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Unlabelled: Atypical hemolytic uremic syndrome (HUS) refers to the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury in the absence of Shiga toxin-producing Escherichia coli exposure or Streptococcus pneumoniae infection. Currently, approximately 50 % of the atypical cases have demonstrable mutations in complement regulatory proteins. Historically, the diagnosis of atypical HUS portends a poor prognosis with a high rate of disease recurrence, progression to end-stage renal disease, and death. However, it is now evident that atypical HUS actually encompasses a heterogeneous group of disorders, and there are reports suggesting that some cases of atypical HUS have a favorable prognosis, similar to that of diarrhea-associated disease. We present three patients with the atypical HUS phenotype who had complete renal recovery and no disease recurrence. We believe it is important to distinguish those cases of atypical HUS associated with disorders of complement regulatory proteins from other idiopathic causes of nondiarrheal HUS given the implications for prognosis and treatment.Conclusion: Given the heterogeneous nature and variable prognosis of atypical HUS, treatment should be carefully considered prior to the use of long-term plasma therapy and/or eculizumab. [ABSTRACT FROM AUTHOR]

Streptococcus pneumoniae-associated hemolytic uremic syndrome (HUS) is an underrecognized condition that mainly occurs in young children. Early diagnosis is important because of the potential to improve morbidity and mortality rates. The purposes of this report are to review the clinical and laboratory features of 14 patients with pneumococcal HUS and present a modified classification to capture cases that may not have been documented with a diagnosis of pneumococcal HUS. We thereby provide a rationale for including patients with concurrent disseminated intravascular coagulopathy and/or those whose culture results were negative, and we highlight the emergence of serotype 19A subsequent to the introduction of 7-valent pneumococcal protein conjugate vaccine (Prevnar). This is the largest series of such subjects (to our knowledge) from a single center. Sixty-four percent of the patients recovered without any long-term sequelae. Three patients developed chronic kidney disease, 1 developed end-stage renal failure, and 1 died in the acute phase. The greatest risk factor for the development of chronic kidney disease is the need for acute dialysis for >20 days, and death in the acute phase is rare unless meningitis is the primary infection. [ABSTRACT FROM AUTHOR]

Presents the correction of an error in the section on "Hypernatremic dehydration" in "Pediatr Nephrol" (2003) issue.

The primary hyperoxalurias (PH 1, 2, and 3) are rare autosomal recessive disorders of glyoxylate metabolism resulting in hepatic overproduction of oxalate. Clinical presentations that should prompt consideration of PH include kidney stones, nephrocalcinosis, and kidney failure of unknown etiology, especially with echogenic kidneys on ultrasound. PH1 is the most common and severe of the primary hyperoxalurias with a high incidence of kidney failure as early as infancy. Until the recent availability of a novel RNA interference (RNAi) agent, PH care was largely supportive of eventual need for kidney/liver transplantation in PH1 and PH2. Together with the Oxalosis and Hyperoxaluria Foundation, the authors developed a diagnostic algorithm for PH1 and in this report outline best clinical practices related to its early diagnosis, supportive treatment, and long-term management, including the use of the novel RNAi. PH1-focused approaches to dialysis and kidney/liver transplantation for PH patients with progression to chronic kidney disease/kidney failure and systemic oxalosis are suggested. Therapeutic advances for this devastating disease heighten the importance of early diagnosis and informed treatment., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Our objective was to examine serum ferritin trends after conversion to permanent vascular access (PVA) among children who started hemodialysis (HD) using tunneled cuffed catheters (TCC). Retrospective chart reviews were completed on 98 subjects from 20 pediatric HD centers. Serum ferritin levels were collected at the creation of PVA and for two years thereafter. There were 11 (11%) arteriovenous grafts (AVG) and 87 (89%) arteriovenous fistulae (AVF). Their mean TCC use was 10.4 ± 17.3 months. Serum ferritin at PVA creation was elevated at 562.64 ± 492.34 ng/mL, increased to 753.84 ± 561.54 ng/mL ( p = < 0.001) in the first year and remained at 759.60 ± 528.11 ng/mL in the second year ( p = 0.004). The serum ferritin levels did not show a statistically significant linear association with respective serum hematocrit values. In a multiple linear regression model, there were three predictors of serum ferritin during the first year of follow-up: steroid-resistant nephrotic syndrome as primary etiology ( p = 0.035), being from a center that enrolled >10 cases ( p = 0.049) and baseline serum ferritin level ( p = 0.017). Increasing serum ferritin after conversion to PVA is concerning. This increase is not associated with serum hematocrit trends. Future studies should investigate the correlation of serum transferrin saturation and ferritin levels in pediatric HD patients.

Background: Fluid overload is associated with morbidity and mortality in children receiving dialysis. Accurate clinical assessment is difficult, and using deuterium oxide (D 2 O) to measure total body water (TBW) is impractical. We investigated the use of ultrasound (US), bioimpedance spectroscopy (BIS), and anthropometry to assess fluid removal in children receiving maintenance hemodialysis (HD)., Methods: Participants completed US, BIS, and anthropometry immediately before and 1-2 h after HD for up to five sessions. US measured inferior vena cava (IVC) diameter, lung B-lines, muscle elastography, and dermal thickness. BIS measured the volume of extracellular (ECF) and intracellular (ICF) fluid. Anthropometry included mid-upper arm, calf and ankle circumferences, and triceps skinfold thickness. D 2 O was performed once pre-HD. We assessed the change in study measures pre- versus post-HD, and the correlation of change in study measures with percent change in body weight (%∆BW). We also assessed the agreement between TBW measured by BIS and D 2 O., Results: Eight participants aged 3.4-18.5 years were enrolled. Comparison of pre- and post-HD measures showed significant decrease in IVC diameters, lung B-lines, dermal thickness, BIS %ECF, mid-upper arm circumference, ankle, and calf circumference. Repeated measures correlation showed significant relationships between %∆BW and changes in BIS ECF (r rm =0.51, 95% CI 0.04, 0.80) and calf circumference (r rm =0.80, 95% CI 0.51, 0.92). BIS TBW correlated with D 2 O TBW but overestimated TBW by 2.2 L (95% LOA, -4.75 to 0.42)., Conclusion: BIS and calf circumference may be helpful to assess changes in fluid status in children receiving maintenance HD. IVC diameter, lung B-lines and dermal thickness are potential candidates for future studies., (© 2023. The Author(s).)

