Subacute infusion of physiological doses of parathyroid hormone raises blood pressure in humans

Background. Acute administration of parathyroid hormone (PTH) causes vasodilation and blood pressure decrease in experimental animals. This effect contrasts with the putative role of secondary hyperparathyroidism in the pathogenesis of hypertension of patients with renal failure. Uraemia is characterized by insulin resistance and hyperinsulinaemia. We therefore investigated whether subacute administration of physiological doses of human 1,34-PTH affects blood pressure under conditions of controlled insulin levels (euglycaemic clamp technique) in humans. Methods. In a double-blind cross-over design 10 healthy male subjects received, on two occasions, in random order, for 2 h, either a sham infusion or an infusion of 200 units of 1,34-PTH. Results. Mean ionized calcium concentration increased significantly (P <0.01) within the normal range during euglycaemic hyperinsulinaemia, both with sham infusion (from 1.25 ± 0.04 to 1.29 ± 0.02 mmol/l) and with infusion of 1,34-PTH, but the increase was more marked with 1,34-PTH administration (from 1.26 ± 0.05 to 1.33 ± 0.07). In addition, mean platelet intracellular calcium concentration (by fluorescence spectroscopy) was unchanged with sham infusion (49.9 ± 4.1 versus 50.3 ± 5.0 nmol), but increased significantly (P <0.05; paired t-test) after 1,34-PTH infusion (from 49.8 ± 5.0 to 52.8 ± 5.8). The infusion of 1,34-PTH resulted in a significant (P <0.01) increase in mean MAP (from 84 ± 5 to 88 ± 5 mmHg) as compared with sham infusion (85 ± 4 versus 86 ± 4). The intra-individual changes in intracellular calcium concentration (&Dgr;[Ca²⁺]I) were significantly correlated to the changes in mean MAP (&Dgr;MAP) (r = 0.87, P <0.001). In contrast to blood pressure, insulin sensitivity was not affected by 1,34-PTH infusion (M-value: 7.2 ± 1.6 mg/kg per min) as compared with sham infusion (7.3 ± 1.4). Conclusion. Subacute administration of physiological doses of parathyroid hormone under hyperinsulinaemic conditions significantly affects intracellular calcium and blood pressure in healthy subjects, but does not affect the action of insulin.     

The effects of menopause and estrogen replacement therapy on the renal handling of calcium

Mineral metabolism was studied in 99 premenopausal and 80 postmenopausal women both before and after 9–14 months of treatment with 50 µg/day transdermal estradiol. In estrogen-repleted subjects (premenopausal women and postmenopausal women on estrogen replacement therapy) total serum calcium was significantly lower (0.065 mmol/l;p<0.001) than in those who were estrogen-depleted (untreated postmenopausal women). This difference was smaller but still significant for calculated ultrafiltrable calcium (UFCa: 0.02–0.03 mmol/l;p<0.001). However, ionized calcium (both calculated and measured) was not different in the two groups of women. This finding explains why estrogen repletion does not induce changes in the serum level of intact parathyroid hormone (PTH), despite lower total or ultrafiltrable serum calcium. In a parallel study we have shown that intravenous administration of aminobutane bisphosphonate, a powerful inhibitor of bone resorption, produces similar decreases in serum calcium which were associated with significant increases in intact PTH.Estrogen-depleted women had, on the one hand, significantly higher serum levels of bicarbonate, anion gap, complexed calcium, pH, phosphate and alkaline phosphatase, and higher rates of tubular reabsorption of phosphate and urinary excretion of calcium and hydroxyproline. On the other hand they had lower serum chloride levels and lower rates of tubular reabsorption of calcium.Altogether these findings might indicate that estrogen deficiency decreases renal sensitivity to PTH. This is responsible for the higher serum phosphate and bicarbonate levels, the resulting mild metabolic alkalosis leading to higher serum levels of complexed ultrafiltrable calcium and higher rates of urinary excretion of calcium, but unchanged serum levels of ionized calcium and PTH.     

