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.

Linear growth of children with X-linked hypophosphatemia treated with burosumab: a real-life observational study.

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% after 12 months of treatment (p = 0.041). The RSS improved from 1.7 ± 1.0 at burosumab initiation to 0.5 ± 0.6 and 0.3 ± 0.6 after 12 and 24 months, respectively (p < 0.001). Both height z-score and weight z-score improved from burosumab initiation to the end of the study: from - 2.07 ± 1.05 to - 1.72 ± 1.04 (p < 0.001) and from - 0.51 ± 1.12 to - 0.11 ± 1.29 (p < 0.001), respectively. Eight children received growth hormone combined with burosumab treatment. Height z-score improved among those who received growth hormone (from - 2.33 ± 1.12 to - 1.94 ± 1.24, p = 0.042) and among those who did not (from - 2.01 ± 1.01 to - 1.66 ± 1.01, p = 0.001). CONCLUSION:  Burosumab treatment in a real-life setting improved phosphate homeostasis and rickets severity and enhanced linear growth. WHAT IS KNOWN: • Compared to conventional therapy, burosumab treatment has been shown to increase serum phosphate levels and reduce the severity of rickets. • The effect of burosumab on growth is still being study. WHAT IS NEW: • Height z-score improved between the start of burosumab treatment and the end of the study (-2.07 ± 1.05 vs. -1.72 ± 1.04, p < 0.001). • Eight children received burosumab combined with growth hormone treatment without side effects during the concomitant treatments.

Blood pressure in girls with central precocious puberty receiving GnRH analogue therapy.

OBJECTIVES: Case reports show hypertension in children treated with GnRH analogues for central precocious puberty (CPP). However, relevant data on blood pressure are scarce. We aimed to evaluate blood pressure (BP) among girls with idiopathic CPP and early-onset puberty before and during GnRH analogue therapy; and to examine associations of blood pressure with clinical parameters. METHODS: For this retrospective longitudinal cohort study, demographic, anthropometric, clinical, and laboratory data were collected from electronic files. The study group included 112 girls with idiopathic CPP or early-onset puberty followed in a tertiary pediatric endocrinology institute, and a control group of 37 healthy pre-pubertal girls. The main outcome measures were BP percentile, before, and during treatment with GnRH analogue. RESULTS: At baseline, similar proportions of the study and control groups had BP values>90th percentile: 64 (53 %) and 17 (46 %), respectively (p=0.57). The mean systolic and diastolic BP percentiles measured under treatment remained unchanged. In the study group, baseline BP>90th percentile compared to normal baseline BP was associated with lower birthweight and a higher body mass index-standard deviation score: 2,821 ± 622 vs. 3,108 ± 485 g and 1.0 ± 0.7 vs. 0.70 ± 0.8, respectively, p=0.01 for both. CONCLUSIONS: GnRH analogue therapy for precocious or early puberty was not associated with increased blood pressure. The stability of mean blood pressure percentile during treatment is reassuring.

Dialysis in Israeli Children between 1990 and 2020: Trends and International Comparisons.

BACKGROUND: Childhood kidney failure is a rare condition with worldwide clinical variability. We used a nationwide multicenter analysis to study the pretransplant course of the entire Israeli pediatric kidney failure population over 30 years. METHODS: In this nationwide, population-based, historical cohort study, we analyzed medical and demographic data of all children treated with KRT and reported to the Israeli kidney failure registry in 1990-2020. Statistical analysis was performed with incidence rate corrected for age, ethnicity, and calendar year, using the appropriate age-related general population as denominator. RESULTS: During the last 30 years, childhood incidence of kidney failure decreased. Average incidence in 2015-2019 was 9.1 cases per million age-related population (pmarp). Arab and Druze children exhibited higher kidney failure incidence rates than Jewish children (18.4 versus 7.0 cases pmarp for minorities versus Jews). The most common kidney failure etiologies among Arab and Jewish children were congenital anomalies of the kidney and urinary tract (approximately 27%), followed by cystic kidney diseases among Arab children (13%) and glomerulonephritis among Jewish children (16%). The most common etiology among Druze children was primary hyperoxaluria type 1 (33%). Israel's national health insurance provides access to primary health care to all citizens. Accordingly, waiting time for deceased-donor transplantation was equal between all ethnicities. Living-donor kidney transplantation rates among minority populations remained low in comparison with Jews over the entire study period. Although all patient groups demonstrated improvement in survival, overall survival rates were mainly etiology dependent. CONCLUSIONS: In Israel, Arab and Druze children had a higher incidence of kidney failure, a unique etiological distribution, and a lower rate of living-donor kidney transplantations compared with Jewish children.