Ichthyosis follicularis, atrichia, and photophobia syndrome (IFAP syndrome) is a rare, X-linked disorder caused by pathogenic variants in membrane-bound transcription factor protease, site 2 (MBTPS2). Pathogenic MBTPS2 variants also cause BRESHECK syndrome, characterized by the IFAP triad plus intellectual disability and multiple congenital anomalies. Here we present a patient with ichthyosis, sparse hair, pulmonic stenosis, kidney dysplasia, hypospadias, growth failure, thrombocytopenia, anemia, bone marrow fibrosis, and chronic diarrhea found by research-based exome sequencing to harbor a novel, maternally inherited MBTPS2 missense variant (c.766 G>A; (p.Val256Leu)). In vitro modeling supports variant pathogenicity, with impaired cell growth in cholesterol-depleted media, attenuated activation of the sterol regulatory element-binding protein pathway, and failure to activate the endoplasmic reticulum stress response pathway. Our case expands both the genetic and phenotypic spectrum of BRESHECK syndrome to include a novel MBTPS2 variant and cytopenias, bone marrow fibrosis, and chronic diarrhea., (© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Background and Objectives: Arteriovenous fistulae (AVF) and grafts (AVG) are preferred permanent vascular access (PVA) for chronic hemodialysis (HD) patients. Our objective was to examine the change in markers of HD efficacy after successful establishment of a PVA among children who started HD with a tunneled cuffed catheter (TCC)., Materials and Methods: Retrospective chart reviews were completed on patients from 20 pediatric dialysis centers. All patients used TCC prior to AVF/AVG, and each patient acted as his/her own control. Data on markers of HD efficacy (single-pool Kt/V, urea reduction ratio (URR), serum albumin and hematocrit (Hct)) were collected at the creation of AVF/AVG and for 2 years thereafter. Statistical methods included hypothesis testing and statistical modeling after adjusting for relevant demographic variables., Results: First PVA was created in 98 individual children: 87 (89%) were AVF and 11 (11%) were AVG. The mean TCC vintage prior to AVF/AVG was 10.4 ± 17.3 months. At 1-year follow-up, Kt/V improved by 0.15 ± 0.06 (p = 0.02) and URR improved by 4.54 ± 1.17% (p < 0.0001). Furthermore, PVA was associated with improved serum albumin by 0.31 ± 0.07 g/dL (p < 0.0001) and Hct by 2.80 ± 0.65% (p < 0.0001) at 1 year. These HD efficacy markers remained statistically significant at 2 nd -year follow-up. These observations were further supported by the adjusted models. Conversion to AVF was associated with statistically significant improvement in all four markers of HD efficacy at 1-year follow-up. This trend was not demonstrated for subjects who were converted to AVG., Conclusion: Switching to PVA was associated with improved markers of HD efficacy, single-pool Kt/V, URR, serum albumin, and Hct. This improvement was mostly demonstrated at 1 year and maintained for the 2 nd year. The potential differential impact of the type of PVA on the trajectory of markers of HD efficacy should be further investigated.

Background: Alport syndrome (AS) is a multisystem condition which can result in progressive kidney disease, hearing loss, and ocular changes. X-linked inheritance is observed in 85% of affected individuals. As a result, most prior studies have focused on males. Girls with AS can also be symptomatic although historically thought to have few clinical manifestations in childhood. The objective of the study was to describe the clinical presentation and course of females with AS., Methods: A single-center retrospective study of all young females with AS between January 1, 1987, and May 20, 2019. Subjects were identified using ICD-9/10 diagnosis codes for AS, familial hematuria, or nephritis. Clinical data were extracted by retrospective chart review., Results: Thirty-six female patients were included in the analysis. Mean age at presentation was 5.58 ± 3.0 years, and mean follow-up was 5.9 ± 3.9 years. Twenty-nine patients (80%) had a family history of AS. At end of the follow-up period, gross hematuria was observed in 15 patients (42%), 20 (56%) developed proteinuria, and 2 (6.7%) had an estimated glomerular filtration rate (eGFR) < 90 ml/min/1.73m 2 with one patient developing stage 5 chronic kidney disease. Four of the twenty-seven (14.8%) who underwent audiologic testing had an abnormal exam., Conclusions: Known family histories of AS or gross hematuria were the most common reasons for the initial presentation in our cohort. Development of proteinuria, eGFR < 90 ml/min/1.73m 2 , and abnormal audiology exam are not exceptional findings, suggesting that close monitoring of young females into adulthood is warranted.

The rising incidence of urinary stone disease in children requires pediatric practitioners to keep abreast of management recommendations which are generally geared towards adults. Medical expulsive therapy (MET) is a non-surgical therapeutic option that can be trialed in patients who present with uncomplicated symptomatic ureteral stones. Seminal articles published and indexed in Medline on the topic of MET were extracted and reviewed. Studies suggest a potential benefit of alpha-blockade for the expulsion of distal ureteral stones that are >5 mm but ≤10 mm in adults and possibly >4 mm in children. Conversely, there does not seem to be any added benefit for MET in smaller stones (<5 mm) in which the spontaneous passage rate is high. Conclusions: The off-label use of these medications is one of the several barriers which contribute to the underutilization of MET in children. However, these may be a reasonable option in particular for older children and adolescents with the appropriate-sized stones.

The purpose of this review is to describe Streptococcus pneumoniae-associated hemolytic uremic syndrome (P-HUS) with emphasis on new insights into the pathophysiology and management over the past 10 years. Even though awareness of this clinico-pathological entity has increased, it likely remains under-recognized. Recent observations indicate that although neuraminidase activity and exposure of the T-antigen are necessary for development of P-HUS, they are not sufficient; activation of the alternate pathway of complement may also contribute. It is unclear, however, whether or not eculizumab and/or plasmapheresis are of value.