Insulin resistance precedes microalbuminuria in patients with insulin-dependent diabetes mellitus

Background. Insulin resistance has been associated with hypertension and with renal complications in patients with type 1 diabetes mellitus. Causal relationships have not been fully explained. Methods. We investigated whether insulin resistance precedes microalbuminuria by measuring insulin resistance with a euglycaemic clamp in combination with indirect calorimetry in 16 uncomplicated type 1 diabetic patients and in six healthy control subjects. The patients had over 10 year duration of diabetes, and were expected to experience either a complication-free or complicated disease course within the next few years. They have thereafter been followed for the development of microalbuminuria for 3 years. Results. In a euglycaemic insulin clamp glucose disposal was lower in diabetic patients compared with control subjects (7.5±2.9 and 12.6±2.0 mg/kg LBM/min; P<0.002), mainly due to impaired glucose storage (4.3±2.3 vs 8.6±1.6 mg/kg LBM/min; P<0.001). Three years later seven IDDM patients had albumin excretion rate over 30 mg/24 h; glucose disposal (5.5±2.1 vs 9.0±2.2 mg/kg LBM/min; P<0.01) had been lower in patients who developed microalbuminuria compared with those who remained normoalbuminuric. Conclusions. Insulin resistance predicts the increment in urinary albumin excretion. Insulin resistance depends mainly on impaired glucose storage in uncomplicated IDDM.     

Prednisolone Induces an Increase in Serum Calcium Concentration: Possible Involvement of the Kidney, the Bone, and the Intestine

To evaluate the early effect of glucocorticoids on calcium metabolism, 15 subjects aged 22–58 years (5 males, 10 females) with chronic glomerulonephritis were orally treated with 40 mg daily of prednisolone. Five of these subjects were diagnosed with nephrotic syndrome and none had a serum creatinine concentration of more than 1.4 mg/dl. Serum specimens and 24-hour urine specimens were obtained just before and 24 hours after a single oral dose of prednisolone. Serum calcium, ionized calcium, phosphate, intact parathyroid hormone (PTH), intact osteocalcin and 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), and urinary excretion of calcium, phosphate, and deoxypyridinoline were measured. Both serum calcium and ionized calcium concentrations were significantly increased from 4.39 ± 0.10 to 4.47 ± 0.09 mEq/liter (P= 0.037) and from 2.48 ± 0.04 to 2.55 ± 0.04 mEq/liter (P= 0.002), respectively, 24 hours following a single oral dose of prednisolone. Serum intact PTH concentration slightly decreased, but the difference was not significant by statistical analysis. Serum intact osteocalcin concentration was markedly suppressed. In contrast, no significant changes were observed in urinary excretion of deoxypyridinoline. Serum 1,25(OH)₂D₃ concentration measured in five patients was significantly increased. No significant changes in urinary excretion of calcium was observed in the face of these findings. It thus follows that a single oral dose of prednisolone administration increases serum calcium and ionized calcium concentrations, possibly mediated by suppressed bone formation, increased intestinal absorption of calcium, and impaired urinary excretion of calcium. Received: 19 February 1998 / Accepted: 12 March 1999     

A 6-hour human parathyroid hormone (1–34) infusion protocol: Studies in normal and hypoparathyroid subjects

Summary Parathyroid hormone (PTH)-resistant states are usually diagnosed by the failure of an acute PTH injection to elicit a rise in urinary cAMP and phosphate or, less commonly, by the failure of repeated PTH injections to raise serum calcium. We have established a 6 hour infusion of human PTH (1–34) which identifies PTH-resistant hypoparathyroid subjects on the basis of serum 1,25-dihydroxyvitamin D (1,25(OH)₂D) and calcium responses. 1.25-Dihydroxyvitamin D levels increased by at least 58 pmol/liter and serum calcium by at least 0.1 mmol/liter in PTH-responsive hypoparathyroid subjects (n=6), whereas in pseudohypoparathyroid subjects (n=5) these levels rose by less than 22 pmol/liter and 0.06 mmol/liter respectively. The responsiveness of urinary phosphate excretion, expressed as the renal threshold phosphate concentration (TmPO₄/GFR), to PTH also clearly separated the pseudohypoparathyroid patients from the other subjects. Differences in urinary calcium responses were observed though this parameter was less reliable in the identification of individual PTH-resistant or PTH-sensitive hypoparathyroid patients. Nephrogenous cAMP did not discriminate between groups when this protocol was used. This test has the potential to facilitate and extend the classification of PTH-resistant states.     

