Oxyphil cells of parathyroid glands in chronic renal failure may not secrete parathyroid hormone

To evaluate the function of parathyroid oxyphil cell in chronic renal failure, we studied the histopathological findings of 148 parathyroid glands of 42 patients (29 males, 13 females) on maintenance hemodialysis. The individual and total weights of resected parathyroid specimens in each patient were recorded. Using the morphometrical analyzing system, we measured the oxyphil cell area and total area in each excised section taken through the maximum diameter, to estimate them in each patients. According to the fractional ratio (R:oxyphil cell area/total area), patients were divided into four groups: group I (R less than 1%), group II (1% less than or equal to 5%), group III (5% less than or equal to R less than 10%) and group IV (10% less than or equal to R). There were no differences in age, duration of hemodialysis and serum C-PTH level among the different groups. There was a positive correlation not only between total glandular weight and serum C-PTH level, but also between total glandular weight and total area, and also a positive correlation was found between serum C-PTH level and total area. No tendency was found between oxyphil cell area and serum C-PTH level. However, in 15 patients whose oxyphil cell area was more than 10 mm2, there was a negative correlation between the area and serum C-PTH level. Also, in 16 patients whose R was more than 5%, there was a negative correlation between the rate and serum C-PTH level. These results suggested that oxyphil cell in chronic renal failure might not secrete PTH.     

Disturbances of lipid metabolism in children with chronic renal failure

This review discusses the pathogenesis, clinical significance and current therapy of hyperlipoproteinaemia (HLP) in children with chronic renal failure. Uraemic dyslipidaemia, characterized by hypertriglyceridaemia and low high-density lipoprotein-cholesterol levels, is present in the majority patients with chronic renal failure. In addition, serum levels of total cholesterol, very lowdensity lipoprotein-cholesterol, low-density lipoproteincholesterol and apolipoprotein B are frequently elevated. The pathophysiological mechanisms causing these disturbances are complex and mainly involve a diminished catabolism of triglyceride-rich lipoproteins. For unknown reasons and independent of other lipoproteins, serum levels of the highly atherogenic and thrombogenic lipoprotein(a) are also often elevated. HLP is an important factor in cardiovascular morbidity and mortality. In addition, dyslipidaemia may enhance progression of renal disease in patients with residual renal function. Therefore, treatment of HLP seems indicated in overtly hyperlipidaemic patients, but until there is more experience with lipid-lowering drugs in children, no safe recommendations for pharmacological treatment of HLP can be given. Dietary modifications can be recommended only to a limited extent.     

Inhibition of immunoglobulin production by parathyroid hormone. Implications in chronic renal failure

Available data indicate that B cell proliferation is inhibited in chronic renal failure and this is due to excess blood levels of PTH. This defect may also affect immunoglobulin production. We examined production of IgG, IgM and IgA by B cells stimulated with Staphylococcus aureus Cowan I (SAC) or with pokeweed mitogen (PWM) after eight days of culture and evaluated the effect of PTH on this process in 34 hemodialysis patients and 44 normal subjects. IgG, IgM and IgA production by B cells from patients was lower (P less than 0.01) than by B cells from normal subjects. Both 1-34 and 1-84 PTH inhibited (P less than 0.01) immunoglobulin production by B cells from normal subjects and dialysis patients. However, this inhibitory effect was evident in dialysis patients only with the higher dose of PTH. The inhibition of immunoglobulin production by PTH occurred only when the hormone was added at the initiation of the B cell culture. Inactivation of PTH abolished its inhibitory effect on immunoglobulin production. Agents that stimulate cAMP production (forskolin, cholera toxin) and the cAMP analogue, 8-bromoadenosine 3',5' cyclic monophosphate inhibited immunoglobulin production by B cells from both normal and dialysis patients, and the degree of inhibition was not different between the two groups. The calcium inophore A23187 also inhibited IgG, IgA and IgM production by B cells from normal subjects and dialysis patients; there was no significant difference in the degree of inhibition between the two groups. The resting levels of cytosolic calcium in B cells of dialysis patients was significantly (P less than 0.01) higher than that of B cells from normal subjects. The data show that: (1) immunoglobulin production is impaired in dialysis patients; (2) B cells of dialysis patients have elevated resting levels of cytosolic calcium; (3) PTH inhibits IgG, IgA and IgM production and this effect is at least partly mediated by PTH-induced cAMP production and alterations in cytosolic calcium into B cells; (4) this inhibitory effect is mediated by events that affect initial stages of B cell proliferation and maturation; (5) the requirement for high dose of PTH for its inhibitory effect on B cells from dialysis patients is probably due to desensitization and/or down-regulation of PTH receptors on B cells. The results are consistent with the proposition that impaired immunoglobulin production by B cells from dialysis patients is at least partly due to the state of secondary hyperparathyroidism in these patients.     