Background & Aims: It is not clear what factors affect risk of chronic kidney disease (CKD) in patients with inflammatory bowel disease (IBD); increased risk has been inconsistently associated with use of 5-aminosalicylates (5-ASAs). We aimed to calculate the relative hazard of CKD among patients with IBD, adjusted for CKD risk factors, and to determine whether IBD medications are associated with change in estimated glomerular filtration rate (eGFR)., Methods: We performed a retrospective cohort study of data from The Health Improvement Network. Patients with IBD (n = 17,807) were matched for age, sex, and practice to individuals without IBD (n = 63,466). The relative hazard of CKD, stages 3 through 5D, in patients with IBD was calculated using a Cox proportional hazards model adjusted for common CKD risk factors. We also evaluated the association of 5-ASAs, azathioprine, and methotrexate with change in eGFR using a longitudinal model., Results: After we controlled for risk factors associated with CKD, we found IBD to be associated with development of CKD in patients 16-77 years old. As patient age increased, the adjusted hazard ratio for CKD decreased monotonically, from 7.88 (95% CI, 2.56-24.19) at age 16 to 1.13 (95% CI, 1.01-1.25) at age 77. In the longitudinal analysis, exposure to 5-ASAs or methotrexate was not associated with change in eGFR, whereas azathioprine was associated with a slightly higher eGFR (0.32 mL/min/1.73 m 2 ; 95% CI, 0.16-0.48)., Conclusions: In a retrospective study of more than 80,000 persons, we found that IBD is associated with increased risk of CKD, and the hazard ratio is highest among younger patients. Commonly used non-biologic therapeutic agents were not associated with lower eGFR., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Urinary stone disease (USD) is increasing in prevalence and recurrence is common. In pediatrics, most stones are composed primarily of calcium with the highest incidence observed in adolescents. Given the morbidity associated with USD, an in depth review of current management strategies is of paramount importance to highlight the data supporting the recommended treatments and the knowledge gaps which still exist., Recent Findings: Several interventions for the management of recurrent calcium USD in children have been recommended based on primarily adult studies. These interventions include modification of diet and fluid intake in addition to the utilization of medications such as thiazide diuretics and citrates when supportive care is inadequate. Overall there is conflicting data in the adult literature which is further complicated by our attempts to extrapolate these data to children., Summary: Based on the currently available literature the management of USD in pediatrics should be individualized to each patient and focused on the particular metabolic risk factors that are identified during the course of their evaluation. Several interventions may be required or trialed in a particular patient to show an effect. Well designed trials to assess the efficacy of each intervention in the pediatric population are needed.

Background: Permanent vascular access (PVA) is preferred for long-term hemodialysis. Arteriovenous fistulae (AVF) have the best patency and the lowest complication rates compared to arteriovenous grafts (AVG) and tunneled cuffed catheters (TCC). However, AVF need time to mature. This study aimed to investigate predictors of time to first cannulation for AVF in pediatric hemodialysis patients., Methods: Data on first AVF and AVG of patients at 20 pediatric dialysis centers were collected retrospectively, including demographics, clinical information, dialysis markers, and surgical data. Statistical modeling was used to investigate predictors of outcome., Results: First PVA was created in 117 children: 103 (88%) AVF and 14 (12%) AVG. Mean age at AVF creation was 15.0 ± 3.3 years. AVF successfully matured in 89 children (86.4%), and mean time to first cannulation was 3.6 ± 2.5 months. In a multivariable regression model, study center, age, duration of non-permanent vascular access (NPVA), and Kt/V at AVF creation predicted time to first cannulation, with study center as the strongest predictor (p < 0.01). Time to first cannulation decreased with increasing age (p = 0.03) and with increasing Kt/V (p = 0.01), and increased with duration of NPVA (p = 0.03). Secondary failure occurred in 10 AVF (11.8%). Time to first cannulation did not predict secondary failure (p = 0.29), but longer time to first cannulation tended towards longer secondary patency (p = 0.06)., Conclusions: Study center is the strongest predictor of time to first cannulation for AVF and deserves further investigation. Time to first cannulation is significantly shorter in older children, with more efficient dialysis treatments, and increases with longer NPVA duration.

Background: Hemodialysis (HD) guidelines recommend permanent vascular access (PVA) in children unlikely to receive kidney transplant within 1 year of starting HD. We aimed to determine predictors of primary and secondary patency of PVA in pediatric HD patients., Methods: Retrospective chart reviews were performed for first PVAs in 20 participating centers. Variables collected included patient demographics, complications, interventions, and final outcome., Results: There were 103 arterio-venous fistulae (AVF) and 14 AV grafts (AVG). AVF demonstrated superior primary (p = 0.0391) and secondary patency (p = 0.0227) compared to AVG. Primary failure occurred in 16 PVA (13.6%) and secondary failure in 14 PVA (12.2%). AVF were more likely to have primary failure (odds ratio (OR) = 2.10) and AVG had more secondary failure (OR = 3.33). No demographic, clinical, or laboratory variable predicted primary failure of PVA. Anatomical location of PVA was predictive of secondary failure, with radial having the lowest risk compared to brachial (OR = 12.425) or femoral PVA (OR = 118.618). Intervention-free survival was predictive of secondary patency for all PVA (p = 0.0252) and directly correlated with overall survival of AVF (p = 0.0197) but not AVG. Study center demonstrated statistically significant effect only on intervention-free AVF survival (p = 0.0082), but not number of complications or interventions, or outcomes., Conclusions: In this multi-center pediatric HD cohort, AVF demonstrated primary and secondary patency advantages over AVG. Radial PVA was least likely to develop secondary failure. Intervention-free survival was the only predictor of secondary patency for AVF and directly correlated with overall access survival. The study center effect on intervention-free survival of AVF deserves further investigation.

