Hyperoxaluria is not a cause of nephrocalcinosis in phosphate-treated patients with hereditary hypophosphatemic rickets

The treatment of X-linked hypophosphatemia (XLH) consists of phosphate and vitamin D3 derivatives. Transient hypercalciuria and hypercalcemia are well-known signs of vitamin D intoxication. Despite urinary calcium excretion control, the danger of nephrocalcinosis in treated patients has been emphasized. It has recently been suggested that hyperoxaluria might be a causative factor of nephrocalcinosis other than calcium in phosphate-treated XLH patients. We measured urinary oxalate and phosphate excretion in 12 patients with the syndrome of hereditary hypophosphatemic rickets with hypercalciuria (HHRH) receiving only oral phosphates and in 5 XLH patients receiving both oral phosphates and vitamin D. No correlation was found between the dosage of phosphate supplements or urinary phosphate excretion and urinary oxalate excretion, in either group of patients. Nephrocalcinosis, presenting as hyperechogenicity of the medullary pyramids, was found in 2 of the 5 XLH patients and only in 2 HHRH patients who had been treated with excessive doses of vitamin D2 and calcium, prior to the true diagnosis being established. We conclude: (1) hyperoxaluria is not a cause of nephrocalcinosis in phosphate-treated patients with hereditary hypophosphatemic rickets; (2) prolonged phosphate treatment alone does not induce nephrocalcinosis in HHRH patients, and (3) we believe that in XLH patients, nephrocalcinosis is essentially due to vitamin D overdosage at some stage, or noncompliance in phosphate intake, leading to repeated undetected hypercalciuric periods.     

Renal tubular reabsorption of phosphate is positively related to the extent of bone metastatic load in patients with prostate cancer

Osteolytic metastases are often associated with decreased renal tubular reabsorption of phosphate. There is, however, no specific data on phosphate metabolism in metastases from prostatic cancer, which are generally osteoblastic. The aim of the present study was to investigate renal handling of inorganic phosphate (Pi) in prostatic cancer, in patients without or with skeletal metastases of various extents. Forty-eight patients were the subjects of this study. There were 39 with malignant disease, of whom 27 had bony metastases. Nine other patients had benign prostate hyperplasia. Biochemical indexes of prostatic tumor, renal tubular reabsorption of calcium and Pi, biochemical markers of bone remodeling, and relevant calciotropic hormones were measured and analyzed in relation to the extent of skeletal metastases, as assessed by bone scintigraphy. A higher bone metastatic load was associated with significantly greater prostate-specific antigen and prostatic acid phosphatase levels (P < 0.05), increased levels of biochemical markers of bone formation (P < 0.05) and resorption (P < 0.001), higher maximal renal tubular reabsorption of Pi (TmPi/GFR; P < 0.05), and higher urinary cAMP excretion (P < 0.05). Nine patients among those with bone metastases (n = 27) had higher TmPi/GFR than metastasis-free patients. These had a greater value of osteocalcin (P < 0.001). Also, 8 of these had relatively more extensive skeletal metastatic load. In patients with prostatic cancer, high skeletal metastatic load was accompanied by increased TmPi/GFR despite higher urinary cAMP excretion, which is supposed to reduce the TmPi/GFR. These results support the hypothesis that renal tubular reabsorption of Pi is capable of adaptation to meet demands for minerals in the face of enhanced bone formation.     

Normal phosphate transport in cells from the S2 and S3 segments of Hyp-mouse proximal renal tubules

