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Differences in bone turnover and intact PTH levels between African American and Caucasian patients with end-stage renal disease.BackgroundEvidence derived from healthy subjects suggests that African Americans have higher serum parathyroid hormone (PTH) levels and decreased bone responsiveness to PTH than Caucasians. African American patients with end-stage renal disease (ESRD) also have higher serum PTH than Caucasians. Studies that correlate intact PTH (iPTH) levels with bone turnover in ESRD patients were performed in a predominantly Caucasian population.MethodsIn this study, serum iPTH and bone histomorphometric data were analyzed for racial differences in 76 ESRD patients (Caucasian = 48, African Americans = 28). Bone turnover was determined by histomorphometric measurement of activation frequency in all patients.ResultsAge, duration of dialysis, and calcium and phosphorus levels were similar between the two groups. iPTH levels (pg/mL; mean ± SE) were significantly higher in the African American group (534 ± 79 vs. 270 ± 46, P < 0.01). Also, alkaline phosphatase levels (IU/L) were significantly higher in the African American group (162 ± 31 vs. 144 ± 43, P < 0.01). Correlations between PTH levels and activation frequency were r = 0.60, P < 0.01 in Caucasians and r = 0.22, P = NS in African Americans. The mean PTH level in African American patients with histologic findings of low bone turnover was 460 ± 115 vs. 168 ± 41 in Caucasian patients with similar bone turnover (P < 0.01). In patients with low bone turnover, African Americans had significantly higher osteoid volume and thickness, number of osteoblasts and osteoclasts, erosion surface, peritrabecular fibrosis, and single-label surface than Caucasians. However, erosion depth, bone formation rate per osteoblast and mineralization apposition rate were similar between the two groups.ConclusionThere is no correlation between iPTH and bone turnover in African Americans with ESRD. A substantial number of African American patients with low bone turnover have very high serum PTH levels. Bone histomorphometric results reveal differences in remodeling dynamics and responses to PTH between African American and Caucasian patients. Further studies utilizing newer PTH measurement assays are needed to better delineate the correlation between PTH and bone turnover in the various racial groups.

Kidney transplantation corrects most of the metabolic abnormalities that cause renal osteodystrophy. However, many transplanted patients develop osteoporosis and other bone lesions that are related, at least in part, to their immunosuppressive regimen. The precise histologic patterns of bone disease after transplantation are not well defined. In a study designed to investigate this issue, 57 adult posttransplant patients agreed to undergo bone biopsies and blood drawings. There were 32 men and 25 women, mean age 45 +/- 2 yr, who had received a kidney transplantation 5.6 +/- 0.8 yr before biopsy. History of bone pain, fractures, and avascular necrosis was found in 22, 12, and 7 patients, respectively. Serum creatinine was 1.68 +/- 0.1 mg/dl, 21% of patients were hypercalcemic, 63.2% had elevated parathyroid hormone (PTH) (65 pg/ml), and 91.2% had normal calcitriol levels. Cancellous bone volume/tissue volume was below normal compared to age- and gender-matched control subjects in 56.1% of patients. Bone turnover (activation frequency) was low in 45.6%, normal in 28.1%, and elevated in 26.3% of patients. Bone formation rate/bone surface was low in 59.7%, normal in 35%, and elevated in 5. 3% of the patients. Erosion surface/bone surface was high in 21.1% of patients. Mineralization was prolonged in 87.5% of patients, including 9 patients with osteomalacia and 12 patients with focal osteomalacia. Cumulative and maintenance doses of prednisone and time elapsed since transplantation correlated negatively with bone volume and bone turnover (r = -0.32 to -0.59, P0.05 to 0.01), whereas cumulative doses of cyclosporine or azathioprine, age, gender, or serum PTH levels did not. Regression analysis identified prednisone as the main factor responsible for low bone volume and bone turnover (r = 0.54 and r = 0.43, P0.01). No factors were found to predict delayed mineralization. The present study shows that low bone volume, low bone turnover, and generalized or focal osteomalacia are frequent histologic features in transplanted patients. The effects of age, gender, PTH, and cyclosporine on bone volume and bone turnover are apparently overridden by the prominent effects of glucocorticoids. The prevalence of mineralization defect in the presence of normal serum levels of calcidiol and calcitriol suggests vitamin D resistance and deserves further study.