Dent disease is an X-linked form of chronic kidney disease characterized by hypercalciuria, low molecular weight proteinuria, nephrocalcinosis, and proximal tubular dysfunction. Clinical presentation is highly variable. Male patients may present with early-onset rickets, recurrent nephrolithiasis, or insidiously with asymptomatic proteinuria or chronic kidney disease. Mutations in both the CLCN5 and OCRL1 genes have been associated with the Dent phenotype and are now classified as Dent-1 and Dent-2, respectively. This article describes the clinical presentation, laboratory evaluation, genetics, pathophysiology, management, and future therapies of Dent disease., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background Although intestinal and urinary microbiome perturbations are associated with nephrolithiasis, whether antibiotics are a risk factor for this condition remains unknown. Methods We determined the association between 12 classes of oral antibiotics and nephrolithiasis in a population-based, case-control study nested within 641 general practices providing electronic health record data for >13 million children and adults from 1994 to 2015 in the United Kingdom. We used incidence density sampling to match 25,981 patients with nephrolithiasis to 259,797 controls by age, sex, and practice at date of diagnosis (index date). Conditional logistic regression models were adjusted for the rate of health care encounters, comorbidities, urinary tract infections, and use of thiazide and loop diuretics, proton-pump inhibitors, and statins. Results Exposure to any of five different antibiotic classes 3-12 months before index date was associated with nephrolithiasis. The adjusted odds ratio (95% confidence interval) was 2.33 (2.19 to 2.48) for sulfas, 1.88 (1.75 to 2.01) for cephalosporins, 1.67 (1.54 to 1.81) for fluoroquinolones, 1.70 (1.55 to 1.88) for nitrofurantoin/methenamine, and 1.27 (1.18 to 1.36) for broad-spectrum penicillins. In exploratory analyses, the magnitude of associations was greatest for exposure at younger ages ( P <0.001) and 3-6 months before index date ( P <0.001), with all but broad-spectrum penicillins remaining statistically significant 3-5 years from exposure. Conclusions Oral antibiotics associated with increased odds of nephrolithiasis, with the greatest odds for recent exposure and exposure at younger age. These results have implications for disease pathogenesis and the rising incidence of nephrolithiasis, particularly among children., (Copyright © 2018 by the American Society of Nephrology.)

Background: Current treatment options for chronic hyperkalemia in children with chronic kidney disease include dietary restrictions or enteral sodium polystyrene sulfonate (SPS); however, dietary restrictions may compromise adequate nutrition and enteral SPS may be limited by palatability, adverse effects and feeding tube obstruction. A potentially safer alternative is to pretreat enteral nutrition (EN) with SPS prior to consumption. The purpose of this study was to evaluate the efficacy and safety of pretreating EN with SPS in pediatric patients with hyperkalemia., Methods: We performed a retrospective cohort study between September 2012 and May 2016 at the Children's Hospital of Philadelphia. In all, 14 patients (age range 0.5-53.2 months) who received 19 courses of SPS pretreatment of EN were evaluated. Serum electrolytes were evaluated at baseline and within 1 week of initiating therapy. The primary endpoint was mean change in potassium at 7 days. Secondary endpoints included the mean change in serum sodium, chloride, bicarbonate, calcium, phosphorous and magnesium, as well as the percentage of patients who developed electrolyte abnormalities within the first week of treatment., Results: Serum potassium levels decreased from 6.0 to 4.4 mmol/L (P < 0.001) and serum sodium levels increased from 135.8 to 141.3 mmol/L (P = 0.008) 1 week after initiating SPS pretreatment. No significant differences in mean serum calcium or magnesium levels were noted. Nevertheless, more than half of the courses resulted in at least one electrolyte abnormality, with hypokalemia (31.6%), hypernatremia (26.3%) and hypocalcemia (21.1%) occurring most frequently., Conclusions: Pretreatment of EN with SPS is an effective method for treating chronic hyperkalemia in pediatric patients; however, close monitoring of electrolytes is warranted.

This quiz will discuss two patients with end-stage kidney disease (ESKD) on dialysis presenting with diaphoresis and hypernatremia.

Background: Variability in measures of mineral metabolism has not been studied in pediatric end stage kidney disease. We sought to determine the intra-individual variability in measures of mineral metabolism in children on hemodialysis (HD) and its impact on clinical decision-making., Methods: We conducted a prospective single-center study of children (3.6-17.3 years old) on chronic HD. Serial twice weekly measures of serum calcium, phosphate and intact parathyroid hormone (PTH), as well as weekly measures of fibroblast growth factor 23 (FGF23) and vitamin D metabolites, were obtained over a 12-week period in 10 children. Samples (n = 226) were assayed in a single batch at the end of the study., Results: The median intra-individual coefficient of variation (CV) calculated by 4-week blocks was 5.1-6.5% for calcium, 9.5-14.9% for phosphate and 32.7-33.4% for PTH. The median overall CV for FGF23 was 44.4%. Using the first value of each block as a reference, subsequent values would dictate a discrepant management decision 33-56%, 19-28%, and 30-33% of the time for calcium, phosphate, and PTH, respectively. Adjusting for sex and age, most of the variability in phosphate and PTH was attributable to within-participant variability. For calcium, 49% of the variability was attributable to day of blood collection (Monday vs. Friday). The median (range) of an individual participant's values within clinical target ranges was 55% (26-86%) for calcium, 58% (0-96%) for phosphate, and 21% (0-64%) for PTH., Conclusions: There is considerable intra-individual variability in measures of mineral metabolism that serve as surrogate markers for bone health in children on HD. Within a 4-week period, at least 20-30% of measures would dictate a discrepant decision from the referent measure of that month. These findings have important implications for clinical decision-making and underscore the need to base therapeutic decisions on trends rather than single measurements.

