Renal Tubular Reabsorption Of Phosphate Research Articles

Retinol Binding Proteinuria and Phosphaturia: Markers of Paracetamol-Induced Nephrotoxicity

The occurrence of hypophosphataemia in paracetamol overdose suggests that nephrotoxicity is common, impaired renal tubular reabsorption of phosphate indicating renal damage. To investigate the potential nephrotoxicity of paracetamol, we studied 148 consecutive patients with paracetamol overdose. Serial clinical and biochemical measurements were made, and a fasting overnight urine collection was obtained for creatinine (Cr), phosphate and retinol-binding protein (RBP) determination. Renal threshold phosphate concentration (TmPO4/GFR) was determined from urinary parameters by an established nomogram. The degree of hypophosphataemia correlated with the severity of overdose, and with TmPO4/GFR. The median RBP/Cr ratio was higher in those patients exhibiting biochemical hepatotoxicity compared with those without hepatotoxicity, in whom median RBP/Cr was not significantly higher than controls. Within the group of patients showing biochemical hepatotoxicity, there was a correlation between log RBP/Cr and TmPO4/GFR. RBP/Cr ratio is a less sensitive marker of renal tubular toxicity than phosphaturia in these patients, and may indicate a different mechanism of toxicity.

X-linked hypophosphatemia: molecular biology and treatment controversies.

X-linked hypophosphatemia, currently one of the most prevalent varieties of familiar rickets, is attributed to renal phosphate wasting secondary to a gene defect localized to X p22 chromosomal region. The proximal tubular phosphate reabsorption defect is associated with blunted 1,25-dihydroxyvitamin D synthesis to hypophosphatemia or parathyroid hormone administration. It is characterized clinically by hypophosphatemia, growth retardation, and rickets especially in male patients. As the affected patients mature, pseudofractures, skeletal deformities, osteomalacic bone pain, progressive ankylosis, and dental caries occur, which may be alleviated and even prevented with adequate medical therapy. Long term treatment combines phosphate supplementation with calcitriol, augmented occasionally by diuretics. Hypercalcemia, hyperparathyroidism, and nephrocalcinosis are potential complications which require careful monitoring and continued investigations. The use of recombinant human growth hormone to augment renal tubular reabsorption of phosphate and to promote linear growth remains to be examined in well controlled, clinical trials.

X-linked hypophosphatemic Gy mice: renal tubular maximum for phosphate vs. brush-border transport after low-P diet.

We examined the effect of the X-linked hypophosphatemic Gy mutation on the maximal renal tubular reabsorption of phosphate (TmP) and compared the effects of phosphate deprivation on both TmP and Na(+)-dependent phosphate transport in renal brush-border membrane vesicles (BBMV). Adult female normal and Gy mice were fed a control (1.0% P) or low-phosphate (0.03% P) diet for 5 days. For TmP measurement, anesthetized mice were infused intravenously with [3H]inulin and increasing increments of phosphate (0, 0.27, 0.54, and 1.08 mumol/min). TmP was significantly reduced in Gy mice on the control diet. Normal mice responded to the low-phosphate diet by raising their TmP [2.35 +/- 0.12 (n = 9) vs. 3.71 +/- 0.16 (n = 9) mumol/ml glomerular filtrate, mean +/- SE, P < 0.001], whereas in Gy mice, the change was not significant [1.46 +/- 0.10 (n = 10) vs. 1.70 +/- 0.11 (n = 10)]. In contrast, Gy mice did respond to phosphate restriction by increasing the initial-rate Na(+)-dependent phosphate transport in the renal BBMV [314 +/- 11 (n = 5) vs. 1,105 +/- 157 (n = 5) pmol.mg protein-1.6 s-1, P < 0.01] as did normal mice [583 +/- 64 (n = 5) vs. 1,692 +/- 203 (n = 5) pmol.mg protein-1.6 s-1, P < 0.01]. In conclusion, the adaptive increase in Na(+)-phosphate cotransport in the brush-border membrane of the proximal tubule is not sufficient for the overall increase in TmP in the whole kidney in response to dietary phosphate deprivation.

