Effect of fasting on tubular phosphorus reabsorption.

In the thyroparathyroidectomized (TPTX) rat, fasting increased urinary phosphorus excretion by decreasing the tubular reabsorption of P1 (TRP) and resulted in hypophosphatemia. The administration of either sucrose or NaHCO3 prevented the metabolic acidosis associated with fasting and decreased the phosphaturia, indicating that the phosphaturia in fasting is in part due to metabolic acidosis. In rats on partial reduction of P1 intake selectively, the phosphaturic response to parathyroid hormone (PTH) was completely suppressed. On the other hand, the fasting rat partially retained the phosphaturic response to PTH, although dietary P1 intake was totally absent. These findings suggest that the renal P1 wasting in fasting may take place by dual mechanisms: a) the PTH-independent decrease in TRP, and b) an inability to totally suppress the response to PTH. Cyclic AMP generation in response to PTH, determined both in vivo and in vitro, was not measurably altered in fasting. However, the phosphaturic response to cyclic AMP was decreased in fasting, suggesting that the mechanism of partial resistance to PTH is probably not at but after cyclic AMP generation.     

Mechanism for the phosphaturia of NH4Cl: dependence on acidemia but not on diet PO4 or PTH

The effects of metabolic acidosis on renal PO4 handling are controversial. Clearance experiments, therefore, were performed in fasted parathyroidectomized rats 1) to test the thesis that NH4Cl per se alters PO4 reabsorption, 2) to characterize the mechanisms responsible for these changes, and 3) to define the interaction of NH4Cl with parathyroid hormone (PTH) in PO4 deprivation. NH4Cl increased the clearance and fractional excretion of PO4 (FEPO4) without altering plasma PO4. Lactic acid and HCl, but not saline loading. NH4HCO3, or glutamine, produced similar effects. At steady-state phosphaturic effects of NH4Cl, neutralization of the acidemia by NaHCO3 abolished the increment. PTH (3.3 U.kg-1.h-1), superimposed on the maximal effective dose of NH4Cl (5.7 mmol.kg-1.h-1), further augmented FEPO4 (from 24.3 to 46.9%). The effects of NH4Cl (delta FEPO4 = 23 vs. 21%) and the synergism with PTH were not affected by PO4 deprivation. In both PO4 repletion and deprivation, NH4Cl increased basal and PTH-stimulated cAMP excretion, but the changes were poorly correlated with FEPO4. We conclude that NH4Cl inhibits PO4 reabsorption independent of PTH, extracellular fluid volume, natriuresis, NH4+ ion, plasma PO4, or the status of PO4 balance. The effects are mediated by mechanisms dependent on acidemia but are quite distinct from those of PTH. Our findings on cAMP are most compatible with the hypothesis that biochemical events beyond cAMP generation mediate both the phosphaturia of NH4Cl and its ability to restore PTH sensitivity in PO4 deprivation.     

Effect of parathyroid hormone on urinary acidification.

The effect of parathyroid hormone (PTH) administration on urinary acidification was studied in intact and thyroparathyroidectomized dogs. PTH administration resulted in a significant increase in urine pH and HCO3 excretion. In dogs with maximally acid urine caused by Na2SO4 infusion PTH administration also led to a significant increase in urine pH and to a decrease in ammonium excretion. To examine the effect of PTH on H+ secretion in the distal nephron we measured the urine-blood (U-B) PCO2 gradient in dogs with maximally alkaline urine (urine pH greater than 7.8) before and after PTH administration. After infusion of the hormone, HCO3 excretion increased significantly but the U-B PCO2 gradient remained unchanged. The effects of PTH infusion on urinary acidification in animals with distal renal tubular acidosis caused by LiCl administration were also studied. PTH administration to these dogs increased HCO3 excretion to the same level seen in normal dogs. These data suggest that PTH does not inhibit distal H+ secretion but increases HCO3 excretion by depressing proximal HCO3 reabsorption.     

Resistance to the phosphaturic effect of parathyroid hormone in the hamster.