We previously found that bone loss occurs as soon as 1 month after ovariohysterectomy (OHX) in beagle dogs. Indirect evidence pointed to an early dramatic increase in bone resorption. To verify this hypothesis and evaluate the effects of a newly developed bisphosphonate, BM 21.0955 (Boehringer Mannheim), 36 beagle dogs were subjected to OHX and 12 dogs were sham operated (Sham). OHX dogs were divided into six groups (n = 6 each) and received subcutaneous injections of vehicle or BM 21.0955 at various doses (0.1, 0.3, 1, 10, and 100 micrograms/kg/day) for 1 month. Sham dogs were given vehicle (n = 6) or BM 21.0955 (1 microgram/kg/day, n = 6). Iliac crest biopsies and blood drawings were done at baseline and at month 1. OHX dogs given vehicle exhibited a decrease in cancellous bone volume associated with an increase in erosion depth and a decrease in serum levels of 1,25-dihydroxyvitamin D. BM 21.0955 prevented the bone loss at a dose > or = 1 microgram/kg and the increase in erosion depth and the decrease in serum levels of 1,25-(OH)2D at a dose > or = 0.3 microgram/kg. No osteomalacia was observed at any dose of BM 21.0955. Bone turnover was reduced only when BM 21.0955 was administered at doses of 10 or 100 micrograms/kg. There were no changes in body weight or serum levels of calcium, phosphorus, creatinine, parathyroid hormone, or osteocalcin in all groups. The increase in erosion depth in OHX dogs given vehicle proves that the early rapid bone loss after cessation of ovarian function is related to an increase in osteoclastic activity. The antiosteoclastic activity of BM 21.0955 at a dose > or = 1 microgram/kg prevents this increase and preserves bone volume. The absence of any signs of osteomalacia at any dose confers a relatively wide therapeutic margin to BM 21.0955. BM 21.0955 at a dose > or = 10 micrograms/kg also acts as an inhibitor of bone turnover. This is not observed at a dose of 1 microgram/kg, at least after 1 month of administration.

The beagle dog model has been established by our laboratory as a useful animal model to study bone loss after cessation of ovarian function. Previously we demonstrated bone loss associated with an osteoblastic insufficiency at 4 months after ovariohysterectomy (OHX). This study was designed to evaluate by four sequential monthly bone biopsies the development and course of the histologic bone abnormalities after OHX. We found cancellous bone volume, trabecular density, and wall thickness to be decreased (p less than 0.05) and trabecular separation increased (p less than 0.05) as early as 1 month after OHX. After 2 months, there was a decrease in mineralizing surface and mineral apposition rate (p less than 0.05). Volume and surface of osteoid were increased after 3 months (p less than 0.05), and there was an increase in the number of osteoblasts (p less than 0.01). No histologic signs of increased resorption were observed during the experiment. However, the findings of low bone volume with decreased trabecular density and increased separation without a change in trabecular plate thickness 4 weeks after OHX suggest that a dramatic increase in resorption must have taken place soon after OHX. These results point to an early phase of initiation of bone loss related to hyperresorption followed by a maintenance phase of low bone mass ascriblastic insufficiency. The events that stimulate the early initiating phase after cessation of ovarian function, the factors contributing to it, and the direct demonstration of hyperresorption await further studies.

SummaryCholera toxin (CT) reduces tubular reabsorption of Na, Cl, Ca, Mg and P most probably through stimulation of a renal adenylate cyclase-cyclic AMP system, and it is possible that an increased production of nephrogenous cyclic AMP during extracellular fluid volume expansion may be partly responsible for the observed natriuresis. In order to further evaluate the role of renal cyclic AMP in renal tubular transport, we studied the effect of CT on glucose (TRG) and bicarbonate reabsorption (TRHCO3).During the period of maximal effect of CT on tubular transport (100-140 min of CT infusion into one renal artery) both the TRG and TRHCO3 were lower in the infused kidney than in the contralateral noninfused kidney; TRG as mg per 100 ml GFR was 254 ± 32.7 vs 363 ± 43.5 (P < .01), and TRHCO3 as mEq per 100 ml GFR was 2.09 ± 0.06 vs 2.53 ± 0.06 (P < .01). The data indicate that CT suppresses glucose and bicarbonate reabsorption together with that of sodium and as such assign to role for renal cyclic AMP in the r...

The effect of unilateral ureteral obstruction (UUO) of 48 h duration on phosphate excretion was studied in dogs. After the relief of UUO, the fraction of filtered phosphate excreted (FEP) was markedly

The sites of clearance of endogenous parathyroid hormone (PTH) were studied in dogs who developed secondary hyperparathyroidism on a vitamin D-deficient diet. Simultaneous blood samples were obtained from the femoral artery, and the hepatic, renal, portal, and femoral veins. Radioimmunoassay of canine immunoreactive PTH (iPTH) in a heterologous bovine PTH (iPTH) system indicated that the kidney and liver extracted 49% and 46%, respectively, of the iPTH circulating through these organs. Characterization of the circulating iPTH in these animals was carried out by gel filtration and radioimmunoassay of the eluant fractions utilizing specific amino- and carboxyl-terminal antisera. The hormone in the peripheral circulation co-eluted with [125I]- iodobPTH and no fragments of iPTH were detected. Immunochemical differences between bovine and canine PTH were detected in the carboxyl-terminal region of the molecule. The results indicate that endogenous PTH in the vitamin D-deficient, hypocalcemic dog is cleared by ...

