Simultaneous Renal Transplantation With Bilateral Nephrectomy and Ureterocystoplasty.

Bladder augmentation (BA) may be required before renal transplantation in children with end stage renal disease (ESRD). Herein we report a case of a 7-year-old boy with ESRD, contracted bladder and severe bilateral reflux secondary to posterior urethral valve (PUV), successfully managed by simultaneous bilateral nephrectomy, bilateral ureterocystoplasty and renal transplantation.

Acute hemodialysis therapy in neonates with inborn errors of metabolism.

BACKGROUND: Inborn errors of metabolism (IEM), including organic acidemias and urea cycle defects, are characterized by systemic accumulation of toxic metabolites with deleterious effect on the developing brain. While hemodialysis (HD) is most efficient in clearing IEM-induced metabolic toxins, data regarding its use during the neonatal period is scarce. METHODS: We retrospectively summarize our experience with HD in 20 neonates with IEM-induced metabolic intoxication (seven with maple syrup urine disease, 13 with primary hyperammonia), over a 16-year period, between 2004 and 2020. All patients presented with IEM-induced neurologic deterioration at 48 h to 14 days post-delivery, and were managed with HD in a pediatric intensive care setting. HD was performed through an internal jugular acute double-lumen catheter (6.5-7.0 French), using an AK-200S (Gambro, Sweden) dialysis machine and tubing, with F3 or FXpaed (Fresenius, Germany) dialyzers. RESULTS: Median (interquartile range) age and weight at presentation were 5 (3-8) days and 2830 (2725-3115) g, respectively. Two consecutive HD sessions decreased the mean leucine levels from 2281 ± 631 to 179 ± 91 µmol/L (92.1% reduction) in MSUD patients, and the mean ammonia levels from 955 ± 444 to 129 ± 55 µmol/L (86.5% reduction), in patients with hyperammonemia. HD was uneventful in all patients, and led to marked clinical improvement in 17 patients (85%). Three patients (15%) died during the neonatal period, and four died during long-term follow-up. CONCLUSIONS: Taken together, our results indicate that HD is safe, effective, and life-saving for most neonates with severe IEM-induced metabolic intoxication, when promptly performed by an experienced and multidisciplinary team. A higher resolution version of the Graphical abstract is available as Supplementary information.

[INTRAVENOUS IMMUNOGLOBULIN TREATMENT TO PREVENT BK NEPHROPATHY IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS WITH BK VIRUS].

AIMS: In this retrospective study we examined the safety and efficacy of high-dose intravenous immunoglobulin (HD-IVIG) therapy in preventing BKVN in pediatric renal transplant recipients with BK-viremia/viruria. BACKGROUND: BK virus nephropathy (BKVN) is diagnosed in 5-16% of pediatric renal transplant recipients and is preceded by BK viremia/viruria. Despite irreversible renal damage associated with BKVN, there is a lack of evidence-based guidelines for preventive measures in patients with BK viremia/viruria. METHODS: All pediatric renal transplant recipients under our care underwent routine testing for urine and blood BK virus, using the polymerase chain reaction (PCR) technique. Patients exhibiting BK-viruria < 107 copies/milliliter (ml) and/or BK-viremia<103 copies/ml without any evidence of BKVN, were managed with 50% dose reduction of the immunosuppressive drug mycophenolate mofetil (MMF). Absence of BK viral load decline within two months from MMF dose reduction was managed with HD-IVIG (at 2 grams/kg body weight). RESULTS: The study included 62 patients over a 6-year period; 31 patients (50%) showed BK-viremia/viruria; 13/31 patients (42%) suffered from significant and persistent BK-viremia/viruria, unresponsive to MMF dose reduction, and were managed with HD-IVIG; 12/13 (92%) showed significant BK viral load reduction within 6 months from HD-IVIG therapy. Except for transient headache, no patient exhibited major adverse effects to HD-IVIG therapy, and none developed overt BKVN during the study period. CONCLUSIONS: Preventive HD-IVIG therapy in pediatric renal transplant recipients with BK viremia/viruria unresponsive to MMF dose reduction is safe and effective in preventing the development of BKVN. Additional large-scale studies are necessary to establish our findings.

A Novel Homozygous In-Frame Deletion in Complement Factor 3 Underlies Early-Onset Autosomal Recessive Atypical Hemolytic Uremic Syndrome - Case Report.

