David A. McCredie

A Familial Syndrome of Hypocalcemia with Hypercalciuria Due to Mutations in the Calcium-Sensing Receptor

BACKGROUND The calcium-sensing receptor regulates the secretion of parathyroid hormone in response to changes in extracellular calcium concentrations, and mutations that result in a loss of function of the receptor are associated with familial hypocalciuric hypercalcemia. Mutations involving a gain of function have been associated with hypocalcemia in two kindreds. We examined the possibility that the latter type of mutation may result in a phenotype of familial hypocalcemia with hypercalciuria. METHODS We studied six kindreds given a diagnosis of autosomal dominant hypoparathyroidism on the basis of their hypocalcemia and normal serum parathyroid hormone concentrations, a combination that suggested a defect of the calcium-sensing receptor. The hypocalcemia was associated with hypercalciuria, and treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment. Mutations in the calcium-sensing-receptor gene were identified by DNA-sequence analysis and expressed in human embryonic kidney cells (HEK-293). RESULTS Five heterozygous missense mutations (Asn118Lys, Phe128Leu, Thr151Met, Glu191Lys, and Phe612Ser) were detected in the extracellular domain of the calcium-sensing-receptor gene and shown to cosegregate with the disease. Analysis of the functional expression of three of the mutant receptors in HEK-293 cells demonstrated shifts in the dose-response curves so that the extracellular calcium concentrations needed to produce half-maximal increases in total inositol phosphate in the cells were significantly (P=0.02 to P<0.001) lower than those required for the wild-type receptor. CONCLUSIONS Gain-of-function mutations in the calcium-sensing receptor are associated with a familial syndrome of hypocalcemia with hypercalciuria that needs to be distinguished from hypoparathyroidism.

Identification of 70 calcium-sensing receptor mutations in hyper- and hypo-calcaemic patients: evidence for clustering of extracellular domain mutations at calcium-binding sites

The calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that has an extracellular bilobed venus flytrap domain (VFTD) predicted to contain five calcium (Ca(2+))-binding sites. To elucidate the structure-function relationships of the VFTD, we investigated 294 unrelated probands with familial hypocalciuric hypercalcaemia (FHH), neonatal severe primary hyperparathyroidism (NSHPT) or autosomal dominant hypocalcaemic hypercalciuria (ADHH) for CaSR mutations and performed in vitro functional expression studies and three-dimensional modelling of mutations involving the VFTD. A total of 70 different CaSR mutations were identified: 35 in FHH, 10 in NSHPT and 25 in ADHH patients. Furthermore, a CaSR variant (Glu250Lys) was identified in FHH and ADHH probands and demonstrated to represent a functionally neutral polymorphism. NSHPT was associated with a large proportion of truncating CaSR mutations that occurred in the homozygous or compound heterozygous state. Thirty-four VFTD missense mutations were identified, and 18 mutations were located within 10 Å of one or more of the predicted Ca(2+)-binding sites, particularly at the VFTD cleft, which is the principal site of Ca(2+) binding. Mutations of residues 173 and 221, which are located at the entrance to the VFTD cleft binding site, were associated with both receptor activation (Leu173Phe and Pro221Leu) and inactivation (Leu173Pro and Pro221Gln), thereby highlighting the importance of these residues for entry and binding of Ca(2+) by the CaSR. Thus, these studies of disease-associated CaSR mutations have further elucidated the role of the VFTD cleft region in Ca(2+) binding and the function of the CaSR.

Low birthweight and renal disease in Australian aborigines

tag=1 data=Low birthweight and renal disease in Australian aborigines tag=2 data=Hoy, W.E., Rees, M., Kile, J.D., McCredie, D.A., Pugsley, D.J., Wang, Z. tag=3 data=The Lancet, tag=4 data=352 tag=6 data=December 5, 1998 tag=7 data=1826-1827. tag=8 data=CHILDBIRTH%DISEASE%ABORIGINES tag=9 data=NORTHERN TERRITORY%URINARY ALBUMIN/CREATININE RATIO%ACR

Post-streptococcal glomerulonephritis is a strong risk factor for chronic kidney disease in later life

Although unusual in western countries and in Australia in general, post-streptococcal glomerulonephritis (PSGN) is still common in Australian Aboriginal children living in remote communities. Here, we evaluated whether episodes of acute PSGN increased the risk for chronic kidney disease in later life in 1519 residents of a remote Aboriginal community (85% of those age eligible), with high rates of renal and cardiovascular disease, who participated in a health screen over a 3-year period. Of these, 200 had had at least one episode of PSGN, with 27 having had multiple episodes, usually in childhood. High levels of albuminuria (albumin/creatinine ratio) with increasing age were confirmed. All PSGN episodes were associated with group A streptococcal skin infections, often related to scabies. In both genders, aged 10-39 years at screening, about one in five had such a history. Among them, PSGN (5 years or more earlier) was significantly associated with higher levels of albuminuria than those without. In women, aged 30-39 years, a history of PSGN was associated with a significantly higher frequency of estimated glomerular filtration rates <60 ml/min. The adjusted odds ratios for an albumin/creatinine ratio over 34 g/mol (overt albuminuria) in males and females with a history of PSGN were 4.6 and 3.1, respectively, compared with those without a history. Thus, PSGN contributes to the very serious burden of chronic kidney disease in this community. Rigorous strategies to prevent scabies and Group A streptococcal infections will reduce this burden.

Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations.

Background/Aims: Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood. Methods: We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing. Results: All patients had bi-allelic FAM20A mutations segregating with the disease; 20 different mutations were identified. Conclusions: This au-tosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis.

Familial hypomagnesaemia--hypercalciuria leading to end-stage renal failure.

Several disorders of hypomagnesaemia of hetary renal origin are now recognised. The cases of two sisters from a consanguineous marriage with the syndrome of renal magnesium wasting, hypercalciuria and nephrocalcinosis are presented. Pathological examination of the heterozygous parental kidneys revealed mild focal interstitial fibrosis. This condition is a previously unreported cause of end-stage renal failure in chilhhood, and this report suggests that transplantation from heterozygous parental donors can be successfully undertaken without recurrence currence of the syndrome.

Persistent familial hematuria in children and the locus for thin basement membrane nephropathy

This study examined how often children with persistent familial hematuria were from families where hematuria segregated with the known genetic locus for the condition known as benign familial hematuria or thin basement membrane nephropathy (TBMN) at COL4A3/COL4A4. Twenty-one unrelated children with persistent familial hematuria as well as their families were studied for segregation of hematuria with haplotypes at the COL4A3/COL4A4 locus for benign familial hematuria and at the COL4A5 locus for X-linked Alport syndrome. Eight families (38%) had hematuria that segregated with COL4A3/COL4A4, and four (19%) had hematuria that segregated with COL4A5. At most, eight of the other nine families could be explained by disease at the COL4A3/COL4A4 locus if de novo mutations, non-penetrant hematuria or coincidental hematuria in unaffected family members was present individually or in combination. This study confirms that persistent familial hematuria is not always linked to COL4A3/COL4A4 (or COL4A5) and suggests the possibility of a further genetic locus for benign familial hematuria. This study also highlights the risk of excluding X-linked Alport syndrome on the basis of the absence of a family history or of kidney failure.

The use of hypothermia in pediatric emergencies

Fifteen critically ill children were treated with hypothermia and chlorpromazine. This was employed for persistent convulsions, peripheral circulatory failure, or increased intracranial pressure with respiratory embarrassment. All patients had failed to respond to conventional measures and a fatal outcome appeared likely. Hypothermia appeared valuable in the management of cerebral anoxia, particularly when associated with convulsions which were well controlled by hypothermia in 6 out of 7 patients. One patient with severe septicemic shock survived and temporary improvement was seen in others, suggesting that hypothermia may be of benefit in these patients. The technique employed at the Royal Childrens Hospital, Melbourne, Australia, is outlined and short summaries of case histories are included.

Towards an epidemiologic definition of renal disease: Rates and associations of albuminuria in a high‐risk Australian Aboriginal community

Summary: An epidemic of renal failure is accompanying the rising rates of hypertension, type 2 diabetes and cardiovascular disease among Aborigines in the Northern Territory of Australia. the rates and associations of the underlying renal disease were studied in a remote Aboriginal community whose renal failure rates are among the highest reported in the world. More than 90% of school‐age children and adults participated in a health screen, in which the urinary albumin/creatinine ratio (ACR) was used as the primary renal disease marker. Albuminuria was evident in early childhood and increased dramatically with age; 26% of adults had microalbuminuria and 24% had overt albuminuria. Most hypertension segregated in persons with albuminuria and all renal failure developed out of a background of overt albuminuria. ACR levels correlated with the presence of scabies at screening, with a history of post‐streptococcal glomerulonephritis, with increasing bodyweight or its surrogates, with increasing blood pressure, glucose, insulin and lipid levels, and with evidence of heavy drinking. ACR also correlated inversely with birthweight. Finally, increasing ACR correlated with an increasing cardiovascular risk factor score. Thus many factors contribute to renal disease in this community; most are the features and consequences of lifestyle change, poverty and disadvantage. Renal disease shares risk factors, including low birthweight, with Syndrome X, which supports the inclusion of renal disease in that syndrome, and explains the excess cardiovascular morbidity in people with chronic renal disease. There is an urgent need for effective programs to modify recognized risk factors, and to identify and treat people with established renal disease to retard the progression of renal insufficiency.

An extreme example of the neonatal form of Bartter’s syndrome

Abstract. A male infant is described who had polyuria over the 4 months of his life with urine volumes exceeding 1,000 ml/kg per day, severe serum electrolyte losses, metabolic alkalosis and increased plasma renin activity (56 ng/ml per hour). He had a normal blood pressure and glomerular filtration rate when fluid replete. The urine flow rate was about 25% of the glomerular filtration rate. Renal histology showed hyperplasia of the juxtaglomerular apparatus and abnormalities of the proximal tubules. The features of this case suggest an extreme form of Bartter’s syndrome presenting from the first days of life.