The effect of alendronate on renal tubular reabsorption of phosphate

We report the effects of alendronate on phosphate homeostasis in two patients. In a woman with postmenopausal osteoporosis, the infusion of alendronate (7.5 mg intravenously daily for 4 consecutive days) was not associated with secondary hyperparathyroidism despite a reduction in serum calcium. This was associated with a rise in serum phosphate and TmP/GFR. This response contrasted with those observed in 14 other patients with osteoporosis, in whom PTH rose significantly following the infusion of alendronate in association with a significant fall in serum phosphate and TmP/GFR. The second patient, a woman with Paget's disease, was treated with intravenous alendronate (10 mg daily for 5 consecutive days) on two occasions for relapse of disease activity. On the first occasion there was a 150% rise in serum PTH associated with a fall in serum phosphate and TmP/GFR. On the second occasion, when the rise in serum PTH was less marked, there was a rise in serum phosphate and TmP/GFR. We conclude that alendronate may increase renal tubular reabsorption of phosphate, but that this effect is usually offset by secondary hyperparathyroidism.

Solomon's Epidermal Nevus Syndrome (Type: Linear Nevus Sebaceus) and Hypophosphatemic Vitamin D—Resistant Rickets

Epidermal nevus syndrome is very variable in symptoms and associated abnormalities. Synonyms of this syndrome are linear nevus sebaceus syndrome or Schimmelpenning-Feuerstein-Mims syndrome or Solomon syndrome. The combination with vitamin D-resistant rickets is rare and only sporadically described. Less than 10 cases with this combination of symptoms have been described in the literature. We describe a boy suffering from epidermal nevus syndrome (type: nevus sebaceus). This child also presented with severe rickets with hyperphosphaturia, resistant to vitamin D. Our patient was seen in consultation at birth, but after a delay of 4 years we were consulted again for a second opinion and treatment; the vitamin D-resistant rickets was recognized. Treatment with 1,25-dihydroxy vitamin D3 and phosphorus resulted in healing of rickets. Removal of parts of the tumors did not influence the rickets. This is in contrast with a formerly described case. Removal of fibroangiomas led in that case to normalization of the alkaline phosphatase, calcium, and phosphate serum levels. The rickets results from massive phosphate excretion by defective renal tubular reabsorption of phosphate. In all patients described, rickets developed at an early age. Clinical symptoms were marked bone abnormalities, muscle weakness, and bone pain.

Intestinal malabsorption of 45calcium in young Gy mice, a second model for X-linked hypophosphatemia

X-linked hypophosphatemia, a common metabolic bone disease in humans and mice (the Hyp and Gy mutations), is characterized by decreased plasma phosphate, decreased renal tubular reabsorption of phosphate, rickets, and osteomalacia. The question of whether intestinal malabsorption of calcium contributes to the bone disease is controversial. Intestinal absorption of 45Ca was studied in three different mouse colonies: Gy on B6C3H background, Hyp on B6C3H background, and Hyp on C57BL/6J background, all at 4 weeks of age. The duodenum was isolated by sutures, and 45Ca in a 150 mM NaCl and 2 mM CaCl2 solution at pH 7.2 was injected into the lumen. Absorption was measured by the amount of 45Ca remaining in the lumen and by the plasma isotope level. The Gy and Hyp mice of both sexes significantly malabsorbed 45Ca at 4 weeks of age compared to normal littermates. Following the 4 week study, intestinal absorption was measured at 2, 7-8, and 12 weeks of age in normal and Gy mice on the B6C3H background. At 2 and 7-8 weeks of age, the Gy males significantly malabsorbed 45Ca compared to their normal littermates. Serum 1,25-dihydroxyvitamin D was not significantly altered in Gy males at 4 weeks of age. This suggests the possibility of resistance of the intestine to stimulation. Malabsorption of calcium in young Gy and Hyp mice may exacerbate the low mineralization in their rachitic bone disease.