Intestinal calcium absorption during hyperinsulinemic euglycemic glucose clamp in healthy humans

Summary The influence of postprandial-like plasma insulin levels on intestinal calcium absorption (CaA) was studied in 9 health men. On separate occasions, they received either an i.v. infusion of 40 mU/m² minute synthetic human insulin as well as a variable glucose infusion in order to clamp the plasma glucose at the baseline level (=glucose clamp), or insulin- and glucose-free vehicle infusions (=vehicle). During these infusions, an oral load containing 326 mg Ca in the form of Ca chloride was administered and CaA was determined thereafter with a⁴⁷Ca/⁸⁵Sr double tracer method. During glucose clamp, mean plasma insulin was 172 ±(1 SEM) 10 as compared to 6±1 μU/ml during vehicle infusions. During the clamp, 3-hour cumulative CaA rose significantly by 14% as compared to vehicle (39.2±2.5 vs. 34.4±2%,P<0.02). At the same time, serum potassium and phosphorus dropped significantly, whereas serum parathyroid hormone (PTH) and 1,25(OH)₂D levels were unchanged as compared to vehicle. The urinary excretions of potassium, sodium, and inorganic phosphorus as well as the urinary specific activity of⁴⁷Ca, dropped significantly during glucose clamp, whereas the urinary excretion of cAMP was unchanged as compared to vehicle. The results suggest that, under the conditions of euglycemic hyper-insulinemic clamp, insulin stimulates CaA of healthy humans in a PTH- and 1,25(OH)₂D-independent manner. Insulin may thus possibly be regarded as a factor participating in the regulation of CaA in humans.     

Stimulatory effect of insulin on tubular sodium reabsorption in normotensive subjects with a positive family history of hypertension

BACKGROUND: Insulin resistance and hyperinsulinaemia has been suggestedas a pathogenetic mechanism in hypertension. METHODS: In this investigation the renal response to insulin was studiedin normotensive subjects with a positive family history of hypertensionin two generations (n = 14), in one weight-matched (n = 11)and one lean (n = 13) control group. During hyperinsulinaemia(euglycaemic hyperinsulinaemic clamp technique) we determinedrenal haemodynamics (clearances of ⁵¹Cr-EDTA and PAH) and urinarysodium excretion. Lithium clearance was used to estimate thesegmental tubular reabsorption of sodium. RESULTS: In subjects with a positive family history of hypertension,hyperinsulinaemia did not influence renal plasma flow (RPF)or glomerular filtration rate (GFR) but urinary sodium excretiondecreased by 50%. Estimated proximal tubular sodium reabsorptionwas unaffected by insulin while estimated distal fractionalsodium reabsorption increased, P<0.01. At the end of theclamp a low-dose infusion of angiotensin II (0.1 ng/kg per min)was superimposed. GFR and RPF then decreased significantly concomitantwith urinary excretion of sodium. In control subjects hyperinsulinaemia caused an unchanged GFRin both groups, increased RPF in the lean control group and15–25% reduction in sodium excretion. No alteration wasseen in estimated proximal tubular sodium reabsorption, butestimated distal tubular sodium reabsorption increased (P<0.05)in the lean control group. Angiotensin II elicited a furtherincrease in distal fractional tubular sodium reabsorption inboth control groups (P<0.05). CONCLUSIONS: In normotensive subjects with a positive family history of hypertension,in contrast to control subjects without such history, hyperinsulinaemiacaused a marked decrease in urinary sodium excretion in presenceof unchanged RPF and GFR indicating a renal tubular effect ofinsulin located at a distal site of the renal tubules. AngiotensinII caused further sodium retention, probably due to an effecton renal haemodynamics.     

