Search

An elevation in intracellular calcium ([Ca2+]i) in rats with chronic renal failure and elevated blood levels of PTH is associated with down-regulation of the mRNA of many proteins. Similarly, in phosphate depleted animals that have normal renal function and low blood levels of PTH, [Ca2+]i is elevated and the mRNA of PTH-PTHrP receptor is down-regulated. The effect of elevation in [Ca2+]i on molecular machinery of many proteins may represent a generalized phenomenon. Diabetes mellitus may also be associated with a rise in [Ca2+]i and therefore down-regulation of the mRNA of proteins may also occur. The present study examined the effect of streptozotocin-induced diabetes mellitus in rats on the [Ca2+]i of the renal proximal tubular cells and on their mRNAs of the PTH-PTHrP, V1a and AT1 receptors. The basal levels of [Ca2+]i of these cells increased significantly (P < 0.01) after one day of diabetes and remained elevated thereafter. There was a significant (r = 0.67, P < 0.01) direct correlation between the [Ca2+]i of the cells and blood levels of glucose up to 350 mg/dl, and the value of [Ca2+]i plateaued with higher concentrations of glucose. Three days of amlodipine therapy prevented and reversed the elevated levels of [Ca2+]i despite marked hyperglycemia. The mRNA of all three receptors in the kidney were down-regulated and this defect was prevented by amlodipine which normalized the [Ca2+]i of the cells. The results show that: (1) the hyperglycemia of IDDM in rats causes a significant elevation in the basal levels of [Ca2+]i of the renal proximal tubular cells and down-regulation of their mRNA of PTH-PTHrP, V1a and AT1 receptors; (2) normalization of the [Ca2+]i of these cells by treatment of the diabetic rats with amlodipine prevented the elevation of [Ca2+]i and the down-regulation of the mRNA of these receptors; (3) these effects occurred in the presence of normal renal function and normal blood of PTH and phosphorus.

Background: High glucose concentration, through the activation of calcium channels, augments in vitro calcium entry into cells and leads to elevation in the basal levels of [Ca2+]i, the latter causes cell dysfunction., Design of Study: The present study examined whether streptozotocin-induced diabetes mellitus in rats causes a rise in [Ca2+]i of PMNL and impairs their phagocytosis and whether treatment of these rats with the calcium channel blocker, amlodipine, prevents and/or reverses these derangements. Amlodipine was given either from day one of diabetes or after 3 or 12 days of established diabetes., Results: The [Ca2+]i of PMNL was elevated and their phagocytosis was reduced after one day of diabetes. These derangements were present and became more marked with longer duration of diabetes. There was a direct and significant correlation (r = 0.88) between [Ca2+]i of PMNL and blood glucose and an inverse relationship between phagocytosis and blood glucose (r = 0.83) or [Ca2+]i (r = 0.67). Three days of amlodipine therapy were required to completely prevent or reverse the elevation in [Ca2+]i of PMNL. This action of the drug occurred despite the hyperglycaemia. Amlodipine produced marked and significant improvements in phagocytosis but the values remained modestly below normal. Amlodipine given to normal rats did not affect [Ca2+]i or phagocytosis of PMNL., Conclusion: The results show that (i) [Ca2+]i of PMNL increases and phagocytosis decreases rapidly after the induction of diabetes; (ii) treatment of diabetic rats with amlodipine normalizes [Ca2+]i of PMNL and markedly improves their phagocytosis, despite hyperglycemia; (iii) high [Ca2+]i is responsible, in major part, for the impaired phagocytosis but other factors are also operative; and (iv) calcium channel blockers could prove useful in the treatment of the metabolic and functional derangements of PMNL in patients with poorly controlled diabetes.

