Renal handling of calcium and magnesium in idiopathic stone disease.
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Biomedical subjects
Publications and source records attributed to R A Sutton.
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Primary hyperparathyroidism and idiopathic hypercalciuria are important causes of calcium stone disease. Hypercalcemia is usually the clue to the presence of primary hyperparathyroidism, but a minority of patients are intermittently or persistently normocalcemic. In these patients there appears to be a resistance to the effect of parathyroid hormone on renal calcium transport, to which calcitriol may contribute. Such patients mimic those with idiopathic hypercalciuria, the commonest metabolic cause of stone formation. The pathophysiology of idiopathic hypercalciuria remains controversial, but abnormalities of renal tubule function and disordered vitamin D metabolism are commonly present. The separation into so-called renal and absorptive types does not appear to be of practical importance, since thiazide diuretics provide effective prophylaxis regardless of type.
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The circadian rhythm of urinary total hydroxyproline (THP) excretion was determined in matched groups of ten male idiopathic calcium stoneformers and ten normal subjects in order to determine whether enhanced resorption of bone might contribute to hypercalciuria in these patients. THP increased progressively in normal subjects in successive eight-hour urine collections from period 1 (8 AM to 4 PM) to period 3 (12 midnight to 8 AM), the nocturnal high level in period 3 being significantly greater than in period 1 (P less than 0.01) and in period 2 (P less than 0.05). By contrast, no significant circadian rhythm was observed in THP excretion in the stoneformers. Their THP excretion was similar to that of normal subjects in period 3, but was significantly higher than that of normal subjects in period 1 (THP/creatinine ratio(mg/mg): 0.026 +/- 0.003 v 0.017 +/- 0.001; P less than 0.05. Indices of parathyroid hormone activity were not significantly different between stoneformers and normal subjects; mean serum 1,25(OH)2 vitamin D levels were higher in the stoneformers than the normal subjects (44 v 37 pg/mL) but the difference was not significant (P greater than 0.05). These studies suggest that increased bone turnover may contribute to hypercalciuria in these calcium stoneformers.
Regional migratory osteoporosis is a disorder of unknown etiology, characterized by successive episodes of joint pain, accompanied by localized osteoporosis. The disorder affects the lower limbs, usually the region of the foot, knee, or hip, and each episode usually lasts several months and is followed by spontaneous recovery. This disorder has not previously been reported to cause episodes of vertebral osteoporosis. We describe three patients in whom regional osteoporosis, involving the lower limbs, was associated with simultaneous vertebral osteoporosis indistinguishable from idiopathic osteoporosis. These cases suggest that this disorder might be responsible for some cases of apparent idiopathic spinal osteoporosis.
A model of cisplatin (cis-diamminedichloroplatinum II) induced hypomagnesemia with renal magnesium wasting was developed in rats. Following three weekly intraperitoneal injections of cisplatin (2.5 mg/kg body weight) hypomagnesemia was evident after the second injection of cisplatin and persisted for at least 24 weeks after the last injection. The plasma magnesium concentration was 0.69 +/- 0.01 mM in cisplatin-treated rats and 0.79 +/- 0.01 mM in control rats 24 h after the second injection (less than 0.01). Despite a lower plasma magnesium concentration in cisplatin-treated rats, the fractional urinary excretion of magnesium was similar in both groups, indicating inappropriate renal magnesium excretion in cisplatin-treated rats. Rat kidneys fixed in situ by arterial infusion were examined by light and electron microscopy at the following times: 24 h after the first and second injections and 48 h and 1, 4, 8, 16, and 24 weeks after the third injection. Focal necrosis of the proximal tubule cells in the outer stripe of the medulla (S3 segment) was noted 24 h after the second injection. Following this, there was dilatation of the S3 segment proximal tubules which were lined by variably flattened epithelial cells devoid of brush borders. Many of these cells had enlarged, hyperchromatic nuclei, and few mitoses were observed. These changes were most extensive at 4 weeks, diminished after this, but were still present focally at 24 weeks. In this model the cisplatin-induced hypomagnesemia persists long after discontinuation of therapy as in humans, and the S3 segment is the prime target of the cisplatin.(ABSTRACT TRUNCATED AT 250 WORDS)
In this method for 4-hydroxyproline in urine, hydroxyproline is derivatized with 4-chloro-7-nitrobenzofurazan, with subsequent estimation by reversed-phase "high-performance" liquid chromatography. The ranges for excretion of free and total hydroxyproline while the subjects were ingesting unrestricted diets were 2-29 and 122-374 mumol/24 h (n = 21), respectively, with no significant sex-related difference. A comparison with results by colorimetry indicated no significant differences: mean (n = 18) concentrations (mumol/L) of hydroxyproline in urine were 180 (SD 149) by the present method, 163 (SD 166) by colorimetry. For protein hydrolysate the respective values were 5.9 (SD 2.7) and 6.7 (SD 2.9).
