Biomedical subjects
Publications and source records attributed to A Rapado.
Nephrolithiasis is presented in 18-40% of patients with primary hyperparathyroidism. Our work suggests that citrate, an inhibitor of calcium salts, could be involved in the presence of renal lithiasis because hyperparathyroid stone formers show less citrate elimination than nonstone formers.
Different mechanisms could explain the elevated calcium elimination, the main cause of calcium oxalate renal stones. Our results suggest that phosphate levels are decreased in patients with absorptive hypercalciuric nephrolithiasis and elevated serum dihydroxyvitamin D. This could be the reason why in this group of patients oral phosphate treatment prevented hypercalciuria and renal lithiasis.
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In order to analyze the role of 1,25(OH)2 D3 in bone and renal presentation forms of primary hyperparathyroidism (PHP), 61 patients, whose diagnosis had been confirmed surgically, were studied. An increase in serum 1,25(OH)2 D3 levels was found in PHP when compared to normal controls (49.1 +/- 2.8 pg/ml vs 34.1 +/- 1.4 pg/ml) (p less than 0.5). This increase directly correlates with serum alkaline phosphatase and creatinine clearance and inversely correlates with age. When patients were divided into two groups: A (n = 35) and B (n = 26) according to normal or increased 1,25(OH)2 D3 respectively, no difference was found in the clinical presentation forms of PHP. However, higher values of the biochemical parameters and bone remodeling markers were found in group B than in group A. This suggests the role of 1,25(OH)2 D3 as a modulator of metabolic activity in PHP and its possible therapeutic character in the clinical control of asymptomatic forms.
A small group of patients with nephrolithiasis who forms mixed (calcium oxalate and uric acid) calculi presents particular problems in their clinical management. In 3,158 stones analyzed in our laboratory, we found 158 mixed calculi in 86 of the patients. In this work, the clinical and biochemical results obtained from 27 patients with mixed stones were compared with those from 27 control patients with calcium oxalate renal lithiasis. A significant difference was found in oxalate and citrate urinary elimination (mean +/- SD) in mixed stone formers versus pure calcium oxalate stone formers: oxaluria (mg/24 h: 38 +/- 15 vs. 28 +/- 12; p less than 0.01) and citraturia (mg/24 h: 214 +/- 139 vs. 437 +/- 303; p less than 0.01). Citraturia was decreased in a high proportion (77%) in mixed stone formers, and only a reduced percentage of them (23%) presented normal values, although in the low limit of normality. As treatment and prophylactic measure, we proposed oral administration of citrates in mixed stone patients because citrate inhibits spontaneous nucleation of calcium salts and crystal growth, and it also increases the urinary pH with a consequent increase in uric acid solubility.
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We have found a cellular immune defect (low CD4 T lymphocyte count, high CD8 T lymphocyte count and a low CD4/CD8 ratio) in 39 PDB patients. This finding is not correlated with the bone metabolic activity of the disease. There was an improvement in the cellular immune defect in fifteen patients after treatment with elcatonin. These changes could be related to the improvement in the metabolic derangement or else could be the consequence of an effect on altered immunity.
Tartrate resistant acid phosphatase (TRAP) has been proposed as a new biochemical marker for bone resorption. We have compared this new marker, TRAP, with the classical biochemical markers of bone remodelling, serum alkaline phosphatase (sAP), serum osteocalcin (sBGP), and with the urinary hydroxyproline/creatinine ratio (uOHProl/creatinine), a routine marker of bone resorption. Serum TRAP was significantly higher in pagetic patients (n = 43) than in control subjects (n = 12) (13.02 +/- 4.7 vs 5.48 +/- 1.31 IU/L, P less than 0.001) and a significantly positive linear correlation was found between the sTRAP and uOHProl/creatinine ratio (y = 0.0051x - 0.0069, r = 0.82, P less than 0.001), between sTRAP and sAP (y = 19.3x - 85.0, r = 0.71, P less than 0.001) and also between sTRAP and sBGP (y = 0.02x + 2.23, r = 0.52, P less than 0.01). Serum TRAP levels were higher than the upper limit of normality in all our pagetic patients except for two, whose uOHProl/creatinine levels were in the normal range. We conclude that (1) sTRAP could be a parameter as sensitive as uOHProl/creatinine in the diagnosis of Paget's disease; (2) sTRAP and uOHProl/creatinine are both good markers of bone resorption; (3) the correlation found between sTRAP and formation markers (sAP and sBGP) makes sTRAP a marker of disease activity in Paget's disease of bone; (4) the assay of sTRAP is easier, faster, and of lower cost than the urinary hydroxyproline determination. We suggest that sTRAP determination could be used as a routine marker of bone resorption in Paget's disease of bone, as is the case with uOHProl determination.