The renal effects of parathyroid hormone (PTH) and dibutyryl 3'5'-cyclic AMP (DBcAMP) were studied in thyroparathyroidectomized hamsters. The hamsters were permitted free access to food and water or fasted for 16 h. PTH caused a phosphaturia in the fed hamster (fractional excretion of phosphate (FEPO4) increased from 5.8 +/- 1.3 to 27.4 +/- 4.6%, P less than 0.001) but not in the fasted hamster (from 9.9 +/- 2.5 to 12.4 +/- 2.5%, NS), whereas calcium excretion decreased significantly in both groups. There was no significant difference in blood acid-base or phosphate levels between the two groups. Insulin did not restore the phosphaturic response to PTH (FEPO4 from 7.7 +/- 2.6 to 5.3 +/- 1.7%), whereas phosphate or NH4Cl infusion did, FEPO4 increasing from 20.9 +/- 3.1 to 38.1 +/- 5.4% (P less than 0.02) and from 19.5 +/- 3.8 to 39.0 +/- 7.5%, respectively. DBcAMP caused a phosphaturia both in the fasted (from 9.6 +/- 2.7 to 20.1 +/- 4.5%, P less than 0.01) and fed (from 2.5 +/- 0.5 to 10.7 +/- 1.5%, P less than 0.02) hamster. A fasting state of up to 64 h did not produce resistance to PTH in the rat. It is concluded that fasting produces resistance to the phosphaturic but not the calcium-retaining effects of PTH in the hamster. The resistance may occur, at least partly, prior to the production of cAMP within the renal tubular cell.     

Interrelationship of chlorothiazide and parathyroid hormone: a micropuncture study.

Sodium and calcium are normally reabsorbed in parallel in the renal tubule. Both parathyroid hormone (PTH) and thiazide diuretics may influence this relationship. This study was designed to show whether the dissociation of Na from Ca transport produced by thiazides is dependent upon the presence of PTH. Hydropenic thyroparathyroidectomized (TPTX) dogs were given chlorothiazide alone and together with PTH. Chlorothiazide alone significantly increased fractional excretion of sodium (0.5 +/- 0.3-5.6 +/- 0.3%) and calcium (0.74 +/- 0.18-1.4 +/- 0.24%). However, the Ca/Na excretion ratio fell markedly from 1.57 to 0.24%. Micropuncture revealed this dissociation to occur at the distal tubule. Proximal reabsorption of water, sodium, and calcium were inhibited to an equal extent. However, distal fractional sodium reabsorption fell 10% whereas calcium reabsorption remained unchanged following chlorothiazide administration in TPTX animals. When phosphaturic doses of PTH were administered with chlorothiazide, no significant changes were observed in calcium or sodium reabsorption. It is concluded that PTH plays no role in the dissociation of sodium from calcium reabsorption resulting from acute chlorothiazide administration.     

Nicotinamide restores phosphaturic effect of PTH and calcitonin in phosphate deprivation

Results of previous studies suggest a potentially important role for nicotinamide adenine dinucleotide (NAD) in the cellular regulation of phosphate transport by the renal proximal tubules. The present clearance studies were performed to evaluate whether intraperitoneal administration of nicotinamide, a precursor of NAD and inhibitor of NAD catabolism, would not only increase phosphate excretion but also restore the phosphaturic response to parathyroid hormone (PTH) in rats fed a low phosphate diet. Rats fed a low phosphate diet were resistant to the phosphaturic effect of PTH, calcitonin, and dibutyryl cAMP (DBcAMP) in spite of the fact that all three agents elicited an increase in the urinary excretion of cAMP. Administration of nicotinamide to rats fed a low phosphate diet increased renal cortical NAD levels, increased phosphate excretion, partially restored the phosphaturic effect of PTH and DBcAMP, and completely restored the phosphaturic response to calcitonin. We conclude that nicotinamide restores the phosphaturic effect of PTH and calcitonin in rats fed a low phosphate diet by acting at a cellular step subsequent to cAMP generation to inhibit tubular reabsorption of phosphate.     

