Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.

Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin 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 in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.

Prevalence of sleep disturbances in children and adolescents with chronic kidney disease.

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.

Peritoneal dialysis technique success during the initial 90 days of therapy.

Comparisons of technique success by peritoneal dialysis (PD) modality have typically excluded the initial 90 days of therapy. We analyzed a database of 51,469 new PD starts from 2004 to 2008 in the United States. The analysis concentrated on the initial 90 days of therapy to determine technique success and the impact of the continuous ambulatory PD (CAPD) and automated PD (APD) modalities. Overall, 13.3% of patients stopped PD within 90 days. Of patients starting directly on APD, 14.3% stopped PD within 90 days. Of patients starting on CAPD, 12.6% stopped PD within 90 days, and 63.4% changed to APD within 90 days. Only 3.3% of the latter patients failed to reach 90 days of therapy. By comparison, technique failure occurred in 28.8% of those initiating with and remaining on CAPD. We conclude that initial training to perform CAPD, with timely transfer to APD within the first 3 months, was associated with the greatest technique success at 90 days. The reasons for that success are unclear, and further research should be directed to determining factors responsible. It is possible that patients trained initially to CAPD but converted to APD have a greater understanding of the total therapy, which improves confidence. Those converted to APD may be more appreciative of the lifestyle benefits of APD, which translates into improved compliance; alternatively, technical factors associated with APD may be responsible. Those technical factors may include improved catheter function in the recumbent position during APD or the reduced infection risk associated with just 2 connect/disconnect procedures in APD compared with 8 in CAPD.

A new, safe and convenient 5-L dual-chamber container for automated peritoneal dialysis.

BACKGROUND: Automated peritoneal dialysis (APD) provides the opportunity for home-based dialysis, enabling the patient to optimize their lifestyle by maintaining their normal daily routine. Use of a larger bag size and biocompatible solution is desirable. In an effort to further improve patient convenience and reduce the probability of infusing only the buffer contents from the outflow chamber, we designed a 5-L dual-chamber container system with a dual-seal system consisting of a long seal between the dextrose chamber and buffer chambers and a short SafetyMoon™ seal between the buffer chamber and container outflow connector. METHODS: The safety and effectiveness of this new container system was assessed in a non-interventional, prospective, open-label, multi-centre, uncontrolled, Baxter-sponsored post-authorization safety study in 249 patients from 7 countries in Europe. RESULTS: No mis-infusion events were noted throughout the study where 68 519 Physioneal™ 5-L bags in Clear-Flex™ were used for an average (SD) of 4.3 (1.9) months per patient. Overall, the percentage of patients and/or care providers rating the 5-L bag preparation as very easy or easy at baseline (0-8 weeks), 9-16, 17-24 and 25-32 weeks ranged from 94 to 97%. Assuming a Poisson distribution for the bag count data, the estimated change in number of bicarbonate/lactate dialysis fluid bags (5 or 2.5 L) as a percent of prior bag use was -36%, while the estimated change in number of bags for ALL solutions as a percent of prior bag use was -31%. The predominant reasons given by the investigators for prescribing 5-L PD solutions at study onset were biocompatibility, easier and convenient for their patients to use, physiological pH and less bag connections. None of the 92 serious adverse events were suspected to be related to the Physioneal 5-L PD solution. CONCLUSIONS: Use of a larger, Physioneal 5-L bag mitigates the concern regarding the possibility of mis-infusing the buffer chamber solution, is convenient to use by the patient/health care provider and is associated with more than a 30% reduction in the weekly number of dialysis solution bags required per patient for their APD therapy.

Urolithiasis with topiramate in nonambulatory children and young adults.

Urolithiasis occurs infrequently in the pediatric population, where metabolic factors play a primary role in the pathogenesis of stone formation. Topiramate, an antiepileptic drug, is associated with a kidney stone in 1.5% of patients in published clinical trials. However, this risk may be much higher in certain populations with multiple preexisting risk factors. We performed a retrospective review of all nonambulatory and neurologically impaired individuals in a long-term care facility. Three groups were involved: those with no exposure to antiepileptic drugs, those on antiepileptic drugs other than topiramate, and those who had been treated with topiramate. Thirteen of 24 (54%) individuals on topiramate monotherapy or polytherapy developed clinical evidence of urolithiasis after a mean duration of 36.4 months. Our results suggest that nonambulatory and neurologically impaired individuals in a long-term care facility appear to be at higher risk of developing kidney stones with topiramate than previously reported.

Relationship between drain volume/fill volume ratio and clinical outcomes associated with overfill complaints in peritoneal dialysis patients.

BACKGROUND: To better understand the spectrum of overfill reports and their corresponding clinical severity and etiology, we conducted a review of overfill reports from the Manufacturer and User Facility Device Experience (MAUDE) database, which is within the Food and Drug Administration (FDA) Web site (www.fda.gov). METHOD: We searched the MAUDE database for events related to overfill reports between 1 January 1995 and 31 December 2008 and recorded drain volume (DV)/fill volume (FV), or DV/FV, and clinical symptoms and signs associated with the overfill report. RESULTS: Among 462 MAUDE reports with a possible overfill event, 440 reports (95.2%) with a confirmed overfill event contained sufficient information to ascertain the clinical severity of the event. The number of reports with a clinical severity rating of minor, moderate, major, or death was 331, 71, 28, and 10, respectively. The median (range) DV/FV for a subgroup of 292 reports with a clinical severity rating of minor, moderate, major, or death was 1.63 (1.06 - 4.29), 1.71 (1.08 - 5.87), 2.14(1.64 - 2.61), and 2.50 (2.28 - 3.33), respectively. Insufficient drain accounted for a majority of overfill reports. CONCLUSION: Our analysis of reports from the MAUDE database suggests an association between DV/FV and clinical severity of the reported overfill event, as well as significant patient-to-patient variability with respect to intraperitoneal volume tolerance.

