Urinary Cyclic AMP Research Articles

Chronic endothelial dopamine receptor stimulation improves endothelial function and hemodynamics in autosomal dominant polycystic kidney disease

Altered polycystin-mediated endothelial flow mechanosensitivity contributes to the development of hypertension and cardiovascular complications in patients with autosomal dominant polycystic kidney disease (ADPKD). Stimulation of endothelial type 5 dopamine receptors (DR5) can acutely compensate for the endothelial consequences of polycystin deficiency, but the chronic impact of this approach must be evaluated in ADPKD. Nineteen patients with ADPKD on standard of care therapy were randomized to receive a 2-month treatment with the DR agonist rotigotine using transdermal patches, nine at 2 mg/24hours and ten at 4 mg/24hours or while ten were untreated. Rotigotine at the dose of 4 mg/24hours significantly increased nitric oxide release (nitrite levels from 10±30 to 46±34 nmol/L) and radial artery endothelium-dependent flow-mediated dilatation (from 16.4±6.3 to 22.5±7.3%) in response to hand skin heating. Systemic hemodynamics were not significantly modified but aplanation tonometry showed that rotigotine at 4 mg/24hours reduced aortic augmentation index and pulse pressure without affecting carotid-to femoral pulse wave velocity. Plasma creatinine and urea, urinary cyclic AMP, which contributes to cyst growth in ADPKD and copeptin, a surrogate marker of vasopressin, were not affected by rotigotine. In mice with a specific deletion of polycystin-1 in endothelial cells, chronic infusion of the peripheral DR5 agonist fenoldopam also improved mesenteric artery flow-mediated dilatation and reduced blood pressure. Thus, our study demonstrates that in patients with ADPKD, chronic administration of rotigotine improves conduit artery endothelial function through the restoration of flow-induced nitric oxide release as well as hemodynamics suggesting that endothelial DR5 activation may represent a promising pharmacological approach to prevent cardiovascular complications of ADPKD.

Short-term impact of kampo goreisan in patients with congestive heart failure refractory to tolvaptan-incorporated medical therapy.

We often encounter patients with congestive heart failure refractory to conventional diuretics therapy. Kampo goreisan (Tsumura &Co. Tokyo, Japan) is receiving great concern in mediating body water balance, particularly for such a cohort. However, its detailed biological mechanism remains uncertain. Patients who received goreisan to treat congestive heart failure refractory to tolvaptan-incorporated medical therapy were prospectively included and observed for one week during the therapeutic period. The change in urine biomarkers during the first 24h was assessed as a primary concern. Baseline factors associated with an increase in urine volume during the first 24h were investigated as a secondary concern. A total of 18 patients were included. Median age was 81 (77, 86) and 12 (67%) were men. During the first 24h after the initiation of goreisan, urine cyclic AMP tended to decrease, urine aquaporin-2 decreased significantly, urine osmolality decreased significantly, and urine volume tended to increase. Baseline higher common logarithm of plasma B-type natriuretic peptide was associated with any increases in urine volume during the first 24h with an odds ratio of 73.2 (95% confidence interval 1.04-5149, p = 0.048). Baseline plasma B-type natriuretic peptide level had a positive correlation with a change in urine volume between baseline and day 1 (r = 0.533, p = 0.026). Goreisan may increase urine volume even in patients with congestive heart failure refractory to tolvaptan-incorporated medical therapy by modulating aquaporin-2 systems in the collecting duct, particularly in individuals with advanced heart failure accompanying significant congestion. Goreisan may have a regulatory effect on body fluid, rather than just forcing aquaresis.