A Clinical Response-Adjusted Steroid Treatment Protocol for Children With Newly Diagnosed Idiopathic Nephrotic Syndrome.

RATIONALE & OBJECTIVE: Prednisone protocols for children with idiopathic nephrotic syndrome (INS) are generally similar in dose and duration, despite wide variations in time to response. We assessed the feasibility of a novel clinical treatment protocol characterized by a shorter duration and lower cumulative dose for children with early clinical response. STUDY DESIGN: Nonrandomized pilot clinical trial. SETTING & PARTICIPANTS: The study population included 59 children with newly diagnosed INS treated between 2014 and 2019 who responded to treatment within 8 days. INTERVENTION: The intervention group (n = 27) was treated with a response-adjusted protocol during which responders received an 8-week course of tapering doses of prednisone. The usual care group (n =32) was treated with the standard protocol (prednisone, 60 mg/m2/24 hours for 6 weeks, followed by 40 mg/m2/48 hours for 4 weeks, followed by a slow taper for a total of 24 weeks). OUTCOME: Consent rate, cumulative prednisone dose, the development of frequently relapsing or steroid-dependent nephrotic syndrome (FRNS or SDNS, respectively), relapses per year, treatment with steroid-sparing therapies, and adverse effects of steroid therapy over 3 years of follow-up observation. RESULTS: The consent rate was 88%. The mean cumulative steroid dose for the initial treatment was 70 mg/kg and 141 mg/kg (P < 0.001) in the intervention and usual care groups, respectively. None of the patients in the intervention group relapsed while on faster steroid taper down. The occurrence of FRNS and SDNS in the intervention group was not statistically different than in the usual care group, hazard ratios were 0.80 (95% CI, 0.37-1.73) and 0.61 (95% CI, 0.30-1.27), respectively. The proportions of relapse-free patients were similar (P = 0.5), and adverse steroid events did not differ between the groups. LIMITATIONS: Lack of randomization and small sample size. CONCLUSIONS: These findings demonstrate the feasibility of a shortened duration of steroid dosing for INS when patients demonstrate an initial clinical response to treatment. A larger study is needed to characterize the relative efficacy and toxicity of this novel treatment regimen. FUNDING: This study received no funding. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCTO2649413.

Headache in Pediatric and Adolescent Patients With Chronic Kidney Disease and After Kidney Transplantation: A Comparative Study.

AIM: This study compared prevalence and characteristics of headaches between pediatric patients with chronic kidney disease and pediatric patients with transplanted kidneys and identify factors associated with headaches in the entire cohort. METHODS: We interviewed 87 children and adolescents with either chronic kidney disease or transplanted kidney, regarding the prevalence of headaches and their characteristics. We reviewed hospital charts for medical history and blood test. RESULTS: Twenty-two patients (25.3%) reported experiencing headaches, of them 15 (68%) had migraine. The prevalence was greater among those with chronic kidney disease than among those after kidney transplant: 36.6% vs 15.2%, P = .03. Headache, mostly migraine, was associated with lower glomerular filtration and higher phosphate level. CONCLUSIONS: In a pediatric population, headaches were less prevalent among patients after kidney transplantation than among patients with chronic kidney disease. The lower headache rate after kidney transplantation may be related to improvement in homeostasis and electrolyte balance.