Parathyroid hormone and extrarenal acid buffering

The role of parathyroid hormone (PTH) on the extrarenal buffering of an acid load was examined during HCl infusion (5 meq x kg-1 x h-1) to bilaterally nephrectomized rats. Thyroparathyroidectomized (TPTX) rats replaced with PTH had significantly higher blood pH and HCO3 values than TPTX rats not infused with PTH. Administration of EDTA, in a dose shown to release PTH, was associated with a significant increase in buffering capacity in intact but not in TPTX rats. Colchicine, given in a dose capable of stimulating PTH release, was also associated with enhanced buffering capacity in intact but not in TPTX rats. In TPTX rats infused with acetazolamide and PTH, the hormone failed to enhance extrarenal buffering of an acid load. Animals with chronic renal failure, induced by infarction of the kidney, also had an enhanced capacity to buffer an acid load. This enhanced buffering capacity in chronic renal failure was abolished by TPTX. Acute renal failure induced by bilateral ureteral ligation was also associated with increased buffering only in the presence of parathyroid glands. These data demonstrated that PTH, from either an exogenous or endogenous source, enhances extrarenal buffering capacity of an acid load. Chronic and acute renal failure are associated with increased buffering capacity, which is dependent on the presence of parathyroid glands. The data suggest that this effect is mediated through carbonic anhydrase.     

Distal site of action of parathyroid hormone on phosphate reabsorption.

The sites of inhibited phosphate transport following administration of bovine parathyroid hormone (bPTH) to thyroparathyroidectomized (TPTX) dogs were investigated. Phosphate reabsorption by the proximal and distal nephron was studied using recollection micropuncture, stop-flow methodology, and electron-probe microanalysis. Following bPTH, delivery of phosphate from the proximal tubule increased from 26 to 37% of the filtered load, P less than .01. Fractional phosphate excretion increased from 2.3 +/- 1.5 to 21.4 +/- 2.3%, P less than .001. The increased delivery of phosphate at the point of micropuncture in the proximal tubule accounted for approximately half of the phosphaturia. In six TPTX dogs, which were saline loaded, similiar increases in phosphate delivery from the proximal tubule from 27 +/- 1 to 36 +/- 2% of the filtered load resulted in a strikingly smaller phosphaturia, 5.1 +/- 1 to 9.8 +/- 2.4%, NS. In stop-flow experiments, phosphate concentratin ratios were slightly increased in the proximal nephron and markedly increased in the distal nephron following bPTH. It is concluded that parathyroid hormone markedly decreases phosphate transport in the distal nephron.     

Calcium absorption in diphosphonate-treated rats: effect of parathyroid function, dietary calcium and phosphorus.

1. The role of parathyroid hormone (PTH) and 1, 25-dihydroxy-cholecalciferol (1,25-(OH)2D3) in modulation of intestinal Ca absorption was studied in rats, using disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP), which is known to reduce 1,25-(OH)2D3 formation. 2. EHDP decreased intestinal Ca absorption. This effect could be abolished by small amounts of 1,25-(OH)2D3, whereas even large doses of PTH were ineffective. EHDP also decreased Ca absorption in thyroparathyroidectomized (TPTX) rats. Therefore the effect of EHDP on 1,25-(OH)2D3 production is unlikely to be mediated through PTH. 3. The correction by PTH of the decreased Ca absorption in TPTX rats was inhibited by EHDP. Since EHDP inhibits formation of 1,25-(OH)2D3 the effect of PTH on Ca absorption is likely to be mediated through this vitamin D3 metabolite. 4. In normal rats both a low Ca and a low P diet stimulated Ca absorption. In EHDP-treated intact rats low Ca still stimulated Ca absorption, whereas the effect of low P abolished. This indicates that low Ca and low P diets affect Ca absorption through different mechanisms. 5. Intestinal adaptation to a low Ca diet was still observed in EHDP-treated TPTX rats. Thus, in the rat, intestinal adaptation to low Ca diet can occur without PTH.     

