Impaired in vivo antibody production in CRF rats: role of secondary hyperparathyroidism.

Antibody responses to antigens are impaired in humans and animals with chronic renal failure (CRF), and parathyroid hormone (PTH) inhibits Staphylococcus aureus Cowan I (SAC) or pokeweed mitogen (PWM)-induced antibody production by B cells from normal subjects. Since CRF is associated with secondary hyperparathyroidism and elevated blood levels of PTH, it is possible that impaired humoral immunity in CRF is due to chronic excess of PTH. To test this hypothesis we examined in vivo antibody production in response to sheep red blood cells (SRBC), BSA and influenza vaccine in normal rats, CRF rats and parathyroidectomized CRF rats maintained normocalcemic (CRF-PTX). The blood levels of PTH in CRF rats were elevated and significantly (P less than 0.01) higher than those in normal and CRF-PTX rats. The latter groups of animals did not have elevated blood levels of PTH. The antibody response to all three antigens in CRF rats were significantly (P less than 0.01) and markedly lower than in normal or CRF-PTX rats. The antibody response to SRBC, the IgG anti-BSA and the IgG and IgM anti-influenza vaccine in CRF-PTX rats were not different from normal, while the IgM anti-BSA was lower than in normal rats but higher than in CRF rats. The data demonstrate that the state of secondary hyperparathyroidism of CRF plays a paramount role in the genesis of impaired humoral immunity in CRF.     

Alpha 1 adrenergic receptors in mesenteric arteries of rats with chronic renal failure

In previous studies we have shown that patients or rats with chronic renal failure display reduced blood pressure response to norepinephrine (NE). This abnormality is related to the high levels of parathyroid hormone (PTH) which stimulates vasodilator prostaglandin production. To determine whether chronic renal failure (CRF) also affects pressor response to NE through changes in the properties of alpha 1 adrenoceptors, we have measured plasma NE and the number of binding sited (Bmax) and the KD of these receptors in isolated mesenteric arteries of normal CRF rats and of CRF rats previously parathyroidectomized (PTX). Plasma NE was greater (P less than 0.01) in CRF than in control (67 +/- 14 vs. 32 +/- 3.1 ng/dl), but it was not different from CRF-PTX rats. The Bmax of alpha 1 adrenoceptors was lower (P less than 0.05) in CRF than control (80 +/- 10 vs. 173 +/- 29 fmol/mg protein), but it was similar in CRF and CRF-PTX rats. The KD was not significantly different among the three groups of rats studied. The data show that the number of alpha 1 adrenoceptors is reduced in CRF and this is not related to excess PTH. This abnormality may contribute to the reduced pressor response to NE in CRF. The effect of PTH, on the vascular response to NE is not related to changes in plasma levels of NE or in binding sites for NE.     

Effect of chronic renal failure on Ca2+ ATPase of brain synaptosomes.

Chronic renal failure (CRF) is associated with a sustained rise in the concentration of cytosolic calcium [( Ca2+]i) of brain synaptosomes. This was attributed to secondary hyperparathyroidism where the excess blood levels of parathyroid hormone (PTH) augment calcium entry into synaptosomes. However, for such an effect of PTH to cause a sustained rise in [Ca2+]i, calcium extrusion out of synaptosomes should be impaired. The study presented here examined the effect of CRF with and without (CRF-PTX) excess PTH and the treatment of CRF rats with verapamil (V) on the Vmax and Km for calcium of synaptosomal Ca2+ ATPase, an enzyme that plays an important role in pumping calcium out of the synaptosomes. The Vmax of synaptosomal Ca2+ ATPase in CRF rats was significantly (P less than 0.01) lower than that of normal, CRF-PTX, CRF-V, and normal-V rats. However, the values in CRF-V were still below normal (P less than 0.05). There were no significant differences in the Km for calcium of synaptosomal Ca2+ ATPase among the five groups of animals. [Ca2+]i was significantly (P less than 0.01) higher in synaptosomes of CRF rats than in normal, CRF-PTX, CRF-V, and normal-V animals, and the values among the latter four groups were not different. The data demonstrate that the activity of synaptosomal Ca2+ ATPase is reduced in CRF rats, and this derangement is related to the excess PTH. This derangement in Ca2+ ATPase activity plays an important role in the genesis of the sustained elevation of synaptosomal [Ca2+]i in CRF.     

