The incidence of transient infantile pseudohypoaldosteronism in Ireland: A prospective study.

AIM: To review the clinical course, outcome and incidence of infantile salt wasting associated with urinary tract infection (UTI) and/or urinary tract malformation (UTM) over a two-year surveillance period on the island of Ireland. METHODS: A two-year (2013-14) prospective surveillance undertaken via the Irish and Ulster Paediatric Surveillance Units. Monthly prepaid postcards were circulated to consultant paediatricians (n = 260) at all paediatric units on the island of Ireland. Infants under one year of age presenting for the first time with hyponatraemia (Na < 130 mmol/L) and/or hyperkalaemia (K > 5.0 mmol/L) associated with urosepsis/UTM were reported. RESULTS: All 7 reported patients (6 male) had culture-proven UTI, and 5 (71%) also had an underlying UTM (one diagnosed antenatally). Four (57%) patients had a documented elevated serum aldosterone supporting secondary pseudohypoaldosteronism (PHA) as the underlying diagnosis. Data on aldosterone were not reported in the other 3 patients, but clinical features were suggestive of secondary PHA. The estimated incidence for the Irish population of transient PHA is 1 per 13,200 total live births per year. CONCLUSIONS: Salt wasting is a rare complication of UTI, especially if associated with underlying UTM. Boys appear to be at particular risk.

Predisposing factors for renal scarring in children with urinary tract infection.

This study was undertaken to determine the predisposing factors for renal scarring in children with urinary tract infection. In this prospective cohort study, 176 children with documented urinary tract infection were categorized into four groups: ≤1 year old, 1-2 years old, 2-7 years and 7-14 years old. Ultrasonography and Technetium-99 m-DMSA scan were used to detect the possible abnormalities. Infants under 12 months old presented as the most common group for renal scarring (27 cases, 52.9%), and vesicoureteral reflux (VUR) was diagnosed in 29 cases (56.8%). Fifteen (41.67%) children between the ages of one and two years had renal scar, and VUR was detected in half of the patients. In the third group, 36.3%, and in fourth group, 41.6% of the patients had renal scar. Also, 38.6% in group three and 50% in the final group had VUR. A co-incidental finding that was observed in this study was the high incidence of pseudohypoaldesteronism (PHA) in our patients: in 39.2% of the children in group one, 22.2% in group two and 4% in group three. In group four however, none of the patients had PHA. Risk of scar formation with urinary tract infection (UTI) was higher in the younger age group and in those with recurrent UTIs.

Autosomal dominant pseudohypoaldosteronism type 1: mechanisms, evidence for neonatal lethality, and phenotypic expression in adults.

Autosomal dominant pseudohypoaldosteronism type 1 (adPHA1) is a rare condition that is characterized by renal resistance to aldosterone, with salt wasting, hyperkalemia, and metabolic acidosis. It is thought of as a mild disorder; affected children's symptoms respond promptly to salt therapy, and treatment is not required after childhood. Mutations in the mineralocorticoid receptor gene (MR) cause adPHA1, but the long-term consequences of MR deficiency in humans are not known. Herein are described six novel adPHA1-causing MR mutations (four de novo) and evidence that haploinsufficiency of MR is sufficient to cause adPHA1. Furthermore, genotype-phenotype correlation is reported in a large adPHA1 kindred. A number of cases of neonatal mortality in infants who were at risk for adPHA1 were identified; coupled with the frequent identification of de novo mutations in affected individuals, this suggests that the seemingly benign adPHA1 may have been a fatal neonatal disorder in previous eras, preventing propagation of disease alleles. In contrast, it is shown that adult patients with adPHA1 are clinically indistinguishable from their wild-type relatives except for presumably lifelong elevation of renin, angiotensin II, and aldosterone levels. These data highlight the critical role of MR in the maintenance of salt homeostasis early in life and illuminate the sodium dependence of pathologic effects of renin and angiotensin II. They furthermore argue that nongenomic effects of aldosterone play no significant role in the long-term development of cardiovascular disease.

Three novel missense mutations of WNK4, a kinase mutated in inherited hypertension, in Japanese hypertensives: implication of clinical phenotypes.

BACKGROUND: Mutations in serine-threonine kinase WNK4 with no lysine (K) at a key catalytic residue cause familial hypertension known as pseudohypoaldosteronism type II (PHAII). The objective of this study was to test whether more subtle changes of WNK4 could be implicated in hypertension or renal failure. METHODS: We screened 956 Japanese patients with hypertension or renal failure for mutations in exons 7 and 17 in the WNK4 gene where the mutations were identified in patients with PHAII. RESULTS: We identified three novel missense mutations, Met546Val (n = 2) and Pro556Thr (n = 2) in exon 7, and Pro1173Thr (n = 1) in exon 17, in a heterozygous state in addition to four single nucleotide polymorphisms including one synonymous mutation (Ala547Ala). Results of genotyping Met546Val and Pro556Thr mutations indicated that these mutations were not present in a Japanese general population (n = 1875). CONCLUSIONS: The present study indicated that a systematic screening of WNK4 in a large set of patients with hypertension or renal failure detected some rare genetic variants. Although substantial contribution of three novel missense mutations in exons 7 and 17 of WNK4 to the genetics of hypertension or renal failure is still unclear, these mutations in the WNK4 gene identified in Japanese hypertensives but not in a general population may contribute to hypertension and progression of hypertensive complications to some extent.