Background and Objectives: Atypical hemolytic uremic syndrome (aHUS) is mostly attributed to dysregulation of the alternative complement pathway (ACP) secondary to disease-causing variants in complement components or regulatory proteins. Hereditary aHUS due to C3 disruption is rare, usually caused by heterozygous activating mutations in the C3 gene, and transmitted as autosomal dominant traits. We studied the molecular basis of early-onset aHUS, associated with an unusual finding of a novel homozygous activating deletion in C3. Design Setting Participants & Measurements: A male neonate with eculizumab-responsive fulminant aHUS and C3 hypocomplementemia, and six of his healthy close relatives were investigated. Genetic analysis on genomic DNA was performed by exome sequencing of the patient, followed by targeted Sanger sequencing for variant detection in his close relatives. Complement components analysis using specific immunoassays was performed on frozen plasma samples from the patient and mother. Results: Exome sequencing revealed a novel homozygous variant in exon 26 of C3 (c.3322_3333del, p.Ile1108_Lys1111del), within the highly conserved thioester-containing domain (TED), fully segregating with the familial disease phenotype, as compatible with autosomal recessive inheritance. Complement profiling of the patient showed decreased C3 and FB levels, with elevated levels of the terminal membrane attack complex, while his healthy heterozygous mother showed intermediate levels of C3 consumption. Conclusions: Our findings represent the first description of aHUS secondary to a novel homozygous deletion in C3 with ensuing unbalanced C3 over-activation, highlighting a critical role for the disrupted C3-TED domain in the disease mechanism.

Hemolytic Uremic Syndrome: A Contemporary Pediatric Experience.

BACKGROUND: Hemolytic uremic syndrome (HUS) is a significant cause for complicated acute kidney injury. In Western countries, >90% of HUS are Shiga toxin Escherichia coli (STEC) associated. METHODS: This is a retrospective review of all Israeli children diagnosed with HUS in 4 major medical centers in Israel during 1999-2016. Patients were categorized into 4 HUS etiological groups according to international guidelines: I, inherited or acquired damage to the complement cascade ("atypical HUS" [aHUS]); II, infection associated ("typical" HUS - STEC associated, Pneumococcus); III, coexisting disease; IV: other and unknown causes. RESULTS: Seventy-five children with HUS were identified; the mean annual incidence was 1.5 ± 0.7 cases/106 per year. Distribution according to etiological groups was: I: 24.0%; II: 14.7%; III: 9.3%; IV: 52.0%. Group I comprised high proportions of Arabs (55.6%), children of consanguineous parents (61.0%), and hypertension. Group II included a high proportion of children with diarrhea on presentation and central nervous system involvement. Only 5 (6.6%) had proven STEC-HUS. Group IV was similar in most characteristics to group II. Logistic regression analysis revealed 3 independent factors associated with the diagnosis of aHUS: consanguinity, lack of diarrhea, and lack of leukocytosis at presentation. Receiver operating analysis curve showed an area under the curve of 0.9 (95% CI 0.82-0.98). CONCLUSIONS: HUS incidence is lower in Israel than in most countries, especially because STEC-HUS is very rare. aHUS is the largest defined etiological group; some distinctive characteristics were identified that could facilitate its diagnosis. The current classification system leaves a high rate of "unknown cause" HUS.

Long-term hemodialysis therapy in neonates and infants with end-stage renal disease: a 16-year experience and outcome.

BACKGROUND: Peritoneal dialysis is the preferred mode of renal replacement therapy in infants with end-stage renal disease (ESRD). Hemodialysis (HD) is seldom used in neonates and infants due to the risk of major complications in the very young. METHODS: Demographic, clinical, laboratory, and imaging data on all infants younger than 12 months with ESRD who received HD in our Pediatric Dialysis Unit between January 1997 and June 2013 were analyzed. RESULTS: Eighteen infants (n = 6 male) with ESRD (median age 3 months; median weight 4.06 kg) received HD through a central venous catheter (CVC) for a total of 543 months (median duration per infant 16 months). Seven of the infants (39%) were neonates, and five (28%) had serious comorbidities. There were five episodes of CVC infection, which is a rate of 0.3/1000 CVC days. Median catheter survival time was 320 days. Most infants had good oral intake, and only four (22%) required a gastric tube; 14 (78%) infants displayed normal growth. Fourteen (78%) infants had hypertension, of whom four (22%) had severe cardiac complications; eight (44%) showed delayed psychomotor development. Eleven (61%) of the infants, including six (86%) of the neonates, survived. Five (28%) infants underwent renal transplantation; 10-year graft survival was 80%. CONCLUSIONS: Based on these results, long-term HD in neonates and infants with ESRD is technically feasible, can be implemented without major complications, carries a very low rate of CVC infection and malfunction, and results in adequate nutrition, good growth, as well as good kidney graft and patient survivals. Future efforts should aim to prevent hypertension and its cardiac sequelae, improve neurodevelopmental outcome, and lower mortality rate in these infants.