Elevated blood levels of cytosolic calcium--[Ca2+]i--appear to mediate the downregulation of the mRNA of the PTH-PTHrP receptor in states with chronic elevation of blood levels of parathyroid hormone (PTH). Data on the effect of hypoparathyroidism on basal levels of [Ca2+]i are not available, while those on the mRNA of the PTH-PTHrP receptor are variable. The present study was performed to measure [Ca2+]i in renal cells, to estimate the concentrations of mRNA of the PTH-PTHrP receptor in kidney, liver, and heart, and to examine the phosphaturic response to PTH and adenine 3',5'-cyclic monophosphate (cAMP) in normal rats as well as in animals after 3 weeks of parathyroidectomy (PTX). The basal levels of [Ca2+]i of the renal proximal tubular cells in PTX animals (163 +/- 5.1 nM) were not different from those in normal rats (160 +/- 4.9 nM). The concentrations of the mRNAs of the PTH-PTHrP receptor in kidney, liver, and heart were not upregulated after PTX. The phosphaturic responses to PTH or cAMP in normal and PTX rats were not different. The results show that PTX of rats with the consequent decrease in their blood levels of PTH is not associated with changes in the basal levels of [Ca2+]i, the concentrations of the mRNA of the PTH-PTHrP receptor, and in the phosphaturic response to PTH. These data lend support to the notion that the regulation of the mRNA of the PTH-PTHrP receptor in the presence of excess PTH or its lack is mediated through changes in basal levels of [Ca2+]i.

Available data indicate that the mRNAs of the PTH-PTH-related protein (PTH-PTHrP) receptor in the kidney, liver and heart are down-regulated in chronic renal failure (CRF). This is due, in major part, to the elevation of cytosolic calcium ([Ca2+]i) in the cells of these organs. If elevation in [Ca2+]i is indeed the culprit, one should be able to demonstrate down-regulation of the mRNA of the PTH-PTHrP receptor in situations without CRF and with low levels of PTH but with elevated [Ca2+]i. Such a combination of events occurs in phosphate depletion (PD). To test this hypothesis, we examined the [Ca2+]i and the concentration of the mRNA of the PTH-PTHrP receptor in the kidneys from 1, 3 and 6 weeks PD, pair-weighed (PW) rats and PD and PW rats treated with verapamil (PD-V, PW-V). To evaluate the effect of a potential rise in [Ca2+]i on urinary phosphate excretion, we also measured the phosphaturic response to PTH and cAMP in all groups of rats after 6 weeks of the dietary intervention. Renal function was normal in all groups of animals. Blood levels of PTH were significantly (p < 0.01) lower in PD and PD-V after 1 week of PD than in PW and PW-V rats, and they remained low throughout the study. The basal levels of [Ca2+]i in the renal proximal tubular cells were normal after 1 week of PD but rose by the third week of the study and remained elevated by the end of the sixth week. These values were significantly (p < 0.01) higher than those in PD-V, PW and PW-V rats. The concentrations of mRNA of the PTH-PTHrP receptor relative to that of the housekeeping gene G3DPH were significantly (p < 0.01) lower in PD rats after 3 and 6 weeks than in the other three groups of rats. The phosphaturic response to PTH or cAMP was significantly (p < 0.01) greater in PD-V rats than in PD animals. The data show that PD is associated with a rise in [Ca2+]i of renal proximal tubular cells and with down-regulation of PTH-PTHrP receptor in the kidney despite low levels of PTH and normal renal function; normalization of the concentration of [Ca2+]i in PD-V rats was associated with normal expression of mRNA of the receptor. These results provide strong support for the proposal that elevated [Ca2+]i down-regulates the mRNA of the PTH-PTHrP receptor even in the absence of CRF and elevated blood PTH levels. The improvement in the phosphaturic response to PTH and cAMP in PD-V rats is consistent with the notion that the elevated [Ca2+]i of the renal cell in PD rats may interfere with the coupling of PTH receptor-adenylate cyclase system and/or with the postreceptor events responsible for the inhibition of phosphate reabsorption by these agonists.