Insulin and growth in chronic renal failure

We studied glucose metabolism using the hyperglycemic technique in a cross-section of 23 children (15 pubertal, 8 prepubertal) with stable chronic renal failure as a possible cause of their poor growth. Linear growth was expressed as growth velocity standard deviation score (GVSDS). GVSDS correlated with glucose disposal rate but not with insulin sensitivity index in the pubertal (r=0.87,P<0.001) and prepubertal (r=0.86,P<0.02) children with chronic renal failure. Thirteen children were followed longitudinally during medical suppression of hyperparathyroidism with dietary phosphate restriction and high-dose phosphate binders. Following significant suppression of serum parathyroid hormone (PTH) levels back to the normal range (932±240 ng/l to 199±50 ng/l), GVSDS, glucose disposal rate and insulin secretion all increased significantly (P<0.01), with no change in insulin sensitivity index and renal function. The changes in GVSDS correlated with the changes in glucose disposal rate (r=0.86,P<0.02) and with the changes in insulin secretion (r=0.80,P<0.01). However, the changes in GVSDS did not correlate with the changes in PTH. The hypothesis that insulin may be more important than PTH in the pathogenesis of growth failure in chronic renal disease deserves further investigation.     

Effects of oyster shell electrolysate (active absorbable calcium) as a phosphate binder

Effect of oral calcium load on calcium metabolism was studied in 6 healthy subjects. Calcium carbonate (3.75 g) and Oyster Shell Electrolysate (OSE, 3.0 g) were orally administrated in a cross-over design to provide 1.5 g elementary calcim to each subject twice at 1 week interval. No significant differences were found in the increments of serum calcium, blood ionized calcium and urinary calcium excretion and in the decrements of serum PTH and urinary phosphorus excretion. The decrease in serum phosphorus level after OSE administration, however, was significantly greater than that after calcium carbonate administration. OSE thus appears to have a more potent phosphate binding capacity than calcium carbonate despite indistinguishable immediate effects on the increments of serum calcium and suppression of serum PTH. OSE may therefore represent a new candidate for a potent phosphate binder with a prospect for replacing calcium carbonate currently on use in chronic renal failure.     

Frequency of renal phosphate leak among patients with calcium nephrolithiasis.

BACKGROUND: Nephrolithiasis is a frequent disorder affecting 10 to 15% of the population in Europe and the United States. More than 80% of renal stones are made of calcium oxalate and calcium phosphate. The main identified risks for calcium renal stone formation are hypercalciuria and urinary saturation. A urine phosphate (Pi) loss is often associated with hypercalciuria; furthermore, hyperphosphaturia increases urinary saturation. METHODS: To determine whether urinary phosphate loss is associated with calcium urolithiasis, we measured renal Pi threshold (TmPi) in 207 stone formers with normal parathyroid hormone (PTH) serum concentration and in 105 control subjects. RESULTS: The TmPi followed a normal distribution in both groups. The mean TmPi was significantly lower in stone formers versus controls (0.72 +/- 0.13 vs. 0.87 +/- 0.18 mmol/L, P < 0.0001) because of a shift to the left of the TmPi distribution curve in the stone former population, with no evidence for bimodal distribution. Five percent of the controls had a TmPi <0.63 versus 19% of the stone formers. Daily urinary calcium excretion was significantly higher in stone formers than in controls. Calcium excretion was also significantly higher in stone formers with TmPi <0.63 mmol/L compared with those with TmPi > or =0.63. Serum PTH and ionized calcium concentrations were not different in stone formers and in control subjects, whatever the TmPi value. CONCLUSIONS:: A low TmPi is more frequently encountered in stone formers with a normal PTH concentration than in control subjects and is associated with a high urinary Ca excretion. The hypophosphatemia induced by a renal phosphate leak may predispose the subject to calcium stone formation by increasing the serum calcitriol level, calcium excretion, and urinary saturation.     