ODP117 Pseudohypoparathyroidism Type IB: A Rare Cause of Hypocalcemia

Abstract Introduction Pseudohypoparathyroidism (PHP) describes disorders of hypoparathyroidism that are the result of resistance of target tissues to the actions of parathyroid hormone (PTH). Studies have estimated the prevalence of PHP to be 0.34 in 100,000 in Japan and 1.1 in 100,000 in Denmark. The first biochemical abnormalities to become apparent are elevated serum levels of PTH and elevated serum levels of phosphorus, followed by hypocalcaemia. We present a patient diagnosed with PHP Type 1B (PHP1B), which was presented to us many years after her initial diagnosis, with other major comorbidities now present. Case description This patient is an 81 year old female presenting to the clinic to discuss her previously diagnosed PHP1B. Her past medical history revealed she began having symptoms of intermittent muscle cramping at the age of 22, followed by carpopedal spasms and periorbital paresthesia a year later. She has also had a physical examination significant for a positive Trousseau sign, but no phenotypical signs of Albright hereditary Osteodystrophy (AHO). Lab evidence from 1977 was recovered showing urinary cyclic AMP level <20 nmol/mg after administration of PTH, consistent with PHP1B. The family history in her parents and children has revealed no similar genetic history so far. Other comorbidities she has developed since her diagnosis are hypokalemia, hypothyroidism, osteoporosis with a femur fracture, obesity, chronic kidney disease and nephrolithiasis. She has been continuing treatment throughout her life with calcium, calcitriol and vitamin D supplementation for hypocalcemia. She has been mostly eucalcemic since then, and complains of occasional carpopedal spasms and perioral numbness. Discussion PHP1B is isolated resistance to PTH in the kidney and normal PTH response in bone without features of AHO. PHP1A and 1C have PTH resistance in bone, and both express AHO. These various forms of PHP are due to defects in the GNAS gene that lead to decreased expression of the alpha-subunit of G protein (Gsa). In the absence of molecular analysis, the clinical and biochemical overlap between PHP and related disorders can lead to challenges in diagnostic classification. There are 2 types of PHP1B cases- autosomal dominant (AD) and sporadic. However, the majority of Patients with PHP1B do not have mutations within the GNAS but they have methylation and imprinting defects that result in absence of maternal Gsa. To emphasize, epimutation study rather than sequencing of the coding region in GNAS should be performed for genetic investigation, which has now become standard practice. Although there is no difference in clinical presentation between AD PHP1B and sporadic PHP1B, their differentiation early during the disease onset can help providers give patients more reliable genetic and reproductive counseling and provide optimal medical management of complications such as hypocalcemia. Presentation: No date and time listed

Prognostic impact of urine cyclic AMP levels in patients with chronic kidney disease

Urine cyclic adenosine monophosphate (cAMP) is a biomarker to assess the residual function of the collecting duct in the kidney. Prognostic implication of urine cAMP levels in patients with chronic kidney disease (CKD) remains unknown. Patients who were followed at our specific outpatient clinic to treat their CKD between December 2015 and December 2019 were included in this prospective study. The impact of urine cAMP levels on the composite of dialysis administration, cardiovascular death, and doubling of serum creatinine concentration was investigated. A total of 106 patients (median 72years old, 80 men, and median estimated glomerular filtration rate 28.4mL/min/1.73 m2) were included. Urine cAMP levels ranged widely between 0.35 and 4.08nmol/mg of creatinine with a median value of 1.99nmol/mg of creatinine. A urine cAMP level was an independent predictor of the primary endpoint with a hazard ratio of 0.41 (95% confidence interval 0.18-0.91, p = 0.029) adjusted for 5 potential confounders with a cutoff of 1.55nmol/mg of creatinine. A lower urine cAMP is an independent predictor of renal deterioration and cardiovascular death in patients with CKD.

A case of nephrogenic syndrome of inappropriate antidiuresis caused by carbamazepine.