Renal hypodysplasia associates with a WNT4 variant that causes aberrant canonical WNT signaling.

Abnormal differentiation of the renal stem/progenitor pool into kidney tissue can lead to renal hypodysplasia (RHD), but the underlying causes of RHD are not well understood. In this multicenter study, we identified 20 Israeli pedigrees with isolated familial, nonsyndromic RHD and screened for mutations in candidate genes involved in kidney development, including PAX2, HNF1B, EYA1, SIX1, SIX2, SALL1, GDNF, WNT4, and WT1. In addition to previously reported RHD-causing genes, we found that two affected brothers were heterozygous for a missense variant in the WNT4 gene. Functional analysis of this variant revealed both antagonistic and agonistic canonical WNT stimuli, dependent on cell type. In HEK293 cells, WNT4 inhibited WNT3A induced canonical activation, and the WNT4 variant significantly enhanced this inhibition of the canonical WNT pathway. In contrast, in primary cultures of human fetal kidney cells, which maintain WNT activation and more closely represent WNT signaling in renal progenitors during nephrogenesis, this mutation caused significant loss of function, resulting in diminished canonical WNT/ß-catenin signaling. In conclusion, heterozygous WNT4 variants are likely to play a causative role in renal hypodysplasia.

Low infection rates and prolonged survival times of hemodialysis catheters in infants and children.

BACKGROUND AND OBJECTIVES: Hemodialysis (HD) catheter-related complications are regarded as the main cause of HD failure in infants and children with ESRD. In this study, we determined HD catheter infection rates and survival times in children. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed demographic, clinical, laboratory, and microbiologic data on all infants and children with ESRD who received HD therapy through a tunneled central venous catheter (CVC) in our Pediatric Dialysis Unit between January 2001 and December 2009. Our strict care of HD-CVCs makes no use of any kind of prophylactic antibiotic therapy. RESULTS: Twenty-nine children with ESRD (median age, 10 years) received HD through a CVC, for a total of 22,892 days during the study period. Eleven (38%) children were infants (<1 year of age) who received HD for a cumulative 3779 days (16% of total). Fifty-nine CVCs were inserted, of which 13 (22%) were in infants. There were 12 episodes of CVC infection-a rate of 0.52/1000 CVC days. Four (33%) episodes occurred in infants-a rate of 1.06/1000 CVC days. Only three (5%) of the CVCs were removed because of infection. Median catheter survival time for all children was 310 days and for infants was 211 days. CONCLUSIONS: Very low CVC infection rates (one infection per 5 CVC years) and prolonged CVC survival times (around 1 year) are achievable in infants and children with ESRD receiving HD therapy by adhering to a strict catheter management protocol and without using prophylactic antibiotic therapy.

Neonatal transient renal failure with renal medullary hyperechogenicity: clinical and laboratory features.

Sonographic findings of renal medullary hyperechogenicity have been observed in the neonate in association with severe perinatal renal injury, kidney malformations or nephrocalcinosis, and, rarely, in newborn infants with transient renal failure. The aim of the study was to describe the entity of neonatal transient renal failure with renal medullary hyperechogenicity (NTRFMH). We studied nine term neonates, born between August 1999 and February 2004 in our institution (0.1% of the live born infants), who developed transient renal dysfunction after birth, and in whom renal sonograms showed bilateral medullary hyperechogenicity. Seven of the infants (78%) had anuria until 30-45 hours of age, and two (22%) had oliguria. Peak serum creatinine levels ranged between 0.61 and 1.62 mg/dL (mean: 1.09+/-0.27 mg/dL) at 2-3 days of life. Additional findings included proteinuria in nine infants (100%), uric acid crystalluria in seven (78%), hyperuricemia in four (44%), and hypertension in one (11%). Hyperuricosuria was demonstrated in one out of the seven patients in whom this parameter was determined. Urinary excretion rates of calcium, phosphorus and oxalic acid were normal, as were urinary levels of amino acids and organic acids. Full clinical recovery accompanied by normalization of all laboratory parameters was observed in all infants by 4-6 days of life. Subsequent follow-up showed normal renal function, no urinary abnormalities, and normal renal sonograms in all infants. Our summary of the nine infants with NTRFMH reported on here and a review of 19 cases of this condition reported in the literature reveal a not-so-rare entity of unclear etiology, but excellent prognosis. Physicians caring for neonates should be aware of this benign and transient condition.