Tubular capacity of phosphate transport in phosphate-deprived rats: effects of nicotinamide and PTH

The present study tested the hypothesis that nicotinamide and/or parathyroid hormone (PTH) would reverse the resistance of phosphate-deprived rats to the phosphaturic effects of phosphate infusions by reducing the tubular capacity for phosphate transport. The response to progressively increasing rates of phosphate infusion (1, 2, and 3 mumol/min) was evaluated in thyroparathyroidectomized (TPTX) rats fed low phosphate diet (0.07%) for 4 days and treated with either vehicle or nicotinamide 2 h before the experiment. Following phosphate infusions, phosphate excretion was unchanged in vehicle-treated rats but increased progressively in nicotinamide-treated rats to 60% of the final rate of infusion. In a second series conducted in the presence of exogenous PTH, vehicle-treated rats responded to phosphate infusions by increasing phosphate excretion to 80-90% of the rate of infusion. In the presence of both nicotinamide and PTH, the rate of phosphate excretion matched the rate of infusion. Vehicle-treated rats displayed the highest reabsorptive rates without reaching a transport maximum, whereas a lower maximum reabsorptive rate was evident in nicotinamide-treated rats. However, in both groups given PTH, not only was the transport maximum lower but it declined with further increases in filtered load. We conclude that nicotinamide and PTH reverse the effects of dietary phosphate deprivation by decreasing the tubular capacity for phosphate transport.     

Regulation of renal adenylate cyclase by parathyroid hormone

This study reports the effects of the removal of endogenous PTH by thyroparathyroidectomy (TPTX) on the recovery of the reduced renal cAMP response to parathyroid hormone (PTH) in rats with chronically elevated PTH secondary to diets deficient in either vitamin D or calcium. After TPTX and infusion with a calcium-glucose solution of the vitamin D-deficient rat, calcium and PTH fell from 5.8 mg/dl and 2,509 pg/ml, respectively, to 4.8 mg/dl and 160 pg/ml at 48 h. There was a partial restoration of response to PTH, assessed by assay of renal cortical adenylate cyclase activity from 64% of control activity prior to TPTX to 84% of control activity at 48 h. When rats fed the diet deficient in calcium were TPTX, serum PTH fell rapidly from 2,811 to 200 pg/ml at 5 h with no further change at 21 h, whereas calcium did not change (5.3 mg/dl). PTH-dependent adenylate cyclase activity increased from 59% of control activity prior to TPTX to 87% at 5 h and 100% of control activity at 21 h after TPTX. Each diet produced similar increases in the serum level of immunoreactive PTH, and the rate of disappearance of the circulating hormone after TPTX was also similar for both groups of rats. The data indicate a slow, partial recovery of the enzyme response to PTH after TPTX of the vitamin D-deficient rat over the time period studied, whereas the recovery was rapid and complete in rats fed the diet deficient in calcium.     

Intrarenal calcium in phosphate handling.

The intrarenal role of plasma ionized calcium (Ca), on fractional phosphate excretion (FE PO4) was investigated in dogs with control of parathyroid hormone (PTH). In series 1, acute thyroparathyroidectomy was immediately followed by a constant infusion of bovine PTH (0.01 U/kg per min). Subsequent calcium chloride infusions increased Cai in plasma phosphate and decreased in the percentage of ultrafiltrable phosphate. A 20% increase in Cai significantly increased FE PO4 by +3.82 +/- 0.97% (P less than 0.01) when infused intravenously and by +2.62 +/- 1.06% (P less than 0.05) when infused in the renal artery. In contrast, a 75% increase in Cai did not significantly change FE PO4. In series 2, dogs were thyroparathyroidectomized 18 h before experiments, and no PTH infusion was initiated. A bolus of bovine PTH (30 U/kg) increased FE PO4 + 8.9 +/- 0.9% (P less than 0.001) in hypocalcemic dogs, +19.1 +/- 4.4% (P less than 0.001) in normolcalcemic dogs, and +15.5 +/- 1.5% (P less than 0.001) in hypercalcemic dogs. We conclude that increases in plasma calcium potentiate the phosphaturic effect of PTH. This potentiating effect is attenuated in marked hypercalcemia by superimposed hemodynamic and/or metabolic changes.     

Renal handling of calcium: influence of parathyroid hormone and 1,25-dihydroxyvitamin D3.