Impaired potassium-induced insulin secretion in chronic renal failure.

Extrarenal disposal of potassium load is impaired in chronic renal failure (CRF). This has been attributed to excess PTH since extrarenal disposition of potassium is normal in CRF-PTX animals. Insulin augments potassium entry into cells and hyperkalemia stimulates insulin secretion. Since glucose-induced insulin secretion is impaired in CRF and normal in CRF-PTX, it is possible that K(+)-induced insulin secretion is also impaired in CRF due to excess PTH. Such a defect would contribute to the abnormality in extrarenal disposal of potassium in CRF. We examined K(+)-induced insulin secretion, cytosolic calcium ([Ca2+]i) and the changes in [Ca2+]i in response to 20 mM KCl of islets from normal, CRF, and CRF-PTX rats; and normal and CRF animals treated with verapamil (normal-V and CRF-V). K(+)-induced insulin secretion by islets isolated from CRF rats was significantly (P less than 0.01) lower than that from normal, CRF-PTX, CRF-V and normal-V rats. Basal level of [Ca2+]i in islets of CRF rats was significantly (P less than 0.01) higher than in islets of the other four groups of animals. The calcium signal (delta [Ca2+]i) and the delta [Ca2+]i/basal [Ca2+]i ratio in response to 20 mM KCl observed in islets from CRF rats were significantly lower than in the other four groups of animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Parathyroid hormone interferes with extrarenal disposition of potassium in chronic renal failure

Available data suggest that the permeability of cellular membranes to potassium is affected by cytosolic calcium. Parathyroid hormone (PTH) has a calcium ionophoric property; it enhances calcium entry into many cells and it increases calcium content in a variety of tissues. Therefore, it is possible that clinical states with excess PTH may affect potassium homeostasis. The present study examined the effect of secondary hyperparathyroidism of chronic renal failure (CFR) on extrarenal potassium disposition of intravenous KCl load in rats with CRF. Experiments were performed after 21-26 days of CRF produced by 7/8 nephrectomy in rats with intact parathyroid glands (CRF control), in normocalcemic parathyroidectomized CRF animals (CFR-PTX) and in adrenalectomized CRF rats (CRF-ADX) maintained with DOCA. The effects of treatment with calcium channel blocker, verapamil, and of PTH administration were also examined. The baseline plasma concentrations of potassium in CRF-PTX rats and in CRF control animals treated with verapamil were significantly (p less than 0.01) lower than those with CRF control and CRF-ADX rats. At the end of 90 min of KCl infusion, the plasma concentrations of potassium as well as the changes from baseline were significantly (p less than 0.01) higher in CRF animals with secondary hyperparathyroidism (CRF control and CRF-ADX) and in those treated with PTH (CRF control with PTH and CRF-PTX with PTH) than in those without secondary hyperparathyroidism CRF-PTX and in those with secondary hyperparathyroidism but treated with verapamil (CRF control with verapamil and CRF-ADX with verapamil).(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin release from pancreatic islets: effects of CRF and excess PTH

Insulin secretion may be impaired in chronic renal failure (CRF) and available data suggest that this abnormality may be related to the state of secondary hyperparathyroidism of renal failure. We directly measured insulin release from isolated islets of Langerhans obtained from normal rats, CRF-control and CRF-PTX (parathyroidectomized) rats, and parathyroid hormone (PTH)-treated animals. Both early and total glucose-induced insulin release from islets of CRF-control were markedly and significantly (P less than 0.01) lower than from islets of normal rats. Insulin release from islets of CRF-PTX rats was significantly (P less than 0.01) higher than that from islets of CRF-control rats, and not different from insulin release from islets of normal rats. Forskolin and IBMX, which cause a rise in cAMP, significantly stimulated glucose-induced insulin release from islets of normal, CRF-control and CRF-PTX rats, but the increments from baseline were not significantly different between the three groups. Both early and total insulin release from islets obtained from PTH-treated rats with normal renal function were markedly and significantly (P less than 0.01) lower than values obtained from normal rats. Calcium contents of the pancreas of CRF-control and PTH-treated rats were significantly (P less than 0.01) higher than that in pancreas of normal rats and CRF-PTX animals, and values in the latter two groups of animals were not significantly different. The results show that: 1) CRF impairs insulin release from pancreatic islets; 2) this abnormality is reversed by prior parathyroidectomy; and 3) hyperparathyroidism induced by PTH-treatment in normal rats impairs insulin release from pancreatic islets.(ABSTRACT TRUNCATED AT 250 WORDS)     