A multidisciplinary nephrogenetic referral clinic for children and adults-diagnostic achievements and insights.

BACKGROUND: Genetic kidney diseases contribute a significant portion of kidney diseases in children and young adults. Nephrogenetics is a rapidly evolving subspecialty; however, in the clinical setting, increased use of genetic testing poses implementation challenges. Consequently, we established a national nephrogenetics clinic to apply a multidisciplinary model. METHODS: Patients were referred from different pediatric or adult nephrology units across the country if their primary nephrologist suspected an undiagnosed genetic kidney disease. We determined the diagnostic rate and observed the effect of diagnosis on medical care. We also discuss the requirements of a nephrogenetics clinic in terms of logistics, recommended indications for referral, and building a multidisciplinary team. RESULTS: Over 24 months, genetic evaluation was completed for a total of 74 unrelated probands, with an age range of 10 days to 72 years. The most common phenotypes included congenital anomalies of the kidneys and urinary tract, nephrotic syndrome or unexplained proteinuria, nephrocalcinosis/nephrolithiasis, tubulopathies, and unexplained kidney failure. Over 80% of patients were referred due to clinical suspicion of an undetermined underlying genetic diagnosis. A molecular diagnosis was reached in 42/74 probands, yielding a diagnostic rate of 57%. Of these, over 71% of diagnoses were made via next generation sequencing (gene panel or exome sequencing). CONCLUSIONS: We identified a substantial fraction of genetic kidney etiologies among previously undiagnosed individuals which influenced subsequent clinical management. Our results support that nephrogenetics, a rapidly evolving field, may benefit from well-defined multidisciplinary co-management administered by a designated team of nephrologist, geneticist, and bioinformatician. A higher resolution version of the Graphical abstract is available as Supplementary information.

Use of Point-of-Care Ultrasound for Evaluation of Extravascular and Intravascular Fluid Status in Pediatric Patients Maintained on Chronic Hemodialysis.

AIMS: Traditional methods that use clinical parameters to determine dry weight in hemodialysis patients are inaccurate. This study aimed to compare clinical assessment of fluid status to sonographic parameters of fluid status in pediatric patients undergoing chronic hemodialysis. METHODS: In a prospective observational study, pediatric patients maintained on chronic hemodialysis (ages 2.3-20 years) were evaluated clinically and sonographically before and after dialysis at 6 consecutive sessions. Sonographic parameters examined were number of lung B-lines as a measure of extravascular volume and inferior vena cava (IVC)/aorta ratio as a measure of intravascular volume. Clinical assessment of fluid status was compared to sonographic assessment. RESULTS: Twelve patients were evaluated during 72 dialysis sessions. Sonographic parameters were significantly lower post-dialysis than pre-dialysis (B-lines number 4.5 ± 5 vs. 7.69 ± 7.46, p < 0.0001; IVC/aorta ratio 0.9 ± 0.2 vs. 1.1 ± 0.2, p < 0.0001, respectively). Ultrafiltration volume correlated with change in B-lines number during dialysis (r = 0.39, p < 0.01). Percent of blood volume drop correlated with post-dialysis IVC/aorta ratio (r = 0.48, p < 0.001). A higher percent of symptomatic episodes occurred with post-dialysis IVC/aorta ratio <0.8 versus ≥0.8 (39.1 vs. 15.2%, p = 0.036). Four patients were hypertensive, a clinical parameter implying fluid overload, in only one sonographic evaluation indicated fluid overload. Eight patients were clinically determined to be euvolemic, in three of them sonographic evaluation discovered covert fluids. CONCLUSION: Bedside ultrasound is a single modality that can be used to assess both extravascular and intravascular fluid status. It may contribute to clinical decisions differentiating fluid-related versus fluid-unrelated hypertension and identifying patients with covert fluids.

EBV, CMV, and BK viral infections in pediatric kidney transplantation: Frequency, risk factors, treatment, and outcomes.