Phosphate metabolism in the red cell of sick prematures

The effect of different amounts of phosphorus supplementation on phosphate metabolism was studied in two groups of sick preterms (B and C) during the first week of life. Group B included prematures that started formula milk feeding from day 3 and group C neonates on total parenteral nutrition with phosphate supplementation for 7 days. Twelve healthy preterm neonates on formula milk feeding from day 2 (group A) were used as controls. On the 7th day of life all phosphate parameters measured in group C (plasma and red cell inorganic phosphate and erythrocyte ATP and 2,3-diphosphoglycerate) were found significantly lower than in the controls (1.60 +/- 0.07; 0.60 +/- 0.08; 1.45 +/- 0.09 and 4.42 +/- 0.18 vs. 2.05 +/- 0.10; 0.94 +/- 0.11; 1.69 +/- 0.07 and 6.24 +/- 0.42 mmol/l, respectively). The renal tubular reabsorption of phosphate was also lower in this group (86.8 +/- 3.2 vs. 97.3 +/- 1.0%). No significant differences were observed between groups B and A. Higher phosphorus intake that was better achieved through early milk feeding prevented phosphate depletion and the decline of 2,3-diphosphoglycerate in the erythrocytes even of sick neonates which in turn might help to improve tissue oxygenation. The amount of parenteral phosphate supplementation that could have beneficial effects on red cell phosphate parameters needs further investigation.

Rapid publication: Flanking markers define the X-linked hypophosphatemic rickets gene locus

X-linked hypophosphatemic rickets (HYP) is an X-linked dominant disorder characterized by decreased renal tubular phosphate reabsorption and consequent hypophosphatemia. The defect in tubular phosphate reabsorption is probably secondary to an unidentified humoral factor. Identification of the humoral factor and a full understanding of the pathophysiology of the disease await the identification of the HYP gene. Previously we demonstrated that DXS257 and DXS41 are flanking markers for the HYP gene. Two markers, DXS365 and DXS274, are tightly linked to the HYP gene, but investigators have been unable to determine whether they are centromeric or telomeric to the disease gene. Since tightly linked flanking markers are necessary prerequisites to obtain the gene by positional cloning techniques, we sought to determine the relative positions of these markers to the HYP gene by expanding our data base for linkage studies. We also investigated a new polymorphic probe for linkage to HYP to construct a more detailed genetic map around the HYP locus. Our data indicate that the markers DXS365, DXS274, and DXS92 are tightly linked to the HYP locus and suggest a locus order of Xtel-(DXS444/DXS315)-DXS43-(DXS257/DXS3 65)-HYP-(DXS274/DXS41/DXS92)-DXS-451- DXS319-Xeen. These results will facilitate attempts further to localize and clone the HYP gene.

Assessment of Hyperphosphatemia and Hypophosphatemia

Methodologic aspects including causes of factitious hyperphosphatemia and hypophosphatemia are summarized. The differential diagnosis of hyperphosphatemia is reviewed under its three broad causes: decreased glomerular filtration rate, increased exogenous or endogenous phosphate load, and increased renal tubular phosphate reabsorption. The differential diagnosis of hypophosphatemia is reviewed under its three broad causes: inadequate gastrointestinal input, excess phosphate losses, and transcellular shifts. The consequences of hyperphosphatemia and hypophosphatemia are outlined with a focus on pathophysiologic and clinicochemical sequelae. A laboratory perspective is emphasized in outlining management strategies.

Effects of long-term treatment with growth hormone on bone and mineral metabolism in children with growth hormone deficiency