The influence of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the renal Ca handling was studied in vitamin D-replete rats. The relation between plasma concentration ([Ca]P) and urinary Ca (UCaV/ml GF) was ascertained by clearance techniques over the [Ca]P range of 1.4-3.4 mM varied by infusion of Ca gluconate. Chronic thyroparathyroidectomy (TPTX) decreased the plasma Ca threshold from about 2.3 to 1.5 mM. Between [Ca]P 1.4 and 3.4 mM there was a linear increase in UCaV/ml GF corresponding to 35-50% of the increment in filtered load. In TPTX, PTH (2.5 IU/h i.v.) shifted the Ca threshold from 1.5 to 2.3 mM, without changing the slope of UCaV/ml GF on [Ca]P. The effect of TPTX on the renal Ca handling was not corrected by doses of 1,25(OH)2D3, which increased the intestinal Ca absorption of TPTX rats to normal level. In intact and TPTX rats disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) given at doses which inhibit the production of 1,25(OH)2D3 did not change the tubular Ca handling. Furthermore, 1,25(OH)2D3 had no effect in EHDP-treated TPTX rats. Therefore, tubular Ca handling does not appear to be altered in response to chronic endogenous variation or physiologic supplementation of 1,25(OH)2D3 in vitamin D-replete rats. This is in contrast to the marked alteration observed after TPTX or PTH administration.     

Tubular response to hormones is blunted in weanling rats

The renal responses to atrial natriuretic peptide (ANP), parathyroid hormone (PTH) and arginine vasopressin (AVP) were studied in anaesthetized weanling and adult rats with clearance methods. In rats receiving PTH, thyroparathyroidectomy (TPTX) was performed prior to the study. The results showed that GRF remained unchanged in both age groups during infusion with ANP, AVP and PTH after TPTX as well as with TPTX alone. During ANP infusion, the urine flow rate increased from 0.01 +/- 0.002 to 0.029 +/- 0.004 ml (100 g body wt)-1 min-1 (P less than 0.001) and the fractional sodium excretion increased from 0.48 +/- 0.1 to 3.0 +/- 0.4% (P less than 0.001) in the adult rats; no significant changes were observed in the weanling rats. Phosphate excretion was not influenced by ANP in either age group. After TPTX, both net and fractional phosphate excretion decreased in both age groups. During PTH infusion in TPTX rats, both net and fractional phosphate excretions increased significantly in the adult rats but were unchanged in the weanling rats. In rats of the same age, the renal concentrating capacity and urinary excretion of prostaglandin E2 (PGE2) were determined after dehydration. The renal concentrating capacity was lower, and the renal excretion of PGE2 was higher, in the weanling than in the adult rats. Furthermore, the concentrating mechanism seems not to be influenced by indomethacin treatment in either age group. It is concluded that the tubular responses to ANP and PTH are blunted in the immature kidney and that the renal excretion of PGE2 is not an important factor in the regulation of the concentrating capacity in the weanling rat.     

Phosphate uptake by superficial and deep nephron brush border membranes

Dietary phosphate restriction and acute parathyroidectomy in rat are known to be associated with a selective increase in phosphate uptake by renal cortical brush border membranes (BBM). Conversely, phosphate loading and parathyroid hormone (PTH) administration result in a decrease of this uptake.In the present study, we investigated whether the response of the membrane to these various stimuli implies similar or different modifications of the kinetic properties of this membrane, whether these modifications affect one or both of the two systems of phosphate transport previously described, whether both superficial and deep nephron populations are involved, and whether the two stimuli: dietary phosphate, and parathyroid activity, are additive or not.Kinetic studies of phosphate (PO₄) uptake by BBM vesicles were performed in seven groups of rats: control (N), acutely thyroparathyroidectomized (TPTX), PTH loaded (PTH), phosphate loaded (P⁺), phosphate depleted (P^–) phosphate depleted with acute thyroparathyroidectomy (P^–TPTX), and phosphate depleted-PTH loaded (P^–PTH). In each of these experimental conditions, superficial and deep nephrons were investigated.Results indicate that 1. BBM from deep nephrons present a greater capacity for PO₄ transport than those from superficial nephrons; 2. Whereas a dual system of PO₄ uptake is observed in superficial BBM, deep BBM present only one single system; 3. Phosphate in the diet influences PO₄ uptake by BBM to a greater extent in the deep than in the superficial nephrons; 4. PTH status on the contrary, equally influences both populations; 5. TPTX does not significantly enhance PO₄ uptake in phosphate depleted rats; however, PTH loading curtails this uptake; 6. In the deep BBM neither the PTH status nor the phosphate content of the diet modify the apparentK _m. In the superficial BBM, the apparentK _m of the high affinity system (low substrate concentrations) varies with the PTH activity.     