Phosphocalcic metabolism: regulation and explorations

Calcium and phosphate play a key role in bone mineralization but have also many other physiological functions. The control of serum phosphate concentration is mandatory to avoid the occurrence of severe metabolic disorders, but is less tightly regulated than serum ionized calcium concentration, which is maintained in a very limited range thanks to parathyroid hormone (PTH) and the active vitamin D metabolite calcitriol. Any change in serum ionized calcium concentration is detected by the calcium sensing receptor (CaSR), a membranous protein located principally in the parathyroid glands and the kidney. A decrease in ionized calcium level inactivates the CaSR, thus stimulating PTH secretion. PTH in turn stimulates the release of calcium and phosphate from bone, renal calcium reabsorption and calcium and phosphate intestinal absorption by inducing renal calcitriol production. Moreover, PTH inhibits phosphate reabsorption in proximal tubular cells, thus contributing towards phosphate homeostasis. Fibroblast growth factor 23 (FGF23) is a circulating factor that decreases serum levels of inorganic phosphate by inhibiting renal phosphate reabsorption and calcitriol production and may have a great physiological role in phosphate homeostasis. Recently, vitamin D actions independent of calcium and phosphate homeostasis were discovered. Basal exploration of phosphocalcic metabolism abnormalities consists in measurement of serum calcium (ionized calcium if possible), phosphate, 25-hydroxy vitamine D and PTH and of 24 hours urinary calcium excretion as well as renal function. Hence, the understanding of physiopathological mechanisms has been improved by newly identified genetic disorders responsible for phophocalcic homeostasis disturbances.     

Studies of calcium metabolism in normal persons and patients with hypercalciuria in relation to therapy with the dietary fiber preparation Farnolith

Farnolith (a dietary fibre preparation) was given to normal patients (n = 6) with absorptive hypercalciuria type I (n = 6) and to one patient with renal hypercalciuria. Farnolith binds calcium and reduces calcium absorption in the intestines. In normal subjects, the urine and serum parameters of calcium metabolism (total and ionized calcium, 1.25-dihydroxy-vitamin D) were unchanged. In absorptive hypercalciuria type I, a significant decrease in calcium excretion was achieved; oxalate excretion decreased as well. Low PTH values normalized; vitamin-D metabolites were not affected. In renal hypercalciuria, PTH and 1.25 DHCC were increased, whereas hypercalciuria persisted. Our investigations show that Farnolith is a reasonable treatment for absorptive hypercalciuria. Calcium homeostasis is rendered normal by Farnolith without producing secondary hyperoxaluria as sodium cellulose phosphate. Patients with primary renal calcium leakage and secondary hyperparathyroidism should not be treated with Farnolith.     

Effect of phosphate on parathyroid hormone secretion in vivo.

Alterations in phosphate homeostasis play an important role in the development of secondary hyperparathyroidism in renal failure. Until recently, it was accepted that phosphate retention only increased parathyroid hormone (PTH) secretion through indirect mechanisms affecting calcium regulation and calcitriol synthesis. However, recent in vitro studies have suggested that phosphate may directly affect PTH secretion. Our goal was to determine whether in vivo an intravenous phosphate infusion stimulated PTH secretion in the absence of changes in serum calcium. Three different doses of phosphate were infused intravenously during 120 minutes to increase the serum phosphate concentration in dogs. Sulfate was also infused intravenously as a separate experimental control. A simultaneous calcium clamp was performed to maintain a normal ionized calcium concentration throughout all studies. At the lowest dose of infused phosphate (1.2 mmol/kg), serum phosphate values increased to approximately 3 mM, but PTH values did not increase. At higher doses of infused phosphate (1.6 mmol/kg and 2.4 mmol/kg), the increase in serum phosphate to values of approximately 4 mM and 5 mM, respectively, was associated with increases in PTH, even though the ionized calcium concentration did not change. Increases in PTH were not observed until 30-60 minutes into the study. These increases were not sustained, since by 120 minutes PTH values were not different from baseline or controls despite the maintenance of marked hyperphosphatemia. During the sulfate infusion, serum sulfate values increased by approximately 3-fold, but no change in PTH values were observed. In conclusion, an acute elevation in serum phosphate stimulated PTH secretion in the intact animal, but the magnitude of hyperphosphatemia exceeded the physiologic range. Future studies are needed to determine whether PTH stimulation is more sensitive to phosphate loading in states of chronic phosphate retention. Moreover, the mechanisms responsible for the delay in PTH stimulation and the failure to sustain the increased PTH secretion need further evaluation.     