BACKGROUND: Improved short- and long-term outcomes of kidney transplantation have been achieved over the past decades due to improved immunosuppression. This may have increased the risk for infections and, particularly, for the viral infections: cytomegalovirus (CMV), Epstein-Barr virus (EBV), and polyoma BK virus (BKV). METHODS: A retrospective review of viremic CMV, EBV, and BKV infections in pediatric renal transplant recipients treated and followed by a national referral center over a 10-year period. RESULTS: Sixty-seven patients (68% males) received 68 kidney grafts (62% from living donors) during the study period; the mean follow-up period was 5.2 ± 2.4 years. Twenty-seven viremic episodes were documented (CMV: 13, EBV: 6, BKV: 8) in 24 patients (35.2%). The median time (interquartile range) to viremia post-transplant was 11 (4-38) months. The viral infection rate was significantly higher in the years 2014-2015 than in previous years (61% vs. 29%, p = .017). Compared to patients who did not develop viremia, patients with viremias were younger at the time of transplantation, were more likely to receive thymoglobulin induction pre-transplant and to develop an acute rejection. Multiple logistic regression modeling identified transplant year and recipient's age as significant risk factors for viremia. Graft outcome and eGFR at the last follow-up was similar between patients who did and did not develop viremia. CONCLUSIONS: Viral infections continue to be a major cause of morbidity in pediatric kidney transplant recipients. However, with close monitoring and prompt intervention, patient and renal outcomes remain favorable.

Childhood Hypercalciuric Hypercalcemia With Elevated Vitamin D and Suppressed Parathyroid Hormone: Long-Term Follow Up.

Purpose: Hypercalcemia with low parathyroid hormone (PTH) level, hypercalciuria, nephrocalcinosis, or nephrolithiasis, was recently reported as caused by mutations in CYP24A1 and SLC34A genes. These encode for vitamin D-24A-hydroxylase and for the renal phosphate transporters NaPiIIa and NaPiIIc, respectively. We aimed to describe the clinical course of these monogenic disorders in patients with and without found mutations during long-term follow-up. Methods: Ten patients with hypercalcemia, hypercalciuria, elevated 1,25-(OH)2D levels and suppressed PTH were followed in our center during 1998-2019. Relevant laboratory and imaging data and results of genetic evaluation were retrieved from medical files. Results: The median age at presentation was 9.5 months (range 1 month-11 years), six were males, and the median follow-up time was 3.8 (1.1-14) years. Mutations in CYP24A1 and SLC34A3 were identified in three and one patients, respectively. Five patients presented with nephrocalcinosis, three with nephrolithiasis, and two had normal renal ultrasound. High blood calcium and 1,25-(OH)2D levels at presentation decreased during follow-up [11.1 ± 1 vs. 9.9 ± 0.5 mg/dl (p = 0.012), and 307 ± 130 vs. 209 ± 65 pmol/l (p = 0.03), respectively]; this paralleled an increase in suppressed PTH levels (5.8 ± 0.9 vs. 11.8 ± 7.3 pg/ml, p = 0.2). Substantial improvements in hypercalciuria and renal sonography findings were not observed. Two patients had impaired renal function (eGFR 84-88 ml/min/1/73 m2) at the last follow up. Interventions included appropriate diet, citrate supplementation, and thiazides. Conclusion: Despite improvement in hypercalcemia and 1,25-(OH)2D levels, not all the patients showed improvements in hypercalciuria and nephrocalcinosis. Deterioration of renal function was also observed. Long-term follow up and intervention to prevent nephrocalcinosis and nephrolithiasis are recommended in these children.

[NEPHROTIC SYNDROME RECURRENCE POST-RENAL TRANSPLANTATION: 10 YEARS' EXPERIENCE AT SCHNEIDER CHILDREN'S MEDICAL CENTER IN ISRAEL].