Skeletal resistance to the calcemic action of PTH in uremia: Role of 1,25(OH) 2 D 3 . Studies were carried out to investigate the role of 1,25 dihydroxy vitamin D [1,25(OH) 2 D 3 ] in the skeletal resistance to the calcemic action of parathyroid hormone. The change in serum calcium after the intravenous infusion of 2 U of parathyroid extract (PTE)/kg body wt/hr for eight hours was evaluated in thyroparathyroidectomized (T-PTX) dogs before, and one, two and three days after, induction of uremia by bilateral ureteral ligation (11 dogs) or by bilateral nephrectomy (8 dogs). In another six nephrectomized and T-PTX dogs, 0.68 µg of 1,25(OH) 2 D 3 /day was given on the day of nephrectomy and for two days thereafter. Serum creatinine in each day of the study was not different among the three groups. The study also included the evaluation of the effect of sham operation (five dogs) and the administration of 1,25(OH) 2 D 3 to dogs with normal renal function (four dogs) on the calcemic response to PTE, as well as the reproducibility of such a response in the same animal. The results showed that 1) the calcemie response to PTE was markedly impaired after one day of bilateral ureteral ligation or nephrectomy, but the impairment was more severe after nephrectomy; 2) the calcemic response to PTE after two or three days of bilateral ureteral ligation was similar to that seen at one day after nephrectomy; 3) 1,25(OH) 2 D 3 partially restored the calcemic response to PTE in the nephrectomized animals to levels similar to those seen after one day of bilateral ureteral ligation; 4) sham operation did not affect the response to PTE, and repeated infusion of PTE produced similar changes in the concentrations of serum calcium. The data indicate that (a) a deficiency of 1,25(OH) 2 D 3 is at least partly responsible for the skeletal resistance to the calcemic action of PTH in uremia; (b) uremia, per se, may also contribute to this phenomenon; and (c) the kidney after one day of complete bilateral ureteral ligation may still produce 1,25(OH) 2 D 3 , but this ability is compromised after two days of ureteral obstruction. Resistance de l'os a l'action hypercalcemiante de la PTH au cours de l'uremie: Role du 1,25(OH) 2 D 3 . Ce travail a pour but d'etudier le role de la 1,25 dihydroxy vitamine D (1,25(OH) 2 D 3 ) dans la resistance de Tos a l'action hypercalcemiante de l'hormone parathyroidienne. Les modifications du calcium du plasma apres la perfusion intra-veineuse de 2 U d'extrait parathyroidien (PTE)/kg de poids corporel/heure pendant 8 heures ont ete mesurees chez des chiens thyroparathyroidectomises (T-PTX) avant puis 1,2 et 3 jours apres, l'induction de l'uremie par ligature bilaterale des ureteres (11 chiens) ou nephzectomie bilaterale (8 chiens). A un autre groupe de 6 chiens nephrectomises et T-PTX, 0,68 µg de 1,25(OH) 2 D 3 ont ete administres le jour de la nephrectomie et les deux jours suivants. La creatinine plasmatique a chaque jour de l'etude etait le meme dans les trois groupes. Le travail a aussi evalue les effets d'un simulacre d'operation (5 chiens) et de l'administration de 1,25(OH) 2 D 3 a des chiens ayant une fonction renale normale (4 chiens) sur la reponse de la calcemie au PTE ainsi que la reproductibilite de la reponse chez le meme animal. Les resultats montrent que: 1) la reponse calcemique au PTE est alteree de facon importante 24 heures apres la ligature ureterale ou la nephrectomie, l'alteration est plus grande apres nephrectomie; 2) la reponse calcemique au PTE apres deux et trois jours de ligature ureterale est semblable a celle observee apres un jour de nephrectomie; 3) le 1,25(OH) 2 D 3 restaure partiellement la reponse calcemique au PTE chez les animaux nephrectomises, la reponse obtenue est semblable a celle observee apres un jour de ligature ureterale bilaterale; 4) le simulacre d'operation n'affecte pas la reponse au PTE et les perfusions repetees de PTE produisent des modifications similaires de la concentration plasmatique de calcium. Ces resultats sont compatibles avec les interpretations suivantes: a) un deficit de 1,25(OH) 2 D 3 est, au moins en partie, responsable de la resistance osseuse a l'action hypercalcemiante de la PTH au cours de l'uremie, b) l'uremie, par elle-meme, peut aussi contribuer a cette modification et c) le rein peut encore produire du 1,25(OH) 2 D 3 apres un jour de ligature ureterale bilaterale mais cette capacite est abolie apres deux jours d'obstruction ureterale.

