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BACKGROUND: A variety of stimuli are involved in the pathogenesis of parathyroid gland hyperplasia in renal failure. Recently, it was shown that blocking the signal from the endothelin-1 (ET-1) receptor (ET(A)R/ET(B)R) by a non-selective receptor antagonist, bosentan, reduced parathyroid cell proliferation, parathyroid gland hyperplasia and parathyroid hormone (PTH) levels in normal rats on a calcium deficient diet. Our goal was to determine whether in 5/6 nephrectomized (NPX) rats with developing or established hyperparathyroidism, the endothelin receptor blocker, bosentan, reduced the increase in parathyroid cell proliferation, parathyroid gland hyperplasia and PTH values. METHODS: High (HPD, 1.2%) or normal phosphorus diets (PD) (NPD, 0.6%) were given to 5/6 NPX rats for 15 days (NPX(15)). In each dietary group, one-half the rats were given bosentan (B) i.p. 100 mg/kg/day. The four groups of rats were: (1) NPX(15)-1.2% P; (2) NPX(15)-1.2% P+B; (3) NPX(15)-0.6% P; and (4) NPX(15)-0.6% P+B. In a second study in which hyperparathyroidism was already established in 5/6 NPX rats fed a HPD for 15 days, rats were divided into two groups in which one group was maintained on a HPD and the other group was changed to very low PD (VLPD, <0.05%) for an additional 15 days. In each dietary group, one-half the rats were given bosentan i.p. 100 mg/kg-day. The four groups of rats were: (1) NPX(30)-1.2% P; (2) NPX(30)-1.2% P+B; (3) NPX(30)-0.05% P and (4) NPX(30)-0.05% P+B. Parathyroid cell proliferation was measured by proliferating cell nuclear antigen (PCNA) staining and ET-1 expression by immunohistochemical techniques. RESULTS: In the study of developing hyperparathyroidism, bosentan reduced ET-1 expression in the parathyroid glands of rats on the NPD and HPD (P<0.05). But only in rats on the NPD did bosentan result in a reduced increase in parathyroid gland weight (P<0.05). In the study of established hyperparathyroidism, in which 5/6 NPX rats were given a HPD for 15 days, bosentan started on day 15 reduced (P<0.05) ET-1 expression in rats maintained for 15 additional days on the HPD or the VLPD. On the VLPD, parathyroid gland weight was less (P<0.05) than that in rats on the HPD sacrificed at 15 or 30 days. Bosentan did not reduce parathyroid cell proliferation or parathyroid gland weight in rats maintained on the HPD or further reduce these parameters beyond that obtained with dietary phosphorus restriction. PTH values were lowest in the VLPD group, intermediate in the NPD group, and highest in the HPD group, but in none of the three groups did bosentan decrease PTH values. CONCLUSIONS: In azotemic rats with developing hyperparathyroidism, bosentan resulted in a reduced increase in parathyroid gland weight when dietary phosphorus content was normal. Despite a reduction in ET-1 expression in rats on a HPD with developing or established hyperparathyroidism, bosentan did not reduce the increase in parathyroid cell proliferation, parathyroid gland growth or PTH values. Thus, ET-1 blockade with bosentan did not prevent parathyroid gland growth in the azotemic rat.