An intrinsic phosphate (Pi) transport defect in the proximal tubule (PT) presumably underlies X-linked hypophosphatemic rickets. We recently reported normal Pi transport in the S1 segment of the Hyp mouse PT. Whether Pi wasting results from an abnormality in the S2 or S3 segment remains unknown. Thus, we compared Pi transport in S2 and S3 immortalized cells from transgenic (simian virus 40) normal and Hyp mice. These cells display biochemical features of PT cells, including alkaline phosphatase- and hormone- stimulated cAMP activity as well as gluconeogenesis. Moreover, kinetic studies in S2 cells reveal a similar Km[0.26 +/- 0.03 (+/-SEM) vs. 0.22 +/- 0.03 mM] and maximum velocity (Vmax; 5.5 +/- 0.66 vs. 5.9 +/- 0.72 nmol/mg x 5 min) in normal and Hyp mice, respectively. Km and Vmax were also similar in cells from the S3 segment; however, the Vmax values in S3 cells in normal and Hyp mice (2.8 +/- 0.45 and 3.0 +/- 0.56 nmol/mg x 5 min) were reduced in both animal models compared to those in S2 cells (P < 0.001), whereas the Km values in S3 cells from normal and Hyp mice (0.10 +/- 0.02 and 0.11 +/- 0.04 mM) were increased relative to those in S2 cells (P < 0.001). These data indicate that Pi transport throughout the PT of Hyp mice is intrinsically normal. Such observations exclude the presence of a nascent defect in renal Pi transport in the kidneys of Hyp mice and support the hypothesis that a humoral abnormality underlies X-linked hypophosphatemic rickets.     

Phenotype resembling Gitelman's syndrome in mice lacking the apical Na+-Cl- cotransporter of the distal convoluted tubule

Mutations in the gene encoding the thiazide-sensitive Na+-Cl- cotransporter (NCC) of the distal convoluted tubule cause Gitelman's syndrome, an inherited hypokalemic alkalosis with hypomagnesemia and hypocalciuria. These metabolic abnormalities are secondary to the deficit in NaCl reabsorption, but the underlying mechanisms are unclear. To gain a better understanding of the role of NCC in sodium and fluid volume homeostasis and in the pathogenesis of Gitelman's syndrome, we used gene targeting to prepare an NCC-deficient mouse. Null mutant (Ncc-/-) mice appear healthy and are normal with respect to acid-base balance, plasma electrolyte concentrations, serum aldosterone levels, and blood pressure. Ncc-/- mice retain Na+ as well as wild-type mice when fed a Na+-depleted diet; however, after 2 weeks of Na+ depletion the mean arterial blood pressure of Ncc-/- mice was significantly lower than that of wild-type mice. In addition, Ncc-/- mice exhibited increased renin mRNA levels in kidney, hypomagnesemia and hypocalciuria, and morphological changes in the distal convoluted tubule. These data indicate that the loss of NCC activity in the mouse causes only subtle perturbations of sodium and fluid volume homeostasis, but renal handling of Mg2+ and Ca2+ are altered, as observed in Gitelman's syndrome.     

Studies on the mechanism of protein-induced hypercalciuria in older men and women

A human metabolic study was conducted to observe the effect of level of protein intake on urinary calcium, calcium absorption and calcium balance in older adults and to further study the mechanisms of protein-induced hypercalciuria. An increase in protein intake from about 47 to 112 g while maintaining calcium, magnesium and phosphorus intakes constant caused an increase in urinary calcium and a decrease in calcium retention. Glomerular filtration rate was increased and fractional renal tubular reabsorption was decreased by the increase in protein intake; total renal acid, ammonium and sulfate excretions more than doubled, whereas urinary sodium decreased by 38%. The changes in urinary calcium were positively correlated with the increase in total renal acid and sulfate excretion as well as with the decrease in fractional renal tubular reabsorption of calcium. Thus, the data indicate that protein-induced hypercalciuria is due to an increase in glomerular filtration rate and a decrease in fractional renal tubular reabsorption of calcium, the latter of which may be caused by the increased acid load on the renal tubular cells.     

Medical management and complications of X-linked hypophosphatemic vitamin D resistant rickets

To improve the growth failure, bowed legs, and biochemical and radiological abnormalities in patients with X-linked hypophosphatemic vitamin D resistant rickets (XLH), combined therapy of phosphate and calcitriol is the best therapeutic approach at present. However, the complications involving combined therapy, such as hypercalcemia, nephrocalcinosis and hyperparathyroidism, are not fully solved. To achieve better control, new therapeutic approaches have been reported recently, for example, growth hormone (GH) or new vitamin D analogs. GH improved linear growth, decreased phosphate reabsorption and increased 1-alpha-hydroxylase activity. Furthermore, 24R,25-dihydroxyvitamin D3 (24,25) improved the bone lesions in hypophosphatemic (Hyp) mice, and also in XLH, without the adverse effects such as hypercalcemia or hypercalciuria compared with 1,25-dihydroxyvitamin D3. These new approaches should be considered for the treatment of patients with XLH.     