Bone loss developing after cessation of ovarian function in humans represents a major health problem. To establish the value of ovariohysterectomy in female beagle dogs as a model for bone loss and to study static and dynamic parameters of bone associated with the negative bone balance occurring after cessation of ovarian function, we performed iliac crest bone biopsies before and 4 months after ovariohysterectomy in eight beagle dogs and in five sham-operated controls. Cessation of ovarian function was documented by an increase in serum levels of LH 4 weeks after ovariohysterectomy. There was no change in serum calcium, phosphorus, and creatinine during the 4 months of the study. Cancellous bone mass and trabecular mean wall thickness decreased significantly after ovariohysterectomy (P less than 0.01). In addition, the number of osteoblasts was increased and the bone formation rate per osteoblast, that is, the activity of bone-forming cells, was decreased (P less than 0.01). Parameters of bone resorption were not significantly altered in the animals with ovariohysterectomy. No changes in histomorphometric parameters of bone structure, formation or resorption were observed in the sham-operated controls. These data indicate that ovariohysterectomy in beagle dogs may serve as a useful model for bone loss associated with cessation of ovarian function. Osteoblastic insufficiency appears to play a major role in the maintenance of bone loss occurring after ovariohysterectomy in beagle dogs.

Renal action of cholera toxin: I. Effects on urinary excretion of electrolytes and cyclic AMP. The infusion of cholera toxin (CT), 4 µg/min, into one renal artery of normal and thyroparathyroidectomized (T-PTX) dogs produced ipsilateral increments in the excretion of Na, K, Ca, Mg and Cl. Phosphate excretion increased from both kidneys, but more from the infused kidney in intact dogs. Unilateral phosphaturia occurred in T-PTX dogs studied five or more days after T-PTX. The changes in electrolyte excretion appeared 40 to 80 min after initiation of CT infusion and the maximal effects were noted after 100 to 140 min. The effects of CT on electrolyte excretion could not be accounted for by changes in glomerular filtration rate or renal plasma flow. Urinary cyclic adenosine monophosphate (AMP) increased from both kidneys but slightly more from the infused kidney. Adenylate cyclase activity of cortex and outer medulla of the infused kidney was 109 to 142% higher than that of the control kidney. The results indicate that CT decreases the net transport of various electrolytes by the renal tubule. This effect is probably mediated by the activation of renal adenylate cyclase(s) sensitive to the enterotoxin.

This report reviews the various factors involved in the control of the renal excretion of phosphate and calcium. We discuss the effects of changes in glomerular filtration rate, renal vasodilatation, extracellular fluid volume expansion, diuretics, state of body stores of phosphate, acid-base status, diet, and various hormones. This physiological knowledge forms a background for the discussion of the abnormalities in the excretion of phosphate and calcium observed in various disease states.

Effect of unilateral renal vasodilatation on sodium excretion by infusing acetylcholine into renal artery of dogs

Boston, Mass.) It has been demonstrated by several recent studies that the regulation of sodium excretion involves factors other than the total filtered load of sodium and the renal tubular effects of mineralocorticoids. Contrary to earlier suggestions that an increase in the filtered load of sodium may be sufficient to account for the natriuresis of saline loading in the dog, de Wardener, Mills, Chapman, and Hayter (1) reported that the administration of saline to dogs receiving an exogenous mineralocorticoid results in an increased excretion of so

Improved assessment of bone turnover by the PTH-(1-84)/large C-PTH fragments ratio in ESRD patients.BackgroundThe “intact” parathyroid hormone (PTH) assay recognizes PTH-(1-84) as well as amino terminally truncated PTH fragments, that is, large carboxyterminal PTH fragments (C-PTH fragments). The present study investigated whether the use of the plasma PTH-(1-84)/C-PTH fragment ratio enhances the noninvasive assessment of bone turnover in patients on dialysis.MethodsBone biopsies and blood samples for determinations of routine indices of bone turnover and PTH peptides were obtained in 51 adult patients on dialysis not treated with drugs affecting bone such as vitamin D or corticosteroids. Blood levels of large C-PTH fragments were calculated by subtracting PTH-(1-84) from “intact” PTH. Patients were classified according to their levels of bone turnover based on histomorphometrically obtained results of activation frequency. Prediction of bone turnover by the various blood indices was done by using proper statistical methods. In addition, hypercalcemia was induced by calcium gluconate infusion in a subset of patients, and levels of PTH-(1-84), “intact” PTH, and PTH-(1-84)/C-PTH fragment ratio were determined.ResultsThe PTH-(1-84)/C-PTH fragment ratio was the best predictor of bone turnover. A ratio> 1 predicted high or normal bone turnover (sensitivity 100%), whereas a ratio