Serum osteocalcin (serum bone Gla protein, sBGP) is elevated in diseases characterized by an enhanced bone turnover. However, in Paget's disease of bone there is a discrepancy between the low increase of sBGP and the high increase of bone remodelling assessed by serum alkaline phosphatase and urinary hydroxyproline. It is possible that the relatively low levels of sBGP reflect an abnormal binding of the molecule to the bone due to an alteration of the BGP molecule and/or of the pagetic mineral phase of bone. Another possibility would be a disregulation of BGP synthesis. In the present work we studied the binding of pagetic sBGP to an experimental model of mineral phase of bone (HPLC hydroxyapatite column). Serum of 14 patients with Paget's disease of bone (sBGP = 7.8 +/- 3.5 ng/ml) and of 14 control subjects (sBGP = 3.3 +/- 0.9 ng/ml) was purified through a Sephadex G-50 medium column (2.6 x 100 cm, 5 mM NH4CO3H). The BGP peak was lyophilized and resuspended in 1 mM KH2PO4, 1 mM CaCl2, 0.02% NaN3, pH 8.4, and then injected into an HPLC gradient system (Waters 660), from 1 to 300 mM KH2PO4 through a hydroxyapatite column (BioGel HPHT, Bio-Rad, 0.78 x 10 cm). A single peak of sBGP was obtained with a retention time of 12 min in control and pagetic patients. From these results we conclude that BGP binding to hydroxyapatite is similar in pagetic patients and in control subjects, suggesting that an alteration in BGP molecule is not responsible for an abnormal binding to the bone. In order to validate our system, the binding of serum BGP from warfarin-treated rats to the hydroxyapatite HPLC column was also studied and compared to binding of serum BGP from normal rats.
The rat Walker carcinosarcoma 256 is an animal model for humoral hypercalcaemia of malignancy (HHM). In this model, the relative contribution of bone and kidney in the hypercalcaemia of tumour-bearing rats was investigated. Daily administration of pamidronate, a bone resorption inhibitor, for 2 days prevented the increased fasting Ca2+ excretion observed in the hypercalcaemic rats, although serum Ca2+ remained high. However, the high serum Ca2+ normalised after the acute injection of ethiofos, an inhibitor of renal Ca2+ reabsorption, which was associated with a marked increase of Ca2+ excretion. Changes in Ca2+ were accompanied by similar changes in Mg2+. The results indicate that altered renal Ca2+ handling has a key role in the hypercalcaemia associated with this HHM model.
We have studied the possible correlation between serum 24,25-dihydroxyvitamin D [24,25-(OH)2D] and osteocalcin levels (sBGP) in Paget's disease of bone. We measured serum calcium, phosphate, PTH, 25-hydroxyvitamin D, 1,25-(OH)2D, 24,25-(OH)2D, alkaline phosphatase (sAP), and the urinary hydroxyproline/creatinine ratio (UOH prol/creat) in 19 patients with Paget's disease of bone and 16 age- and sex-matched controls. As expected, sAP, UOH prol/creat, and sBGP levels were significantly elevated, and there was a tendency to a decrease in serum levels of 24,25-(OH)2D in Pagetic patients with respect to the control group. There was no significant difference between patients and controls in serum calcium, phosphate, PTH, 25-hydroxyvitamin D, and 1,25-(OH)2D. The Pagetic patients were subdivided into two subgroups; subgroup A had normal sBGP levels (less than 5 ng/mL), and subgroup B had increased sBGP levels (greater than 5 ng/mL). Serum 24,25-(OH)2D levels in subgroup B were significantly lower than those in controls, while subgroup A showed levels similar to those in the control group. We also found a positive linear correlation between sAP and sBGP and between sAP and UOH prol/creat as well as a negative linear correlation between sBGP and 24,25-(OH)2D and between 24,25-(OH)2D and UOH prol/creat in Pagetic patients. These results point to a possible role of 24,25-(OH)2D in disease activity.
To determinate which type of bone is damaged in IDDM, we assessed the bone mineral content (BMC) in both cortical and trabecular bones, in a group of 48 IDDM patients without hepatic or kidney diseases, or any other pathology with implications in the mineral metabolism. For the evaluation techniques of single photon absorptiometry (SPA) and double photon absorptiometry (DPA) were used. All the patients controlled their disease with insulin. The results showed the presence of osteopenia in both types of bone. It was more evident in male group. In the patients group the mean value of serum osteocalcin (BGP) was significantly decreased (2.34 +/- 1.05) in comparison with the controls (p less than 0.001). The deficient of BMC is neither related with the parameters of new bone formation nor with the time of disease evolution.
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We tested the existence of 25-hydroxyvitamin D-1 alpha-hydroxylase activity in the Walker carcinosarcoma 256 implanted in rats. This tumour has been shown to induce hypercalcaemia in the host animal. We found this enzyme activity in tumour homogenates, which was in the same range as that in the kidney of tumour-bearing rats. Our results suggest that 1,25-dihydroxyvitamin D synthesized by the Walker tumour might be involved in the mechanism responsible for the hypercalcaemia in the host rat.
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