The effects of growth hormone (GH) deficiency and recombinant human GH replacement (0.6 IU/kg per week) on bone and mineral metabolism in 26 GH-deficient children were studied for 12 months. Before therapy, all children had significantly reduced serum levels of osteocalcin, carboxyl-terminal propeptide of procollagen type I, and 1,25-dihydroxyvitamin D, whereas serum ionized calcium, phosphate, intact parathyroid hormone, calcitonin, and 25-hydroxyvitamin D concentrations were in the normal range. All children had significant reduction of bone density for their chronologic, statural, and bone ages. During therapy with recombinant human GH, a decrease of serum ionized calcium levels and increases of phosphate, osteocalcin, carboxyl-terminal propeptide of procollagen type I, and intact serum levels of parathyroid hormone were found. A significant increase of serum levels of 1,25-dihydroxyvitamin D was found at 12 months. The urinary phosphate/urinary creatinine ratio decreased, whereas values for nephrogenous cyclic adenosine monophosphate and the ratio of the maximum rate of renal tubular reabsorption of phosphate to the glomerular filtration rate increased. Bone density significantly improved at 12 months, with a complete recovery in 12 children (46.2%). Significant relationships were found among growth velocity, bone density, maximum tubular reabsorption/glomerular filtration rate ratio, and serum levels of carboxyl-terminal propeptide of type I procollagen. The changes in serum levels of this propeptide during the first week of recombinant human GH treatment were positively related to growth velocity at 6 and 12 months and to bone density at 12 months of treatment, whereas the changes in osteocalcin levels were not. We conclude that recombinant human GH treatment caused significant modifications of mineral metabolism and significantly increased bone density, and that measurement of serum levels of the propeptide during the first week of recombinant human GH administration may be a useful tool in predicting improved growth velocity and bone density during long-term recombinant human GH replacement.

Towards a molecular view of renal proximal tubular reabsorption of phosphate.

Apical sodium-dependent transport of inorganic phosphate (Pi) in the proximal tubule plays a crucial role in renal Pi reabsorption and consequently in the maintenance of Pi homeostasis. This transport system represents a main target for acute and long-term regulation such as by parathyroid hormone, by growth factors and dietary intake of phosphate. In this short review we briefly describe the currently established cellular mechanism of proximal tubular Pi reabsorption and its regulation via the apical Na/Pi cotransport system. In a second part we will outline recent progress made with respect to the molecular cloning of renal Na/Pi cotransport systems. Knowledge about the molecular identity of these transport systems will make it possible to resolve yet unanswered questions about the molecular mechanisms involved in the physiology of the regulation of renal Pi reabsorption.

Chronic metabolic acidosis increases the serum concentration of 1,25-dihydroxyvitamin D in humans by stimulating its production rate. Critical role of acidosis-induced renal hypophosphatemia.

Chronic metabolic acidosis results in metabolic bone disease, calcium nephrolithiasis, and growth retardation. The pathogenesis of each of these sequelae is poorly understood in humans. We therefore investigated the effects of chronic extrarenal metabolic acidosis on the regulation of 1,25-(OH)2D, parathyroid hormone, calcium, and phosphate metabolism in normal humans. Chronic extrarenal metabolic acidosis was induced by administering two different doses of NH4Cl [2.1 (low dose) and 4.2 (high dose) mmol/kg body wt per d, respectively] to four male volunteers each during metabolic balance conditions. Plasma [HCO3-] decreased by 4.5 +/- 0.4 mmol/liter in the low dose and by 9.1 +/- 0.3 mmol/liter (P < 0.001) in the high dose group. Metabolic acidosis induced renal hypophosphatemia, which strongly correlated with the severity of acidosis (Plasma [PO4] on plasma [HCO3-]; r = 0.721, P < 0.001). Both metabolic clearance and production rates of 1,25-(OH)2D increased in both groups. In the high dose group, the percentage increase in production rate was much greater than the percentage increase in metabolic clearance rate, resulting in a significantly increased serum 1,25-(OH)2D concentration. A strong inverse correlation was observed for serum 1,25-(OH)2D concentration on both plasma [PO4] (r = -0.711, P < 0.001) and plasma [HCO3-] (r = -0.725, P < 0.001). Plasma ionized calcium concentration did not change in either group whereas intact serum parathyroid hormone concentration decreased significantly in the high dose group. In conclusion, metabolic acidosis results in graded increases in serum 1,25-(OH)2D concentration by stimulating its production rate in humans. The increased production rate is explained by acidosis-induced hypophosphatemia/cellular phosphate depletion resulting at least in part from decreased renal tubular phosphate reabsorption. The decreased serum intact parathyroid hormone levels in more severe acidosis may be the consequence of hypophosphatemia and/or increased serum 1,25-(OH)2D concentrations.

Multilocus mapping of the X-linked hypophosphatemic rickets gene.