22-Oxacalcitriol suppresses secondary hyperparathyroidism without inducing low bone turnover in dogs with renal failure. Background Calcitriol therapy suppresses serum levels of parathyroid hormone (PTH) in patients with renal failure but has several drawbacks, including hypercalcemia and/or marked suppression of bone turnover, which may lead to adynamic bone disease. A new vitamin D analogue, 22-oxacalcitriol (OCT), has been shown to have promising characteristics. This study was undertaken to determine the effects of OCT on serum PTH levels and bone turnover in states of normal or impaired renal function. Methods Sixty dogs were either nephrectomized (Nx, N = 38) or sham-operated (Sham, N = 22). The animals received supplemental phosphate to enhance PTH secretion. Fourteen weeks after the start of phosphate supplementation, half of the Nx and Sham dogs received doses of OCT (three times per week); the other half were given vehicle for 60 weeks. Thereafter, the treatment modalities for a subset of animals were crossed over for an additional eight months. Biochemical and hormonal indices of calcium and bone metabolism were measured throughout the study, and bone biopsies were done at baseline, 60 weeks after OCT or vehicle treatment, and at the end of the crossover period. Results In Nx dogs, OCT significantly decreased serum PTH levels soon after the induction of renal insufficiency. In long-standing secondary hyperparathyroidism, OCT (0.03 μg/kg) stabilized serum PTH levels during the first months. Serum PTH levels rose thereafter, but the rise was less pronounced compared with baseline than the rise seen in Nx control. These effects were accompanied by episodes of hypercalcemia and hyperphosphatemia. In animals with normal renal function, OCT induced a transient decrease in serum PTH levels at a dose of 0.1 μg/kg, which was not sustained with lowering of the doses. In Nx dogs, OCT reversed abnormal bone formation, such as woven osteoid and fibrosis, but did not significantly alter the level of bone turnover. In addition, OCT improved mineralization lag time, (that is, the rate at which osteoid mineralizes) in both Nx and Sham dogs. Conclusions These results indicate that even though OCT does not completely prevent the occurrence of hypercalcemia in experimental dogs with renal insufficiency, it may be of use in the management of secondary hyperparathyroidism because it does not induce low bone turnover and, therefore, does not increase the risk of adynamic bone disease.

SummaryChronic ligation of the common bile duct (CBDL) is dogs causes sodium retention and a blunted natriuretic response to extracellular volume expansion (ECVE). Since increased sympatho-adrenal activity plays an important role in other sodium retaining states, the present study was undertaken to evaluate the role of renal denervation and a-adrenergic blockade on the renal handling of sodium in dogs with CBDL. Both renal denervation and the infusion of dibenzyline into the renal artery produced a slight but significant increment in urinary sodium excretion, but these changes were not different from those observed after renal denervation in normal animals. Also, these procedures did not improve the response to saline infusion in dogs with CBDL. These data indicate that the sympatho-adrenal activity does not play an important role in the salt retaining state that follows chronic ligation of the common bile duct.Anne Harrington and Miriam Bick provided technical help and Mrs. Catherine Hoyt provided secret...

Renal action of cholera toxin: II. Effects on adenylate cyclase-cyclic AMP system. The effects of cholera toxin (CT) on the adenylate cyclase-adenosine 3′,5′-cyclic monophosphate (cAMP) system(s) in renal cortex were examined using the isolated renal cortical tubules of rat. Unlike parathyroid hormone, catecholamines or prostaglandins, CT had no immediate effects on cAMP production by the tubules or on adenylate cyclase activity. However, after 30 min of incubation at 37°C, cAMP production by the tubules started to rise and reached a plateau between 60 and 90 min. This rise in cAMP production was not abolished by protein synthesis inhibitors (actinomycin D and cycloheximide) nor by the inhibitors of prostaglandin synthesis (acetyl-salicylate and indomethacin). Repeated washings of the tubules exposed to the toxin for five minutes at 0 or 37°C did not abolish the effect of CT to stimulate cAMP production. Assays of adenylate cyclase activity using homogenates prepared from isolated tubules which were incubated for 60 min with CT revealed an increase in the basal adenylate cyclase activity without any change in NaF-sensitive enzyme activity. It is concluded that CT binds to renal tubule cells rapidly, possibly through energy-independent process. CT stimulates adenylate cyclase activity and increases cAMP production by the renal tubule cells after a latent period of 30 min. The stimulatory effects of CT are not due to new protein synthesis or prostaglandin formation.

This report reviews the interrelationship between the activity of the parathyroid glands and renal function. Among the topics discussed are: effects of parathyroid hormone on various aspects of renal function such as: (1) glomerular filtration rate and renal blood flow; (2) renal handling of phosphorus, calcium, magnesium, sodium and potassium; (3) renal production of 1,25-dihydroxycholecalciferol; (4) renal handling of bicarbonate and acid-base metabolism, and (5) mechanism of action of parathyroid hormone on the renal cell. Further topics include: renal metabolism of parathyroid hormone; the kidney in hyperparathyroidism, and effects of renal failure on structure and function of the parathyroid glands.