Basal levels of [Ca2+]i are elevated in diabetes mellitus. Such an abnormality is most likely due to both increased calcium influx into cells and decreased efflux of this ion out of the cells. The present study examined the cellular pathways that are responsible for hyperglycemia-induced acute rise in polymorphonuclear leukocytes (PMNL), and explored whether such a rise is due to increased calcium entry into PMNL and/or to calcium release from their intracellular stores. There were dose dependent and time dependent rises in the [Ca2+]i of PMNL exposed to high concentrations of glucose. Similar effects were observed when the PMNL were exposed to high concentrations of choline chloride or mannitol. A substantial part of the rise in [Ca2+]i was inhibited when the media contained verapamil or nifedipine or when the PMNL were placed in calcium free media, and the rise in [Ca2+]i was completely abolished when the PMNL were placed in calcium free media containing ryanodine. GDP beta S or pertussis toxin almost completely prevented the glucose-induced rise in [Ca2+]i of PMNL. Rp-cAMP, H-89 or staurosporine produced significant inhibition of the rise in [Ca2+]i. High concentrations of glucose produced a dose dependent shrinkage of PMNL volume over a period of two hours. The volume of PMNL, however, was normal after 24 hours in vitro incubation studies as well as after 1, 2 and 12 days of streptozotocin-induced hyperglycemia in rats. The results are consistent with the formulation that the osmotic activity (cell shrinkage) of the high glucose concentrations activates G protein(s) which then stimulates the adenylate-cAMP-protein kinase A pathway, phospholipase C system and calcium channels. The stimulation of these cellular pathways permits both calcium influx into the PMNL as well as mobilization of calcium from their intracellular stores. Both of these events contribute to the acute rise in their [Ca2+]i. It is possible that the rise in [Ca2+]i is critical for the stimulation of the events that lead to the generation and accumulation of inorganic osmolytes to restore cell volume to normal.

The study aimed to assess the influence of long-term rhuEPO treatment on secretion of pancreatic hormones (insulin, glucagon). A total of 27 haemodialyzed and 9 healthy subjects were examined. Nine patients with uraemic anaemia were treated with rhuEPO for 12 months (EPO group) while another nine patients did not receive rhu-EPO (non-EPO group), but were monitored biochemically and clinically as patients of the EPO group. The third group (HD) comprised nine haemodialyzed patients with a haematocrit value of > 30%, without rhu-EPO therapy. In all subjects plasma levels of glucose, insulin (IRI) and glucagon (Glu) were estimated before and after administration of the test meal. Patients of the EPO and non-EPO group were examined before and after 6 and 12 months of rhu-EPO treatment (EPO group) or clinical monitoring (non-EPO group) respectively, while only one test was performed in patients of the HD group and healthy subjects. During the observation period fasting glicaemia did not change. Six months of rhu-EPO therapy was followed by an increase of fasting insulinaemia and decrease of basal plasma level of glucagon. At that time point rhu-EPO therapy also increased the response of IRI and Glu to the test meal and the insulin/glucose index. After 12 months of rhu-EPO therapy basal insulinaemia and insulin/glucose index returned to the pretreatment value while plasma level of glucagon and the response to the test meal were lower than pretreatment one. Our results suggest that rhu-EPO treatment exerts a profound effect on carbohydrate metabolism and secretion of IRI. Glu, which seems to be dependent upon duration of rhu-EPO therapy and not only, or exclusively to improvement of the haematological status.

Among 94 women with diagnosed "primary" gestosis during pregnancy, 67 patients demonstrated (3-6 months after delivery) chronic glomerulonephritis (25 women) or chronic pyelonephritis (28 women) or hypertension caused by others than nephrologic reasons. "Primary" gestosis was diagnosed correctly only in 29% cases. The most often reason of "secondary" gestosis was undiagnosed chronic nephropathy before and during pregnancy. Obtained results confirm other data informing that "primary" gestosis is a rare phenomenon.