X-linked hypophosphatemic rickets (HYP), the most common form of familial hypophosphatemic (vitamin D-resistant) rickets, is an X-linked dominant disorder characterized by decreased renal tubular phosphate reabsorption and consequent hypophosphatemia. Despite the application of a wide variety of biochemical and cell biology techniques, controversy exists regarding whether a primary renal abnormality underlies the abnormal phosphate transport or if this defect is secondary to the effects of a hormonal/metabolic factor. Thus localization of the HYP gene and its ultimate cloning may be necessary to elucidate the pathophysiology of the disorder. In order to map the human HYP gene we investigated several new polymorphic probes for linkage to HYP and constructed a map of markers around the gene. The database used to ascertain linkage and perform mapping included 5 large HYP kindreds, 40 Centre d'Etudie Polymorphisms Humain reference pedigrees, and 19 kindreds which had been obtained for other disease linkage studies. Two point LOD scores (odds of linkage, log10) indicate that the probes DXS365, DXS257, DXS451, and DXS41 are tightly linked to the HYP locus. Indeed, there were no cross-overs between DXS365 and HYP with a peak LOD score of 13.98 [recombination fraction (theta) = 0.00]. Moreover, multipoint analysis reveals a probable locus order of: Xtel-DXS315-DXS43-DXS257-HYP-DXS41-DXS4 51-Xcen. The likelihood of HYP occurring between DXS257 and DXS41 is 407:1 over the next most likely position. DXS365 is located between DXS41 and DXS43 but could not be located with respect to HYP and DXS257. Regardless, we have located the HYP gene between the flanking markers DXS257 (telomeric) and DXS41 (centromeric) which are 3.5 centiMorgans apart. Thus, the results of this study will facilitate attempts to further localize and eventually clone the gene.

Renal handling of phosphate can predict height velocity during growth hormone therapy for short children

Renal tubular reabsorption of phosphate in response to GH administration was studied in 28 short Japanese children, aged 5-11 yr (height SD score, less than -2.0 SD). Three groups included a classical GH deficiency (group 1; n = 12), a partial GH deficiency (group 2; n = 7), and children with non-GH deficiency (group 3; n = 9), depending on the peak response of serum GH in four provocative tests. Serum phosphorus, alkaline phosphatase, insulin-like growth factor-I (IGF-I), osteocalcin, and ratio of the maximum tubular reabsorption rate for phosphorus to the glomerular filtration rate (Tmp/GFR) were all significantly lower in group 1 compared with findings in groups 2 and 3 (P less than 0.05, P less than 0.01, and P less than 0.001). After the administration of GH (0.1 U/kg.day) for 4 consecutive days, increments in serum phosphorus and Tmp/GFR were significantly higher in group 1 than in group 2 (P less than 0.01 and P less than 0.01) or group 3 (P less than 0.01 and P less than 0.01), whereas the increment in IGF-I was similar in all 3 groups, and the levels of serum alkaline phosphatase and osteocalcin remained unchanged in all 3 groups. The calculated ratio of the increment in Tmp/GFR to the increment in IGF-I (delta Tmp/GFR/delta IGF-I) was highest in group 1, intermediate in group 2, and lowest in group 3 (P less than 0.001). One year after the GH treatment (0.5 U/kg.week), height velocity was 7.9 +/- 2.2 cm/yr in group 1 and 5.9 +/- 1.2 cm/yr in group 2; no child in group 3 was treated. When the above calculated parameters, delta Tmp/GFR/delta IGF-I and increment in height velocity (difference between pre- and posttherapy values), were taken into account, there was a significant positive correlation (n = 19; r = 0.78; P less than 0.001). This parameter can be used for purposes of predicting the outcome after 1 yr of GH therapy.

Renal handling of phosphate can predict height velocity during growth hormone therapy for short children.

