Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. A rare Mendelian syndrome, pseudohypoaldosteronism type II (PHAII), featuring hypertension, hyperkalemia, and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption versus K+ and H+ excretion1. We used exome sequencing to identify mutations in Kelch-like 3 (KLHL3) or Cullin 3 (CUL3) in 41 PHAII kindreds. KLHL3 mutations are either recessive or dominant, while CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-Kelch proteins such as KLHL3 are components of Cullin/RING E3 ligase complexes (CRLs) that ubiquitinate substrates bound to Kelch propeller domains2–8. Dominant KLHL3 mutations are clustered in short segments within the Kelch propeller and BTB domains implicated in substrate9 and Cullin5 binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter (NCC) in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3/CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite combined complexities of locus heterogeneity, mixed models of transmission, and frequent de novo mutation, and establish a fundamental role for KLHL3/CUL3 in blood pressure, K+, and pH homeostasis.

We studied 124 children, 62 patient-subjects who had end-stage renal disease (ESRD) and 62 sibling-controls who closely matched the patient-subjects in terms of their ethnicity and their socioeconomic status, to discern whether children with ESRD would perform less well than their siblings on standardized achievement and intelligence quotient (IQ) tests, and to determine whether ethnicity would influence such results. The subjects were recruited from nine pediatric transplant and dialysis centers across the United States. Thirty-one subjects were white (Euro-American), 17 were African-American, and 14 were categorized as 'other'. The average age of the patient-subjects was 13.7 +/- 0.44 yr; and of the sibling-controls 13.7 +/- 0.38 yr. Most patients (61%) and siblings (84%) were in regular school classes, and most (87% and 92%, respectively) attended school full-time. The average IQ percentile rank for the patients was significantly lower than their siblings (31 +/- 4 vs. 44 +/- 5, respectively, with normal = 50). Patients tended to score lower on achievement tests compared with their siblings (spelling: 88.7 +/- 4 vs. 94.6 +/- 2; arithmetic: 88.5 +/- 2 vs. 94.0 +/- 2; reading: 91.9 +/- 2 vs. 100 +/- 3, respectively). Patients scores on achievement tests were influenced by age at diagnosis and by the mother/caregiver's lower achievement. Also, increased time on dialysis predicted lower scores on achievement tests. Neither dialysis/transplant status nor ethnicity significantly affected outcome. Our data suggest that ESRD, but not ethnicity or dialysis/transplant status, is a risk factor for lower IQ and academic achievement, especially in younger children, in children who spend more time living with ESRD, and in children whose mother's/caregiver's have lower educational levels.

Childhood PKD encompasses the diagnoses of AR and ADPKD, glomerulocystic disease, and syndromes such as tuberous sclerosis or Jeune's syndrome. Given the fact that a majority of PKD children with ESRD carry the diagnosis of ARPKD, natural history studies assessing the long-term prognosis of PKD patients following renal transplantation must focus on morbidity and mortality issues related to complications from congenital hepatic fibrosis. Using the NAPRTCS registry, we analyzed the patient and graft survival rates of 203 PKD patients and 7044 non-PKD patients undergoing renal transplantation between 1987 and 2001. Deceased PKD patients, all with a diagnosis of ARPKD, were further identified and characterized using a special questionnaire submitted to the principal investigators. Overall graft and patient survival rates were not significantly different between PKD and non-PKD patients. No differences in rates of acute rejection or time to first rejection were noted between PKD and non-PKD patients. The relative risk of living longer than 3 yr in the PKD patients was not significantly different from non-PKD patients (RR = 0.70, p = 0.28). Sepsis was identified as a likely factor in the cause of death in nine (64%) ARPKD patients and was comfirmed with a positive blood culture in four patients. Despite similar graft and patient survival rates among PKD and non-PKD children following renal transplantation, our results suggest that ARPKD transplant recipients appear to be at increased risk for sepsis that may be related to hepatic fibrosis and ascending cholangitis. The utility of early liver transplantation in ARPKD patients with significant hepatobiliary disease is discussed.

Sleep disorders are common in adult dialysis patients, with a prevalence of 60%-80%. To date, sleep disturbances have not been assessed in the pediatric dialysis population. Therefore, the objective of this study is to describe the prevalence of sleep disturbance symptoms in a pediatric dialysis population. We conducted a telephone- or clinic-based interview of 21 children (aged 6-20 years) and their parents in our academic tertiary pediatric dialysis center with questionnaires that assessed four symptom domains of sleep disorders: (1) sleep-disordered breathing, (2) restless leg syndrome or period limb movements (RLS/PLMs), (3) excessive daytime sleepiness, and (4) inadequate sleep time. The presence of a "sleep disturbance" was defined by positive responses in any of the four symptom domains. Overall, 18 (86%) of the children undergoing dialysis [mean age (SD) 14.2 years (1.1), gender (M/F) 11/10] endorsed sleep disturbance symptoms: sleep-disordered breathing (46%), RLS/PLMs (29%), and excessive daytime sleepiness (60%). We conclude that sleep disturbances are very common in pediatric dialysis patients, but may be underrecognized. Given the adverse neurocognitive and physiological outcomes associated with poor sleep, it is important for practitioners caring for children on dialysis to anticipate and screen for treatable sleep conditions.

Although sleep disorders are common in adults with chronic kidney disease, little is known about the prevalence of sleep problems in children and adolescents with chronic kidney disease and their relationship to health-related quality of life measurements. We performed a clinic-based survey of sleep habits and common symptoms of sleep disturbances in 159 school-aged patients with chronic kidney disease. Three patient groups of chronic kidney disease were assessed: group 1, those not on dialysis and not transplanted; group 2, those on dialysis; and group 3, those with a functioning renal allograft. Four symptom domains for sleep disorders were assessed: excessive daytime sleepiness; sleep disordered breathing; restless legs syndrome symptoms; and insufficient sleep. Patients and the parent-proxy also completed the Pediatric Quality of Life Inventory Version 4.0 Generic Core Scales questionnaire. Ninety-three (93) patients (58.5%) had symptoms of a sleep disturbance. The presence of a sleep disturbance correlated with a decrease in health-related quality of life scores that was independent of the chronic kidney disease study group or estimated glomerular filtration rate. We conclude that sleep disturbances are common throughout the spectrum of chronic kidney disease in children and adolescents and are associated with diminished health-related quality of life scores.

Trials in children with chronic kidney disease do not consistently report outcomes that are critically important to patients and caregivers. This can diminish the relevance and reliability of evidence for decision making, limiting the implementation of results into practice and policy. As part of the Standardized Outcomes in Nephrology-Children and Adolescents (SONG-Kids) initiative, we convened 2 consensus workshops in San Diego, California (7 patients, 24 caregivers, 43 health professionals) and Melbourne, Australia (7 patients, 23 caregivers, 49 health professionals). This report summarizes the discussions on the identification and implementation of the SONG-Kids core outcomes set. Four themes were identified; survival and life participation are common high priority goals, capturing the whole child and family, ensuring broad relevance across the patient journey, and requiring feasible and valid measures. Stakeholders supported the inclusion of mortality, infection, life participation, and kidney function as the core outcomes domains for children with chronic kidney disease.

Background: While studies have shown sleep disorders to be common in adults with chronic kidney disease (CKD), pediatric data are scarce. Objective: To characterize the prevalence of sleep disorders among children and adolescents with non-dialysisdependent CKD.

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