INTRODUCTION: A total of 30-50% of pediatric patients presenting with steroid resistant nephrotic syndrome (SRNS) will reach end stage renal disease (ESRD). In patients with primary SRNS, the risk of post-transplant recurrence is around 60% with poor graft outcomes. In the past decade new treatment modalities have emerged in an attempt to improve graft outcomes. AIMS: To describe the clinical experience at the Schneider Children's Medical Center in Israel in treating children with post-transplant recurrent SRNS in the past decade, and compare its results to a similar study conducted at the same center in previous years. METHODS: A retrospective chart review was conducted. Data regarding demographic characteristics, clinical course and treatment modalities of patients with post-transplant recurrent SRNS were extracted from patients' charts. RESULTS: Eight patients with post-transplant recurrent SRNS were identified. Median age at initial nephrotic syndrome presentation was 4 (range: 0.8-15) years. Median time to reach ESRD was 43 (range: 12-132) months. All patients were treated with plasmapheresis, seven patients were treated with Rituximab. Low-density lipoprotein (LDL) apheresis, Ofatumumab and Abatacept were used in 1-2 patients each. Median follow-up time post-transplant was 47 (range: 15-93) months. Four patients (50%) responded to treatment, two achieved complete and two partial remission. Four patients reached ESRD within a median time of 24 (range: 12-84) months. Lower rates of acute tubular necrosis and immediate graft loss were observed during the last decade compared to previous years (37.5% vs. 64%; 0% vs. 28.6% respectively). CONCLUSIONS: Post-transplant recurrence of SRNS continues to pose a significant treatment challenge. Similar to previous reports, only 50% of our patients responded to treatment while 50% were unresponsive to all treatment modalities and reached ESRD. Immediate post-operative management improved over the last decade, however long-term outcome continues to be grim. There is a need to better identify disease mechanisms that will allow us to tailor more effective treatment modalities to improve patients' outcome.

Children with Intestinal Failure Maintain Their Renal Function on Long-Term Parenteral Nutrition.

BACKGROUND: Long-term parenteral nutrition (PN) has been associated with renal complications, including hypercalciuria, nephrocalcinosis, proteinuria and reduced glomerular filtration rate (GFR). Pediatric data are scarce and mostly short-term. Our study aimed to evaluate renal complications in children with intestinal failure (IF) receiving long-term PN. METHODS: A cross-sectional study was performed in a tertiary pediatric IF clinic of patients receiving home-PN treatment for more than 1 year. Data regarding medical background, anthropometrics, laboratory investigations and abdominal sonography were retrieved. RESULTS: Complete data were available for 15 children (67% males), with a median age of 6 (range 1.5-15) years and a median (IQR) PN duration of 4 (1.5-6) years. Low-grade proteinuria was identified in 61% and microalbuminuria in 30% of the cohort. Hypercalciuria and hyperoxaluria were present in 50% and 46%, respectively. One patient had nephrocalcinosis. The estimated GFR was normal in all but one patient who had pre-existing kidney disease. CONCLUSIONS: Pediatric IF patients can present with preserved kidney function after years of PN treatment. Despite the high prevalence of hypercalciuria, nephrocalcinosis was not common. Base line and long-term monitoring of various aspects of renal function would be essential to characterize the effects of prolonged PN on kidney functions in pediatric patients.

Long-term follow-up of premature infants with urinary tract infection.

