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

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

Hyponatremic hypertensive syndrome in pediatric patients: is it really so rare?

BACKGROUND: Hyponatremic hypertensive syndrome (HHS) is characterized by unilateral renal artery stenosis with secondary hypertension and glomerular and tubular dysfunction due to hyperfiltration and activation of the renin-angiotensin system (RAS). CASE-DIAGNOSIS/TREATMENT: We describe four children with HHS. All presented with polyuria and polydipsia, electrolyte disturbances, metabolic alkalosis, variable tubular dysfunction, and nephrotic range proteinuria along with hypertension. Interestingly, in one patient, glomerular and tubular abnormalities preceded the development of hypertension. All symptoms resolved after the underlying renal ischemia was corrected by percutaneous angioplasty. CONCLUSION: Hyponatremic hypertensive syndrome may be more common in children than previously thought. Clinicians should be alert of the signs and symptoms because cure is possible with timely diagnosis and treatment.

Peritonitis in a pediatric dialysis unit: local profile and implications.

BACKGROUND: Peritonitis is a major complication of chronic peritoneal dialysis therapy. It is recommended that each center monitor infection rates in order to define the local microbiological profile and implement an appropriate empiric antibiotic regimen. OBJECTIVES: To analyze the microbiologic profile of peritonitis in our pediatric dialysis unit and identify local predisposing factors. METHODS: In this retrospective study we reviewed the files of children treated with chronic PD during the 10 year period 1997-2007. RESULTS: Eighty peritonitis episodes were recorded in 29 children (20 male, 9 female) aged 0.1-18.5 years (median 11.75) treated with peritoneal dialysis for 6-69 months (median 19) for a total of 578 patient-months. The annual peritonitis rate was 1.66/patient. The main pathogens were coagulase-negative Staphyloccocus (32.5%) and Pseudomonas spp. (16%), which were also cultured in most cases (64-69%) from the exit site during the 3 months preceding peritonitis. No peritonitis occurred in 31% of the patients (median age 12.5 years). All patients less than 5 years old had at least one peritonitis episode. Contaminating conditions (gastrostomy, enuresis, diaper use), found in 44% of the study group, and first infection within 6 months from starting PD were significantly associated with an increased peritonitis rate (P = 0.01, P = 0.009, respectively). Recurrent peritonitis led to a switch to hemodialysis in 18% of patients. There were no deaths. CONCLUSIONS: The risk factors for peritonitis in our study were: first infection within less than 6 months from starting treatment, Pseudomonas exit-site colonization, and contaminating conditions (gastrostomies, diaper use, enuresis). These susceptible subgroups as well as very young age (< 5 years) at starting PD should be especially targeted during training of caregivers and follow-up to prevent later complications.

Ocular complications in children and adolescents following renal transplantation.

Ocular complications after renal transplantation are common in adults. Nevertheless, data regarding these complications in children are insufficient. The purpose of the present study was to assess ocular morbidity in pediatric renal graft recipients. A retrospective observational study of 71 patients aged 11.2 +/- 5.5 yr was conducted. Mean duration of follow-up was 5.6 +/- 3.5 yr. A total of 16 ocular complications were found in 12 (17%) of the patients. Three patients suffered from more than one complication. Cataract was the most common finding (six patients, 8.4%) followed by swollen disk and hypertensive retinopathy in four patients (5.7%) each and increased intra-ocular pressure in two patients (3%). Mean time interval between transplantation and occurrence of first abnormal ocular finding was 37 +/- 34.5 months. The follow-up time was significantly longer in patients with ophthalmological problems than in those without complications (7.8 yr vs. 5.2 yr, p < 0.02). No statistically significant association was found between the occurrence of ocular complications and the age of the patients at transplantation, donor source, duration of dialysis prior to transplantation, previous corticosteroid therapy or presence of acute rejection episodes. The results of the study point to the importance of regular concurrent ophthalmological follow-up in pediatric renal graft recipients to reduce/prevent ocular morbidity.

Changes in behavior as an early symptom of renovascular hypertension in children.

Renovascular hypertension in children is usually asymptomatic and diagnosed incidentally. Behavioral changes have not yet been well recognized as a part of the clinical spectrum of renovascular disease in children. We surveyed all children diagnosed with renovascular hypertension in our institute over a 15-year period. Eleven children were identified, of whom five (45%) had abnormal behavior, which had preceded the diagnosis of hypertension by 3-12 months. The symptoms included restlessness, sleep disturbances, temper tantrums, hyperactivity, aggressive behavior and attention deficit. In three children all behavioral symptoms disappeared following blood pressure normalization, and, in the other two a significant improvement was noted. It was concluded that behavioral symptoms may be a common and early manifestation of renovascular hypertension. Awareness of this association may bring about earlier diagnosis of the disease and prevent end-organ damage as well as unnecessary investigations for behavioral abnormalities.