Insulin's acute effects on glomerular filtration rate correlate with insulin sensitivity whereas insulin's acute effects on proximal tubular sodium reabsorption correlation with salt sensitivity in normal subjects.

BACKGROUND: Insulin induces sodium retention by increasing distal tubular sodium reabsorption. Opposite effects of insulin to offset insulin-induced sodium retention are supposedly increases in glomerular filtration rate (GFR) and decreases in proximal tubular sodium reabsorption. Defects in these opposing effects could link insulin resistance to blood-pressure elevation and salt sensitivity. METHODS: We assessed the relationship between the effects of sequential physiological and supraphysiological insulin dosages (50 and 150 mU/kg/h) on renal sodium handling, and insulin sensitivity and salt sensitivity using the euglycaemic clamp technique and clearances of [131I]hippuran, [125I]iothalamate, sodium, and lithium in 20 normal subjects displaying a wide range of insulin sensitivity. Time-control experiments were performed in the same subjects. Salt sensitivity was determined using a diet method. RESULTS: During the successive insulin infusions, GFR increased by 5.9% (P = 0.003) and 10.9% (P<0.001), while fractional sodium excretion decreased by 34 and 50% (both P<0.001). Distal tubular sodium reabsorption increased and proximal tubular sodium reabsorption decreased. Insulin sensitivity correlated with changes in GFR during physiological (r = 0.60, P = 0.005) and supraphysiological (r = 0.58, P = 0.007) hyperinsulinaemia, but not with changes in proximal tubular sodium reabsorption. Salt sensitivity correlated with changes in proximal tubular sodium reabsorption (r = 0.49, P = 0.028), but not in GFR, during physiological hyperinsulinaemia. Neither insulin sensitivity or salt sensitivity correlated with changes in overall fractional sodium excretion. CONCLUSIONS: Insulin sensitivity and salt sensitivity correlate with changes in different elements of renal sodium handling, but not with overall sodium excretion, during insulin infusion. The relevance for blood pressure regulation remains to be proved.     

Intact parathyroid hormone levels in renal insufficiency

To define the onset of the rise in intact parathyroid hormone (PTH) levels in renal insufficiency, we conducted a cross-sectional study of parameters of mineral metabolism in patients with varying degrees of renal impairment. Using an immunoradiometric assay to measure intact PTH levels, we found elevations in intact PTH levels as creatinine clearance approaches 60 ml/minute (serum creatinine near 1.8) and a significant inverse relationship between indices of renal function and intact PTH levels (r=-0.60, P<0.001 for intact PTH and creatinine clearance). Calcium and phosphate levels correlate less strongly with the degree of hyperparathyroidism (r=-0.39, P<0.001 for total calcium; r=0.31, P<0.05 for phosphate). As a group, only patients with severe renal failure (creatinine clearance <20 ml/minute) had 1,25-dihydroxyvitamin D levels below normal (11±4 [SEM] pg/dl, normal range 15–60). Intact and n-terminal PTH measurements correlate well in this patient population with varying degrees of renal insufficiency (r=0.9, P<0.001). Intact PTH can be elevated in patients with mild to moderate renal insufficiency, thus efforts to prevent the development of secondary hyperparathyroidism in renal failure should be undertaken early in the course of renal insufficiency.     