Sleep disturbances in children and adolescents with non-dialysis-dependent 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-dialysis-dependent CKD. DESIGN: Prospective, questionnaire-based, cross-sectional study. SETTING: Tertiary pediatric nephrology center. PARTICIPANTS: Children aged 6 to 18 years with non-dialysis-dependent CKD. Those with renal transplants were also considered to have CKD and were included, provided it was at least 3 months after the transplant. INTERVENTIONS: A validated pediatric sleep questionnaire. OUTCOME MEASURES: Four domains of sleep disturbance were assessed: sleep-disordered breathing, restless leg syndrome/paroxysmal leg movement (RLS/PLM), insomnia, and excessive daytime sleepiness. Positive responses to any of these signified the presence of a sleep disorder. RESULTS: A total of 49 non-dialysis-dependent children (30 with non-renal transplant CKD and 19 with post-renal transplant CKD; median age, 14 years; interquartile range, 6-18 years) were administered the pediatric sleep questionnaire; 71% (n = 35) of the patients were male; 37% (n = 18) were identified as having a sleep disorder; 40% (n = 12) were in the nontransplant CKD group and 32% (n = 6) in the transplant CKD group. The most common type of sleep disorder was RLS/PLM, affecting 27% (n = 8) in the nontransplant CKD group and 32% (n = 6) in the transplant CKD group. There was no correlation between stage of CKD and prevalence of sleep problems (P = .22). CONCLUSIONS: Disordered sleep was identified in more than one-third of our study population, and the most common type was RLS/PLM. Pediatricians should be aware of the relatively high incidence of sleep disorder among children and adolescents with CKD.

Sleep disturbances in pediatric dialysis patients.

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.

Survival of childhood polycystic kidney disease following renal transplantation: the impact of advanced hepatobiliary disease.

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.

Complications of peritoneal dialysis in children with Eagle-Barrett syndrome.

Eagle Barrett syndrome (EBS) is characterized by the triad of abdominal muscle deficiency, urinary tract abnormalities, and cryptorchidism. Approximately 25% of patients with EBS progress to end-stage renal disease. It is speculated that the abdominal muscular defects in EBS pose technical problems in achieving successful peritoneal dialysis (PD). In this retrospective analysis, we reviewed the medical records of EBS and non-EBS PD patients cared for at Rainbow Babies and Children's Hospital from 1985 to 2002; 5 EBS and 9 non-EBS patients were analyzed. PD duration, total complication rates, and catheter usage rates in the two groups were not significantly different. The two most frequent complications were peritonitis and catheter mechanical malfunction during 103 patient-months in EBS patients and 296 patient-months in non-EBS patients. Peritonitis occurred 1 episode every 20.6 patient-months and 14.8 patient-months in EBS and non-EBS patients, respectively. The time from PD initiation to onset of any complication, including first peritonitis, was not significantly different in the two groups. Although the age at PD initiation was significantly different between the groups, there was no correlation between age at onset of PD and complication rates or time to first complication. Despite their abdominal muscle defects, EBS patients do not have more-frequent PD complications.

Effect of the peritoneal dialysis prescription on pentosidine in children.

Enhanced formation of advanced glycation end products (AGEs) by peritoneal dialysate containing high dextrose concentrations has been implicated as a source of peritoneal membrane toxicity and loss of viability in patients treated with peritoneal dialysis (PD). The goal of this project was to elucidate the relationship between the structurally defined AGE pentosidine accumulation on peritoneal and plasma proteins and peritoneal membrane function, and to identify clinical factors leading to alterations in these parameters. The study comprised 27 pediatric patients (14 continuous ambulatory PD, 13 chronic cycling PD) on PD for a mean duration of 37.0+/-22.8 months (range 1-120 months) and with a mean age of 13.3+/-4.4 years (range 2.4-20 years). The pentosidine contents of plasma and peritoneal proteins were significantly lower in patients with residual renal function than in patients who were anuric (plasma pentosidine 11.2+/-8.8 vs. 24.1+/-16.6, P=0.02, respectively, peritoneal pentosidine 14.9+/-11.9 vs. 31.1+/-3.7, P=0.01, respectively). There was no effect of treatment modality on plasma pentosidine (18.1+/-11.2, 18.8+/-19.3, CAPD vs. CCPD, P>0.05) or peritoneal pentosidine content (24.1+/-14.1, 24.9+/-19.6, CAPD vs. CCPD, P>0.05). There was no evidence that increased levels of pentosidine on peritoneal proteins reflect or affect peritoneal membrane function in these patients. Furthermore, there was no effect of peritonitis on the pentosidine content of peritoneal proteins or peritoneal function as measured by peritoneal equilibration test. In conclusion, PD represents a well-tolerated therapy in children with no evidence that current practice causes changes in peritoneal membrane function, or in the peritoneal clearance of plasma or peritoneal proteins rich in pentosidine.