We report a case of nephrogenic syndrome of inappropriate antidiuresis caused by carbamazepine (CBZ). CBZ, an antiepileptic drug, is known to cause hyponatremia. The mechanism is generally considered to be inappropriate secretion of antidiuretic hormone, whereas an experimental study suggests a direct effect of CBZ on the kidney by stimulating vasopressin receptor. An 18-year-old male with atypical autism and epilepsy has been treated with CBZ and clobazam since age 9 and 10years, respectively. At age 11, he was found to have asymptomatic hyponatremia. He had the habit of drinking tea approximately 3L/day. The low plasma osmolality and high urine osmolality and sodium concentration in the presence of normal thyroid and adrenal function were compatible with syndrome of inappropriate excretion of antidiuretic hormone. His plasma vasopressin level, however, was undetectable. Urine cyclic AMP level was higher than expected from urine osmolality despite the suppressed plasma arginine vasopressin. With fluid restriction, hyponatremia improved. CBZ tapering begun later in the course maintained normal serum sodium concentrations with less strict water intake. This case demonstrates the direct effect of CBZ stimulating vasopressin receptor in the kidney leading to nephrogenic syndrome of inappropriate diuresis.

Calcium Mediates the Phosphaturia in Hypercalcemia of Malignancy

Background: Humoral hypercalcemia of malignancy (HHM) is claimed to be caused by circulating parathyroid hormone like peptide (PTHrP) that shares several of the cardinal biochemical and skeletal histological features with hyperparathyroidism (HPT). Both syndromes are characterized by hypercalcemia from increased renal tubular reabsorption of filtered calcium, increased urinary cyclic AMP, renal phosphate wasting and hypophosphatemia, in contrast to low 1,25(OH)2D levels, metabolic alkalosis, and uncoupled bone formation-resorption rate in HHM. The aim of the study was to reassess if phosphaturia of HHM can be attributed to hypercalcemia rather than to humoral effect of PTHrP. Methods: A prospective study was conducted at Mount Sinai Services at Queens Hospital Center, NY. Results: Nine (four females and five males) out of 20 patients with hypercalcemia of malignancy documented having elevated PTHrP, normal renal function, and low PTH levels were finalized for the study. Serum calcium, phosphate, creatinine, albumin, and PTHrP concentration were determined. On the initiation of hydration, 24 h urine for creatinine, calcium and phosphorous were also collected. Blood and urine tests were repeated after serum calcium levels had been decreased by at least 1.5 mg/dL. All patients received vigorous intravenous hydration with normal saline at 200 cc/h. After the first 24 h, small doses of furosemide were given to two out of nine patients for 48 - 72 h. Hydration has shown statistically significant decrease in serum calcium concentration (13.9 ± 2.1 to 10.8 ± 1.48 mg/dL; P < 0.001) and increase in tubular reabsorption of phosphate (TRP) (69.54±8.16% to 77.85±12.24%; P < 0.01). However, PTHrP levels have shown no statistically significant difference on hydration therapy. Conclusion: Improvement of hypercalcemia by hydration reverses phosphaturia without reducing PTHrP levels. It is being proposed that in HHM, PTHrP can lead to hypercalcemia from uncoupled bone formation-resorption rate through a local autocrine or paracrine action produced by bony micrometastases that could not be demonstrated radiologically, rather than from PTHrP’s humoral effect. J Endocrinol Metab. 2017;7(2):55-60 doi: https://doi.org/10.14740/jem402w

Dipeptidyl peptidase-4 inhibitor ameliorates early renal injury through its anti-inflammatory action in a rat model of type 1 diabetes

IntroductionDipeptidyl peptidase-4 (DPP-4) inhibitors are incretin-based drugs in patients with type 2 diabetes. In our previous study, we showed that glucagon-like peptide-1 (GLP-1) receptor agonist has reno-protective effects through anti-inflammatory action. The mechanism of action of DPP-4 inhibitor is different from that of GLP-1 receptor agonists. It is not obvious whether DPP-4 inhibitor prevents the exacerbation of diabetic nephropathy through anti-inflammatory effects besides lowering blood glucose or not. The purpose of this study is to clarify the reno-protective effects of DPP-4 inhibitor through anti-inflammatory actions in the early diabetic nephropathy. Materials and methodsFive-week-old male Sprague–Dawley (SD) rats were divided into three groups; non-diabetes, diabetes and diabetes treated with DPP-4 inhibitor (PKF275-055; 3mg/kg/day). PKF275-055 was administered orally for 8weeks. ResultsPKF275-055 increased the serum active GLP-1 concentration and the production of urinary cyclic AMP. PKF275-055 decreased urinary albumin excretion and ameliorated histological change of diabetic nephropathy. Macrophage infiltration was inhibited, and inflammatory molecules were down-regulated by PKF275-055 in the glomeruli. In addition, nuclear factor-κB (NF-κB) activity was suppressed in the kidney. ConclusionsThese results indicate that DPP-4 inhibitor, PKF275-055, have reno-protective effects through anti-inflammatory action in the early stage of diabetic nephropathy. The endogenous biological active GLP-1 might be beneficial on diabetic nephropathy besides lowering blood glucose.