This population-based retrospective cohort study sought to determine if anorexia nervosa (AN) is associated with a higher risk of urolithiasis. Nine thousand three hundred two females with AN were compared to 92 959 randomly selected age-matched and practice-matched females. Cox regression was used to estimate the hazard ratio (HR) for urolithiasis and evaluate effect modification by age. Twenty-three participants with AN (0.25%) developed urolithiasis compared with 154 unexposed participants (0.17%) over a median of 4 years of observation. The risk of urolithiasis varied significantly with age (interaction p = 0.02). AN was associated with a more than threefold higher risk of urolithiasis in females ≤25 years of age (HR 3.49, 95% CI: 1.56-7.81; p = 0.002), but not in females over 25 years (HR 1.18, 95% CI: 0.69-2.02; p = 0.54). The distribution of diagnosis codes for urolithiasis differed between groups (p = 0.04), with a higher proportion of codes for uric acid urolithiasis in the AN (16.2%) versus unexposed group (5.0%). Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association., (Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.)

Purpose: We determined the association between dietary zinc intake and incident calcium kidney stones in adolescents. We also examined the relationship between dietary zinc intake and urinary zinc excretion between cases and controls., Materials and Methods: We conducted a nested case-control study within a large pediatric health care system. Three 24-hour dietary recalls and spot urine chemistry analyses were obtained for 30 participants 12 to 18 years old with a first idiopathic calcium based kidney stone and 30 healthy controls matched for age, sex, race and month of enrollment. Conditional logistic regression models were used to estimate the association between daily zinc intake and incident calcium kidney stones, adjusting for dietary phytate, protein, calcium, sodium and oxalate. Multivariable linear regression was used to estimate the association between dietary and urine zinc, adjusting for urine creatinine and dietary phytate and calcium., Results: Cases had lower daily zinc intake (8.1 mg) than controls (10 mg, p = 0.029). Daily zinc intake of boys and girls with calcium stones was 2 mg and 1.2 mg less, respectively, than the daily intake recommended by the Institute of Medicine. Odds of incident stones were reduced by 13% for every 1 mg increase in daily zinc intake (OR 0.87, 95% CI 0.75-0.99). There was an estimated 4.5 μg/dl increase in urine zinc for every 1 mg increase in dietary zinc (p = 0.009), with weak evidence of a smaller increase in urine zinc in cases than in controls (interaction p = 0.08)., Conclusions: Decreased dietary zinc intake was independently associated with incident calcium nephrolithiasis in this population of adolescents., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Though previous studies have demonstrated an increased fracture risk in females with anorexia nervosa (AN), fracture risk in males is not well characterized. The objective of this study was to examine sex differences in fracture risk and site-specific fracture incidence in AN. We performed a population-based retrospective cohort study using The Health Improvement Network (THIN; a large database of anonymized electronic medical records collected at primary care clinics throughout the United Kingdom). The median calendar year for the start of the observation period was 2004-2005. We identified 9239 females and 556 males <60 years of age with AN, and 97,889 randomly selected sex-, age-, and practice-matched participants without eating disorders (92,329 females and 5560 males). Multivariable Cox regression was used to estimate the hazard ratio (HR) for incident fracture. Median age at start of observation was 29.8 years in females and 30.2 years in males. The HR for fracture associated with AN differed by sex and age (interaction p = 0.002). Females with AN had an increased fracture risk at all ages (HR, 1.59; 95% confidence interval [CI], 1.45 to 1.75). AN was associated with a higher risk of fracture among males >40 years of age (HR, 2.54; 95% CI, 1.32 to 4.90; p = 0.005) but not among males ≤40 years. Females with AN had a higher risk of fracture at nearly all anatomic sites. The greatest excess fracture risk was noted at the hip/femur (HR, 5.59; 95% CI, 3.44 to 9.09) and pelvis (HR, 4.54; 95% CI, 2.42 to 8.50) in females and at the vertebrae (HR, 7.25; 95% CI, 1.21 to 43.45) for males with AN. AN was associated with higher incident fracture risk in females across all age groups and in males >40 years old. Sites of highest fracture risk include the hip/femur and pelvis in females and vertebrae in males with AN. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

Background and Objectives: Dent disease is a rare X-linked disorder characterized by low molecular weight proteinuria and often considered a renal tubular disease. However, glomerulosclerosis was recently reported in several patients. Thus, Dent disease renal histopathologic features were characterized and assessed, and their association with kidney function was assessed., Design, Setting, Participants, & Measurements: Clinical renal pathology reports and slides (where available) were collected from 30 boys and men in eight countries who had undergone clinical renal biopsy between 1995 and 2014., Results: Median (25th, 75th percentiles) age at biopsy was 7.5 (5, 19) years with an eGFR of 69 (44, 94) ml/min per 1.73 m 2 and a 24-hour urine protein of 2000 (1325, 2936) mg. A repeat biopsy for steroid-resistant proteinuria was performed in 13% (four of 30) of the patients. Prominent histologic findings included focal global glomerulosclerosis in 83% (25 of 30; affecting 16%±19% glomeruli), mild segmental foot process effacement in 57% (13 of 23), focal interstitial fibrosis in 60% (18 of 30), interstitial lymphocytic infiltration in 53% (16 of 30), and tubular damage in 70% (21 of 30). Higher percentages of globally sclerotic glomeruli, foot process effacement, and interstitial inflammation were associated with lower eGFR at biopsy, whereas foot process effacement was associated with steeper annual eGFR decline., Conclusions: These associations suggest a potential role for glomerular pathology, specifically involving the podocyte, in disease progression, which deserves further study. Furthermore, Dent disease should be suspected in boys and men who have unexplained proteinuria with focal global glomerulosclerosis and segmental foot process effacement on renal biopsy., (Copyright © 2016 by the American Society of Nephrology.)

Pediatric stone disease is increasing in incidence and healthcare costs. With more years at-risk for stone recurrence during their lifetimes, children with nephrolithiasis constitute a high-risk patient population that requires focused intervention through both medical and surgical means. Through high-quality future studies to compare methods of stone prevention and treatment, the burden of stone disease on the youngest members of society may be ameliorated., Competing Interests: David I. Chu has received grant number T32-DK07785 from the National Institute of Diabetes and Digestive and Kidney Diseases. Gregory E. Tasian and Lawrence Copelovitch declare that they have no conflict of interest.