Downregulation of hepatic cytochrome P450 in chronic renal failure

Chronic renal failure (CRF) is associated with a decrease in drug metabolism. The mechanism remains poorly understood. The present study investigated the repercussions of CRF on liver cytochrome P450 (CYP450). Three groups of rats were defined: control, control paired-fed, and CRF. Total CYP450 activity, protein expression of several CYP450 isoforms as well as their mRNA, and the in vitro N-demethylation of erythromycin were assessed in liver microsomes. The regulation of liver CYP450 by dexamethasone and phenobarbital was assessed in CRF rats. Compared with control and control paired-fed rats, creatinine clearance was reduced by 60% (P: < 0.01) in CRF rats. Weight was reduced by 30% (P: < 0.01) in control paired-fed and CRF rats, compared with control animals. There was no difference in the CYP450 parameters between control and control paired-fed. Compared with control paired-fed rats, total CYP450 was reduced by 47% (P: < 0.001) in CRF rats. Protein expression of CYP2C11, CYP3A1, and CYP3A2 were considerably reduced (>40%, P: < 0.001) in rats with CRF. The levels of CYP1A2, CYP2C6, CYP2D, and CYP2E1 were the same in the three groups. Northern blot analysis revealed a marked downregulation in gene expression of CYP2C11, 3A1, and 3A2 in CRF rats. Although liver CYP450 was reduced in CRF, its induction by dexamethasone and phenobarbital was present. N-demethylation of erythromycin was decreased by 50% in CRF rats compared with control (P: < 0.001). In conclusion, CRF in rats is associated with a decrease in liver cytochrome P450 activity (mainly in CYP2C11, CYP3A1, and 3A2), secondary to reduced gene expression.     

Restoration of Bone Mineralization by Cinacalcet is Associated with a Significant Reduction in Calcitriol-Induced Vascular Calcification in Uremic Rats

The present study investigated to what extent normalization of bone turnover goes along with a reduction of high-dose calcitriol-induced vascular calcifications in uremic rats. Five groups of male Sprague–Dawley rats were studied: sham-operated controls (n?=?7), subtotally nephrectomized (SNX) uremic (CRF) animals (n?=?12), CRF?+?calcitriol (vitD) (0.25?μg/kg/day) (n?=?12), CRF?+?vitD?+?cinacalcet (CIN) (10?mg/kg/day) (n?=?12), and CRF?+?vitD?+?parathyroidectomy (PTX) (n?=?12). Treatment started 2?weeks after SNX and continued for the next 14?weeks. High-dose calcitriol treatment in hyperparathyroid rats went along with the development of distinct vascular calcification, which was significantly reduced by >50?%, in both CIN-treated and PTX animals. Compared to control animals and those of the CRF group, calcitriol treatment either in combination with CIN or PTX or not was associated with a significant increase in bone area comprising ±50?% of the total tissue area. However, whereas excessive woven bone accompanied by a dramatically increased osteoid width/area was seen in the CRF?+?vitD group, CIN treatment and PTX resulted in significantly reduced serum PTH level, which was accompanied by a distinct reduction of both the bone formation rate and the amount of osteoid. These data indicate that less efficient calcium and phosphorus incorporation in bone inherent to the severe hyperparathyroidism in vitamin D-treated uremic rats goes along with excessive vascular calcification, a process which is partially reversed by CIN treatment in combination with a more efficacious bone mineralization, thus restricting the availability of calcium and phosphate for being deposited in the vessel wall.     

Impaired phagocytosis in chronic renal failure is mediated by secondary hyperparathyroidism.