Urinary tract infection (UTI) is common in preterm infants and may have long-term sequela, such as recurrent infections and renal scarring in older children. We assessed long-term outcomes of preterm infants with UTI, born during 1996-2008 in Schneider Children's Medical Center's neonatal intensive care unit (NICU), and incidence of UTI recurrence. Of 89 preterm infants, seven were excluded due to prenatal diagnosis of congenital anomalies of the kidney and urinary tract (CAKUT), 41 interviewed by phone, 18 presented for follow-up evaluation in the nephrology clinic, and 23 lost to follow-up. No patient who completed follow-up reported additional UTI episodes or issues related to kidney and urinary tract. Clinically evaluated participants were 17.1 ± 3.6 years, born prematurely at 29.4 ± 4 weeks. All had a normal estimated glomerular filtration rate of >90 ml/min/1.73m2; four (22%) had systolic blood pressure >90th percentile; none had proteinuria (mean protein/creatinine ratio 0.09 ± 0.04 mg/mg) or albuminuria (mean albumin/creatinine ratio 10.2 ± 6.3 mcg/mg). Renal ultrasonography done in the first years of life in 12 (66%) patients demonstrated normal kidney size and structure.Conclusion: In this pilot study, a single episode of UTI in premature infants without CAKUT did not constitute a risk factor for recurrence of infections or kidney injury in their first two decades of life. Thus, normal ultrasound in NICU excluding CAKUT may be sufficient for premature patients with UTI, with no need of further imaging or long-term nephrology follow-up. What is Known: • Urinary tract infection (UTI) is one of the most common bacterial infections in neonates and premature infants. Risk factors for UTI recurrence in children are congenital anomalies of the kidney and urinary tract (CAKUT) and bladder and bowel dysfunction. • The recurrence rate and long-term renal sequela of UTI in preterm infants have not been studied. Guidelines regarding management and long-term follow-up for infants less than 2 months old are lacking. What is New: • A single episode of UTI in premature infants without CAKUT probably does not constitute a risk factor for UTI recurrence, and it is unlikely to cause renal injury in the first two decades of life. • For premature infants with UTI without sonographic diagnosis of CAKUT in NICU, prophylactic antibiotic treatment, further imaging, or long-term nephrology follow-up may be unnecessary.

Is the prognosis of congenital single functioning kidney benign? A population-based study.

BACKGROUND: We investigated the risk of kidney injury among adolescents with and without a congenital single functioning kidney (SFK). METHODS: This retrospective study is based on a medical evaluation database of 17-year-old Israeli conscripts, born during 1989-1999. Those with congenital SFK diagnosis, verified by a pediatric nephrologist's review of the original military medical committee classifications, were compared to the rest of the cohort. Kidney injury (KI) was defined as proteinuria, high blood pressure (BP), or estimated glomerular filtration rate (eGFR) < 90 ml/min/1.73 m2 prior to army recruitment. Risk factors for KI were examined using logistic regression. RESULTS: Of 979,630 screened candidates, 353 were diagnosed with SFK. The yearly incidence of SFK gradually increased in the first years of the study, reaching a plateau in 1995 (5.5 ± 1.2/10,000 births/year). The male to female ratio was 2.7:1. Concomitant genital malformations were documented in 5.5% of those with SFK. KI was more prevalent in the SFK than the control group (42.2% vs. 23.5%, p < 0.001). All three components of KI were more common in the SFK than the control group: high BP (31.7% vs. 23.1%, p < 0.001), proteinuria (18.2% vs. 0.4%, p < 0.001), and eGFR <90 ml/min/1.73m2 (12.0% vs 0.1%, p < 0.001). Multivariate analysis of the SFK group revealed associations of higher mean BMI, male sex, and smaller ultrasonographic kidney length with KI. CONCLUSIONS: This large population-based study documents a significant risk for KI among adolescents with SFK. Obesity represents a major modifiable risk factor for KI, implicating the need for closer follow-up in this group during childhood.

Long-term outcomes during 37 years of pediatric kidney transplantation: a cohort study comparing ethnic groups.