Renal tubular reabsorption of phosphate in response to GH administration was studied in 28 short Japanese children, aged 5-11 yr (height SD score, less than -2.0 SD). Three groups included a classical GH deficiency (group 1; n = 12), a partial GH deficiency (group 2; n = 7), and children with non-GH deficiency (group 3; n = 9), depending on the peak response of serum GH in four provocative tests. Serum phosphorus, alkaline phosphatase, insulin-like growth factor-I (IGF-I), osteocalcin, and ratio of the maximum tubular reabsorption rate for phosphorus to the glomerular filtration rate (Tmp/GFR) were all significantly lower in group 1 compared with findings in groups 2 and 3 (P less than 0.05, P less than 0.01, and P less than 0.001). After the administration of GH (0.1 U/kg.day) for 4 consecutive days, increments in serum phosphorus and Tmp/GFR were significantly higher in group 1 than in group 2 (P less than 0.01 and P less than 0.01) or group 3 (P less than 0.01 and P less than 0.01), whereas the increment in IGF-I was similar in all 3 groups, and the levels of serum alkaline phosphatase and osteocalcin remained unchanged in all 3 groups. The calculated ratio of the increment in Tmp/GFR to the increment in IGF-I (delta Tmp/GFR/delta IGF-I) was highest in group 1, intermediate in group 2, and lowest in group 3 (P less than 0.001). One year after the GH treatment (0.5 U/kg.week), height velocity was 7.9 +/- 2.2 cm/yr in group 1 and 5.9 +/- 1.2 cm/yr in group 2; no child in group 3 was treated. When the above calculated parameters, delta Tmp/GFR/delta IGF-I and increment in height velocity (difference between pre- and posttherapy values), were taken into account, there was a significant positive correlation (n = 19; r = 0.78; P less than 0.001). This parameter can be used for purposes of predicting the outcome after 1 yr of GH therapy.

Parathyroid hormone-related protein of malignancy: immunohistochemical and biochemical studies in normocalcaemic and hypercalcaemic patients with cancer.

Immunohistochemical staining for parathyroid hormone-related protein was performed in 27 tumours from 19 normocalcaemic and eight hypercalcaemic patients with cancer. All the tumours from hypercalcaemic patients stained positively for the protein, as did 17 tumours from normocalcaemic patients. Only hypercalcaemic patients had biochemical evidence of increased bone resorption and abnormalities of renal tubular reabsorption of calcium and phosphate, consistent with the presence of parathyroid hormone-related protein. While tumour mass was higher in hypercalcaemic patients, only one of the initially normocalcaemic patients with positively staining tumours subsequently went on to develop hypercalcaemia and more advanced disease. These data confirm the importance of parathyroid hormone-related protein as a mediator of humoral hypercalcaemia in patients with solid tumours and suggest that low tumour mass may be one reason why serum calcium values are not increased in all patients with tumours containing parathyroid hormone-related protein. None the less normocalcaemia, despite tumour progression in patients whose tumours stained positively for parathyroid hormone-related protein, suggests that other factors may also be important, such as differences in the rate of secretion of the protein by different tumours, or the production of different forms of parathyroid hormone-related protein with varying biological effects.

Growth Hormone and Bone

Bone and mineral metabolism is regulated by numerous hormones and local growth factors. Growth hormone (GH), directly and/or indirectly through local IGF1 and IGF2 production, stimulates bone turnover as it increases osteoblast number and function. It also stimulates bone resorption through unknown mechanisms. GH (by IGF1) stimulates the renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity and therefore enhances calcium and phosphate absorption in the intestine. It also increases the maximal renal tubular reabsorption of phosphate. The overall effect of GH on bone therefore seems beneficial as bone mass is increased together with the lean body mass. Large excess of GH, however, also increases the risk of osteoarthritis and has other serious metabolic side effects, so that its place in the treatment/prevention of osteoporosis is yet to be defined.

Evaluation of bone resorption and renal tubular reabsorption of calcium and phosphate in malignant and nonmalignant hypercalcemia