The relationship between the torque applied to the loading screw and the load required to pull off Cone's type of skull traction caliper was established on cadavers. It was found that at a torque of 0.7 Newton metres (Nm), which corresponds to a compressive force of 13 lb (58 N) on the skull, the caliper became detached at the maximum traction load of 60 lb, but still held during this traction load at compressive forces above 18 lb (80 N). Clinically, an instrumented load cell was incorporated into one of the fixing pins on a skull traction caliper and it was found that the compressive load fell on average by 15 per cent over a period of 21 days of traction. Taking into account this fall in load with time and the limiting torque for pull-out with a traction force of 60 lb (265 N) it is suggested, for complete clinical safety, that a compressive load of 20 lb (88 N) obtained at a torque of 0.85 Nm should be applied to the loading screw of a Cone's type of caliper. Using these values in a loading analysis of the securing pins, suggestions are made as to the ideal design of skull traction calipers and the shortcomings of various designs of existing calipers are discussed, in particular the pins' lengths, compressive load and the pins' placement.
In this review the normal renal tubular handling of calcium is briefly described. A detailed examination follows of the sites and modes of action of furosemide and thiazide diuretics on renal calcium handling and overall calcium metabolism. The clinical applications of these effects are also considered. Finally, the use of diuretics with different tubular sites of action on calcium transport as probes to study disorders of calcium excretion is discussed.
After three weekly intraperitoneal injections of cisplatin (2.5 mg/kg body wt), male Wistar rats developed chronic hypomagnesemia, which was evident from the second week and persisted throughout the 8-week experiments. Plasma magnesium concentration was 0.69 +/- 0.01 mM in cisplatin-treated rats compared to 0.80 +/- 0.02 mM in pair-fed control rats (P less than 0.01) in the eighth week of experimentation. Despite a similar dietary magnesium intake, urinary excretion of magnesium in cisplatin-treated rats was inappropriately high, relative to the lower plasma magnesium concentration, indicating the presence of renal magnesium wasting induced by cisplatin. During the 3 weeks of cisplatin injections, metabolic balance studies indicated abnormal renal excretion and a reduction in the fractional intestinal absorption of magnesium. A compensatory period of significantly greater retention of magnesium then occurred in cisplatin-treated rats beginning in the fourth week. Clearance and recollection micropuncture studies in a separate group of rats revealed normal magnesium and calcium transport in the superficial proximal and distal nephron. Following acute MgCl2 infusion, the urinary excretion of magnesium and calcium were significantly higher in cisplatin-treated rats than in control rats; however, micropuncture studies of superficial nephrons failed to demonstrate abnormal transport of these divalent cations. It is possible, therefore, that 7 weeks of cisplatin treatment led to tubular adaptation that might have obscured the defect in magnesium reabsorption. Morphological examination indicated that pathological changes were confined to the S3 segment of proximal corticomedullary nephrons.(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of 1,25(OH)2D3 on the renal handling of calcium (Ca), magnesium (Mg), and phosphate (Pi) in the thyroparathyroidectomized (TPTX) hamster were studied in the presence of exogenous PTH. Clearance experiments were performed in the following groups: acutely TPTX animals (group 1), acute TPTX plus continuous infusion of PTH in low or high doses sufficient to (1) reduce or (2) abolish the hypocalcemic effect of TPTX (groups 2 and 3, respectively), and acute TPTX plus Ca (group 4) or Pi (group 5) infusion. Each group was subdivided into control and experimental subgroups. In all animals an initial control phase was followed by a second phase in which experimental animals received an infusion of 1,25(OH)2D3 (1 U prime + 0.5 U/hr) while control animals received only the ethanol vehicle. GFR and urine flow rate, were not altered significantly in any of the groups. PCa and PMg increased significantly in group 3 only. Group 2 showed an increase in FECa (5.2 +/- 1.4 to 13.2 +/ 2.2%, P less than 0.001) and FEMg (7.3 +/- 1.3 to 17.3 +/- 2.2%, P less than 0.001) in response to 1,25(OH)2D3. Group 3 showed a significant increase in FEMg only (2.2 +/- 0.4 to 5.5 +/- 1.0%, P less than 0.01). The changes in the control groups were not significant. The administration of 1,25(OH)2D3 reduced phosphate excretion only in the presence of PTH. The FEPi decreased from 11.9 +/- 2.1 to 3.6 +/- 0.9% (P less than 0.001) in group 2 and 29.2 +/- 4.0 to 16.5 +/- 2.5% (P less than 0.02) in group 3.(ABSTRACT TRUNCATED AT 250 WORDS)