Time-dependent changes in skeletal response to teriparatide: Escalating vs. constant dose teriparatide (PTH 1–34) in osteoporotic women

Once-daily injections of teriparatide initially increase biochemical markers of bone formation and resorption, but markers peak after 6–12months and then decline despite continued treatment. We sought to determine whether increasing teriparatide doses in a stepwise fashion could prolong skeletal responsiveness. We randomized 52 postmenopausal women with low spine and/or hip bone mineral density (BMD) to either a constant or an escalating subcutaneous teriparatide dose (30 μg daily for 18months or 20 μg daily for 6months, then 30 μg daily for 6months, and then 40 μg daily for 6months). Serum procollagen I N-terminal propeptide, osteocalcin, and C-terminal telopeptide of type I collagen were assessed frequently. BMD of the spine, hip, radius, and total body was measured every 6months. Acute changes in urinary cyclic AMP in response to teriparatide were examined in a subset of women in the constant dose group. All bone markers differed significantly between the two treatment groups. During the final six months, bone markers declined in the constant dose group but remained stable or increased in the escalating dose group (all markers, p<0.017). Nonetheless, mean area under the curve did not differ between treatments for any bone marker, and BMD increases were equivalent in both treatment groups. Acute renal response to teriparatide, as assessed by urinary cyclic AMP, did not change over 18months of teriparatide administration. In conclusion, stepwise increases in teriparatide prevented the decline in bone turnover markers that is observed with chronic administration without altering BMD increases. The time-dependent waning of the response to teriparatide appears to be bone-specific.

Urine osmolality, cyclic AMP and aquaporin-2 in urine of patients under lithium treatment in response to water loading followed by vasopressin administration

Lithium is the drug that is most frequently associated with acquired nephrogenic diabetes insipidus (NDI). The exact mechanism of lithium-induced NDI in man is unknown. The aim of the present study was to investigate the kidney response to minimal and maximal stimulation of the kidney urine concentrating mechanism by measuring urine osmolality, and urine levels of cAMP and AQP-2 in urine of patients under long-term lithium treatment. Twenty patients under long-term lithium treatment were included. The kidney urinary 3′,5′-cyclic adenosine monophosphate (cyclic AMP), aquaporin-2 levels and urine osmolality were determined during a situation of minimal kidney urine concentrating activity (induced by water loading) and during a situation following maximal stimulation of kidney urine concentrating activity (induced by 1-desamino-8- d-arginine-vasopressin). Patients were classified as NDI, partial NDI and non-NDI based on maximal reached urine osmolality. The partial correlation ( r) between urinary cyclic AMP levels (mol/l) and urine osmolality was 0.94 ( P < 0.001). No significant correlation was observed between urinary aquaporin-2 levels (mol/mol creatinine) and osmolality nor between urinary cyclic AMP and aquaporin-2 levels. The rise in urinary cyclic AMP but not aquaporin-2 levels upon 1-desamino-8- d-arginine-vasopressin administration after water loading significantly differed between the three categories, decreasing with increasing NDI category. In conclusion we found that in lithium-induced kidney urine concentrating deficit in man, the cyclic AMP generation in response to 1-desamino-8- d-arginine-vasopressin administration after water loading, is impaired. It remains to be elucidated whether principal cells, G-proteins or adenylate cyclase e.g. are the major targets for the mechanism underlying lithium-induced NDI in man.