Inhibition of erythropoiesis in chronic renal failure: the role of parathyroid hormone

Sera from 20 anemic patients with chronic renal failure (CFR) were studied for their effect on bone marrow in vitro erythroid colony formation (CFUE) and the observations correlated with parathyroid hormone (PTH) and ionized calcium levels in the patients' sera. Results demonstrated that 17 out of 20 patients' sera significantly inhibited in vitro erythropoiesis by 47% to 97%. No significant elevation in ionized calcium was found in 16 of the patients tested. Furthermore, assay of PTH levels in these patients revealed that 9 out of 20 had elevated levels of PTH. No correlation was found between PTH serum levels and the degree of in vitro inhibition of erythropoiesis (CFUE) by the patients' sera. Addition of up to 2,000 pg/mL (far above the patients' levels) of exogenous N-terminal or C-terminal PTH with in vitro bone marrow cultures resulted in no inhibitory effect on CFUE. It is concluded that the circulating inhibitor of erythropoiesis which has been shown to exist in the sera of this particular group of patients with CRF, is not PTH.     

Lack of relationship between parathyroid hormone and 1,25-dihydroxyvitamin D in chronic renal failure

In the present study, concentrations of parathyroid hormone (PTH), determined by an intact PTH assay and a midregion/C-terminal PTH assay, 1,25-dihydroxyvitamin D [1,25(OH)2D3], ionized calcium and phosphate were measured in 15 patients with a stable creatinine clearance (Ccr) of 21.2 +/- 14.4 ml/min (mean +/- SD; group 1) and in 10 patients with a Ccr regularly undergoing hemodialysis (group 2, Ccr not measured). In group 1, the mean concentration of 1,25(OH)2D3 was significantly increased compared with the level in group 2, whereas no differences were found concerning the concentrations of intact PTH, midregion/C-terminal PTH, ionized calcium and phosphate. In group 1, the PTH concentration correlated inversely with ionized calcium concentration and Ccr, which in turn, was directly correlated. The concentration of 1,25(OH)2D3 correlated inversely with phosphate concentration, but did not correlate with either PTH or ionized calcium concentrations. In group 2 no correlation was found between any of the biochemical variables. The data demonstrate that in patients with stable renal failure, the concentration of ionized calcium still regulates PTH secretion but other variables such as parathyroid cell mass and setpoint may interfere with the interrelation. The elevated concentration of phosphate in renal failure may override PTH as a regulator of the renal 1,25(OH)2D3 formation. The lack of correlation in the hemodialyzed patients may be attributed to extrarenal production of 1,25(OH)2D3, reduced binding of 1,25(OH)2D3 to parathyroid tissue or the major changes in calcium homeostasis caused by the hemodialysis.     

Regulation of parathyroid function in chronic renal failure

This review summarizes the factors involved in the development of hyperparathyroidism secondary (2nd-HPTH) to chronic kidney disease (CKD). Calcium and calcitriol act on their respective specific parathyroid cell receptors to inhibit parathyroid function. As well as the well-known effect of calcium and calcitriol on parathyroid cell function, there is experimental work that demonstrates that phosphate, changes in pH, PTHrP, estrogens, and some cytokines also have an effect on PTH secretion. These factors are relevant in patients with chronic kidney disease. However, low calcium, vitamin D deficiency, and an accumulation of phosphate due to the decrease in renal function are the main pathogenic factors involved in the pathogenesis of 2nd-HPTH in CKD patients.     