The present study aimed to assess the influence of long-term therapy with recombinant human erythropoietin (rHuEPO) for 12 months on follitropin (FSH), lutropin (LH), testosterone (TE) and estradiol (E2) serum concentrations in hemodialyzed males with chronic renal failure. Two groups of hemodialyzed males with chronic renal failure were examined. The first one consisted of 20 male patients with uraemia and renal anaemia (haematocrit value < 28%). Eleven of them were treated with rHuEPO for 12 months in order to achieve and maintain a target haematocrit value (Hct) of 30-35% (EPO group). The remaining 9 male patients were only carefully monitored both clinically and biochemically (No-EPO group). Patients of both groups (EPO and No-EPO) were intensively supervised according to the same clinical and biochemical protocol. Before (0) and after 3, 6, 9 and 12 months of the study, blood samples were withdrawn for the estimation of blood haemoglobin concentration, Hct, erythrocyte count, serum ferritin concentration, transferrin saturation and serum concentrations of FSH, LH, TE and E2. In patients of the EPO group a marked increase while of the No-EPO group, a slight, but statistically significant increase of the Hct value was found after 9 and 12 months and of E2 concentration after 3, 6, 9 and 12 months of clinical monitoring. In contrast in patients of the EPO group a statistically significant decrease of serum FSH and LH concentrations (during the first 9 months of treatment) and an increase of serum TE and E2 concentrations was observed. From results obtained in this study the following conclusions may be drawn: 1. The degree of anaemia does influence significantly the hormonal profile of the pituitary-gonadal axis in haemodialyzed males with chronic renal failure. 2. rHuEPO therapy for 12 months does exert a significant, although transitory (confined to the first 6-9 months of therapy) suppressive effect on serum follitropin and lutropin levels but increases serum testosterone and estradiol levels in these patients. 3. Alterations of both haematological parameters and of hormone serum levels of the pituitary-gonadal axis observed in EPO treated patients do not seem to be due only to the administration of this hormone.

Endocrine abnormalities in patients with chronic renal failure are well documented. The present study aimed to assess the influence of long-term erythropoietin (EPO) therapy on endocrine abnormalities in hemodialyzed patients. Two groups of hemodialyzed patients, each of which comprised 17 subjects, were examined. The first group was treated by EPO (EPO group) while the second one did not receive this hormone (No-EPO group). A complete biochemical and hormonal check-up was performed before and at the 3, 6, 9, and 12 month points of the study period. Normal values for the estimated parameters were obtained in appropriately selected sex- and age-matched healthy subjects. After EPO therapy, an increase of the hematocrit value from 21.8 +/- 0.9 to 32.6 +/- 0.9% was observed, which was accompanied by a significant decline of plasma ferritin and saturation of transferrin. In patients of the No-EPO group, a significant although less marked rise of the hematocrit value (21.4 +/- 0.4 to 24.2 +/- 0.6%) was also noticed. EPO therapy did not change plasma levels of electrolytes (Na, K, Ca, inorganic phosphate), osteocalcin, creatinine, glucose, and alkaline phosphatase as well as plasma concentrations of calcium-related hormones (PTH, calcitonin, 1,25[OH]2D3), vasopressin, and triiodothyronine. EPO treatment induced a significant decrease in somatotropin, prolactin, follitropin, lutropin, ACTH, cortisol, plasma renin activity, aldosterone, noradrenaline, adrenaline, dopamine, glucagon, pancreatic polypeptide, and gastrin plasma levels and an increase in plasma insulin, estradiol, testosterone, atrial natriuretic peptide, thyrotropin, and thyroxine.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study aimed to assess the influence of long-term recombinant human erythropoietin therapy on selected parameters of sexual function in haemodialyzed males with chronic renal failure and severe nephrogenic anaemia. All patients were randomized into two groups. The first one consisted of 11 patients treated for 12 months with rHuEPO in order to achieve and maintain a target Hct value of 30-35% (EPO group). The other 9 male patients were only carefully monitored clinically and biochemically for 12 months similarly as patients of the EPO group but were not treated with rHuEPO (No-EPO group). After 12 months of monitoringan an anonimous questionnaire was completed by the patients describing selected parameters of quality of life and sexual function. Haemodialyzed males treated with rHuEPO showed a significantly higher score of improvement of well-being, exercise tolerance, erection quality and libido as compared with patients not treated with rHuEPO. Results obtained in this study suggest, that EPO therapy shows a beneficial effect on sexual function in haemodialyzed patients with chronic renal failure.