A Metabolic Study of Patients with Lung Cancer and Hyponatremia of Malignancy

One-third of patients with lung cancer and hyponatremia have no evidence of ectopic arginine vasopressin (AVP) production and the cause of their hyponatremia is not conclusively established. We sought to distinguish patients with hyponatremia caused by elevated AVP versus those with ectopic atrial natriuretic peptide (ANP) via this detailed metabolic study. We enrolled 24 patients recently diagnosed with lung cancer in a metabolic study in which patients were placed on sodium and fluid restriction for 4 days. Serum electrolytes, osmolality, urine electrolytes and osmolality, plasma AVP, ANP, aldosterone, urinary cyclic AMP and cyclic guanosine 3',5'-monophosphate were measured daily and tumor tissue was obtained to measure ectopic hormone production. We attempted to characterize the pathophysiology of hyponatremia caused by ectopic ANP production in patients with small cell lung cancer (SCLC) and to determine its effect on the aldosterone axis. Seven of the nine patients with SCLC presented with hyponatremia and three had elevated ANP levels at presentation without elevation of AVP. All three patients who presented with hyponatremia and elevated ANP showed a decline in serum sodium following fluid restriction, whereas two patients with SCLC and elevated AVP had normalized serum sodium levels. The combination of hyponatremia and elevated ANP was associated with a persistent natriuresis and inappropriately low aldosterone levels despite sodium restriction, suggesting ANP suppression of the aldosterone axis. Management of patients with hyponatremia and SCLC should be guided by the knowledge that some patients with SCLC have ectopic production of ANP as the cause of their hyponatremia.

Down-regulation of urinary AQP2 and unaffected response to hypertonic saline after 24 hours of fasting in humans

In rats, 24 hours of fasting impairs urinary concentrating ability by down-regulation of aquaporin-2 (AQP2). We tested the hypothesis that 24 hours of fasting in humans reduces the capability to form AQP2 and impairs the antidiuretic response to hypertonic saline infusion. In a crossover study of 14 healthy subjects, the effect of 24 hours of fasting was compared to a nonfasting control experiment on urinary excretion of AQP2 (u-AQP2), free water clearance (C(H(2)O)), plasma arginine vasopressin (AVP), urinary cyclic AMP (u-cAMP), and natriuretic peptides. The following response to 3% sodium infusion was measured using the same effect variables. U-AQP2, AVP, and u-cAMP were determined by radioimmunoassays. Fasting during 24 hours reduced u-AQP2 (14%), increased AVP (30%) despite a reduction in serum osmolality (P < 0.05), and depleted volume. C(H(2)O) and urine volume were not reduced, thus relatively increased after fasting. u-cAMP was not significantly different between the two procedures. Three percent saline resulted in the same relative increases in AVP, serum osmolality, u-AQP2, and u-cAMP and decreases in C(H(2)O) and urine volume independently of fasting. The reduced u-AQP2 and increased AVP after fasting were maintained during and after saline infusion. Twenty-four hours of fasting decreased u-AQP2 and reduced urine osmolality likely as a result of decreased sensitivity of collecting duct cells to AVP. Fasting-related insensitivity of collecting duct cells to AVP was restored by 3% saline infusion. Finally, after saline infusion, other factors such as the increased plasma atrial natriuretic peptide (p-ANP) levels could contribute to the u-AQP2 regulation.

Hypercalcémie grave secondaire à une hyperparathyroïdie induite par le lithium

Lithium treatment, which is still extensively used in bipolar affective disorders, may give rise to hypercalcaemia induced by hyperparathyroidism. We present a patient of 50-year-old treated with lithium for 19 years for bipollar illness and who developed an important hypercalcaemia. After symptomatic treatment of the hypercalcaemia and extrarenal dialysis the clinical evolution was favorable but measurements of serum calcium and parathormon showed that he had developed hyperparathyroidism. Neck exploration was performed and parathyroid adenomas, which had been detected by scintigraphy was removed. The lithium treatment expose to many side effects. Among other biologically and clinically important effects of lithium the possible induction of hyperparathyroidism was first suggested in 1973. Since, 1973, since about forty case reports have been described. Few cross-sectional studies show a relationship of lithium to hyperparathyroidism. Unusual metabolic features are associated with hyperparathyroidism and long-term lithium treatment: low urinary calcium excretion, normal urinary cyclic AMP excretion. The mechanism probably results from lithium linking with the calcium receptor on the parathyroid and then stimulating PTH secretion. The cessation of lithium therapy does not lead to normocalocaemia and a parathyroidectomy is usualy indicated.