Influence of dietary phosphorus on renal phosphate reabsorption in the parathyroidectomized rat

Inorganic phosphate (Pi) reabsorption was studied during Pi infusion, after acute or chronic thyroparathyroidectomy (TPTX), in rats stabilized on a high-phosphorus (1% P) or a low-phosphorus (0.02% P) diet. After acute TPTX, there were no consistent differences in Pi reabsorption between the high- and low-phosphorus dietary groups. After chronic TPTX, the rats stabilized on the low-phosphorus diet exhibited nearly complete Pi reabsorption at every plasma Pi level, while the animals receiving the high-phosphorus diet manifested a marked phosphaturic response to Pi infusion. In addition, Pi reabsorption was significantly increased in the chronic TPTX low-phosphorus rats which achieved the highest filtered Pi loads, while their urine remained essentially phosphate-free. Dietary phosphorus-dependent alterations in Pi reabsorption may play a significant role in establishing the rate of Pi excretion per nephron under certain circumstances and should be considered in the interpretation of studies investigating renal Pi handling. The ability of phosphorus-depleted animals to maintain a phosphate-free urine during Pi loading would favor the rapid repletion of body phosphorus stores.     

Effect of renal perfusion pressure on excretion of calcium, magnesium, and phosphate in the rat

Abnormalities in renal handling of calcium, magnesium, or phosphate have been implicated in the development and/or maintenance of human hypertension. We have shown recently that renal excretion of these ions is correlated to blood pressure in Dahl salt-sensitive as well as salt-resistant rats. The present study was designed to determine whether renal perfusion pressure per se could affect excretion of these ions. Urinary excretion of calcium, magnesium, and phosphate was studied in anaesthetized Sprague-Dawley rats under basal conditions and during an intravenous infusion of angiotensin II (ANG II), vasopressin (AVP) or phenylephrine (PE). A cuff, placed around the aorta between the two renal arteries, allowed maintenance of normal perfusion pressure in the left kidney, while that in the right kidney was allowed to rise. Infusion of pressor agents raised mean arterial blood pressure to comparable levels (means +/- SE): ANG II (n = 7), before = 102 +/- 4, during = 133 +/- 3 mmHg, AVP (n = 8), before = 110 +/- 7, during = 136 +/- 5 mmHg, PE (n = 6), before = 111 +/- 6, during = 141 +/- 6 mmHg. Although there was no difference in excretion of calcium, magnesium and phosphate between the two kidneys under basal conditions, infusion of ANG II or PE induced hypercalciuria, hypermagnesiuria and hyperphosphaturia in the right kidney which was exposed to the increased arterial pressure. Such effects did not appear in the pressure-controlled left kidney. Infusion of AVP was associated with reduced excretion of calcium and magnesium, and increased excretion of phosphate, in the normotensive kidney. The response to the similarly increased renal perfusion pressure in this group was also reduced for calcium and magnesium, and enhanced for phosphate. The results indicate (1) renal excretion of calcium, magnesium and phosphate is renal perfusion pressure-dependent; the higher the renal perfusion pressure, the greater the excretion of these ions. (2) Independently of perfusion pressure, AVP can inhibit phosphate reabsorption and stimulate divalent cation reabsorption.     

Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice

1,25-Dihydroxyvitamin D3 plays a major role in intestinal calcium transport. To determine what phenotypic abnormalities observed in vitamin D receptor (VDR)-ablated mice are secondary to impaired intestinal calcium absorption rather than receptor deficiency, mineral ion levels were normalized by dietary means. VDR-ablated mice and control littermates were fed a diet that has been shown to prevent secondary hyperparathyroidism in vitamin D-deficient rats. This diet normalized growth and random serum ionized calcium levels in the VDR-ablated mice. The correction of ionized calcium levels prevented the development of parathyroid hyperplasia and the increases in PTH messenger RNA synthesis and in serum PTH levels. VDR-ablated animals fed this diet did not develop rickets or osteomalacia. However, alopecia was still observed in the VDR-ablated mice with normal mineral ions, suggesting that the VDR is required for normal hair growth. This study demonstrates that normalization of mineral ion homeostasis can prevent the development of hyperparathyroidism, osteomalacia, and rickets in the absence of the genomic actions of 1,25-dihydroxyvitamin D3.     

Increased reabsorptive capacity after ureteral obstruction reduces the ability of glucose to inhibit phosphate reabsorption in rat kidney

BACKGROUND: Proximal tubular reabsorption of glucose (G), phosphate (Pi) and amino acids is energized by the transmembrane Na+ gradient, which explains why decreased concentration of one solute can enhance the transport of another. Accordingly, we postulated that the consistent increase in Pi reabsorption seen in the post-obstructed kidney (POK) could be caused, in part, by the low filtered load of glucose and reversed by glucose loading. METHODS: Renal function was examined before and after i.v. glucose loading in POKs (after release of 24 h of unilateral ureteral obstruction) and control kidneys (CK) of 10 adult rats. Brush-border membrane vesicle (BBMV) transports of Pi and glucose were assessed in POKs and CKs. RESULTS: In POKs GFR, urine flow and Na+ excretion were significantly reduced and tubular reabsorption of both Pi (T(P)/GFR) and glucose (TG/GFR) were significantly increased: T(P)/GFR, 2.0 +/- 0.2 vs 1.36 +/- 0.1; TmG/GFR, 23.4 +/- 1.7 vs 18.9 +/- 1.1 mmol/l. Glucose loading inhibited T(P)/GFR only in the CK. Initial Na+ gradient-dependent uptakes of D-glucose and Pi were similar in BBMVs from POK and CK. CONCLUSIONS: The increases in T(P)/GFR and TG/GFR seen in the POK do not result from decreased glucose delivery or from alterations in BBM Pi and glucose transporters. The reduced ability of glucose to inhibit Pi reabsorption in the POK results primarily from a generalized increase in proximal tubular reabsorption of Na+ and cotransported Pi and glucose. A specific rise in distal Pi transport capacity may be an additional adaptive response to the low filtered load of Pi in the POK. In addition, absent distal glucose reabsorption may further facilitate Pi reclamation at these sites.     

Molecular cloning of human GATA-6 DNA binding protein: high levels of expression in heart and gut

The aim of the study was to explore the relationship between protein nutritional status and the development of rickets in children living in northern Nigeria. The diagnosis of rickets in 16 children between the ages of 10 months and 7 years was confirmed using established, and recently developed clinical and biochemical parameters. Twenty-seven children devoid of skeletal stigmata were age- and sex-matched to the rachitic patients. A battery of clinical laboratory and anthropometric measurements designed to assess calcium homeostasis, skeletal growth, the extent of bone remodeling or resorption, and protein nutritional status were performed on all subjects. Our central finding was that although the rachitic children were moderately malnourished, their protein nutritional status was significantly better as measured by the serum prealbumin concentration (15.4 v. 12.5 mg/dl, P = 0.0012) when compared with the severely malnourished children who were devoid of any indication of rickets. This may be due, in part, to the fact that actively growing children are more likely to develop rickets than are children whose linear growth is impeded. Unexpectedly, we found that the mean concentrations of serum 1,25-dihydroxyvitamin D in both the rachitic and control group were higher than any values for the active vitamin D metabolite previously reported in the literature.     

