerulopathy, maternal oligohydramnios, small for gestational age, prematurity (under 34 weeks), post-term delivery, and small for gestational age at birth were significant risk factors for ever-CKD (odds ratio (95% confidence interval): 44.34(26.43-74.39), 64.60(32.42-128.70), 5.54(3.01-10.19), 2.02(1.25-3.28), 4.45(2.13-9.28), 2.96(1.28-6.86 and 2.02(1.25-3.28), respectively). Seventy children with ever-CKD (85.4%) had a depressed eGFR (< 90 ml/min/1.73 m2) on the last assessment (current-CKD), yielding a prevalence of 882/million. CONCLUSIONS: CKD is more prevalent among children in southern Israel than previously reported, even after excluding those with aborted-CKD. Prenatal conditions increase the risk to develop CKD in childhood. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information.

Glomerular involvement in children with H syndrome.

BACKGROUND: H syndrome is a multisystem inflammatory disease caused by mutations in the SLC29A3 gene (OMIM #602782). The protein product, hENT3, is a nucleoside transporter essential for DNA salvage synthesis. Clinical manifestations are hyperpigmentation, hypertrichosis, hepatosplenomegaly, hearing loss, heart anomalies, hypogonadism, short stature, skeletal deformities, and diabetes mellitus. Laboratory findings are consistent with inflammatory processes. Structural kidney anomalies have been described in 6% of patients. CASE REPORTS: Three family members with genetically diagnosed H syndrome (c.1279G>A, p.Gly427Ser). Two of them presented with hypoalbuminemia and nephrotic range proteinuria. Kidney ultrasound was normal. Kidney biopsy performed in one patient presenting with generalized peripheral pitting edema revealed membranous nephropathy. Different treatments including ACE inhibitors, corticosteroids, and immunomodulatory agents failed to improve the clinical outcome. CONCLUSIONS: Generalized peripheral pitting edema and glomerulopathy broaden the clinical spectrum of H syndrome. Periodic bloodwork and urinalysis are recommended.

[RENAL TUBULAR DYSGENESIS SECONDARY TO MUTATIONS IN GENES ENCODING THE RENIN-ANGIOTENSIN SYSTEM].

INTRODUCTION: Autosomal recessive renal tubular dysgenesis (RTD;OMIM: 267430) is a rare kidney disease secondary to mutations in genes encoding the renin-angiotensin system which have a role in renal tissue development during fetal life and in the maintenance of blood pressure and electrolyte balance. The disease is characterized by oligohydramnios, prematurity, neonatal renal failure, hypotension and abnormalities in cranial bone development. Nearly all affected individuals die either in-utero or within the first few days of life, although a few long term survivors were reported during the last decade. We describe the management of 5 newborns diagnosed with RTD in pregnancy who survived the neonatal period, four of them belong to an extended Bedouin family. In 4/5 patients we identified a mutation in angiotensin converting enzyme (ACE) gene. Variable presentation was noticed in the patients, starting with peritoneal dialysis and extreme low blood pressure treated with vasopressors and plasma infusions and ending with no symptoms. Currently, the patients are 5-20 years old with variable stages of chronic kidney disease. In conclusion, the spectrum of RTD is wider than previously reported. Prompt diagnosis is necessary for optimal decision-making by families and physicians. Intensive treatment of low blood pressure in the postnatal period is critical for their survival and better prognosis.

A novel SLC12A1 mutation in Bedouin kindred with antenatal Bartter syndrome type I.

Four affected individuals of consanguineous kindred presented at infancy with an apparently autosomal recessive syndrome of polyuria and hypokalemic metabolic alkalosis, following maternal polyhydramnios and premature delivery, culminating in severe failure to thrive. Hypercalciuria, nephrocalcinosis, and hyperaldosteronism were further apparent as well as an unusual finding of intermittent hypernatremia. Additionally, all patients demonstrated variable micrognathia with upper respiratory airway abnormalities. As neither postnatal hyperkalemia nor permanent hearing deficits were shown, clinical assessment was consistent with antenatal Bartter syndrome (ABS) type I, which was never described before in the Israeli Bedouin population. Through genome-wide linkage analysis, we identified a single ∼3.3 Mbp disease-associated locus on chromosome 15q21.1, segregating within the pedigree. Whole-exome sequencing revealed a single novel homozygous missense mutation within this locus, in SLC12A1, encoding the Na-K-Cl cotransporter, NKCC2, in accordance with the clinical diagnosis. In this concise study, we report a novel missense mutation within the SLC12A1 gene, causing a severe form of ABS type I, the first to be described in Israeli Bedouins, with unusual clinical features of hypernatremia caused by nephrogenic diabetes insipidus and putatively related micrognathia with upper airway abnormalities .