Background and Objectives: The prevalence of nephrolithiasis in the United States has increased substantially, but recent changes in incidence with respect to age, sex, and race are not well characterized. This study examined temporal trends in the annual incidence and cumulative risk of nephrolithiasis among children and adults living in South Carolina over a 16-year period., Design, Setting, Participants, & Measurements: We performed a population-based, repeated cross-sectional study using the US Census and South Carolina Medical Encounter data, which capture all emergency department visits, surgeries, and admissions in the state. The annual incidence of nephrolithiasis in South Carolina from 1997 to 2012 was estimated, and linear mixed models were used to estimate incidence rate ratios for age, sex, and racial groups. The cumulative risk of nephrolithiasis during childhood and over the lifetime was estimated for males and females in 1997 and 2012., Results: Among an at-risk population of 4,625,364 people, 152,925 unique patients received emergency, inpatient, or surgical care for nephrolithiasis. Between 1997 and 2012, the mean annual incidence of nephrolithiasis increased 1% annually from 206 to 239 per 100,000 persons. Among age groups, the greatest increase was observed among 15-19 year olds, in whom incidence increased 26% per 5 years (incidence rate ratio, 1.26; 95% confidence interval, 1.22 to 1.29). Adjusting for age and race, incidence increased 15% per 5 years among females (incidence rate ratio, 1.15; 95% confidence interval, 1.14 to 1.16) but remained stable for males. The incidence among blacks increased 15% more per 5 years compared with whites (incidence rate ratio, 1.15; 95% confidence interval, 1.14 to 1.17). These changes in incidence resulted in doubling of the risk of nephrolithiasis during childhood and a 45% increase in the lifetime risk of nephrolithiasis for women over the study period., Conclusions: The incidence of kidney stones has increased among young patients, particularly women, and blacks., (Copyright © 2016 by the American Society of Nephrology.)

In this study we sought to determine if among individuals with urolithiasis, extracorporeal shock wave lithotripsy (SWL) and ureteroscopy are associated with a higher risk of incident arterial hypertension (HTN) and/or chronic kidney disease (CKD). This was measured in a population-based retrospective study of 11,570 participants with incident urolithiasis and 127,464 without urolithiasis in The Health Improvement Network. Patients with pre-existing HTN and CKD were excluded. The study included 1319 and 919 urolithiasis patients with at least one SWL or URS procedure, respectively. Multivariable Cox regression was used to estimate the hazard ratio for incident CKD stage 3-5 and HTN in separate analyses. Over a median of 3.7 and 4.1 years, 1423 and 595 of urolithiasis participants developed HTN and CKD, respectively. Urolithiasis was associated with a significant hazard ratio each for HTN of 1.42 (95% CI: 1.35, 1.51) and for CKD of 1.82 (1.67, 1.98). SWL was associated with a significant increased risk of HTN 1.34 (1.15, 1.57), while ureteroscopy was not. When further stratified as SWL to the kidney or ureter, only SWL to the kidney was significantly and independently associated with HTN 1.40 (1.19, 1.66). Neither SWL nor ureteroscopy was associated with incident CKD. Since urolithiasis itself was associated with a hazard ratio of 1.42 for HTN, an individual who undergoes SWL to the kidney can be expected to have a significantly increased hazard ratio for HTN of 1.96 (1.67, 2.29) compared with an individual without urolithiasis., (Copyright © 2015 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Studies have shown decreased bone mineral density in individuals with urolithiasis, but their burden of fracture remains unclear. This study sought to determine whether urolithiasis is associated with increased fracture risk across the lifespan and to delineate sex effects., Design, Setting, Participants, & Measurements: A population-based retrospective cohort study using The Health Improvement Network was performed. The median calendar year for the start of the observation period was 2004 (1994-2012). This study identified 51,785 participants with ≥1 of 87 diagnostic codes for urolithiasis and 517,267 randomly selected age-, sex-, and practice-matched participants. Cox regression was used to estimate the hazard ratio (HR) for first fracture. Fractures identified using diagnostic codes were classified by anatomic site., Results: Median age was 53 years, and 67% of participants were men, confirming their greater urolithiasis burden. Median time from urolithiasis diagnosis to fracture was 10 years. The HR for fracture associated with urolithiasis differed by sex and age (P for interactions, P≤0.003). In men, the adjusted HR was greatest in adolescence (1.55; 95% confidence interval [95% CI], 1.07 to 2.25) with an overall HR of 1.10 (95% CI, 1.05 to 1.16). Urolithiasis was associated with higher fracture risk in women aged 30-79 years (HR, 1.17-1.52), and was highest in women aged 30-39 years (HR, 1.52; 95% CI, 1.23 to 1.87). Peak background fracture rates were highest in boys aged 10-19 years and in women aged 70-79 years. The incidence per 10,000 person-years in participants with versus without urolithiasis was 392 versus 258 in male participants aged 10-19 years, and 263 versus 218 in women aged 70-79 years. Distribution of fracture site within sex did not differ between participants with versus without urolithiasis., Conclusions: Urolithiasis was associated with higher incident fracture risk. The significantly higher risk at times of peak background fracture incidence in adolescent boys and elderly women has profound public health implications., (Copyright © 2014 by the American Society of Nephrology.)