Abnormalities of calcium, phosphorous and vitamin D metabolism with proximal renal tubular dysfunction in subjects environmentally exposed to cadmium

Calcium, phosphorus and vitamin D metabolism were examined in 21 male and 13 female subjects with renal tubular dysfunction in the cadmium-polluted Jinzu River basin in Toyama prefecture, Japan. Multiple proximal renal tubular dysfunction was detected in all subjects showing increased FE beta 2-m and FFua, generalized aminoaciduria and renal glucosuria. Reduced ability of tubular reabsorption of phosphate resulted in hypophosphatemia in 31% of the women. Despite decreased tubular reabsorption of calcium, the level of serum calcium remained normal in all subjects. Serum 1,25-dihydroxyvitamin-D [1,25(OH)2D], which is produced in the proximal tubules through 1 alpha-hydroxylation from 25-hydroxyvitamin-D [25OHD], was normal or increased to more than 60pg/ml. The serum level of 1,25(OH)2D was inversely related to creatinine clearance in both the men (p < 0.05) and women (p < 0.01). Serum iPTH was slightly increased to more than 0.9 mg/ml, whereas the levels of other hormones, including 25OHD, calcitonin, thyroxine (T4) and triiodothyronine (T3) were normal. The serum alkaline phosphatase activity and serum osteocalcin concentration were significantly increased compared to those of controls in both sexes. Bone loss detected by the measurement of bone density was prominent in female subjects. These results support the hypothesis that the serum phosphate concentration is more important than the serum concentration of 1,25(OH)2D for abnormalities of bone metabolism in cadmium-induced renal tubular dysfunction.     

Long-term nephrotoxicity of cisplatin, ifosfamide, and methotrexate in osteosarcoma

The acute renal effects of chemotherapy are known, but long-term nephrotoxicity has rarely been investigated. The aim of the present study was to assess long-term renal function in children and adolescents who received at-risk chemotherapy, including cisplatin, ifosfamide, and methotrexate, to treat an osteosarcoma. Renal function tests [creatinine clearance, microalbuminuria, and renal excretion of sodium, potassium, chloride, calcium, magnesium (Mg), phosphorus (P), and uric acid] were prospectively performed 5.4+/-2.2 (+/-SD) years after chemotherapy (total cumulative dose: methotrexate 41+/-31 g/m2, ifosfamide 39+/-14 g/m2, cisplatin 674+/-188 mg/m2) in 18 children and adolescents. The results were compared with 13 normal volunteers matched for age and sex. Creatinine clearance, which was greater than 80 ml/min per 1.73 m2 in all patients, correlated with the total dose of ifosfamide (r=0.55, P<0.05) and cisplatin (r=0.48, P<0.05). Microalbuminuria was noted in 4 patients. Hypomagnesemia was present in 4 and hypercalciuria in 3 patients; renal excretion of P, Mg, and uric acid was higher in patients than in controls. Glomerular function was not significantly altered and only mild tubular dysfunction was present. Since renal excretion of P and Mg were increased in patients compared with normal volunteers and hypercalciuria was occasionally seen, divalent ion disorders are the most-likely potential complications.     

Endogenous dopamine regulates phosphate reabsorption but not NaK-ATPase in spontaneously hypertensive rat kidneys

Dopamine's modulatory actions on signal transduction in the spontaneously hypertensive rat (SHR) proximal tubule are blunted; therefore, it was predicted that dopamine does not regulate phosphate (Pi) reabsorption in SHR. To test this hypothesis, dopamine production was inhibited with carbidopa (10 mg/kg ip) 18 h before and during clearance measurements of chronically denervated SHR and Wistar-Kyoto (WKY) rat kidneys. Dopamine excretion decreased 80% from SHR and 85% from WKY rats. Pi excretion decreased 60 to 67%. Plasma Pi and calcium, inulin clearance, and Na excretion did not change. Citrate excretion, which reflects proton secretion by proximal tubules, decreased 72% from WKY rats. Citrate excretion was significantly lower from SHR (5 +/- 10 pmol/min) than from WKY rats (73 +/- 11 pmol/min) and was not altered by carbidopa. Carbidopa, injected 18 and 1 h before kidneys were collected, increased NaK-ATPase in cortical basolateral membranes from WKY rats (27%) but not in membranes from SHR. After the incubation of renal cortical minceates for 15 min with L-DOPA (10(-5) M), there was no change in brush border membrane vesicle uptake of 32Pi, (3H)glucose, or (14C)citrate. Incubation with carbidopa (10(-4) M) increased 32Pi uptake by 11% (P < 0.001) and (3H)glucose uptake by 9% (P = 0.02). (14C)citrate uptake was not increased by carbidopa but was higher in SHR (977 +/- 2 pmol/10 s.mg) than in WKY rats (823 +/- 43 pmol/10 s.mg; P = 0.04). In summary, dopamine produced in WKY rat and SHR proximal tubules decreases Pi uptake by using a signaling process distinct from those that regulate NaK-ATPase and the antiporter.(ABSTRACT TRUNCATED AT 250 WORDS)     