Hodgkin's lymphoma, nephrotic syndrome, and echinococcosis cysts: an unusual association and literature review.

We present a 5-year-old female with minimal change nephrotic syndrome (MCNS). Within several months, she became steroid-dependent with progression of edema and ascites. Imaging studies revealed abnormal solid mass and liver cysts and she was diagnosed with both abdominal Hodgkin's lymphoma (cHD) and large hepatic cystic echinococcosis (CE). Association between MCNS and cHL or with CE has been described in the literature in adults and rarely in the pediatric population. We report, for the first time, a simultaneous occurrence of all three: MCNS, cHL, and CE. Literature review and suggested pathophysiologic mechanisms underlying this phenomenon are presented.

Severe neutropenia in children after renal transplantation: incidence, course, and treatment with granulocyte colony-stimulating factor.

BACKGROUND: Infections are an important cause of morbidity and mortality in solid organ transplant recipients. Neutrophils play a crucial role in the initial host defense against bacterial pathogens. Neutropenia is not uncommon after renal transplantation in adults; however, there are scarce published data in children. We conducted a historical cohort study to evaluate the incidence, clinical course, and management of severe neutropenia after renal transplantation in children. METHODS: In a single-center study, we collected clinical and laboratory data on all children (<20 years) who underwent renal transplantation from January 2005 to March 2014. All post-transplantation blood counts were reviewed; the lowest absolute neutrophil count was recorded and correlated with clinical information and other laboratory findings. RESULTS: Of the 72 patients studied, 46 (64%) had at least one episode of neutropenia [absolute neutrophil count (ANC) <1500/µl] during the study period, 16 of whom (22%) had severe neutropenia (ANC < 500/µl), 2-11 months (median, 3.5) after renal transplantation. Work-up for viral infection or malignancy was performed. Initial management included dose decrease and subsequent discontinuation of antimetabolite, stopping co-trimoxazole and valganciclovir. Bone marrow aspiration in four children revealed normal marrow cellularity in all cases, with myelocyte maturational arrest in two. Eight children (11%) were treated with granulocyte colony-stimulating factor (G-CSF) (5 mcg/kg/day) 1-4 doses (median, 2), with excellent response in all and no adverse effects. Eight children presented with fever during severe neutropenia, and were treated with empiric antibiotics. Mycophenolate/azathioprine were resumed in all patients unless contraindicated (pre-existing BK viremia -1, PTLD -1). Recurrence of neutropenia was seen in five patients, only one of whom required further treatment with G-CSF. Graft function was preserved during and after resolution of neutropenia. Post-transplant neutropenia in children is common, and mostly occurs in the first few months. Its etiology is probably primarily a result of the combination of immunosuppressive agents and prophylactic treatment of infections in the early post-transplant period. CONCLUSIONS: Decreasing immunosuppressive or antimicrobial medications carries the risk of acute rejection or infection. Off-label treatment with G-CSF may present a safe and effective alternative.

X-linked C1GALT1C1 mutation causes atypical hemolytic uremic syndrome.

Hemolytic-uremic syndrome (HUS), mostly secondary to infectious diseases, is a common cause of acute kidney injury in children. It is characterized by progressive acute kidney failure due to severe thrombotic microangiopathy, associated with nonimmune, Coombs-negative hemolytic anemia and thrombocytopenia. HUS is caused mostly by Shiga toxin-producing E. Coli, and to a lesser extent by Streptococcus pneumonia. In Streptococcus pneumonia HUS (pHUS), bacterial neuraminidase A exposes masked O-glycan sugar residues on erythrocytes, known as the T antigen, triggering a complement cascade causing thrombotic microangiopathy. Atypical HUS (aHUS) is a life-threatening genetic form of the disease, whose molecular mechanism is only partly understood. Through genetic studies, we demonstrate a novel X-linked form of aHUS that is caused by a de-novo missense mutation in C1GALT1C1:c.266 C > T,p.(T89I), encoding a T-synthase chaperone essential for the proper formation and incorporation of the T antigen on erythrocytes. We demonstrate the presence of exposed T antigen on the surface of mutant erythrocytes, causing aHUS in a mechanism similar to that suggested in pHUS. Our findings suggest that both aHUS caused by mutated C1GALT1C1 and pHUS are mediated by the lectin-complement-pathway, not comprehensively studied in aHUS. We thus delineate a shared molecular basis of aHUS and pHUS, highlighting possible therapeutic opportunities.

Diagnostic Utility of Exome Sequencing Among Israeli Children With Kidney Failure.

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.