Patients with chronic renal failure (CRF) display impaired phagocytosis by the polymorphonuclear leucocytes (PMNL), and these cells have elevated basal levels of cytosolic calcium ([Ca2+]i) and reduced ATP content. It has been suggested that these changes in PMNL metabolism and function are mediated by the state of secondary hyperparathyroidism of CRF. To examine the role of excess PTH in these derangements of PMNL, we studied [Ca2+]i, ATP and phagocytic ability of PMNL in five groups of rats including: CRF, CRF normocalcemic parathyroidectomized (CRF-PTX), CRF and normal animals treated with verapamil (CRF-V), and normal-V, respectively. The level of [Ca2+]i in the PMNL of CRF rats (149 +/- 2.7 nM) was significantly (P less than 0.01) higher and the ATP content (4.2 +/- 0.17 nmol/5 x 10(6) PMNL) significantly lower (P less than 0.01) than in normal (108 +/- 2.4 nM; 9.5 +/- 0.15 nmol/5 x 10(6) PMNL), CRF-PTX (103 +/- 2.9 nM; 9.2 +/- 0.19 nmol/5 x 10(6) PMNL), CRF-V (107 +/- 2.2 nM; 9.0 +/- 0.2 nmol/5 x 10(6) PMNL) and normal-V (106 +/- 1.8 nM; 9.2 +/- 0.2 nmol/5 x 10(6) PMNL), despite sustained elevation in blood PTH in the CRF-V group. Phagocytosis was significantly (P less than 0.01) impaired in CRF animals (5.6 +/- 0.25 micrograms oil/10(7) PMNL/min) but was normal in CRF-PTX (9.3 +/- 0.21 micrograms oil/10(7) PMNL/min) and CRF-V (9.5 +/- 0.22 micrograms oil/10(7) PMNL/min) rats. The values of phagocytosis in normal and normal-V rats were 9.6 +/- 44 and 9.6 +/- 0.18 micrograms oil/10(7) PMNL/min, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Downregulation of intestinal cytochrome p450 in chronic renal failure

Chronic renal failure (CRF) is associated with a decrease in intestinal drug metabolism. The mechanisms remain poorly understood, but one hypothesis involves a reduction in cytochrome P450 levels. This study aimed to investigate the effects of CRF on intestinal cytochrome P450. Two groups of rats were defined, i.e., rats with CRF (induced by 5/6 nephrectomy) and control pair-fed rats. Total cytochrome P450 levels and protein and mRNA expression of cytochrome P450 isoforms, as well as in vitro N-demethylation of erythromycin (a probe for CYP3A activity) and 7-ethoxyresorufin o-deethylase activity (a probe for CYP1A), were assessed in intestinal microsomes. Body weights were similar in the two groups. Creatinine clearance was reduced by 77% (P < 0.001) in CRF rats, compared with control pair-fed animals. Total intestinal cytochrome P450 activity was reduced by 32% (P < 0.001) in CRF rats. CYP1A1 and CYP3A2 protein expression was considerably reduced (>40%, P < 0.001) in rats with CRF. CYP2B1, CYP2C6, and CYP2C11 levels were the same in the two groups. RT-PCR assays revealed marked downregulation of CYP1A1 and CYP3A2 gene expression in CRF rats (P < 0.001). Although intestinal cytochrome P450 levels were reduced in CRF, induction by dexamethasone was present. N-Demethylation of erythromycin and 7-ethoxyresorufin o-deethylase activity were decreased by 25% (P < 0.05) in CRF rats, compared with control rats. In conclusion, CRF in rats is associated with decreases in intestinal cytochrome P450 activity (mainly CYP1A1 and CYP3A2) secondary to reduced gene expression.     

Calcitonin, an important factor in the calcemic response to parathyroid hormone in the rat

The role of calcitonin on the calcemic response to parathyroid hormone (PTH) in renal failure has not been evaluated previously. Often animal studies evaluating the calcemic response to PTH in renal failure are performed in thyroparathyroidectomized (TPTX) animals, and thus eliminate any potential physiologic effect of calcitonin. In addition, parathyroidectomy (PTX), presumably by reduction of high PTH levels, has corrected the calcemic response to PTH in animals with renal failure. The present study was designed to evaluate the effect of endogenous calcitonin production on the calcemic response to PTH in rats with renal failure and secondary hyperparathyroidism, and in rats with normal renal function with diet induced hyperparathyroidism. Four groups of rats were evaluated: 1) chronic renal failure plus TPTX with autotransplant of the parathyroid gland, (CT-) CRF; 2) chronic renal failure plus selective PTX with autotransplant of the parathyroid gland, (CT+) CRF; 3) normal renal function plus TPTX with autotransplant of the parathyroid gland, (CT-) NRF; and 4) normal renal function plus selective PTX with autotransplant of the parathyroid gland, (CT+) NRF. Renal failure was surgically induced by a two-stage 5/6 nephrectomy, and exogenous thyroxine was administered to the two thyroidectomized (CT-) groups. Hyperparathyroidism was induced with a high phosphate diet (1.2%), and thus at the time of PTH infusion, PTH levels were (CT-) CRF 84 +/- 16, (CT+) CRF 89 +/- 21, (CT-) NRF 37 +/- 7, and (CT+) NRF 31 +/- 4 pg/ml, respectively (normal 21 +/- 3 pg/ml). Rat 1-34 PTH (2.6 U/hr) was infused for 48 hours via a subcutaneously implanted Alzet pump.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hyperplasia of the parathyroid gland without secondary hyperparathyroidism