Effect of colchicine on urinary phosphate and regulation by parathyroid hormone.

The possible role of cytoplasmic microtubules in the renal handling of phosphate and its regulation by parathyroid hormone (PTH) was evaluated with colchicine, a microtubule-disrupting agent. Colchicine-treated rats were thyroparathyroidectomized (TPTX) and subsequently infused with PTH. Treatment with a total dose of 1 mg colchicine had no effect on glomerular filtration rate or fractional excretions of sodium and potassium. Fractional excretion of phosphate in colchicine-treated TPTX rats was significantly higher compared with TPTX controls. After PTH infusion, control rats responded with increases in fractional excretion of phosphate and urinary cyclic AMP but colchicine-treated rats had variable and insignificant changes in both parameters. Fractional excretion of sodium and potassium did not change significantly after PTH. Renal cortical activities of cyclic AMP phosphodiesterase, soluble alkaline phosphatase, cytochrome oxidase, leucine aminopeptidase, or basal adenylate cyclase were not significantly affected by colchicine treatment. On the other hand, stimulation of adenylate cyclase by a submaximal dose of PTH was markedly decreased in colchicine-treated rats, and the activity of membrane-bound alkaline phosphatase was also significantly decreased. The binding of radioactive colchicine in renal cortical extracts from rats treated with colchicine was significantly diminished. These results suggest that disruption of cytoplasmic microtubules in renal cortical cells interferes with phosphate transport and its regulation by PTH.     

Distal site of calcium reabsorption in the rat nephron

The sites of outflux of⁴⁵Ca along the nephron were investigated using microinfusion technique in acutely thyroparathyroidectomized (TPTX), intact and TPTX Wistar rats substituted with parathyroid hormone (PTH). In all three groups⁴⁵Ca outflux occurred along the proximal tubule, the loop of Henle and along the distal tubule. After microinfusion into late distal tubules⁴⁵Ca recovery in ipsilateral urine was essentially complete for the TPTX group but was only 83 and 65% for the intact and the PTH substituted animals. Increases in microinfusion flow rate from 2–20 nl/min into early and middle distal tubules resulted in increased urinary recovery of⁴⁵Ca for all three groups. Similarily, increases in microinfusate Ca concentration from 0.2–2.0 and 5.0 mmol/l resulted in increased fractional urinary recovery of⁴⁵Ca both in the presence and absence of PTH. When⁴⁵Ca and³H inulin containing solutions were continuously microinfused into early distal tubules for one hour periods an anticalciuric effect of PTH could be demonstrated. It is concluded that Ca, in addition to its outflux in the proximal tubule and in the loop of Henle, is reabsorbed in the distal tubule accessible to micropuncture. PTH acts anticalciuric at this latter site.     

Impaired renal response to parathyroid hormone in potassium depletion.

In potassium depletion, a possible alteration of the proximal tubular response to parathyroid hormone (PTH) was evaluated in rat kidney. 1) There were impairments of both phosphaturic and urinary cyclic AMP responses to PTH. The site of the impairment was further investigated by studying the PTH-dependent cycle AMP system in renal cortex. 2) There was a lesser increase of cyclic AMP concentration by PTH in potassium-depleted slices, indicating the lesser urinary cyclic AMP was due to the specific impairment of PTH-dependent cyclic AMP in the kidney. 3). The activation of adenylate cyclase by PTH was impaired , but phosphodiesterase activity was not affected by potassium depletion, indicating the impairment of cyclic AMP generation was due to inhibition of adenylate cyclase. 4) The phosphaturic response to dibutyryl cyclic AMP infusion was also significantly less in the potassium-depleted animals, indicating the step subsquent to the cyclic AMP generation is also impaired. All above results indicate that, in potassium depletion, the renal response to PTH is impaired, and the impairment is both within the step of cyclic AMP generation and after the cyclic AMP generation.     