Insulin causes renal vasodilatation independently of renal prostaglandins in healthy humans

The effect of physiological hyperinsulinaemia on renal haemodynamicsand renal sodium handling was studied in nine healthy maleson two separate study occasions with and without indomethacinpretreatment, using the euglycaemic insulin clamp technique.Renal haemodynamics and segmental tubular sodium handling wereevaluated by determining the inulin, PAH, sodium and lithiumclearances. Changes in urinary dopamine excretion were alsostudied. Insulin infusion caused similar increases in renalplasma flow with as well as without indomethacin pretreatment,but no change in glomerular filtration rate in both experimentalsettings. Following indo methacin pretreatment, the basal sodiumclearance decreased from 1.6 ±0.2 to 0.8± 0.2ml/min and the basal urinary dopamine excretion decreased from107±8 to 86±6 nmol/h. In conclusion, the presentstudy demonstrates a direct renal vasodilatory effect of insulinin healthy subjects that does not seem to be dependent on renalprostaglandins. Moreover, under the present experimental circumstancesindomethacin reduced the basal urinary dopamine output, whichcould reflect a reduction in the filtered load of sodium followingindomethacin pretreatment.     

Lack of relationship between parathyroid hormone and 1,25-dihydroxyvitamin D in chronic renal failure

In the present study, concentrations of parathyroid hormone (PTH), determined by an intact PTH assay and a midregion/C-terminal PTH assay, 1,25-dihydroxyvitamin D [1,25(OH)2D3], ionized calcium and phosphate were measured in 15 patients with a stable creatinine clearance (Ccr) of 21.2 +/- 14.4 ml/min (mean +/- SD; group 1) and in 10 patients with a Ccr regularly undergoing hemodialysis (group 2, Ccr not measured). In group 1, the mean concentration of 1,25(OH)2D3 was significantly increased compared with the level in group 2, whereas no differences were found concerning the concentrations of intact PTH, midregion/C-terminal PTH, ionized calcium and phosphate. In group 1, the PTH concentration correlated inversely with ionized calcium concentration and Ccr, which in turn, was directly correlated. The concentration of 1,25(OH)2D3 correlated inversely with phosphate concentration, but did not correlate with either PTH or ionized calcium concentrations. In group 2 no correlation was found between any of the biochemical variables. The data demonstrate that in patients with stable renal failure, the concentration of ionized calcium still regulates PTH secretion but other variables such as parathyroid cell mass and setpoint may interfere with the interrelation. The elevated concentration of phosphate in renal failure may override PTH as a regulator of the renal 1,25(OH)2D3 formation. The lack of correlation in the hemodialyzed patients may be attributed to extrarenal production of 1,25(OH)2D3, reduced binding of 1,25(OH)2D3 to parathyroid tissue or the major changes in calcium homeostasis caused by the hemodialysis.     

Urinary phosphate excretion in the pathophysiology of idiopathic recurrent calcium urolithiasis: Hormonal interactions and lipid metabolism

Previous work in younger males with recurrent idiopathic calcium urolithiasis (RCU) demonstrated inappropriately high postprandial phosphaturia, hyperinsulinemia and insulin resistance, but normal glycemia. To investigate further whether these abnormalities occur also in RCU patients with a mean age corresponding to the life period with peak formation of calcium-containing stones, two trials were carried out in 155 males of comparable age and body mass index. All participants underwent a standardized laboratory examination, including collection of urine and blood before and following a test meal rich in carbohydrate and calcium but low in phosphorus. In trial 1, comprising control subjects (n = 12, mean age 42 years) and RCU patients (n = 24, mean age 41 years), phosphate (Pi) excretion and fractional Pi excretion in postprandial urine of controls did not change compared with the values in fasting urine, but were significantly increased in RCU, despite the fact that there was almost equal suppression of serum parathyroid hormone (PTH) and increase in serum calcitonin. Postprandially, RCU patients were hyperinsulinemic but still normoglycemic versus controls. In trial 2, carried out in unclassified (in terms of calciuria) RCU patients (n = 119, mean age 40 years) only, the post-load Pi-uria was similar in magnitude to Pi-uria of RCU patients in trial l; increased postprandial Pi-uria was a phenomenon also of normocalciuria but was slightly more pronounced in hypercalciuria, while changes in calcium phosphate (brushite) and calcium oxalate supersaturation of urine were unrelated to calciuria. In RCU patients, but not controls, there was a tendency toward higher urinary glucose in post-load as compared with fasting urine. When urinary Pi and fractional Pi excretion in trial 2 were considered as dependent variables in multivariate regression analysis, they appeared unrelated to age, but positively associated with postprandial glycemia as the best predictor, followed by insulinemia, insulin resistance, to a lesser degree fasting serum PTH and the metabolic activity of stone disease, negatively associated with blood total lipids and very low density lipoprotein (VLDL) cholesterol. It was concluded that RCU males (1) show low Piuria during fasting but impaired renal Pi conservation in response to a mixed meal, a situation carrying the risk of Pi deficiency over the long term; (2) represent a population developing hyperei-uria despite suppressed PTH; (3) exhibit insulin resistance but are still able to maintain normoglycemia at the expense of hyperinsulinemia. It is suggested that calcium-containing renal stones are related to impaired Pi and glucose translocation across cell membranes, and that the role of lipids in this setting deserves further investigation.     