Salt intake, urinary sodium, and hypercalciuria

Several studies have reported that high sodium (Na) intake increases not only urinary Na but also urinary calcium (Ca), suggesting that high Na intake could be involved in the pathogenesis of hypercalciuria. No research data are available on the relationship of Na intake to the prevalence of hypercalciuria within the general population. Moreover, it is not clear if Na intake relates only to urinary Ca or also to other indices of Ca homeostasis, including intestinal Ca absorption. In the present paper, two distinct studies addressed these points using 24-hour urinary Na as an index of salt intake in individuals on their habitual unrestricted free diet. Study 1 analyzed the relationship between 24-hour urinary Na and hypercalciuria (24-hour urinary Ca > or = 7.5 mmol in men, > or = 6.25 mmol in women) in a population sample of 203 men and women, aged 20-59 years. Study 2 analyzed the relationship between 24-hour urinary Na and intestinal strontium (Sr) absorption, used as an index of intestinal Ca absorption, urinary (24-hour and fasting) and plasma Ca, and plasma parathyroid hormone in 36 healthy men and women, aged 18-65 years. Within the population sample (study 1), 24-hour urinary Na was directly and significantly correlated with prevalence of hypercalciuria when controlling for gender, age, weight, and urinary creatinine: the relationship was continuous and linear for urinary Na ranging between 40 and 200 mmol/24 h. In the 36 volunteers (study 2), 24-hour urinary Na was related to 24-hour and fasting urinary Ca (p < 0.001) but not to intestinal Sr absorption: the relationship between 24-hour urinary Na and urinary Ca (both 24 h and fasting) was also significant, controlling for other variables. The results indicate that in adults on their habitual diet, urinary Na, which reflects dietary salt intake, correlates with the prevalence of hypercalciuria independently of intestinal Ca absorption and mainly via renal mechanisms.     

Low calcium diet in hypercalciuric calcium nephrolithiasis: first do no harm

Many studies indicate that up-regulated production of 1,25(OH)2-vitamin D3 (calcitriol) with increased intestinal absorption of calcium is the primary event causing idiopathic hypercalciuria. Thus, a low calcium diet appears to be a straightforward strategy in calcium stone formers with hypercalciuria (HCSF). However, the efficacy of such a regimen has never been established, and lowering calcium intake from 1000 to 400 mg/day further enhances calcitriol production. On a diet chronically restricted in calcium, many stone formers increase their intake of animal flesh protein. The latter is known to increase renal mass, and calcitriol levels indeed are positively correlated with renal mass in animals as well as in HCSF. Thus, low calcium and high animal flesh protein consumption are independent stimuli for further up-regulation of calcitriol production. The rise in calcitriol suppresses parathyroid hormone synthesis thereby diminishing renal tubular calcium reabsorption, and increasing urinary calcium losses. Since calcitriol up-regulation also increases bone resorption, the combination of low calcium and high protein intake is particularly likely to induce negative calcium balance and thus osteopenia. Finally, low calcium intake carries the risk of insufficient intestinal binding of oxalate with subsequent increases in intestinal absorption and urinary excretion of oxalate. Indeed, most recent studies suggest that high amounts of calcium, when ingested simultaneously with oxalate-containing meals, are able to prevent hyperoxaluria during severe oral oxalate loading.     

