Autosomal dominant hypophosphataemia with elevated serum 1,25 dihydroxyvitamin D and hypercalciuria

A 14-year-old boy presented with the clinical and radiological features of rickets. Serum inorganic phosphate levels were constantly low, whereas serum calcium and parathyroid hormone levels were within the normal range. Laboratory investigation did not show any evidence for vitamin-D deficiency, chronic renal insufficiency, Fanconi syndrome, tubular acidosis, hepatic disease or intestinal malabsorption. A family study comprising 34 members over four generations revealed 10 other individuals to be affected and the mode of inheritance to be autosomal dominant. In addition to hypophosphataemia and normocalcaemia, the diasease is characterized by elevated serum 1,25 dihydroxyvitamin D levels and hypercalciuria. This hereditary syndrome of renal hypophosphataemia differs from the common familial X-linked hypophosphataemia and the recently described autosomal recessive hypophosphataemic rickets with hypercalciuria by its dominant mode of inheritance; it differs from hypophosphataemic non-rachitic bone disease by the elevated serum 1,25 dihydroxyvitamin D levels and hypercalciuria.     

CELLULOSE PHOSPHATE AND CHLOROTHIAZIDE IN CHILDHOOD IDIOPATHIC HYPERCALCIURIA

Abstract A calcium loading test performed on seven of eight children with idiopathic hypercalciuria identified the hyperabsorptive form of hypercalciuria in five and renal hypercalciuria in one. The type of hypercalciuria was not identified in the other patient. Three children presented with hematuria without calculus formation. Chlorothiazide reduced the urinary calcium excretion level in two of six patients to the normal range. The addition of cellulose phosphate to chlorothiazide reduced the urinary calcium excretion level to the normal range in those four patients who showed an incomplete response to chlorothiazide alone. There was clinical improvement with cellulose phosphate in another child whose symptoms did not disappear after chlorothiazide had reduced urinary calcium level to the normal range. Cellulose phosphate is effective in children with recurrent stone formation who have shown inadequate response to chlorothiazide.     

Renal tubular disorders and arteriopathy of the lower limbs: Risk factors for osteoporosis in men?

In order to clarify the risk-factors for men with vertebral fractures due to osteoporosis, we carried out a study of 51 cases. Twenty-five percent of patients had an endocrine disorder (hyperparathyroidism, hypogonadism, hyperthyroidism) or had received corticosteroids. These patients were compared with 26 age-matched controls. Eleven patients compared with 2 of the 26 control subjects had arteriopathy of the lower limbs; 11 patients had hypercalciuria or hyperphosphaturia compared with 3 of the control subjects. Arteriopathy appears to be associated with osteoporosis in older patients (mean age 71 years), whereas renal tubular disorders were found in younger patients (mean age 45 years).     

Long-term renal follow-up of extremely low birth weight infants

There is evidence that low birth weight caused by intrauterine growth retardation adversely affects normal renal development. Very little information on this issue is available on children born very prematurely. This investigation examined clinical and functional renal parameters in 40 children (23 boys, 17 girls) ranging in age between 6.1 and 12.4 years and weighing less than 1000 g at birth. Results were compared to those obtained in 43 healthy children of similar age and gender. Study subjects were significantly smaller and thinner than control subjects (mean height SDS: –0.36 vs. +0.70; and mean BMI SDS: –0.56 vs. +1.18). Systolic, diastolic, and mean blood pressures did not differ from those of controls. Renal sonography revealed no abnormality, and mean percentiles for renal length and volume appeared normal. In comparison with controls, plasma creatinine concentration (0.62±0.1 vs. 0.53±0.1 mg/dl) and estimated creatinine clearance (117±17 vs. 131±17 ml min^–1 1.73 m^–2) differed significantly. No significant differences were observed in microalbuminuria values, but five study subjects (12.5%) presented values above the upper limit of normality. A defect in tubular phosphate transport was also evident: TmP/GFR (3.6±0.4 vs. 4.2±0.8 mg/dl) and TRP (83±5% vs. 90±4%) were significantly lower, and urinary P excretion, estimated by the ratio UP/UCr, was significantly higher (1.2±0.4 vs. 0.9±0.4 mg/mg) than controls. Urinary calcium excretion, estimated by the UCa/UCr ratio, was also significantly higher (0.15±0.07 vs. 0.12±0.09 mg/mg). These data clearly demonstrate that both GFR and tubular phosphate transport are significantly diminished in school-age children born with extreme prematurity, probably as a consequence of impaired postnatal nephrogenesis.     