Early performance of voiding cystourethrogram after urinary tract infection in children.

BACKGROUND: Voiding cystourethrogram is performed 3-6 weeks after urinary tract infection. This prolongs the interval of prophylactics, reducing the likelihood of having to perform the procedure. OBJECTIVES: To investigate the yield and potential risks/benefits of early compared to late performance of VCUG after UTI. METHODS: We conducted a prospective study of 84 previously healthy children < 5 years old admitted from October 2001 to November 2002 with first documented UTI. We then divided the 78 patients who had VCUG into two groups and compared them to a control group: group A--49 children in whom VCUG was performed within 10 days, group B--29 children in whom VCUG was performed > 10 days after UTI, and a historical control group C--82 children in whom VCUG was performed > 4 weeks following UTI. RESULTS: VCUG was performed in 48/48 (100%), 6/35 patients (17.1%) and 34/116 patients (29.3%), and vesicoureteral reflux was demonstrated in 38.8%, 37.9% and 39% in groups A, B and C respectively. No significant difference was found between these groups in terms of incidence of VUR and severity and grading of reflux within each group. One case of UTI secondary to VCUG occurred in a patient in whom the procedure was performed 4 months after the diagnosis. CONCLUSIONS: Performing VCUG early does not influence the detection rate, severity of the VUR, or risk of secondary infection; it shortens the period of prophylactic use and increases performance rate of VCUG, thereby minimizing the risk of failure to detect VUR. The traditional recommendation of performing VCUG 3-6 weeks after the diagnosis of UTI should be reevaluated.

Schimke immuno-osseous dysplasia: expression of SMARCAL1 in blood and kidney provides novel insight into disease phenotype.

Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive disorder caused by loss-of-function mutations in SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1), with clinical features of growth retardation, spondylo-epiphyseal dysplasia, nephrotic syndrome, and immunodeficiency. We report a patient with SIOD and SMARCAL1 splice mutation (IVS4-2 A>G) in a nonconsanguineous Ashkenazi family, who came to our attention at 1 mo of age due to renal malformation and only later developed signs compatible with Schimke. Interestingly, residual SMARCAL1 mRNA levels in the patient's peripheral blood were lower compared with those observed in both asymptomatic brothers' carrying the same bi-allelic mutation, whereas the latter had levels similar to those found in heterozygous carriers (parents and sister). Examination of the carrier frequency of the splice mutation in the Ashkenazi population demonstrated 1 carrier in 760 DNA samples. In situ localization of SMARCAL1 in human kidneys as well as analysis of its temporal expression during murine nephrogenesis and in the metanephric organ culture suggested a role in the early renal progenitor population and after renal maturation. Thus, disease severity within the same family might be modified by the splicing machinery. The renal expression pattern of SMARCAL1 explains a broader spectrum of renal disease in SIOD than previously described.

Hemodialysis in children weighing less than 15 kg: a single-center experience.

Despite significant technical improvements, hemodialysis in infants with end-stage renal disease (ESRD) is still associated with significant morbidity and mortality. The files of patients weighing less than 15 kg with ESRD who were treated with hemodialysis at our institute between 1995 and 2005 were reviewed for background and treatment characteristics, morbidity and outcome. The study group included 11 patients aged 7-75 months (mean 34.2 months) weighing 7.2-14.9 kg (mean 10.9 kg). Mean duration of dialysis was 11.3 months. Vascular access posed the major problem. Ten patients were dialyzed through a central venous cuffed catheter and one through an arteriovenous fistula. An average of three different vascular accesses was required per patient (range 1-9). Mechanical difficulties were the most common cause of central-line removal (56.5%), followed by infections (15.6%). Major complications causing significant morbidity were intradialytic hemodynamic instability, hyperkalemia, coagulation within the dialysis set, anemia, hypertension, inadequate fluid removal, and recurrent hospitalizations. Analysis of outcome revealed that eight patients underwent successful transplantation, one returned for hemodialysis after 4.5 years due to graft failure, and two died. Hemodialysis is a suitable option for low-weight pediatric patients with ESRD awaiting transplantation when performed in highly qualified centers.