Effect of aluminum and parathyroid hormone on osteoblasts and bone mineralization in chronic renal failure

Bone aluminum, quantitative bone histology, and plasma parathyroid hormone (PTH) were compared in 29 patients undergoing chronic hemodialysis. Histologic techniques included double tetracycline labeling and histochemical identification of osteoclasts and osteoblasts. Bone aluminum was measured chemically by flameless atomic absorption spectrophotometry, and histochemically. When measured chemically, the bone aluminum was 67 +/- 46 (SD) mg/kg dry weight (normal 2.4 +/- 1.2 mg/kg); histochemically, aluminum was present at 2.9 +/- 4.4% of trabecular surface. The biochemical and histochemical results agreed well (r = 0.80, P less than 0.001). No double tetracycline labels were seen at the mineralization front where aluminum was deposited, indicating cessation of mineralization at these sites. The osteoblast surface correlated positively with plasma PTH (r = 0.67, P less than 0.001) and negatively with bone aluminum level (r = -0.42, P less than 0.05). Multiple linear regression showed a correlation of aluminum with osteoblasts additional to that of PTH, consistent with a direct effect of aluminum in depressing osteoblast numbers. Though a relationship between PTH and chemically determined bone aluminum level could not be demonstrated, there was a negative correlation between osteoclast count and aluminum, and the nine patients with severe hyperparathyroid bone disease had lower chemically determined aluminum levels than the other patients. These results suggest that aluminum (a) directly inhibits mineralization, (b) is associated with decreased PTH activity and hence osteoblast numbers, and (c) directly reduces osteoblast numbers. In addition to inducing severe, resistant osteomalacia, aluminum appears to contribute to the mild osteomalacia commonly seen in renal failure, characterized by extensive thin osteoid and low tetracycline and osteoblast surfaces.     

Effect of aluminum and parathyroid hormone on osteoblasts and bone mineralization in chronic renal failure

Summary Bone aluminum, quantitative bone histology, and plasma parathyroid hormone (PTH) were compared in 29 patients undergoing chronic hemodialysis. Histologic techniques included double tetracycline labeling and histochemical identification of osteoclasts and osteoblasts. Bone aluminum was measured chemically by flameless atomic absorption spectrophotometry, and histochemically. When measured chemically, the bone aluminum was 67±46 (SD) mg/kg dry weight (normal 2.4±1.2 mg/kg); histochemically, aluminum was present at 2.9±4.4% of trabecular surface. The biochemical and histochemical results agreed well (r=0.80,P<0.001). No double tetracycline labels were seen at the mineralization front where aluminum was deposited, indicating cessation of mineralization at these sites. The osteoblast surface correlated positively with plasma PTH (r=0.67,P<0.001) and negatively with bone aluminum level (r=−0.42,P<0.05). Multiple linear regression showed a correlation of aluminum with osteoblasts additional to that of PTH, consistent with a direct effect of aluminum in depressing osteoblast numbers. Though a relationship between PTH and chemically determined bone aluminum level could not be demonstrated, there was a negative correlation between osteoclast count and aluminum, and the nine patients with severe hyperparathyroid bone disease had lower chemically determined aluminum levels than the other patients. These results suggest that aluminum (a) directly inhibits mineralization, (b) is associated with decreased PTH activity and hence osteoblast numbers, and (c) directly reduces osteoblast numbers. In addition to inducing severe, resistant osteomalacia, aluminum appears to contribute to the mild osteomalacia commonly seen in renal failure, characterized by extensive thin osteoid and low tetracycline and osteoblast surfaces.     

Aluminium accumulation in chronic renal failure affects erythropoiesis

Summary: Aluminium (Al) toxicity has been associated with anaemia in exposed patients with chronic renal failure (CRF). the present study was undertaken to determine whether the ingestion of Al citrate was able to affect erythropoiesis in rats with normal or impaired renal function. the renal insufficiency was induced by surgical procedures and control rats were sham operated. Twenty-four rats were allocated to four groups of six rats each: (A) Sham; (B) Sham+Al; (C) CRF; and (D) CRF+Al. the groups B and D received daily doses of Al citrate (0.5 μmol/g bodyweight) and the groups A and C, deionized water, via the intragastric route. At the end of the experimental period (15 weeks) cultures of late erythroid progenitor cells (CFU-E) stimulated with erythropoietin were performed and haematological parameters determined. the liver, kidney, brain, bone and serum Al amounts were quantified. the results are expressed as median and interquartile range. the CFU-E growth was found inhibited in B and D groups (A: 100; B: 74/54-83; C: 86/54-98; D: 46/39-53 %). the haematocrit values were significantly diminished in rats with renal insufficiency when compared to controls (A: 42/40-43; B: 45/42-46; C: 37/32-40 and D: 37/24-39 %). Serum Al accumulation was observed in B and D groups receiving Al (A: 8/5-12; B: 36/36-44; C: 5/5-6; D: 45/26-132 μg Al/l). No differences among groups were found in the liver and kidney Al contents, but uraemic state favoured Al accumulation in brain (A: 6/5.0-9.0; B: 4/3.8-4.3; C: 2/1.0-3.0; D: 15/12.0-21.0 μg Al/g tissue) and bone (A: 29/27-31; B: 30/29-39; C: 42/33-48; D: 68/56-79 μg Al/g tissue). We suggest that the heavy accumulation of Al in the bone compartment may result in a protracted endogenous exposure of bone marrow cells, affecting the erythropoiesis in vivo.     