BACKGROUND: This study aimed to evaluate short- and long-term outcomes of kidney transplantation over 37 years in a national referral center and compare outcomes between Israeli Jewish and Arab children. METHODS: Data on 599 pediatric transplantations performed in 545 children during 1981-2017, including demographic parameters, kidney failure disease profile, and pre-transplant dialysis duration, were retrieved from our computerized database and patient files. Patient and graft survival were estimated using the Kaplan-Meier method. RESULTS: Twenty-year patient survival was 91.4% for live donor (LD) and 80.2% for deceased donor (DD) kidney recipients. Respective 10-year and 20-year graft survival rates for first kidney-only transplants were 75.2% and 47.0% for LD and 60.7% and 38.4% for DD grafts. Long-term graft survival improved significantly (p < 0.001) over the study period for recipients of both LD and DD allografts and reached 7-year graft survival of 92.0% and 71.3%, respectively. The proportion of DD transplantations was higher in the Arab subpopulation: 73.8% vs. 48.4% (p < 0.001). Graft survival was not associated with age at transplantation and did not differ between the Arab (N = 202) and Jewish children (N = 343). Median (IQR) waiting time on dialysis did not differ significantly between the Arab and Jewish children: 18 (10-30) and 15 (9-30) months, respectively (p Mann-Whitney = 0.312). CONCLUSIONS: Good and progressively improving long-term results were obtained in pediatric kidney transplantation at our national referral center, apparently due to expertise gained over time and advances in immunosuppression. Equal access to DD kidney transplant and similar graft survival were found between ethnic groups.

Fluid overload and renal function in children after living-donor renal transplantation: a single-center retrospective analysis.

BACKGROUND: We aimed to compare renal function after kidney transplantation in children who were treated with higher vs. lower fluid volumes. METHODS: A retrospective analysis of 81 living-donor renal transplantation pediatric patients was performed between the years 2007 and 2018. We analyzed associations of the decrease in serum creatinine (delta creatinine) with fluid balance, central venous pressure (CVP), pulmonary congestion, mean arterial pressure (MAP), and MAP-CVP percentiles in the first 3 postoperative days. After correcting creatinine for fluid overload, we also assessed associations of these variables with the above parameters. Finally, we evaluated the association between delta creatinine and estimated glomerular filtration rate (eGFR) at 3 months follow-up. RESULTS: Both delta creatinine and delta-corrected creatinine were found to be associated with pulmonary congestion on the second and third postoperative days (p < 0.02). In addition, trends for positive correlations were found of delta creatinine with fluid balance/kg (p = 0.07), and of delta-corrected creatinine with fluid balance/kg and CVP (p = 0.06-0.07) on the second postoperative day. An association was also demonstrated between the accumulated fluid balance of the first 2 days and eGFR at 3 months after transplantation (p = 0.03). CONCLUSIONS: An association was demonstrated between indices of fluid overload, >80 ml/kg, and greater improvement in renal function. IMPACT: There is no consensus regarding the optimal fluid treatment after pediatric renal transplantation. In our cohort, indices of fluid overload were associated with better renal function immediately after the transplantation and 3 months thereafter. Fluid overload after living-donor renal transplantation in children may have short- and long-term benefits on renal function.

Salivary Cytokines in Children with Nephrotic Syndrome versus Healthy Children: A Comparative Study.

BACKGROUND: The aims of this study were to compare salivary cytokines and total protein between children with nephrotic syndrome (NS) and healthy children, and to examine whether saliva parameters can differentiate between steroid sensitivity and resistance and between disease remission and relapse. METHODS: Twenty-seven children with nephrotic syndrome were classified according to steroid sensitivity and resistance, and disease remission and relapse. Twenty healthy children served as controls. Whole saliva samples were collected from all the participants. Urine and blood tests done on the same day as the saliva collection were recorded. Salivary total protein was quantified using bicinchoninic acid and IFNγ, IL-4, IL-8, IL-6, and IL1ß levels using ELISA. RESULTS: The mean ages of the nephrotic syndrome and control groups were 11.3 ± 2.4 and 9 ± 4.2, respectively. Compared to the control group, for the nephrotic syndrome group, total salivary protein was significantly lower, as were the levels of all the cytokines examined except IFNγ. Statistically significant differences were not found in any of the salivary markers examined between the children with nephrotic syndrome who were treatment sensitive (n = 19) and resistant (n = 8). Protein and IL-8 salivary levels were lower in the active (n = 7) than in the remission (n = 20) group. CONCLUSIONS: Salivary parameters distinguished children with nephrotic syndrome in relapse from healthy children. This may be due to decreased salivary protein excretion, which reflects decreased plasma levels, consequent to proteinuria. Accordingly, salivary markers may be developed as a diagnostic or screening tool for NS activity.