Purpose: We review the current literature on the diagnostic evaluation and dietary and pharmacological management of children with nephrolithiasis., Materials and Methods: We searched MEDLINE(®), Embase(®) and the Cochrane Library from their inceptions to March 2014 for published articles in English on kidney stones and therapy in children 0 to 18 years old. Based on review of the titles and abstracts, 110 of the 1,014 articles (11%) were potentially relevant to the diagnostic evaluation and medical management of nephrolithiasis in children. We summarized this literature and drew on studies performed in adult populations to augment areas in which no studies of sufficient quality have been performed in children, and to highlight areas in need of research., Results: During the last 25 years the incidence of nephrolithiasis in children has increased by approximately 6% to 10% annually and is now 50 per 100,000 adolescents. Kidney stones that form during childhood have a similar composition to those that form in adulthood. Approximately 75% to 80% of stones are composed of predominantly calcium oxalate, 5% to 10% are predominantly calcium phosphate, 10% to 20% are struvite and 5% are pure uric acid. The recurrence rate of nephrolithiasis in patients with stones that form during childhood is poorly defined. Ultrasound should be used as the initial imaging study to evaluate children with suspected nephrolithiasis, with noncontrast computerized tomography reserved for those in whom ultrasound is nondiagnostic and the suspicion of nephrolithiasis remains high. Current treatment strategies for children with kidney stone disease are based largely on extrapolation of studies performed in adult stone formers and single institution cohort or case series studies of children. Tamsulosin likely increases the spontaneous passage of ureteral stones in children. Increased water intake and reduction of salt consumption should be recommended for all children with a history of kidney stones. Potassium citrate is a potentially effective medication for children with calcium oxalate stones and concomitant hypocitraturia, as well as children with uric acid stones. However, long-term compliance with therapy and the effect on decreasing stone recurrence in children are unknown. Based largely on efficacy in adult populations, thiazide diuretics should be considered in the treatment of children with calcium based stones and persistent hypercalciuria refractory to reductions in salt intake., Conclusions: The incidence of kidney stone disease in children is increasing, yet few randomized clinical trials or high quality observational studies have assessed whether dietary or pharmacological interventions decrease the recurrence of kidney stones in children. Collaborative efforts and randomized clinical trials are needed to determine the efficacy and effectiveness of alternative treatments for children with nephrolithiasis, particularly those with calcium oxalate stones and concomitant hypercalciuria and hypocitraturia. Additional areas in need of study are the optimal length of time for a trial of stone passage in children, the cost-effectiveness of medical expulsive therapy vs analgesics alone, and the size and location of stones for which medical expulsive therapy is most effective., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Tremendous advances have been made in understanding the pathogenesis of atypical Hemolytic Uremic Syndrome (aHUS), an extremely rare disease. Insights into the molecular biology of aHUS resulted in rapid advances in treatment with eculizumab (Soliris(®), Alexion Pharmaceuticals Inc.). Historically, aHUS was associated with very high rates of mortality and morbidity. Prior therapies included plasma therapy and/or liver transplantation. Although often life saving, these were imperfect and had many complications. We review the conditions included under the rubric of aHUS: S. pneumoniae HUS (SpHUS), inborn errors of metabolism, and disorders of complement regulation, emphasizing their differences and similarities. We focus on the clinical features, diagnosis, and pathogenesis, and treatment of aHUS that results from mutations in genes encoding alternative complement regulators, SpHUS and HUS associated with inborn errors of metabolism. Mutations in complement genes, or antibodies to their protein products, result in unregulated activity of the alternate complement pathway, endothelial injury, and thrombotic microangiopathy (TMA). Eculizumab is a humanized monoclonal antibody that inhibits the production of the terminal complement components C5a and the membrane attack complex (C5b-9) by binding to complement protein C5a. This blocks the proinflammatory and cytolytic effects of terminal complement activation. Eculizumab use has been reported in many case reports, and retrospective and prospective clinical trials in aHUS. There have been few serious side effects and no reports of tachphylaxis or drug resistance. The results are very encouraging and eculizumab is now recognized as the treatment of choice for aHUS.

Background: Tyrosine kinase (TK) inhibitors are increasingly being used to treat a variety of pediatric malignancies. Reports in adult patients describe a range of effects of TK inhibitors on the kidney, including hypertension, proteinuria, acute kidney injury, and thrombotic microangiopathy (TMA); however, there are only a few reports of TK-inhibitor-associated nephrotic syndrome., Methods: We report four pediatric patients with various malignancies (chronic myelogenous leukemia, acute lymphoblastic leukemia, and glioma/renal cell carcinoma) who developed nephrotic syndrome during treatment with TK inhibitors (imatinib, sunitinib, dasatinib, and quizartinib). One of the four patients also had clinical features of TMA., Results: Three of the four patients achieved complete remission of nephrotic syndrome with discontinuation of the TK inhibitor and have had no additional nephrotic syndrome relapses to date. The temporal relationship of nephrotic syndrome onset to TK-inhibitor therapy and resolution of nephrotic syndrome with cessation of therapy strongly imply an association in these patients., Conclusions: TK inhibitors are important therapies in pediatric cancer, and their use is expanding. Nephrotic syndrome with or without features of TMA is a potential complication of these therapies in children.

Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) is an important cause of acute kidney injury (AKI). The outcomes of STEC HUS have improved, and the acute mortality rate in children is 1-4%. About 70% of patients recover completely from the acute episode and the remainder have varying degrees of sequelae. Only a few retrospective studies have reviewed these patients over long periods. Methodological flaws include a lack of strict definitions, changing modes of treatment, ascertainment bias and loss of subjects to follow-up. The kidneys bear the brunt of the long-term damage: proteinuria (15-30% of cases); hypertension (5-15%); chronic kidney disease (CKD; 9-18%); and end-stage kidney disease (ESKD; 3%). A smaller number have extra-renal sequelae: colonic strictures, cholelithiasis, diabetes mellitus or brain injury. Most renal sequelae are minor abnormalities, such as treatable hypertension and/or variable proteinuria. Most of the patients who progress to ESKD do not recover normal renal function after the acute episode. Length of anuria (more than 10 days) and prolonged dialysis are the most important risk factors for a poor acute and long-term renal outcome. After the acute episode all patients must be followed for at least 5 years, and severely affected patients should be followed indefinitely if there is proteinuria, hypertension or a reduced glomerular filtration rate (GFR).

We report on five consecutive sibs three with fatal renal-hepatic-pancreatic dysplastic (RHPD) syndrome and two pregnancies ending in early abortion. Three of the fetuses reached term and two survived for 15 and 58 days. They had diffusely cystic kidneys with absence of the distal collecting tubules, hepatic fibrosis, bile duct paucity, and pancreatic fibrosis with irregularly dilated ducts. These findings correspond to many of those reported by Ivemark et al. [Ivemark et al. (1959); Acta Paediat Scand 48: 1-11] as part of the RHPD syndrome. There are several notable differences in this family: one patient had hypocalvaria and a choroid plexus cyst at the right foramen of Luschka, multiple bone abnormalities including widened growth plates and abnormal development of the trabeculae of the ribs, "handle-bar" clavicles, wedge defects of the inferior margin of several thoracic vertebrae; the second patient had hypocalvaria and abnormally developed brain with bilateral exposure of the insulae; and a third patient had anencephaly. Mutational analysis of the two who survived beyond post-delivery demonstrated compound heterozygous novel frameshift mutations in the nephronophthisis type 3 gene (NPHP3)., (Copyright © 2013 Wiley Periodicals, Inc.)

