X-linked hypophosphatemia: Normal renal function despite medullary nephrocalcinosis 25 years after transient vitamin D2-induced renal azotemia

Nephrocalcinosis (NC) detected by ultrasound is a recognized abnormality for some patients with X-linked hypophosphatemia (XLH) who received vitamin D₂ and inorganic phosphate therapy, but is commonly observed in XLH patients treated with 1,25-dihydroxyvitamin D₃ and inorganic phosphate supplementation. Nevertheless, long-term follow-up of kidney function in XLH patients with NC detected ultrasonographically has not been reported. We investigated two women with XLH, ages 31 (patient 1) and 39 (patient 2) years, each of whom had suffered at least one documented episode of vitamin D₂-induced hypercalcemia and renal azotemia during childhood. Patient 2 had also been treated with inorganic phosphate. No medications for XLH had been taken during adulthood. Renal ultrasonography at our institution demonstrated marked bilateral medullary NC in both women. No other explanation was found for their NC that apparently occurred several decades earlier from medical therapy for XLH. Detailed studies (including creatinine clearance, β₂-microglobulin excretion, and fasting urinary osmolality and acidification) revealed no impairment of kidney function in either patient. Our findings indicate that subradiographic medullary NC acquired during medical therapy for XLH may persist for decades, but with no adverse renal sequelae. Definitive (long-term) assessment of kidney function in the XLH population with NC, however, will be necessary to fully understand the risk of current medical treatment for this most common heritable form of rickets.     

Glomerular and tubular function in glycogen storage disease

Urinary protein and calcium excretion were assessed in 77 patients with the hepatic glycogen storage diseases (GSD): 30 with GSD-I (median age 12.4 years, range 3.2–32.9 years), 25 with GSD-III (median age 10.5 years, range 4.2–31.3 years) and 22 with GSD-IX (median age 11.8 years, range 1.2–35.4 years). Inulin (C _inulin) and para-aminohippuric acid (C _PAH) clearances were also measured in 33 of these patients. Those with GSD-I had significantly greater albumin (F=15.07,P<0.001), retinolbinding protein (RBP) (F=14.66,P<0.001),N-acetyl--d glucosaminidase (NAG) (F=9.41,P<0.001) and calcium (F=7.41,P=0.001) excretion than those with GSD-III and GSD-IX. GSD-I patients (n=18) also had significantly higherC _inulin (F=5.57,P=0.009), butC _PAH did not differ (F=0.77, NS). Renal function was normal in GSD-III and GSD-IX patients. In GSD-I,C _inulin (r=–0.51,P=0.03) and NAG excretion (r=–0.40,P=0.03) were inversely correlated with age, whereas albumin excretion was positively correlated with age (r=+0.41,P=0.03). RBP and calcium excretion were generally high throughout all age groups. Hyperfiltration in GSD-I is associated with renal tubular proteinuria that occurs before the onset of significant albuminuria. Deficiency of glucose-6-phosphatase within the proximal renal tubule may primarily cause tubular dysfunction, glomerular hyperfiltration being a secondary phenomenon.     

Loss of regulation of circulating 1,25-dihydroxyvitamin D with paradoxically decreased serum phosphate levels in individuals with recurrent kidney stones

A low serum phosphate concentration is characteristic in individuals in whom kidney stones form, this being related to serum 1,25-dihydroxyvitamin D, parathyroid hormone and urinary phosphate excretion. In order to determine whether these parameters are related to recurrence of stone formation, they were analyzed in single and recurrent stone formers as well as controls. An inverse correlation between serum levels of phosphate and 1,25-dihydroxyvitamin D was observed in control subjects, indicating that a drop in serum phosphate results in upregulated circulating 1,25-dihydroxyvitamin D level in controls. While the circulating low phosphate level upregulated the 1,25-dihydroxyvitamin D level in single stone formers, the elevation was less than expected from the drop in serum phosphate in recurrent stone formers. The results thus suggest that loss of upregulation of 1,25-dihydroxyvitamin D by serum levels of phosphate might be important for stone formation. The possibility of deregulation of 1,25-dihydroxyvitamin D to maintain physiological requirements in stone formers and prevent further nephrolithiasis therefore warrants attention. Received: 27 January 1999 / Accepted: 25 June 1999     

Comparación de los efectos inducidos sobre la calciuria por tiazidas y diferentes dosis de sal en la dieta: implicaciones en la práctica clínica

Introduction

Both dietary restriction of sodium chloride (NaCl) and treatment with thiazides have been used in hypercalciuric patients.

Hypercalciuria in children with monosymptomatic nocturnal enuresis

ObjectiveThe aim of this study was to measure the 24 h urinary calcium content in children with monosymptomatic nocturnal enuresis (MNE) and compare with those in healthy children to investigate whether there is any relation with enuresis and hypercalciuria.Material and methodsThis study included 120 children and adolescents with MNE aged between 7 and 14 years. Eighty age- and sex-matched healthy children served as a control group. To determine urinary calcium excretion, 24 h urine samples were collected. The children with enuresis were divided into two sub-groups as hypercalciuric and normocalciuric groups according to the amount of urinary calcium excretion.ResultsHypercalciuria was found in 27 (23%) of the MNE patients compared with two (4%) of continent children (p < 0.001). In addition, the mean 24 h urine calcium/body weight ratio was higher in the enuresis group than in the control group, 2.94 ± 2.42 versus 1.59 ± 1.72, respectively (p = 0.002). When the children with enuresis were divided into two groups as normokalsiuric and hypercalciuric, the hypercalciuric children were younger and the majority of this group were boys..ConclusionsOur study showed that hypercalciuria is common in children with MNE, so we suggested measuring urine calcium levels in NE patients. However, further studies are needed to clarify the relationship between hypercalciuria and NE in larger series..     