Inappropriate phosphate excretion in idiopathic hypercalciuria: the key to a common cause and future treatment?

AIMS: To present experimental evidence in support of a proposed common cause for absorptive hypercalciuria, renal hypercalciuria, renal phosphate leak and enhancement of 1,25-(OH)2-vitamin D concentrations in patients presenting with renal stone disease; and to suggest further investigation with a view to new management. METHODS: An oral calcium loading test was administered to 15 patients with renal stones and 10 normal controls in the fasting state: urine and blood were collected hourly. After the second urine sample, 400 mg calcium dissolved in water was administered orally. Serum calcium, albumin, parathyroid hormone (PTH), and phosphate were measured together with urine calcium clearance and urinary phosphate from which the TmPO4/glomerular filtration rate (GFR) ratio was calculated. Serum 1,25-(OH)2-vitamin D was measured in the first serum sample. In addition, 24 hour urine calcium results were collected retrospectively from the patients' case notes over the previous 18 months. RESULTS: In the basal state, renal stone patients had an overall greater phosphaturia (lower TmPO4/GFR: median 1.72 compared with 2.10 in controls) and increased calcium clearance. Serum corrected calcium and PTH concentrations did not differ between the groups. After calcium loading, serum calcium and urine calcium clearance rose in both groups, with patients with renal stones experiencing a greater percentage fall in phosphaturia. In both groups TmPO4/GFR fell (greater phosphaturia) with increased serum corrected calcium, with the patients showing notably greater phosphaturia for any given calcium concentration. Patients also had notably greater phosphaturia compared with the serum calcium concentration for any given PTH value. Serum 1,25-(OH)2-vitamin D was higher in patients than controls and for any 1,25-(OH)2-vitamin D concentration phosphaturia measured against serum calcium was greater in patients than controls. 1,25-(OH)2-vitamin D did not correlate with phosphaturia relative to serum calcium concentrations within the patient and control groups. CONCLUSIONS: It is proposed that patients with idiopathic hypercalciuria have an "inappropriately' high phosphate excretion for any given serum calcium concentration. Loss of phosphate may induce increased activation of 1,25-(OH)2-vitamin D. Some of the commonly described causes of stone formation may be manifestations of a single mechanism.     

A multiresponse parathyroid hormone assay: an inhibitor has agonist properties in vivo

Vitamin D-deficient rats subjected to thyroparathyroidectomy (TPTX) were used to evaluate in vivo the biological properties of native bovine parathyroid hormone (bPTH) and chemically synthesized fragments and analogues of the hormone on several parameters of hormone action: calcium and phosphorus fluxes, generation of cyclic adenosine 3',5'-monophosphate (cAMP), and the metabolism of 25-hydroxyvitamin D3 [25(OH)D3]. Vitamin D-deficient rats, after TPTX or sham operation, were intravenously infused with a nutrient containing 7.5 mM CaCl2 for 30 h. During the last 7 h, PTH or one of its analogues was infused intravenously at rates between 0.04 and 20 nmol/h. One hour after the start of the peptide infusion, tritiated 25(OH)D3 was injected. Urine was collected hourly for phosphate and cAMP determinations and, at the end of the experiment, blood was obtained to determine the relative accumulation of tritiated 1,25-dihydroxyvitamin D3 ([3H]1,25(OH)2D3). Infusion of bPTH-(1--84), bPTH-(1--34), human (h)PTH-(1--34), or [Nle8, Nle18, Tyr34]bPTH-(1--34) amide was accompanied by a comparable dose-dependent decrease in plasma phosphate and a dose-dependent increase in plasma calcium and [3H]-1,25(OH)2D3, and urinary excretion of phosphate and cAMP. An evaluation of [Nle8, Nle18, Tyr34]bPTH-(3--34) amide, a potent inhibitor of PTH action in vitro in the renal adenylate cyclase assay, revealed that the analogue possessed weak agonist properties in vivo. The analogue increased excretion of both cAMP and phosphate in the urine, decreased plasma phosphate levels, and increased the accumulation of [3H]-1,25(OH)2D3 in the plasma. This multiparameter model system should aid in the elucidation of the in vivo biological effects of PTH and its analogues.