Values of ultrasonography, sestamibi scintigraphy, and intraoperative measurement of 1-84 PTH for unilateral neck exploration of primary hyperparathyroidism.

Unilateral neck exploration (UNE) is a controversial approach to the treatment of primary hyperparathyroidism (PHP), and most surgeons favor bilateral neck exploration. The aim of this study was to assess the value of ultrasonography, sestamibi scintigraphy, and intraoperative measurement of urinary cyclic AMP (UcAMP) or 1-84 PTH in 200 patients undergoing unilateral neck exploration under local anesthesia. Conditions for UNE were (1) a presumed solitary adenoma detected by ultrasonography, (2) no thyroid disease, and (3) no family history of PHP or multiple endocrine neoplasia. Patient's consent was obtained for conversion to bilateral exploration according to surgical and biologic findings. Sensitivity of ultrasonography was 92.5%. Sestamibi scintigraphy, performed in 70 patients, was less sensitive than ultrasonography (80%). Persistent PHP was accurately detected by intraoperative measurement of UcAMP or 1-84 PTH in all cases. At follow-up, 96.0% of the patients were cured either after unilateral neck exploration only (90.5%), or after conversion into bilateral exploration. Ultrasonography and intraoperative measurement of 1-84 PTH allow unilateral neck exploration with excellent results in a selected group of patients with PHP.

22-Oxacalcitriol does not interfere with parathyroid hormone-induced phosphaturia or cyclic-AMP excretion.

The vitamin D analogue, 22-oxacalcitriol [22-oxa-1,25(OH)2 vitamin D3], has pleiotropic effects similar to or greater than calcitriol but has markedly fewer calcemic and phosphatemic effects. To test the hypothesis that the lesser phosphatemic effect of 22-oxacalcitriol is due, at least in part, to a lack of interference with the phosphaturic effect of parathyroid hormone, acute clearance experiments were performed in parathyroidectomized rats receiving continuous 1-34 parathyroid hormone (PTH) infusion together with 22-oxacalcitriol (200 pmol.100 g body weight-1.min-1) or vehicle. In contrast to the previously reported inhibitory effect of calcitriol on PTH-induced phosphaturia, fractional excretion of phosphorus increased similarly in both groups, from 0.05 +/- 0.01 to 0.26 +/- 0.02 (p < 0.01) in the vehicle-infused animals and from 0.04 +/- 0.01 to 0.24 +/- 0.02 (p < 0.01) in the 22-oxacalcitriol-treated rats (p between groups not significant [n.s.]). Urinary cyclic AMP excretion also increased similarly, from 45.5 +/- 5.2 to 101.6 +/- 21.6 (p < 0.01) and from 45.4 +/- 5.6 to 102.6 +/- 16.7 pmol/min (p < 0.01), respectively (p between groups n.s.). In search for a nongenomic mechanism that might account for the disparate effects of 22-oxacalcitriol and calcitriol, OK cells, which are reminiscent of the mammalian proximal tubule cell, were stimulated with calcitriol and 22-oxacalcitriol and free intracellular calcium concentration was determined. At high concentrations, calcitriol caused a dose-dependent increase in [Ca2+]i; 22-oxacalcitriol had no effect on [Ca2+]i at any concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasectomy in the Rat--Effects on Mineral Metabolism, with Emphasis on Renal Tissue Minerals and Occurrence of Urinary Stones