The study aimed to assess the influence of long-term rhu-EPO treatment on secretion of pancreatic polypeptide (PP) and gastrin. A total of 27 haemodialysed patients and nine healthy subjects were examined. Nine patients with uraemic anaemia were treated with rhu-EPO for 12 months (EPO group), while another nine patients did not receive rhu-EPO (non-EPO group), but were monitored biochemically and clinically as patients of the EPO group. The third group (HD) comparised nine haemodialysed patients with a haematocrit value > or = 30% without rhu-EPO therapy. In all subjects plasma levels of PP and gastrin were estimated before and after administration of a test meal. Patients of the EPO and non-EPO group were examined before and after 6 and 12 months of rhu-EPO therapy (EPO group) or clinical monitoring (non-EPO group) respectively, while only one test was performed in patients of the HD group and healthy subjects. Six months rhu-EPO therapy was followed by an decrease of basal plasma level of PP and increased response of gastrin to the test meal. After 12 months of rhu-EPO therapy basal plasma level of PP was still lower, the response of PP secretion to a test meal was higher, while that of gastrin secretion lower that the pretreatment ones. Our results suggest, that rhu-EPO treatment exerts effect on secretion of PP and gastrin. These alterations seem not to be related to improvement of the haematological status.

This study aimed to assess the effect of anaemia on volume related hormones in dialyzed patients with chronic uraemia. Three groups of subjects were examined. The first one comprised 34 hemodialyzed patients with severe anaemia (haematocrit value < 28%). 17 patients were treated with EPO for 1 year (EPO group) while the other 17 patients did not receive rHuEPO (no-EPO group) but were intensively monitored biochemically and clinically as patients of the EPO group. The second group (HD) consisted of 12 hemodialyzed uraemic patients with a Hct > 30% without rHuEPO treatment, while the third one comprised 15 healthy subjects. In patients of the EPO and no-EPO group plasma renin activity (PRA), plasma concentration of aldosterone (Ald) atrial natriuretic peptide (ANP and vasopressin (AVP) were assessed before (0) and after 3, 6, 9 and 12 months of clinical monitoring, while in patients of the HD group and in normals the above mentioned parameters were estimated only once. EPO treatment improved significantly the Hct value already after three months of therapy. No significant changes in PRA and plasma concentrations of Ald, ANP and AVP in the noEPO group were noticed during 12 months of monitoring. In contrast EPO treatment induced a significant, although transitory decrease of PRA, Ald and AVP, but an increase of plasma ANP. No influence of rHuEPO therapy on blood pressure was noticed.(ABSTRACT TRUNCATED AT 250 WORDS)

As already reported short-term rHuEpo treatment influences plasma insulin, glucagon, pancreatic polypeptide (PP), and gastrin secretion in haemodialysed patients. The present study aimed to assess the influence of long-term rHuEpo treatment on secretion of above mentioned hormones. A total of 27 haemodialysed patients and nine healthy subjects were examined. Nine patients with uraemic anaemia were treated with rHuEpo for 12 months (Epo group) while another nine patients did not receive rHuEpo (non-Epo group), but were monitored biochemically and clinically as patients of the Epo group. The third group (HD) comprised nine haemodialysed patients with a haematocrit value of > or = 30% without rHuEpo therapy. In all subjects plasma levels of insulin, glucagon, gastrin, and PP were estimated before and after administration of a test meal. Patients of the Epo group were examined before and after 6 and 12 months of rHuEpo treatment (patients of the Epo group) or clinical monitoring (patients of the non-Epo group) respectively, while only one test was performed in patients of the HD group and healthy subjects. Six months of rHuEpo treatment was followed by an increase of fasting insulinaemia and a decrease of basal plasma level of glucagon and PP. At that time point rHuEpo therapy also increased the response of insulin, glucagon, and gastrin to the test meal.(ABSTRACT TRUNCATED AT 250 WORDS)