The renal response to exogenous insulin in non-insulin-dependent diabetes mellitus in relation to blood pressure and cardiovascular hormonal status

BACKGROUND: Non-insulin-dependent diabetes mellitus (NIDDM) is characterizedby insulin resistance, hyperinsulinaemia and a high frequencyof hypertension. It has recently been shown that insulin exertsa sodium-retaining effect, which is preserved in NIDDM. We soughtto determine whether insulin affected renal sodium handlingdifferently in hypertensive and normotensive NIDDM patients. METHODS: After a baseline period of 2 h, eight normotensive (N-) NIDDMpatients and eight NIDDM patients with hypertension (H-) underwenta euglycaemic clamp with infusion of two sequential doses ofinsulin (50 and 500 mU/kg/h) or vehicle (time control) during2-h periods each. Fractional clearances of sodium and lithiumwere determined according to standard methods. Fractional lithiumclearance was used to assess segmental tubular sodium handling. RESULTS: Insulin induced similar decrements in fractional sodium excretion(N-NIDDM: 43±5.9 and 57±9.1%, H-NIDDM: 48±16.4and 62±12.5%, low and high insulin dose respectively).Distal tubular sodium absorption increased simultaneously. Afall in fractional proximal sodium reabsorption was observedin N-NIDDM (4.4±2.7 and 29.8±5.1%, low and highinsulin dose respectively), which was attenuated in H-NIDDM(–5.0±7.3 and –2.1±13.9% respectively).The latter appeared to be related to a defective atrial natriureticfactor (ANF) and renal cyclic GMP response. A modest decreasein blood pressure occurred during insulin infusion that wasnot related to changes in ANF or Fe_Li. CONCLUSION: The findings suggest that insulin-induced sodium retention maycontribute to hypertension in NIDDM if the homeostatic responseto offset this effect fails.     

Basal parathyroid activity and renal calcium handling during an intravenous calcium load

Urinary excretion of calcium and urinary cyclic AMP (cAMP), plasma parathyroid hormone (PTH) and ionized serum calcium concentration, and creatinine clearance were measured in 15 healthy humans. In the same subjects, renal tubular reabsorption of calcium was evaluated by analyzing the regression line of urinary calcium excretion rate on rising the level of serum calcium during an intravenous calcium infusion. The regression line intercept on the y-axis, which has been proposed to depend on the calcium reabsorption in the renal distal tubule, was found to be significantly related to both urinary cAMP and PTH levels. The theoretical renal threshold for calcium excretion was directly related to the y-axis intercept and thus also to the index of parathyroid activity. No relationship was found between urinary cAMP or plasma PTH levels and the regression line slope of urinary calcium to serum calcium. In healthy subjects, parathyroid activity significantly affects the extrapolated regression line of urinary calcium to serum calcium by changing the intercept, but not the slope.