BACKGROUND: Low dietary phosphorus (P) prevents parathyroid gland (PTG) hyperplasia and the development of secondary hyperparathyroidism (SH) in uremic rats. The present study explores the effects of P restriction on parathyroid hormone (PTH) synthesis and secretion and PT cell growth in rats with established SH and PTG hyperplasia. METHODS: Normal and 5/6 nephrectomized rats were fed a high P (0.8%) diet. After two weeks, the normal rats and half of the uremic rats were sacrificed (U-HP) while the remaining uremic rats were switched to a low P (0.2%) diet (U-HP-LP). RESULTS: High dietary P induced a significant increase in serum P, PTH, and PTG weight, but not ionized calcium compared to normal animals fed the same diet (N-HP). P restriction returned serum P and PTH to normal levels by one week. In contrast, PTG size did not regress and glands remained enlarged for up to eight weeks with no evidence of apoptosis. Ribonuclease protection assay and metabolic labeling studies demonstrated similar PTH/actin mRNA ratios and 35S-labeled PTH among the three groups. Intracellular intact PTH was higher in U-HP and U-HP-LP rats compared to N-HP animals with no differences between the two uremic groups. PTG-PTH content correlated only with PTG weight, and serum PTH only with serum P. The PTG secretory response to calcium remained intact. CONCLUSIONS: In established chief-cell hyperplasia, P restriction restores normal serum PTH levels without affecting PTG hyperplasia, PTH synthesis, PTG cytosolic PTH or the PTH secretory response to calcium, suggesting an impaired exocytosis of PTH.     

Indoxyl sulfate exacerbates low bone turnover induced by parathyroidectomy in young adult rats

Low-turnover bone disease is one of the bone abnormalities observed in patients with chronic kidney disease (CKD) and is recognized to be associated with low serum parathyroid hormone (PTH) level and skeletal resistance to PTH. Indoxyl sulfate (IS) is a representative uremic toxin that accumulates in the blood as renal dysfunction progresses in CKD patients. A recent in vitro study using an osteoblastic cell culture system suggests that IS has an important role in the pathogenesis of low bone turnover through induction of skeletal resistance to PTH. However, the effects of IS on the progression of low bone turnover have not been elucidated. In the present study, we produced rats with low bone turnover by performing parathyroidectomy (PTX) and fed these rats a diet containing indole, a precursor of IS, to elevate blood IS level from indole metabolism. Bone metabolism was evaluated by measuring histomorphometric parameters of secondary spongiosa of the femur. Histomorphometric analyses revealed significant decreases in both bone formation–related parameters and bone resorption–related parameters in PTX rats. In indole-treated PTX rats, further decreases in bone formation–related parameters were observed. In addition, serum alkaline phosphatase activity, a bone formation marker, and bone mineral density of the tibia tended to decrease in indole-treated PTX rats. These findings strongly suggest that IS exacerbates low bone turnover through inhibition of bone formation by mechanisms unrelated to skeletal resistance to PTH.     