Vascular calcification: contribution of parathyroid hormone in renal failure

Hyperphosphatemia is a driving force in the pathogenesis of vascular calcification (VC) and secondary hyperparathyroidism associated with renal failure. To test for the possible contribution of parathyroid hormone (PTH) to cardiovascular calcification, we removed the parathyroid glands from rats but infused synthetic hormone at a supraphysiologic rate. All rats were pair-fed low, normal, or high phosphorus diets and subjected to a sham or 5/6 nephrectomy (remnant kidney). Control rats were given a normal diet and underwent both sham parathyroidectomy and 5/6 nephrectomy. Heart weight/body weight ratios and serum creatinine levels were higher in remnant kidney rats than in the sham-operated rats. Remnant kidney rats on the high phosphorus diet and PTH replacement developed hyperphosphatemia and hypocalcemia along with low bone trabecular volume. Remnant kidney rats on the low phosphorus diet or intact kidney rats on a normal phosphorus diet, each with hormone replacement, developed hypercalcemia. All rats on PTH replacement developed intense aortic medial calcification, and some animals presented coronary calcification. We suggest that high PTH levels induce high bone turnover and medial calcification resembling M?mckeberg's sclerosis independent of uremia. This model may be useful in defining mechanisms underlying VC.     

Role of parathyroid hormone in the downregulation of liver cytochrome P450 in chronic renal failure

Chronic renal failure (CRF) is associated with a decrease in drug metabolism secondary to a decrease in liver cytochrome P450 (P450). The predominant theory to explain this decrease is the presence of factors in the blood of uremic patients. This study tested the hypothesis that parathyroid hormone (PTH) could be this factor. The objectives of this study were to determine (1) the role of PTH in the downregulation of hepatocyte P450 induced by rat uremic serum, (2) the role of PTH in the downregulation of liver P450 in rats with CRF, and (3) the effects of PTH on P450 in hepatocytes. For this purpose, (1) hepatocytes were incubated with serum from rat with CRF that was depleted with anti-PTH antibodies or with serum from parathyroidectomized (CRF-PTX) rat with CRF, (2) the effect of PTX on liver P450 was evaluated in rats with CRF, and (3) the effects of PTH on P450 in hepatocytes were determined. The depletion of PTH from CRF serum completely reversed the downregulating effect of CRF serum on P450 in hepatocytes. Addition of PTH (10(-9) M) to depleted CRF serum induced a decrease in P450 similar to nondepleted CRF serum. The serum of CRF-PTX rats had no effect on P450 in hepatocytes compared with CRF serum. Adding PTH to CRF-PTX serum induced a similar decrease in P450 as obtained with CRF serum. Finally, PTX prevented the decrease of liver P450 in rats with CRF. In summary, PTH is the major mediator implicated in the downregulation of liver P450 in rats with CRF.     

Phosphate excretion in chronic renal failure: evidence for a mechanism other than circulating parathyroid hormone

The mechanism of the increased phosphaturia of chronic renal failure was investigated in seven patients with creatinine clearances ranging from 22 to 63 ml/min. Phosphorus deprivation for 2 to 7 weeks resulted in a marked and rapid reduction in urinary total and fractional phosphate excretion. Serum immunoreactive parathyroid hormone concentration initially remained unchanged and eventually decreased slowly from 330 +/- 50 microliterEq per ml (control) to 252 +/- 58 microliterEq per ml (P less than 0.025), but persisted substantially elevated above the normal range (10-60 microliterEq per ml). Thus, phosphate excretion in chronic renal failure can be regulated to a major extent by the dietary phosphorus intake independently of parathyroid hormone.     

Erythrocyte peroxide metabolism,plasma lipid pattern and hemorheological profile in chronic renal failure

We analysed the main alterations of the erythrocyte peroxide metabolism and plasma lipid pattern, and their direct or indirect influence on erythrocyte rheology in subjects with mild and stable chronic renal failure in conservative treatment. In particular, we describe the red cell metabolic parameters and macro- and microrheological make-up in this clinical condition.