A novel gain-of-function mutation (<Emphasis Type="Italic">F821L</Emphasis>) in the transmembrane domain of calcium-sensing receptor is a cause of severe sporadic hypoparathyroidism

Gain-of-function mutations of the extracellular calcium (Ca²⁺e)-sensing receptor (CaR) have been identified in patients with familial and sporadic hypercalciuric hypocalcaemia. We describe a patient with sporadic severe hypercalciuric hypocalcaemia with undetectable or very low levels of serum parathyroid hormone, carrying a de novo heterozygous missense mutation (F821L), localized in the sixth transmembrane domain of CaR. Analysis of in vitro functional properties of the mutant receptor to measure Ca²⁺e-evoked changes in intracellular Ca²⁺ revealed a leftward shift in the concentration-response curve for the mutant compared to wild-type receptor. Conclusion:the F821L mutation is therefore a novel gain-of-function mutation which can cause severe hypoparathyroidism. Thiazide diuretics lowered urinary calcium excretion of the patient treated with calcium supplementation and 1-hydroxyvitamin D_3. Abbreviations Ca ²⁺ e extracellular calcium - Ca ²⁺ i intracellular calcium - CaR calcium-sensing receptor - PTH parathyroid hormone     

Are changes in urinary parameters during pregnancy clinically significant?

We aimed to objectively determine changes in the various urinary parameters along with CaOx saturation level during pregnancy. The study included 15 pregnant women who had no known diseases and were taking no medication except prenatal supplements. Mean age of the patients was 26 years (range 20–30). In all of them, this study was carried out in each trimester and 3 months post partum. All participants were followed up, and blood and urine samples were obtained during the pregnancy and during 3 months post partum. All subjects collected 24-h urine samples. The pregnant women had hypercalciuria in all three trimesters. Except for the first trimester, urine calcium levels in all trimesters were significantly higher when compared with the post-partum period (P<0.01 for second trimester, P<0.05 for third trimester). Urine oxalate level in post-partum period was significantly higher than urine oxalate levels in each trimester (P<0.05). The urine citrate levels were similarly higher than normal levels in three trimesters. Urine citrate level of the post-partum period was in normal reference ranges. This difference was not stastistically significant (P>0.05). We believe that hypercalciuria encountered at pregnancy is a reversible physiologic condition. Also, citrate and magnesium as urinary inhibitors increased in urine during gestation preventing stone formation. We think that long time periods are needed for hypercalciuria to be able to lead to the formation of urinary calculi in pregnant women (except women having a positive family history). Therefore, we think that the pregnancy alone does not predispose to a suitable condition for calculi.An erratum to this article can be found at     

Reference values for urinary calcium excretion and screening for hypercalciuria in children and adolescents

Hypercalciuria is of continuing interest as on of the risk factors for stone disease in children, but the definition, incidence and pathogenesis are controversial. Therefore reference values for the urinary calcium/creatinine (Ca/Cr) ratios were established in 564 healthy children aged 6–17.9 years during the fasting state (09.00 h) and in 236 of them also in the post-absorptive state about 2 h after lunch (14.00–16.00 h). The Ca/Cr ratios in both urine specimens were independent of age and sex, rendering it possible to determine a common normal range and to calculate centiles for Ca excretion in a large sample of healthy children and adolescents. To provide information about the incidence of hypercalciuria the Ca/Cr ratios of 1013 other apparently healthy children aged 6–17.9 years were measured during the post-absorptive state on two consecutive days. In 39 (3.8%) of them, 21 girls, and 18 boys, the Ca excretion was elevated in both urine specimens. Thirtysix of these children, all presenting without renal complaints, underwent further investigations to elucidate the possible mechanisms of the hypercalciuria.On the basis of the Ca/Cr concentration during the fasting state and the calciuric response to a standardised oral Ca tolerance test the children were subclassified into three groups: (1) Absorptive hypercalciuria (AH, n=12): Increased calciuric response to the Ca load, but normal fasting Ca/Cr; (2) Renal hypercalciuria (RH, n=8): Increased Ca/Cr after Ca load and during the fasting state; (3) Normal Ca excretion during the fasting state and after the Ca tolerance test, but increased sodium excretion (dietary hypercalciuria, DH, n=16).The serum prolactin levels were increased in AH, and the serum P and tubular P reabsorption rates were decreased in RH, while the parathyroid function and bone turnover were unimpaired in all groups.The study provides evidence that the measurement of Ca/Cr ratios in untimed random urine specimens during the post-absorptive state may be a reasonable screening test for elevated Ca excretion and that idiopathic hypercalciuria seems to be as prevalent in children as it is in adults.Abbreviations Ca/Cr calcium/creatinine - AH absorptive hypercalciuria - RH renal hypercalciuria - P inorganic phosphate - AP alkaline phosphatase activity - 25OHD 25-hydroxyvitamin D - iPTH immunoreactive parathyroid hormone - cAMP cyclic adenosine-3,5-monophosphate - GFR glomerular filtration rate - DH dietary hypercalciuria - OH-P total hydroxyproline     