Histologic studies of bone in patients with hyperparathyroid bone disease reveal that the hallmark of the pathologic changes is an increase in bone forming and resorbing cells (1,2). In contrast, administration of vitamin D to patients with secondary hyperparathyroidism results in a decrease in number of bone forming and resorbing cells (3). Based on these data we advanced the hypothesis that vitamin D and parathyroid hormone may have opposite effects on bone i.e., parathyroid hormone induces an increase and 1.25 Vit D3 a decrease in number of bane cells. This hypothesis was tested in an animal model in which experimental beagle dogs were rendered deficient in 1.25 Vit D3 and parathyroid hormone by 5/6 nephrectomy and thyroparathyroidectany. Thyroid hormone was replaced and then both parathyroid hormone and 1.25 Vit D3 were exogenously substituted to produce all combinations between the two hormones, i.e., 1.25D+/PTH+ (n=5), 1. 25D−/PTH− (n=7), 1.25D+/PTH− (n=9), 1.25D−/PTH+ (n=5). Six normal control dogs were sham operated and injected with vehicle. Bone biopsies were done after eight months of experimental administration of these hormones. Histomorphometry of bone for static and dynamic parameters of bone cells revealed that deficiency in parathyroid hormone results in a decrease in the number of bone forming and resorbing cells. This decrease in cell number was observed independent of the presence or absence of deficiency in 1.25 Vit D3. In addition, administration of parathyroid hormone increased the number of bane cells independent of the status in 1.25 Vit D3. In contrast, deficiency in 1.25 Vit D3 resulted in a decreased cellular activity without an alteration in cell number and administration of 1.25 Vit D3 increased the cellular activity without an increase in numbers of bone cells.

Abnormal relationship between sodium intake and sympathetic nervous system activity in salt-sensitive patients with essential hypertension. To examine the mechanisms underlying the sensitivity to sodium intake in a subset of patients with essential hypertension, we studied the effects of different sodium intake (10, 100, 200 mEq/day) on blood pressure, the function of the renin-angiotensin-aldosterone system, and on blood levels of catecholamines in 20 patients with essential hypertension and 10 normal subjects. Mean blood pressure (MBP) was not different in hypertensive and normal subjects during low sodium diet. But, with high sodium intake, MBP increased by at least 10% in 12 patients (salt-sensitive), whereas in the remaining 8 patients (salt-resistant) and in normal subjects, MBP did not change significantly. This phenomenon cannot be attributed to differences in sodium retention because the percent change in body weight and the urinary sodium excretion in the salt-sensitive patients was not different than it was in salt-resistant patients or in normal subjects. The observed difference in blood pressure response to high sodium intake in salt-sensitive patients is also not dependent on an impaired suppressibility of the renin-angiotensin-aldosterone system because there were no significant differences in the basal levels of PRA and aldosterone between the groups, and because the orthostatic increments in PRA were significantly lower in salt sensitive than they were in the salt-resistant patients and in normal subjects. Plasma norepinephrine (NE) levels were not significantly different between normal subjects or hypertensive patients while on low sodium intake. But during high sodium intake, they decreased significantly (P < 0.05) in normal subjects (from 22 ± 3.4 to 12 ± 2.3 ng/dl) and in salt-resistant patients (from 17 ± 4.5 to 13 ± 2.4 ng/dl) but not in salt-sensitive patients (from 20 ± 1.9 to 22 ± 3.2 ng/dl). Furthermore, the majority of salt-sensitive patients displayed inappropriately high plasma NE in relation to their urine excretion of sodium during high sodium intake. Finally, the increments in plasma NE after 5min of standing were significantly greater in salt-sensitive patients than they were in salt-resistant patients and normal subjects during both low or high sodium intake. These data indicate that a subset of patients with essential hypertension may have impaired suppressibility of plasma NE during high sodium intake, which suggests hyperactivity of the sympathetic nervous system in these patients. These aberrations may be responsible for the increase in MBP in the salt-sensitive patients during high sodium intake.Relation anormale entre l'ingestion de sodium et l'activité du système nerveux sympathique chez les malades atteints d'hypertension essentielle sensibles au sel. Afin d'étudier les mécanismes qui sous-tendent la sensibilité à l'apport de sodium dans un sous-groupe de malades atteints d'hypertension essentielle, les effets de différents apports de sodium (10, 100, 200 mEq/jour) sur la pression artérielle, la fonction du système rénine-angiotensine-aldostérone, et les concentrations sanguines de catécholamines ont été évaluées chez 20 malades atteints d'hypertension essentielle et chez 10 sujets normaux. La pression artérielle moyenne (MBP) n'était pas différente chez les malades hypertendu et les sujets normaux recevant une alimentation pauvre en sodium. Mais, avec le régime riche en sodium, MBP a augmenté d'au moins 10% chez 12 malades (sensibles au sel) alors que chez les autres 8 malades (résistants au sel) et chez les sujets normaux MBP n'a pas changé de façon significative. Ce phénomène ne peut pas être attribué à des différences de rétention de sodium parce que le pourcentage de modifications du poids corporel et l'excrétion urinaire de sodium chez les malades sensibles au sel ne sont pas différents de ceux observés chez les malades résistants au sel ou chez les sujets normaux. La différence de pression artérielle observée chez les malades sensibles au sel au cours de l'alimentation riche en sodium n'est pas non plus dépendante d'une altération du freinage du système rénine-angiotensine-aldostérone parce qu'il n'a pas été observé de différences significatives dans les concentrations basales de PRA et d'aldostérone entre les groupes, et parce que l'augmentation orthostatique de PRA était significativement plus faible chez les malades sensibles au sel que chez les malades résistants au sel et les sujets normaux. Les concentrations plasmatiques de la norépinéphrine (NE) n'étaient pas significativement différentes entre les sujets normaux et les malades hypertendus soumis à un régime pauvre en sel. Mais, au cours du régime riche en sel ils ont diminué significativement (P < 0,05) chez les sujets normaux (de 22 ± 3,4 à 12 ± 2,3 ng/dl) et chez les malades résistants au sel (de 17 ± 4,5 à 13 ± 2,4 ng/dl) mais non chez les malades sensibles au sel (de 20 ± 1,9 à 22 ± 3,2 ng/dl). De plus, la majorité des malades sensibles au sel ont eu une concentration plasmatique de NE élevée de façon inappropriée par rapport à leur excrétion urinaire de sodium au cours du régime riche en sel. Enfin, les augmentations de NE plasmatique après 5min de position debout ont été significativement plus grandes chez les malades sensibles au sel que chez les malades résistants au sel et les sujets normaux aussi bien au cours du régime riche que du régime pauvre en sodium. Ces résultats indiquent qu'un sous-groupe de malades atteints d'hypertension essentielle peut avoir une altération du freinage de la NE plasmatique au cours de l'ingestion d'un régime riche en sodium ce qui suggère une hyperactivité du système nerveux sympathique chez ces malades. Ces désordres peuvent être responsables de l'augmentation de MBP chez les malades sensibles au sel au cours de l'ingestion d'une régime riche en sodium.