Infections in Children With Nephrotic Syndrome: Twenty Years of Experience.

Infections is a common complication of nephrotic syndrome (NS). Our objective was to evaluate the frequency and risk factors for serious bacterial infections (SBI) in febrile children with NS. We reviewed 239 admissions of 107 children with NS who were admitted with fever to a tertiary hospital in Israel, during 1995 to 2016. SBI was diagnosed in 35 admissions (14.6%), most commonly with pneumonia (n = 12), bacteremia/sepsis (n = 8), and urinary tract infection (n = 6). Patients with SBI were more likely to be female (60.0% vs 36.3%, P = .008) and have nephrotic-range proteinuria (71.4% vs 43.6%, P = .010) and edema (62.9% vs 27.0%, P < .001) on admission. No differences were found between the SBI and non-SBI groups in the clinical and histopathological type of NS, immunosuppressive treatment, rate of pneumococcal vaccination, and prophylactic antibiotics. In summary, 1 of 7 children had SBI, most commonly pneumonia, bacteremia/sepsis, and urinary tract infection. Active nephrosis was associated with an increased risk for SBI.

Lower prednisone dosing for steroid-sensitive nephrotic syndrome relapse: a prospective randomized pilot study.

Relapses of steroid-sensitive nephrotic syndrome are traditionally treated with prednisone 2 mg/kg/day or 60 mg/m2/day. Retrospective data support the use of lower doses. We designed a prospective randomized pilot study to investigate the efficacy of different doses in achieving remission of steroid sensitive nephrotic syndrome relapse. The cohort included 30 children with relapsed steroid sensitive nephrotic syndrome, mean age 6.3 ± 3 years and mean disease duration 2.2 ± 1.8 years. The children were randomized to receive 2, 1.5, or 1 mg/kg/day prednisone. The corresponding times to response, defined as the first of 3 consecutive days without proteinuria, were 7.2 ± 1.4, 10.2 ± 5.1, and 9 ± 3.3 days; the difference between the 1.5 and 2 mg/kg/day groups was statistically significant. One patient each in the 1 mg/kg/day and the 1.5 mg/kg/day groups failed to respond and were switched to 2 mg/kg/day, leading to a response after 3 and 10 days, respectively. Mean cumulative prednisone doses in the 3 groups were 45.5 ± 3.4, 42.7 ± 25.9, and 24.9 ± 7.4 mg/kg, respectively (P < 0.05).Conclusion: In the present study, treatment of childhood steroid sensitive nephrotic syndrome relapse with prednisone 1-1.5 mg/kg/day led to a significantly lower cumulative dose than the standard dose. Treatment with a lower dose may be equally safe and effective to the standard dose.What is Known:• Relapses of steroid-sensitive nephrotic syndrome are traditionally treated with standard-dose steroids.• Treatment with corticosteroids may have significant adverse effects mainly with long-term use.What is New:• Treatment of steroid sensitive nephrotic syndrome relapse with 1-1.5 mg/kg/day prednisone may lead to a significantly lower cumulative dose.• Treatment with a lower steroid dose may be as effective as the standard dose in achieving remission of steroid sensitive nephrotic syndrome relapse.

Is eculizumab indicated in patients with atypical hemolytic uremic syndrome already on prolonged dialysis? A case report and review of the literature.

BACKGROUND: Eculizumab has caused a revolution in the treatment and prognosis of atypical hemolytic uremic syndrome. Early initiation of treatment is recommended to increase chances of renal recovery. CASE-DIAGNOSIS/TREATMENT: We describe a boy with atypical hemolytic uremic syndrome who started eculizumab therapy after being on dialysis for 4.5 months, with complete anuria. With treatment, he was weaned off dialysis. CONCLUSION: We review the evidence in the literature and discuss the possible mechanism by which eculizumab induces renal recovery even in patients already on prolonged dialysis. This case report highlights the importance of a treatment trial with eculizumab, even in patients already on prolonged dialysis.