Comparison between the fractional isotopic calcium absorption and an oral calcium tolerance test

Summary In 27 subjects with several disorders of calcium metabolism, the fractional intestinal absorption of⁴⁷CaCl₂ was rather poorly correlated with the urinary output of calcium or with the maximal increase of serum calcium after an oral calcium load. Conversely, a good correlation was observed with the product of these parameters. We propose that this product be used as an estimate of intestinal calcium absorption when a radioisotopic method is not available.     

Central/diffuse abdominal perception of urological pain in children

AIM: In children with recurrent abdominal pain (RAP), the location of pain to the flank may suggest the involvement of the urinary apparatus. We aimed to evaluate the location of pain in different age groups of children with idiopathic hypercalciuria (HC) and/or hyperuricosuria (HU) and RAP. METHODS: Location of pain was assessed in 180 consecutive HC/HU children with RAP, aged 3-17.6 y, presenting to a single centre. RESULTS: Considering four age groups, central/diffuse was more prevalent than lateral location of pain in youngsters, with a progressive and significant (p<0.0001, chi2 test for trend) decrease of the prevalence of central/diffuse location with rising age, and with the most relevant drop after age 8 y. Location of pain was central/diffuse in 81% of patients under and lateral in 79% of those over 8 y of age (p<0.0001). The location of pain changed from central/diffuse to lateral in 16/18 children followed at least 1 y, within 1 to 2 y by age 8. CONCLUSION: Only after 8 y of age did the lateral location of abdominal pain become the rule in children with HC/HU and RAP. This has to be kept in mind in order to avoid overlooking the urologic origin of pain.     

Pediatric urolithiasis in a non-endemic country: A single center experience from The Netherlands

ObjectiveTo provide insight in causative factors of pediatric urolithiasis in The Netherlands, a non-endemic country.Patients and methodsData from 71 children with urolithiasis and stone analyses between 1996 and 2010 in the Radboud University Nijmegen Medical Centre were studied retrospectively. Patients (48 boys, 23 girls, ratio 2.1:1) were aged 0.5–18.3 years (mean 8.8, SD 5.6). All stone analyses were performed with FTIR spectroscopy.ResultsOf the 49 patients with metabolic analysis, 78% showed one (n = 15) or more (n = 23) metabolic abnormalities. Forty-seven percent had hypercalciuria (n = 23), 31% had hyperoxaluria (n = 15), 29% hypocitraturia (n = 14), 10% hyperuricosuria (n = 5), 10% cystinuria (n = 5), and 6% had hypomagnesiuria (n = 3).Sixty-one percent of the stones were composed of calcium phosphate, calcium oxalate, or a combination of those. Twenty-six percent consisted of pure or mixed magnesium ammonium phosphate, 8.3% pure or mixed urate, and 8.3% cystine.ConclusionChildren with urolithiasis in The Netherlands show stone composition similar to other Western European countries. However, a high percentage of metabolic abnormalities (78%) was found, indicating the need for extensive evaluation of pediatric urolithiasis to find underlying causes and thereby prevent stone recurrences. A close collaboration between a pediatric nephrologist and urologist is mandatory for optimal surgical and medical treatment.