An increased stone frequency and hypotestosteronemia after vasectomy were reported and suggest development of some disturbance of homeostasis of minerals and hormones. The objective of the present study in the rat was to assess the effects of vasectomy (n = 14) and vasovasostomy (n = 12) on gonadal state, intestinal absorption of minerals and mineral concentrations in serum, urine and 3 renal tissue regions. Sham-operated animals (n = 12) served as controls. Seven months after surgery the combined results show that vasectomy induced a significant decrease in gonadal weight, but not in serum and urinary testosterone; serum magnesium was decreased (p = 0.014 versus controls) and phosphaturia was increased (p = 0.025), whereas serum calcium, parathyroid hormone and urinary cyclic AMP were unchanged. Also, after vasectomy there was a significant accumulation of phosphorus, calcium and magnesium in renal papillae and additionally of phosphorus in the renal cortical and medullary region; oxalate was unchanged. Renal stones containing calcium phosphate were found in 2 vasectomized rats, but in none of the vasovasostomized ones. In contrast, in vasovasostomized rats, mineral accumulation in renal tissues was abolished, and the associated concentration of serum free testosterone was 3 times higher (p = 0.018) than in control rats. It was concluded that vasectomy in the rat 1) may not be neutral to gonadal function in terms of gonadal weight; 2) disturbs the homeostasis of magnesium, calcium and phosphorus at the level of the kidney; and 3) induces mild hypomagnesemia and marked hyperphosphaturia in the presence of normal parathyroid gland function. It is suggested that these sequelae of vasectomy and vasovasostomy may be traced back to a disturbance of autonomous nerve tone.

Biochemical effects of oral sodium phosphate

Our objective was to monitor serum and urine biochemical changes after oral sodium phosphate cleansing in a prospectively designed study. The study subjects were seven healthy, asymptomatic adults. Sodium phosphate 45 ml diluted in 45 ml water was given orally at baseline and 12 hr later. Calcium, ionized calcium, phosphorus, sodium, potassium, creatinine, and PTH were analyzed at 2, 4, 6, 9, 12, 14, 16, 18, 21 and 24 hr after the first challenge. Urinary calcium, phosphorus, sodium, potassium, and cyclic AMP were analyzed at baseline and every 2 hr after oral sodium phosphate. Blood pressure, pulse, and respiratory rate were recorded every 2 hr and symptom questionnaires using visual analog scales were completed. A marked rise in phosphorus (peak range 3.6-12.4 mg/dl, P < 0.001) and falls in calcium (P < 0.001) and ionized calcium (P < 0.001) were seen. Rises seen in PTH and urinary cAMP confirmed the physiologic significance of the biochemical effect. There were no significant changes in other serum and urine laboratory or clinical assessments. Reported significant symptoms included bloating, cramps, abdominal pain, and nausea. Significant hypocalcemia and hyperphosphatemia after oral sodium phosphate raises concern about its use in normal individuals. Oral sodium phosphate should not be administered in patients with cardiopulmonary, renal, or hepatic disease.

High-dose glucocorticoids in multiple sclerosis patients exert direct effects on the kidney and skeleton

The effects of acute pharmacologic steroid treatment on skeletal and mineral metabolism were assessed in 56 multiple sclerosis patients who were to receive 1 g intravenous methylprednisolone for 10 days, followed by a 4 day intravenous and 28 day oral glucocorticoid taper. Serum and urine samples were obtained at baseline and then within 3 days, 1, 2, and 3 weeks after beginning steroids. A subset of patients (n = 11) had sampling throughout the 6 weeks of steroid administration and up to 8 weeks afterward. All mean basal biochemistries were normal except 25(OH)D, which was in the "insufficient" range (25-50 nM) at 10 nM. During and after steroid administration, there were no changes in ionized calcium, 25(OH)D, urinary hydroxyproline, or pyridinoline. There was an increase in 1,25(OH)2D and a decrease in serum phosphorus, accompanied by an increase in urinary phosphate clearance, within 3 days of administration (p < 0.006). Serum osteocalcin (BGP) decreased to below assay sensitivity limits within 3 days of steroid administration (p < 0.0002), increasing thereafter but remaining at 50% of baseline by the third week. PTH(1-84) increased to a peak at week 2 (p < 0.02), after both the 1,25(OH)2D peak and the serum phosphorus nadir. Tartrate-resistant acid phosphatase, urinary calcium, and urinary cyclic AMP all increased above baseline (p < 0.05) with a pattern similar to that of PTH. To investigate further the immediate effects of steroid administration, serum samples were obtained at the same four times on both the day before and the day after the first intravenous methylprednisolone dose in a randomly chosen subset of patients (n = 9).(ABSTRACT TRUNCATED AT 250 WORDS)