Nephrocalcinosis in preterm infants: a single center experience

The risk of nephrocalcinosis in preterm infants is considerable, but conflicting numbers are given for the actual incidence (10–65%). Furosemide induced hypercalciuria is said to be the main risk factor. We examined retrospectively the incidence, causes and outcome of nephrocalcinosis in preterm infants born in our hospital from 1988 to 1998 (n=2190). An abnormal renal echogenicity or nephrocalcinosis was seen in 31 infants (29.7±3.3 weeks gestational age; 1307±690 g birth weight). Nephrocalcinosis was diagnosed in 16, hyperechoic kidneys (HK) in 10 and Tamm-Horsfall kidneys in 5 infants. Main risk factors were low gestation age and birth weight, length of hospitalization, variations in acid-base status, length of assistant ventilation and hypercalciuria at diagnosis. The incidence of nephrocalcinosis was 0.73% [1.7% for low birth weight infants (VLBW)]. Taking the cases of nephrocalcinosis and HK together, incidence was calculated to be 1.2% overall and 2.5% for VLBW infants, but increased to 7% in 1998. The follow-up showed persisting nephrocalcinosis or hyperechoic kidneys in 8/26 preterm infants. In conclusion, the incidence of nephrocalcinosis was lower in our population than is usually reported. The numbers have, however, increased over the past few years. From the follow-up it was obvious that long-term observation of preterm infants is necessary and that complications might arise in the long run. Received: 9 July 2001 / Revised: 14 November 2001 / Accepted: 18 November 2001     

Clinical presentation and natural course of idiopathic hypercalciuria in children

Idiopathic hypercalciuria (IHC) has been reported mainly in children with hematuria in the 1980s and early 1990s, when renal sonography was just becoming routine. The presence of microcalculi, i.e., of hyperechogenic spots <3 mm in diameter in renal calyces, was not taken into account in those studies. We attempted to outline clinical presentation and natural course of IHC not only in children with hematuria, but also in those with dysuria and/or recurrent abdominal/flank pain and a family history of nephrolithiasis, taking into account the finding of microcalculi. We analyzed retrospectively the data at diagnosis from 74 consecutive children aged 2.4–18 years (mean 8.6) with IHC (calciuria 4.1–15.1 mg kg^–1 24 h^–1, mean 6.1) and the outcome of 30 of them who were followed ≥1 years (mean 3.2) with no specific therapy. At diagnosis, 38 patients (51%) had no hematuria, 42 (57%) had microcalculi and four (5%) had calculi. Of the patients with normal urinalysis, 71% had microcalculi or stones. The subjects with microcalculi and those with stones were significantly older than those without microcalculi and stones (P=0.004 and 0.007). A normal urinalysis at our evaluation and a history of abdominal/flank pain were significantly more frequent in patients with microcalculi than in those without (P=0.02 and 0.0001, respectively). During the follow-up, four of 30 patients formed stones 1–3 years after first diagnosis of IHC. More than half of children with IHC have microcalculi. The risk of formation of microcalculi or stones increases with age. The lack of hematuria does not exclude the presence of microcalculi or calculi. Hypercalciuria has to be suspected in children with dysuria and/or recurrent abdominal/ flank pain and a family history of nephrolithiasis, even when they have no hematuria. Received: 13 December 1999 / Revised: 26 April 2000 / Accepted: 19 May 2000     

A survey of calcium urolithiasis in normocalcemic hypercalciuria: Possible role of nutrients and diet-mediated factors

Summary Three types of hypercalciuria are described; their existence and frequent association with calcium urolithiasis in humans are accepted. Various dietary factors such as minerals, electrolytes, fluids, vitamin D, carbohydrates, proteins are discussed with regard to their ability to alter the nature and the degree of calcium excretion following their ingestion. It is emphasised that at present we have only limited knowledge on the chain of events linking calorie intake and the response of the kidney.     

Hypomagnesemia with hypercalciuria and nephrocalcinosis: case report and a family study

A 7-month-old male infant was referred for investigation after a documented febrile urinary tract infection. His past medical history was characterized by episodes of unexplained fever and mild dehydration. The ultrasound examination of his kidneys demonstrated bilateral diffuse medullary nephrocalcinosis. His serum and urine biochemistry revealed hypomagnesemia (0.4 mmol/l), hyperuricaemia (506 µmol/l), mildly increased iPTH (71 pg/ml) and hypercalciuria (16.0 mg/kg/day). The diagnosis of familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) was confirmed by mutational analysis of the CLDN16 gene, encoding paracellin-1. Sequencing displayed a homozygous Leu151Phe exchange affecting the first extracellular loop of paracellin-1. There were eight family relatives who underwent biochemical analysis, renal ultrasound and genetic investigation for CLDN16 mutations. Five of them were found to be heterozygous for the Leu151Phe mutation. Two heterozygotes (the mother and the maternal grandfather) presented with hypercalciuria. The grandfather had a history of recurrent passage of calculi. These findings point to the role of heterozygous CLDN16 gene mutations in renal pathophysiology. In conclusion, patients suspected of having FHHNC should be screened for CLDN16 mutations, especially with respect to genetic counseling. In addition, heterozygotes at risk should be clinically assessed in order to prevent renal complications of hypercalciuria.