The relationship between the applied torque and the load required to pull off the calipers was established on cadavers. Torques of 0.7, 0.8 and 0.9 Newton-metres were applied to a specially adapted skull traction caliper whilst attached to the skull in the normal position when used clinically, and loads were applied in steps of 2 lb up to a maximum of 60 lb. It was found that at a torque of 0.7 Newton-metres, the caliper became detached at the maximum load, but still held during traction at torques above this value. Taking into account the fall in load with time that may occur clinically and the limiting torque for pull-out with a traction load of 60 lb, it is suggested for complete clinical safety that a torque of 0.9 Newton-metres should be applied. An open-ended torque release spanner was set for 0.9 Newton-metres for clinical use such that the compressive load is sufficient to prevent pull-out even in the unlikely event of 60 lb being applied for up to 21 days.
The effect of acute potassium infusion on renal tubular reabsorption of potassium by magnesium-deficient and pair-fed control rats has been studied by the recollection micropuncture method. During potassium chloride infusion, the amount of potassium remaining in the distal tubule is lower in magnesium-deficient than in pair-fed rats. This could be due to a reduction in potassium secretion or to an enhancement of potassium reabsorption. The present study demonstrates enhanced renal potassium retention in the magnesium-deficient rat, and is in contrast to previous reports of renal potassium wasting in this circumstance.
The effect of phosphate infusion on renal tubular handling of calcium and phosphate was examined in dogs which had been thyroparathyroidectomized (TPTX) immediately prior to the studies. Phosphate infusions in TPTX animals caused a small decrease in total and ultrafilterable plasma calcium, and decreased phosphate reabsorptive capacity in the proximal tubule and loop segment. Infusion of CaCl2 during phosphate loading to offset the fall in plasma calcium prevented the reduction in proximal phosphate reabsorptive capacity. However, between the proximal and distal sampling site, the reduction in phosphate reabsorptive capacity could not be prevented by CaCl2 administration. These data are consistent with the presence of two phosphate transport systems; one in the early proximal tubule, modulated by changes in plasma calcium level, and a second in the loop segment, which is independent of calcium. While the data suggest that the depression of proximal phosphate reabsorption during phosphate infusion may be secondary to the fall in plasma calcium concentration, they do not exclude a direct effect of infused phosphate on proximal phosphate reabsorption that may be antagonized by an opposing direct effect of the calcium infusion.
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A device has been developed that can display underseat pressure distributions during sitting. We have found this device to be particularly useful in monitoring the effect of pressure sore surgery on the underseat pressure patterns, in the design of pressure-relieving cushions, and as a device to enable spinal injury staff to locate areas of high pressure at which tissue breakdown (pressure sores) may occur.
Idiopathic calcium stone-formers with hypercalciuria during fasting have significantly lower urinary cyclic AMP levels (nmol/dl of glomerular filtrate) than fasting normocalciuric stone-formers. Female subjects, including both normal subjects and idiopathic calcium stone-formers, have higher urinary cyclic AMP levels than their male counterparts, and this difference is significant when urinary cyclic AMP is expressed in the units mumol/g of creatinine. Expressing urinary cyclic AMP in nmol/dl of glomerular filtrate reduces this difference but does not abolish it. Thus, in comparing urinary cyclic AMP levels in various subgroups of the calcium stone-formers and in normal subjects, both sex differences and the units of urinary cyclic AMP expression must be taken into consideration. The magnitude of the change in urinary cyclic AMP in response to an oral calcium load appears to depend on the antecedent urinary cyclic AMP excretion rate, whereby those individuals (either normal subjects or calcium stone-formers) having the highest urinary cyclic AMP levels demonstrate the greatest fall in urinary cyclic AMP after a calcium load.