Exacerbation of secondary hyperparathyroidism (as manifested by calcium deposits and local inflammation in periarticular tissues) has been reported in haemodialyzed (HD) uraemic patients treated with recombinant human erythropoietin. However, short-term treatment with recombinant human erythropoietin (r-Hu EPO) did not influence significantly plasma levels of parathyroid hormone (PTH), calcitonin (CT) and 25-hydroxycholecalciferol (25-OHD3) in uraemic HD patients. The present study aimed to assess the effect of long-term r-Hu EPO therapy for 12 months on plasma PTH, CT, 25-OHD3 and 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) in uraemic HD patients.

Eleven uraemic predialysis patients have been selected for the treatment of anaemia with rhuEPO. Administration of rhuEPO was followed by a significant increase of the Hct value and haemoglobin concentration as well as an improvement of well being. The main adverse effects of rhuEPO therapy were the following: increase of blood pressure, reduction of the residual renal function and increase of serum potassium and phosphorous concentration. Monitoring of the iron status in uraemic predialysis patients on rhuEPO therapy seems to be mandatory.

Endocrine abnormalities in patients with chronic renal failure are well documented. The present study aimed to assess the influence of long-term erythropoietin (EPO) therapy on endocrine abnormalities in haemodialyzed patients. Two groups of haemodialyzed patients, each of which comprised 17 subjects, were examined. The first one treated by EPO (EPO group) while the second one did not receive this hormone (NO-EPO group). A complete biochemical and hormonal check-up was performed before and at the 3, 6, 9 and 12 months of the study period. Normal values for the estimated parameters were obtained in appropriately selected sex and age-matched healthy subjects. After EPO therapy an increase of the haematocrit value from 21.8 +/- 0.9% to 32.6 +/- 0.9% was observed which was accompanied by a significant decline of plasma ferritin and saturation of transferrin. In patients of the NO-EPO group a significant although less marked rise of the haematocrit value (21.4 +/- 0.4% to 24.2 +/- 0.6%) was also noticed. EPO therapy did not change electrolytes (Na, K, Ca, inorganic phosphate), osteocalcin, creatinine, glucose and alkaline phosphatase plasma levels as well as plasma concentrations of calcium related hormones (PTH, calcitonin, 1.25(OH)2D3) and vasopressin (AVP). EPO treatment induced a significant decline of somatotropin (HGH), prolactin (PRO), follitropin (FSH), lutropin (LH), ACTH, cortisol, plasma renin activity, aldosterone, insulin (IRI), glucagon (IR-G), pancreatic polypeptide (PP) and gastrin plasma levels and an increase of plasma estradiol, testosterone and atrial natriuretic peptide (ANP). These EPO induced endocrine alterations were restricted mostly to the first 6 months of EPO administration.(ABSTRACT TRUNCATED AT 250 WORDS)

In 30 patients with renovascular hypertension, 50 with hypertension in a course of arteries, 71 hypertensive subjects with coexisting parenchymal nephropathy and in 63 with primary hypertension the captopril test was performed after 8 hours night rest and within high sodium diet. Positive test result was stated in 76.67% of patients with renovascular hypertension, in 70.59% of patients with arteritis, in 53.52% of patients with hypertension and coexisting parenchymal nephropathy and in 63.49% of patients with primary hypertension. Significant correlation between increase of plasma renin activity and blood pressure decrease after captopril administration was only stated in patients with renovascular hypertension and in those with arteritis. Results of performed studies impaired the captopril test value in diagnostics of renin-dependent hypertension.