Expression of bone type 1 PTH receptor in rats with chronic renal failure

Some researchers have speculated that a decrease in bone type 1 PTH receptor (PTH1R) may be among the causes of “skeletal resistance” in chronic renal failure (CRF). Indeed, the down-regulation of PTH1R mRNA has been identified in uremic bones. However, few studies have identified the patterns of PTH1R protein expression. In this article we compare the bone expression of PTH1R protein and mRNA under control and CRF conditions. Sprague–Dawley rats underwent 5/6 nephrectomies (Nx) or sham operations (control), and were killed 16 weeks later. Blood urea nitrogen (BUN), serum Cr, P, and parathyroid hormone (PTH) were higher in the Nx group than in the controls, while serum Ca and 1,25(OH)₂D₃ were lower in the Nx group. Immunohistochemical images of lumbar bone samples were analyzed by an image processing system. PTH1R was essentially identified in all osteoblasts. The expression of osteoblast PTH1R protein was quantified based on the gray value of PTH1R staining. The mean gray scale of osteoblasts was 25% lower in Nx rats than in control rats (P < 0.01), whereas osteoblast cell counts and cell sizes were not significantly different between the two groups. Thus, down-regulation of PTH1R protein expression under the CRF condition appeared likely. Total RNA extracted from the bone samples was reverse transcribed for real-time polymerase chain reaction (PCR). PTH1R mRNA expression was 33% lower in the Nx group than in the control group in the quantitative PCR analysis (P < 0.05). Our findings suggested that osteoblast PTH1R expression is down-regulated at both the protein and mRNA levels in the steady state of CRF.     

Abnormal skeletal response to parathyroid hormone and the expression of its receptor in chronic uremia

Chronic renal failure is characterized by a resistance to the hypercalcemic action of parathyroid hormone (PTH). This resistance probably involves several mechanisms, including a disturbance of vitamin D metabolism, a desensitization of the skeleton by high PTH levels, hyperphosphatemia, uremic toxins, and acidosis. We have explored the possibility that a downregulation of the recently cloned PTH/PTHrp receptor might also be involved. We found a marked decrease in the expression of the receptor mRNA in the kidney and the bone of uremic rats; other authors have found a decrease in the heart and the liver. The reduced expression in the kidney was accompanied by a diminished stimulability of renal adenylate cyclase activity, suggestive of a functional depression of the hormonal response in this target tissue. It is probable that the downregulation of the PTH/PTHrp receptor plays an important role in the skeletal resistance to the calcemic effect of PTH in chronic renal failure.     

Impaired glucose-induced calcium signal in pancreatic islets in chronic renal failure.

Basal level of cytosolic calcium ([Ca2+]i) is elevated in islets of rats with chronic renal failure (CRF). The high [Ca2+]i level was implicated in the impaired insulin secretion of CRF, and its effect is due, in part, to a reduction in ATP content and impaired glucose metabolism by the islets. However, elevated [Ca2+]i may interfere with insulin secretion via another pathway. Exposure of the islets to glucose causes an acute rise in [Ca2+]i which generates events leading to insulin secretion. It is possible that a sustained rise in [Ca2+]i interferes with the magnitude of glucose-induced calcium signal and the ratio between this signal and basal [Ca2+]i. We examined this question in normal, CRF, normocalcemic CRF-PTX rats and in CRF rats treated with verapamil (CRF-V). Basal [Ca2+]i was higher (p less than 0.01) in CRF (130 +/- 7.0 nM) than in normal (82 +/- 5.5 nM), CRF-PTX (75 +/- 3.6 nM) and CRF-V rats (84 +/- 3.8 nM). Glucose-induced calcium signal (95 +/- 10.4 nM) and the ratio between this signal and basal [Ca2+]i (0.73 +/- 0.07) in CRF rats were lower (p less than 0.01) than in normal (153 +/- 14.4 nM; 1.90 +/- 0.24), CRF-PTX (130 +/- 16.7 nM; 1.75 +/- 0.25) and CRF-V (124 +/- 5.8 nM; 1.90 +/- 0.12) rats despite high PTH in the latter. The data indicate that a sustained rise in [Ca2+]i of islets interferes with the glucose-induced calcium signal which in turn plays a role in impaired insulin secretion.     