Boron and silicon: Effects on growth, plasma lipids, urinary cyclic amp and bone and brain mineral composition of male rats

AbstractBecause boron resembles silicon in its chemical properties, an experiment was performed to determine if excessive dietary boron would affect the response to silicon deprivation and, conversely, if silicon would influence the effects of an excessive intake of boron. Male weanling Sprague‐Dawley rats were assigned to groups of six or 12 in a two‐by‐two factorially arranged experiment. Supplemented to a ground corn/casein diet containing 1.2 μg silicon and 3 μg boron per gram were silicon as sodium metasilicate at 0 or 50 μg/g and boron as orthoboric acid at 0 or 500 μg/g diet. At nine weeks, animals fed high dietary boron had significantly decreased final body weights, liver‐weight‐to‐body‐weight ratios, urinary cAMP concentrations, plasma triglyceride, cholesterol, glycine, valine, leucine, and lysine concentrations and skull copper, sodium, and manganese concentrations. High dietary boron also significantly increased brain‐weight‐to‐body‐weight ratios, magnesium concentrations of femur, brain, and plasma, zinc concentration of femur, and iron concentration of skull. The bone mineral findings suggest that excess dietary boron exerts subtle effects on bone composition. Dietary silicon affected blood urea nitrogen, hematocrit, hemoglobin, and the concentrations of plasma threonine and aspartic acid in animals fed excess boron. Depression of the testes‐weight‐to‐body‐weight ratio of animals fed 500 μg boron per gram diet was most marked in animals not fed silicon. Although excessive dietary boron did not markedly enhance the response of rats to silicon deprivation, dietary silicon affected their response to high dietary boron. Thus, dietary silicon apparently can influence boron toxicity.

Erythrocytosis in pseudohypoparathyroidism type I

Pseudohypoparathyroidism (PHP) is characterized by target-organ resistance to parathyroid hormone and is classified as type I or type II depending on the urinary cyclic AMP response to exogenous parathyroid hormone. Mild erythrocytosis has been observed in patients with PHP type I. Measurements of serum levels of erythropoietin (Epo) are useful for the differential diagnosis of subgroups of erythrocytosis [1]. We measured serum Epo to investigate the mechanism of erythrocytosis in PHP type I. PHP and idiopathic hypoparathyroidism were diagnosed as previously described [3], and the patients were treated with l~-hydroxylated metabolites of vitamin D 3 (Table 1).

Effect of Experimental Colitis on Bone Metabolism in the Rat

The influence of experimental colitis, induced by trinitrobenzenesulphonic acid with ethanol, on bone mineralisation and mineral metabolism was investigated in male rats. Three days after colitis induction, there was a significant rise (p < 0.01) in urinary calcium excretion, which was still present 20 days later (p < 0.05). Three weeks after colitis induction, urinary hydroxyproline excretion was significantly increased (p < 0.01), while urinary cyclic AMP and phosphorus decreased. Colitis was associated with reduced bone density (p < 0.025), ash weight (p < 0.05) and calcium/volume ratio (p < 0.05), whereas no change was found for bone volume and the phosphorus/volume and magnesium/volume ratios. Serum minerals remained unchanged. We conclude that chronic experimental colitis in the rat leads to resorptive hypercalciuria, increased urinary hydroxyproline and osteopenia. Considering site of inflammation, diet, sex, and absence of therapy, inflammatory mediators, e.g. cytokines, with known catabolic effects on bone, might be involved in the pathogenesis of osteopenia.