Previous studies in our laboratory support the notion that an increase in the production of cyclic AMP (cAMP) by the kidney may play a role in the natriuresis of extracellular fluid volume expansion (

Accumulation of aluminum in bone is a frequent finding in patients requiring chronic dialysis and is associated with considerable morbidity and/or mortality. Until now, evidence seemed to point to relatively low circulating levels of parathyroid hormone as a contributing factor, but because levels of parathyroid hormone and calcitriol are interrelated, calcitriol might be also involved. In this study we employed an animal model to evaluate the single and combined effects of parathyroid hormone and calcitriol on bone aluminum accumulation. The results show significantly less aluminum accumulation in calcitriol-replete dogs independent of the presence or absence of parathyroid hormone. These results indicate that low levels of calcitriol may play a role in the development of aluminum related bone disease. Further studies are needed to demonstrate whether administration of calcitriol in patients with renal insufficiency will prevent development of aluminum-related bone disease.

Twenty-one patients developed acute renal failure in association with nontraumatic rhabdomyolysis and myoglobinuria. The illness followed an overdose of ethanol, heroin, or other depressant drug in 18 patients. Lethargy or coma was present in 17 patients and muscle swelling in 11. Evidence of rhabdomyolysis included markedly elevated creatine phosphokinase, myoglobinuria, and aldolase in blood. Initial biochemical findings were similar to those of acute renal failure due to other causes, but the abnormalities were exaggerated. There was a disproportionate rise in serum creatinine concentration in relation to serum urea nitrogen concentration. Profound hyperuricemia was present in most patients. Transient hypercalcemia developed during the diuretic phase in 5 patients. One patient died. We conclude that nontraumatic myoglobinuria with acute renal failure is not infrequent and may occur after an overdose of ethanol or heroin. The disease has good prognosis despite severe hypercatbolism and untreated profound hyperuricemia.

The singular and combined effects of 1,25-dihydroxyvitamin D [1,25-(OH)2D] and PTH on bone were evaluated in a long term in vivo study in dogs. Dogs were rendered deficient in 1,25-(OH)2D and PTH by five sixths nephrectomy and parathyroidectomy. A control group was sham operated. Various combinations in status of 1,25-(OH)2D and PTH were produced by daily sc injections of 1,25-(OH)2D (1.25) and/or continuous infusion of 1-34 bovine PTH. These were 1.25+/PTH+, 1.25-/PTH-, 1.25+/PTH-, 1.25-/PTH+. Serum calcium levels were kept in the normal range by the administration of one or two of the hormones or by oral supplementation of calcium lactate. Histomorphometric evaluation of static and dynamic parameters of bone after 8 months of experimental observation revealed that deficiency in 1,25-(OH)2D and PTH resulted in decreased number and activity of bone-forming and resorbing cells. Administration of 1,25-(OH)2D increased the activity but not the number of bone cells. In contrast, administration of PTH increased the number but not the activity of bone cells. Tissue level activity was decreased when one or both hormones were deficient, and normal tissue level activity was found only when both hormones were given. These data are relevant for understanding and management of diseases with perturbations in vitamin D and/or PTH.