Purpose of Review: Streptococcus pneumoniae associated hemolytic uremic syndrome (SpHUS) is defined by the occurrence of acute hemolytic anemia, thrombocytopenia and acute kidney injury in a patient with a S. pneumoniae infection. We review the pathophysiology, clinical course, treatment and prognosis for SpHUS. We also describe an expanded classification system that uses additional diagnostic criteria to identify more patients with a high likelihood of having SpHUS., Recent Findings: SpHUS often may be underdiagnosed because of overlapping features with disseminated intravascular coagulation (DIC) and the lack of strict diagnostic criteria. The epidemiology has changed with the emergence of different pneumococcal serotypes as newer pneumococcal vaccines have been introduced., Summary: SpHUS accounts for 5-15% of all HUS cases. The majority of SpHUS patients have pneumonia and a low mortality rate in contrast to those with meningitis, who have a more severe clinical course. Although the pathogenesis of SpHUS remains unknown, the Thomsen-Friedenreich antigen seems to play a central role. S. pneumoniae produces neuraminidase, thereby exposing the Thomsen-Friedenreich antigen on the surface of cell membranes. Thomsen-Friedenreich antigen exposure can result in hemolysis and direct endothelial injury leading to HUS phenotype. Early identification of these patients is critical so that fresh frozen plasma may be avoided.

Childhood urolithiasis is an evolving condition with an increasing incidence and prevalence over the last 2 decades. Over that time the underlying cause has shifted from predominantly infectious to metabolic in nature. This review describes the pathophysiology, underlying metabolic abnormalities, clinical presentation, evaluation, and management of childhood urolithiasis. A comprehensive metabolic evaluation is essential for all children with renal calculi, given the high rate of recurrence and the importance of excluding inherited progressive conditions., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Epithelial sodium channels (ENaC) are critically important in the regulation of ion and fluid balance in both renal and respiratory epithelia. ENaC functional polymorphisms may contribute to alterations in blood pressure in the general population. We previously reported that the A663T polymorphism in the C terminus of the α-subunit altered ENaC functional and surface expression in Xenopus laevis oocytes (Samaha FF, Rubenstein RC, Yan W, Ramkumar M, Levy DI, Ahn YJ, Sheng S, Kleyman TR. J Biol Chem 279: 23900-23907, 2004). We examined whether sites in the vicinity of 663 influenced channel activity by performing scanning Ala mutagenesis. Interestingly, only αT663/G667Aβγ channels exhibited increased currents compared with αT663βγ. This increase in channel activity reflected an increase in channel open probability and not an increase in channel surface expression. In contrast, decreases in channel activity were observed with both αT663/C664Aβγ and αT663/C664Mβγ channels. The decrease in functional expression of αT663/C664Mβγ channels correlated with decreased surface expression, suggesting that the αC664M mutation altered the intracellular trafficking of the channel. While cytoplasmic Cys residues may be modified by the addition of palmitate, we did not observe palmitoylation of αC664. Our results suggest that multiple residues in the distal part of the cytoplasmic C terminus have roles in modulating channel activity.

Background: To better characterize Streptococcus pneumoniae-associated hemolytic-uremic syndrome (SP-HUS), we report the largest series of SP-HUS among children in North America., Methods: We surveyed pediatric members of the Emerging Infections Network to identify SP-HUS cases. Respondents contributed clinical and laboratory features of these pediatric cases., Results: A total of 37 cases occurring between 1997 and 2009 were submitted. Of them, 33 cases (89%) were culture-confirmed and 4 (11%) were diagnosed clinically. The median patient age was 2 years, and 28 (76%) patients had completed their heptavalent pneumococcal conjugate vaccination (PCV7) series. Most patients presented with pneumonia (84%) and bacteremia (78%), whereas other clinical manifestations such as pericardial effusion (14%) and meningitis (11%) were less common. Of 29 patients, with bacteremia 6 (21%) had S. pneumoniae concurrently isolated from cerebrospinal fluid or pleural fluid. Severe illness was common with 35 (95%) patients requiring admission to the intensive care unit, over half requiring mechanical ventilation and chest tube placement or video-assisted thoracoscopic surgery, and 27 (73%) requiring dialysis during hospitalization. Among 30 patients with follow-up of 6 months, 7 (23%) remained dialysis dependent, 3 (10%) had undergone renal transplantation, 4 (13%) had neurologic sequelae, and 1 (3%) died. Among 24 serotyped isolates, 96% were non-PCV7 serotypes, most commonly 19A (50%), 92% are included in PCV13, and 10% were penicillin nonsusceptible (minimal inhibitory concentration >2 μg/mL)., Conclusions: North American children with SP-HUS had severe clinical manifestations and significant morbidity. In this series, nearly all cases were caused by serotypes that are not in PCV7 but are included in PCV13.

Over the last 5 years, the Chronic Kidney Disease in Children (CKiD) prospective cohort study has enrolled close to 600 children ages 1 to 16 years with mild to moderate chronic kidney disease (CKD). The main purpose of this interim report is to review the initial cross-sectional data and conclusions derived from the clinical studies conducted within CKiD in the context of findings from other pediatric CKD and end-stage renal disease (ESRD) registry and cohort studies. In particular, special emphasis was placed on studying four aspects of chronic kidney disease in children, including the identification of risk factors related to disease progression, the impact of CKD on neurocognition and quality of life (QoL), the cardiovascular morbidity associated with CKD, and identifying the causes and effects of growth failure in the context of mild to moderate kidney failure.