Mechanism of increased renal clearnace of amylase/creatinine in acute pancreatitis

We investigated three possible causes of the increased ratio of amylase/creatinine clearance observed in acute pancreatitis. The presence of rapidly cleared isoamylase was excluded by studies of serum and urine, which demonstrated no anomalous isoamylases. In pancreatitis, the ratios (+/-1 S.E.M.) of both pancreatic isoamylase (9.2+/-0.6 per cent) and salivary isoamylase (8.6+/-1.6 per cent) were significantly (P less than 0.01) elevated over respective control values (2.4+/-0.2 and 1.8+/-0.2 per cent). Increased glomerular permeability to amylase was excluded by the demonstration of normal renal clearance of dextrans. We tested tubular reabsorption of protein by measuring the renal clearance of beta2-microglobulin, which is relatively freely filtered at the glomerulus and then avidly reabsorbed by the normal tubule. During acute pancreatitis the ratio of the renal clearance of beta2-microglobulin to that of creatinine was 1.22+/-0.52 per cent, an 80-fold increase over normal (0.015+/-0.002 per cent), with a rapid return toward normal during convalescence. Presumably, this reversible renal tubular defect also reduces amylase reabsorption and accounts for the elevated renal clearance of amylase/creatinine observed in acute pancreatitis.     

High resolution mapping of the renal sodium-phosphate cotransporter gene (NPT2) confirms its localization to human chromosome 5q35

The precise chromosomal localization of the type II renal-specific Na+-phosphate (Pi) cotransporter (NPT2) gene (gene symbol SLC17A2) is necessary for the identification of closely linked polymorphic markers to determine whether NPT2 is a candidate gene for inherited disorders of renal Pi reabsorption. Recent studies by two different groups localized NPT2 to human chromosome 5q35 and 5q13, respectively. To resolve this discrepancy, we used three independent methods. The results using a human chromosome 5/rodent somatic cell hybrid deletion panel, fluorescence in situ hybridization with a PAC clone containing the NPT2 locus, and analysis of a chromosome 5-specific radiation hybrid panel were all consistent with the 5q35 assignment of the NPT2 gene. The radiation hybrid results placed NPT2 between polymorphic microsatellite markers D5S498 and D5S469. These findings will allow the initiation of linkage analysis to determine if NPT2 has a causative role in Mendelian disorders of renal Pi wasting.     

Effect of enalapril on proteinuria, phosphaturia, and calciuria in insulin-dependent diabetes

Elevated urinary calcium and phosphate excretion have been observed in children with insulin-dependent diabetes mellitus (IDDM). This may be related to a defect in tubular reabsorption. It is well known that converting enzyme inhibition decreases microalbuminuria and may prevent or retard diabetic nephropathy. We investigated whether enalapril also improves the defect in calcium and phosphate reabsorption. We studied 16 children and young adults (age 12-21 years) with IDDM and persistent microalbuminuria before and during 12 weeks of enalapril treatment. Before treatment microalbuminuria, urinary calcium excretion, and fractional tubular phosphorus reabsorption (TPR) were 153+/-53 microg/min, 5.5+/-0.9 mg/kg per day, and 71.4+/-3.6%, respectively. At the end of the 12th week, microalbuminuria had decreased to 20.3+/-7.9 microg/min and calcium excretion to 3.3+/-0.4 mg/kg per day (P<0.01), while the TPR increased to 80.1+/-3.8% (NS). The renal threshold phosphate concentration increased from 1.8+/-0.15 to 2.92+/-0.23 mg/dl (P<0.01). The fasting serum glucose and hemoglobin Alc levels did not change significantly during the study. Systolic and diastolic blood pressures were 120.4+/-2.2 / 79.3+/-1.4 mm Hg and 110.5+/-1.8 / 71.3+/-0.9 mm Hg before and after 12 weeks, respectively. We conclude that enalapril treatment improves not only microalbuminuria but also abnormal calcium and phosphate excretion in microalbuminuric children with IDDM.