The decrease in intestinal calcium absorption and lower blood levels of 1,25-dihydroxyvitamin D [1,25-(OH)2D3] have been implicated in the pathogenesis of postmenopausal osteoporosis. This study evaluates the effects on bone of 1,25-(OH)2D3 therapy using the ovariohysterectomized dog model. The cessation of ovarian function was ascertained by an increase in serum LH levels 4 weeks after ovariohysterectomy, and significant bone loss was revealed four months after ovariohysterectomy. The bone loss was associated with an increase in the number of bone-forming cells and a decrease in the activity of these cells. The administration of 1,25-(OH)2D3 increased the activity of the bone cells and resulted in a reversal of all abnormalities in structural parameters of bone, including cancellous bone mass, trabecular wall thickness, trabecular plate separation, trabecular plate density, and trabecular plate thickness (which increased above normal). However, 1,25-(OH)2D3 therapy was also associated with a significant decrease in the number of bone-forming cells, resulting in lower bone formation at the tissue level. The results of this study indicate that 1,25-(OH)2D3 therapy can reverse the bone loss and osteoblastic insufficiency responsible for the maintenance of negative bone balance after the cessation of ovarian function. However, this therapy has a suppressive effect on bone cell number and bone turnover. This undesired side-effect of 1,25-(OH)2D3 therapy renders a chronic therapeutic regimen inefficient for the long term management of patients with osteoporosis. Intermittent 1,25-(OH)2D3 therapy or a sequential therapy using 1,25-(OH)2D3 along with substances known to increase the number of bone-forming cells is strongly suggested by these results.

The effect of the state of sodium balance on the activity of the sympathetic nervous system has been evaluated previously by measuring urinary catecholamine excretion. Since urinary catecholamine may be affected by factors such as renal function or renal production of catecholamines, blood catecholamines may provide a better index of the activity of the sympathetic nervous system. The present study was undertaken to evaluate the effect of varying sodium intake on blood catecholamines. Thirteen normal subjects were studied for a period of 3 weeks in a metabolic ward. They received during the first, second, and third week 10, 100, and 200 meq sodium/day, respectively. On the seventh day of each week, when the patients had achieved sodium balance, urinary sodium excretion as well as blood levels of PRA, norepinephrine (NE), epinephrine (Ep), and dopamine (D) were measured in the supine position, at 5, 10, 15, and 20 min of upright posture, and at the end of 40 min of ambulation. The results show that: 1) blo...

It has been demonstrated by several recent studies that saline loading in the dog may result in decreased net tubular reabsorption of sodium independent of mineralocorticoids (1–5). On the basis of recent studies from this laboratory it was suggested that decreased tubular reabsorption of sodium during saline loading may result in part from an increased renal medullary blood flow(4,5). Increased medullary blood flow should decrease medullary interstitial hyper tonicity, and, in turn, the passive loss of water from the descending limb of Henle' Loop should diminish. The resulting increased rate of flow of fluid with a lower concentration of sodium could limit the absolute reabsorption of sodium by the ascending limb (4,5). If extracellular volume expansion does increase renal medullary blood flow, and if the reabsorption of sodium by the ascending limb of Henle' Loop is influenced by the concentration of sodium in the tubular fluid, then the concentrating mechanism (as measured by TcH2O) should be influenc...

Combination of renal vasodilation and angiotensin infusion effect large changes in renal hemodynamics, excretion and reabsorption of sodium in anesthetized hydropenic dogs

Sodium excretion during extracellular volume expansion and associated changes in renal blood flow and intrarenal blood distribution during natriuresis accompanying saline loading in dogs

Studies were carried out to evaluate the mechanism of hypocalcemia in magnesium depletion. Day old chicks fed a magnesium deficient diet developed marked hypocalcemia, with a direct relation between serum calcium (y) and magnesium (x): y = 2.68 x + 4.24, r = 0.84 (both in mg/100 ml). Injections of parathyroid extract that increased serum calcium 2-3 mg/100 ml in normals had no effect in Mg-depleted birds. Very large dietary supplements of calcium or vitamin D(3) increased mean serum calcium only from 5.3 to 7.7 and 7.8 mg/100 ml, respectively, while a normal magnesium diet for 3 days increased calcium from 5.3 to 9.9 mg/100 ml despite absence of dietary calcium. Intestinal calcium transport, studied in vitro, and the calcium concentration of the carcass was significantly increased in magnesium-depleted chicks, making it unlikely that reduced intestinal absorption of calcium caused the hypocalcemia. In magnesium-deficient chicks, the bone content of magnesium was decreased by 74%, the calcium content was unchanged, and the cortical thickness of bone was markedly increased. After 3 days of magnesium-repletion, cortical thickness was reduced with increased endosteal resorption. There was an increase in unmineralized osteoid tissue in the magnesium-depleted chicks. Parathyroid gland size and histology did not differ in magnesium-depleted and control birds. The results suggest that hypocalcemia develops due to altered equilibrium of calcium between extracellular fluid and bone, favoring increased net movement into the latter. Failure of parathyroid gland function could also exist, and unresponsiveness to parathyroid hormone (PTH) may also contribute to the hypocalcemia. However, failure of PTH action is probably due to the presence of excess osteoid tissue rather than a primary event leading to hypocalcemia.