Efficacy of 19-Nor-1,25-(OH)2D2 in the prevention and treatment of hyperparathyroid bone disease in experimental uremia

BACKGROUND: The control of parathyroid hyperplasia and high circulating parathyroid hormone (PTH) levels is crucial in preventing secondary hyperparathyroidism (SH) in renal failure. Parathyroid gland enlargement and elevated levels of PTH are major contributors to increase bone resorption, a feature of renal osteodystrophy. METHODS: These studies assessed the efficacy of the 1,25(OH)2D3 analog, 19-Nor-1,25(OH)2D2 (19-Nor), in the prevention (protocol I) and treatment (protocol II) of SH and renal osteodystrophy in uremic rats. In protocol I, normal and uremic rats were fed a high phosphorus diet for 2 months; uremic rats were administered intraperitoneal injections of either vehicle or 19-Nor (200 ng three times a week). In protocol II, normal and uremic rats were fed a high phosphorus diet for 4 months; 2 months after the onset of uremia, rats were administered either intraperitoneal vehicle or 19-Nor (200 ng three times a week). Serum PTH and bone histology were used to assess the degree of SH. RESULTS: 19-Nor was effective in preventing (protocol I) and suppressing (protocol II) the significant SH induced by uremia and further enhanced by a high phosphorus diet. In protocol I, bone histology in uremic controls showed a threefold increase in the cancellous bone mass compared to normal rats. This expansion in unmineralized bone was accompanied by 5-, 1.5-, and 7-fold increases in eroded surface, mineralization lag time (MLT), and bone formation rate (BFR/BS), respectively. Moreover, cortical bone porosity in untreated uremic rats increased 267-fold compared to normal animals. 19-Nor ameliorated these changes in cancellous and cortical bone. In protocol II, the reported indices worsened even further. In contrast, 2 months of 19-Nor treatment improved bone histology by reducing cortical bone porosity, woven bone formation, MLT, and BFR/BS. CONCLUSION: In an experimental model of chronic renal failure (CRF), 19-Nor prevents SH and ameliorates the histomorphometric changes induced by uremia and high phosphorus diet. In addition, 19-Nor suppresses serum PTH and improves bone histology in uremic rats with established severe SH. Further studies in patients with CRF are necessary to define the clinical applicability of 19-Nor on bone histology in humans.     

Sigmoidal relationship between calcitonin and calcium: studies in normal, parathyroidectomized, and azotemic rats.

Calcitonin secretion is stimulated by acute hypercalcemia. Furthermore, in the rat, the calcemic response to parathyroid hormone (PTH) is decreased by calcitonin stimulation. However, in renal failure, it is not known if an increase in the serum calcium concentration within the physiologic range of serum calcium stimulates calcitonin and whether the increased calcitonin decreases the calcemic response to PTH. In the present study, four groups of pair-fed rats were evaluated: normals (N); parathyroidectomy (PTX); and two groups with renal failure (RF)--basal serum calcium less than 8.5 mg/dl (RFa) and basal serum calcium greater than 8.5 mg/dl (RFb). Hypocalcemia was induced by parathyroidectomy or in the RFa group, by a high phosphate diet. Increases in the serum calcium were produced by a 48 hour infusion of rat 1-34 PTH. In the RFa and PTX groups, stimulation of calcitonin was observed as the serum calcium increased from hypocalcemia to normal levels of calcium (P less than 0.01). In all four groups, increasing the serum calcium from normal levels to hypercalcemia increased the serum calcitonin level (P less than 0.05). The relationship between serum calcitonin and calcium was best expressed as a sigmoidal curve. In the two groups with basal hypocalcemia, PTX and RFa, the calcitonin-calcium curve was shifted to the left of the N and RFb groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired insulin secretion of aging: role of renal failure and hyperparathyroidism.

Available data indicate that insulin secretion is impaired with aging. Almost all the studies that examined insulin secretion by old animals did not take into consideration the state of renal function or the blood levels of parathyroid hormone (PTH). Old animals may have chronic renal failure (CRF) and secondary hyperparathyroidism, and both of these conditions impair insulin secretion. It is possible, therefore, that the impaired insulin secretion of aging is not due to old age per se, but rather to associated CRF and excess PTH. The present study examined this issue in adult (6 month old) and senescent rats (2 year old) with and without CRF and excess PTH. Senescent rats without CRF had normal renal function and normal blood levels of PTH, and the values were not different from those observed in adult rats. Creatinine clearance in senescent rats with CRF was significantly (P less than 0.01) lower and serum levels of PTH were significantly (P less than 0.01) higher than in senescent animals without CRF and than in the adult rats as well. Only the senescent rats with CRF displayed glucose intolerance during intravenous glucose tolerance test. For any given level of blood glucose, plasma insulin levels were lower in senescent rats with CRF than in the adult rat or senescent animals without CRF.(ABSTRACT TRUNCATED AT 250 WORDS)