Tubular reabsorption of calcium (Ca) is becoming recognized as a determinant of malignant hypercalcemia. However, its importance as compared to increased bone resorption has not yet been widely investigated. We determined Ca fluxes of bone resorption and tubular reabsorption in 141 rehydrated patients with hypercalcemia of malignant or benign origin, before any specific treatment. Bone resorption (BRI) was evaluated by fasting urinary Ca excretion and Ca tubular reabsorption using an index (TRCaI) calculated from a nomogram relating fasting urinary Ca excretion and calcemia. The relationship between alterations in TRCaI and in the tubular capacity to reabsorb inorganic phosphate (Pi), as judged by TmPi/GFR, was also examined for each cause of hypercalcemia. Among 101 cases with malignancy, 67% had overt bone metastases, but all displayed increased BRI. Calcemia was highest in breast cancer and lowest in prostate carcinoma. BRI was markedly increased in breast cancer, lymphoma, and multiple myeloma, whereas it was slightly elevated in lung squamous cell, renal, and liver carcinomas. TRCaI was increased in 49% of malignant hypercalcemia, particularly in epidermoid (above the upper normal limit in 71% of the cases), renal, and liver carcinomas. It was elevated in 54% of breast cancer and normal in multiple myeloma and prostate cancer. In nonmalignant hypercalcemia, BRI was markedly increased in vitamin D intoxication, sarcoidosis, and immobilization. In primary hyperparathyroidism (PHP), BRI was moderately increased. TRCaI was abnormally elevated in PHP, but normal in vitamin D intoxication, sarcoidosis, and immobilization. In malignant hypercalcemia, TmPi/GFR was low in 77% of patients and in all types of tumors, except in prostate carcinoma. The index ratio [TRCaI/(TmPi/GFR)] gave a better discrimination of PHP from other causes of nonmalignant hypercalcemia than the use of either TRCaI or TmPi/GFR taken alone. Thus, in malignant hypercalcemia, increased bone resorption is associated with an elevation in tubular Ca reabsorption in half the patients surveyed, whereas low tubular Pi reabsorption is observed in more than 75%. Increased TRCaI is restricted to some types of tumor, whereas decreased TmPi/GFR is observed in all types except prostate carcinoma. In nonmalignant hypercalcemia, a significant increase in mean TRCaI was only observed in PHP, of which individual cases can be fully discriminated from other conditions by using a new index taking into account alteration in the renal transport capacity of both Ca and Pi.

Parathyroid hormone‐related protein and hypercalcemia in pancreatic neuro‐endocrine tumors

We investigated the possible involvement of parathyroid hormone-related protein (PTHrP) in 2 cases of metastatic pancreatic neuro-endocrine tumors associated with severe hypercalcemia. Both patients displayed biochemical alterations in renal tubular reabsorption of calcium and phosphate, as well as in urinary cAMP excretion, similar to those encountered in primary hyperparathyroidism, although plasma levels of parathyroid hormone were within the normal range. Tumor protein extracts stimulated cAMP production, which was inhibited by the PTH-antagonist (8,18 Nle, 34 Tyr)bPTH-(3-34)amide, in the PTH-responsive osteoblastic cell line UMR-106. Northern blot analysis of tumor extracts revealed the presence of PTHrP mRNA transcripts, while PTH mRNA was undetectable. In contrast, neither PTHrP mRNA(s) nor cAMP-stimulating activity was detectable in other neuroendocrine tumors not accompanied by hypercalcemia. These results demonstrate that certain pancreatic neuroendocrine tumors associated with hypercalcemia can synthesize and release PTHrP.

Hypercalcemic hyperparathyroidism and hypophosphatemic osteomalacia complicating neurofibromatosis

Neurofibromatosis is sometimes complicated by impaired renal tubular reabsorption of phosphate, hypophosphatemia, and osteomalacia. Hyperparathyroidism has also been reported in patients with neurofibromatosis. When hypercalcemia and elevated levels of parathyroid hormone are found in osteomalacia, however, it may be difficult to determine if the hyperparathyroidism was primary or tertiary. We describe a patient with neurofibromatosis, hypercalcemic hyperparathyroidism, hypophosphatemic osteomalacia, vitamin D deficiency, and clear-cell hyperplasia of all four parathyroid glands. Serial biomechanical, bone biopsy, and densitometric studies confirmed that treatment with ergocalciferol, calcium, and phosphate supplements significantly improved the osteomalacia but caused increased parathyroid overactivity. After subtotal parathyroidectomy, the parathyroid hormone concentration became normal and the bone mineral content increased at the spine and hip, but inappropriate phosphaturia persisted. The findings indicate that hyperparathyroidism, osteomalacia, and vitamin D deficiency adversely affect each other.