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BACKGROUND: Both dietary phosphorus restriction and the ingestion of ammonium chloride (NH(4)Cl) given to rats on a high-phosphorus diet have been shown to preserve renal function in the azotaemic rat. Parathyroidectomy also has been reported to preserve renal function and, in addition, to prevent kidney hypertrophy in the remnant kidney model. Our goals were (i) to evaluate in azotaemic rats the effect of dietary phosphorus on renal function in a shorter time frame than previously studied and (ii) to determine whether NH(4)Cl administration (a) enhances the renoprotective effect of dietary phosphorus restriction and (b) improves renal function in the absence of parathyroid hormone (PTH). METHODS: High (H; 1.2%), normal (N; 0.6%) and low (L; <0.05%) phosphorus diets (PD) were given for 30 days to 5/6 nephrectomized rats. In each dietary group, one-half of the rats were given NH(4)Cl in the drinking water. The six groups were HPD + NH(4)Cl, HPD, NPD + NH(4)Cl, NPD, LPD + NH(4)Cl and LPD. The effect of NH(4)Cl administration was also evaluated in 5/6 nephrectomized, parathyroidectomized (PTX) rats on NPD. RESULTS: In each of the three dietary phosphorus groups, creatinine and urea clearances were greater (P<0.01) in rats receiving NH(4)Cl. Neither creatinine nor urea clearance was reduced by high dietary phosphorus. Urine calcium excretion was greatest in the LPD group and was increased (P < or = 0.001) in all three groups by NH(4)Cl ingestion. An inverse correlation was present between plasma calcium and phosphorus in the parathyroid intact (r = -0.79, P<0.001) and PTX groups (r = -0.46, P = 0.02). In PTX rats, NH(4)Cl ingestion increased (P < or = 0.01) creatinine and urea clearances and both an increasing plasma calcium concentration (r = 0.67, P<0.001) and urine calcium excretion (r = 0.73, P<0.001) increased urine phosphorus excretion. CONCLUSIONS: At 30 days of renal failure (i) NH(4)Cl ingestion increased creatinine and urea clearances, irrespective of dietary phosphorus; (ii) high urine calcium excretion, induced by dietary phosphorus restriction and NH(4)Cl ingestion, did not adversely affect renal function; (iii) high dietary phosphorus did not decrease renal function; (iv) the absence of PTH did not preserve renal function or prevent NH(4)Cl from improving renal function; and (v) both an increasing plasma calcium concentration and urine calcium excretion resulted in an increase in urine phosphorus excretion in PTX rats.

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BACKGROUND: Kidney hypertrophy is stimulated by both partial nephrectomy and NH(4)Cl administration. Also, parathyroidectomy (PTX) has been reported to prevent kidney hypertrophy induced by a high protein diet. Our goal was to determine in the azotaemic rat: (i) the combined effects of NH(4)Cl administration and dietary phosphorus on the development of kidney hypertrophy and calcium deposition in the kidney and (ii) whether the absence of parathyroid hormone (PTH) affected the development of kidney hypertrophy and calcium deposition. METHODS: High (HPD, 1.2%), normal (NPD, 0.6%) or low (LPD, <0.05%) phosphorus diets were given to 5/6 nephrectomized rats for 30 days. In each dietary group, one-half of the rats were given NH(4)Cl in the drinking water. The six groups of rats were: (i) HPD + NH(4)Cl; (ii) HPD; (iii) NPD + NH(4)Cl; (iv) NPD; (v) LPD + NH(4)Cl and (vi) LPD. In a separate study, PTX was performed to determine whether PTH affected renal hypertrophy in 5/6 nephrectomized rats given NH(4)Cl. RESULTS: Both with and without NH(4)Cl (+/-NH(4)Cl), kidney weight was greatest (P<0.05) in the HPD groups. In each dietary phosphorus group, kidney weight was greater (P<0.05) in the NH(4)Cl group. In both the +/-NH(4)Cl groups, kidney calcium content was greatest (P<0.05) in the HPD group, but was less (P<0.05) in the NPD and HPD groups given NH(4)Cl. An inverse correlation was present between creatinine clearance and kidney calcium content (r = -0.51, P<0.001). When factored for kidney weight, creatinine clearance was less (P<0.05) in the HPD group in both the +/-NH(4)Cl groups, but was greater in the HPD + NH(4)Cl than in the HPD group. In PTX rats, kidney weight was greater (P<0.05) and kidney calcium deposition was less (P<0.05) in rats given NH(4)Cl. CONCLUSIONS: In azotaemic rats studied for 30 days, NH(4)Cl administration induced kidney hypertrophy. A HPD also induced kidney hypertrophy. The effects on kidney calcium deposition were divergent for which NH(4)Cl administration decreased and a HPD increased calcium deposition. The inverse correlation between kidney calcium content and creatinine clearance suggests that kidney calcium deposition is harmful to renal function. When factored for kidney weight, the lower creatinine clearance in the high phosphorus group suggests that kidney hypertrophy does not completely compensate for the harmful effects of a HPD. This result also suggests that a longer study would probably result in more rapid deterioration in the high phosphorus group. In PTX rats, the absence of PTH did not prevent NH(4)Cl from inducing kidney hypertrophy and reducing kidney calcium deposition. In conclusion, NH(4)Cl and dietary phosphorus each independently affect kidney growth and calcium deposition in the growing rat with renal failure.

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BACKGROUND/AIMS: In in vitro studies, a high phosphate concentration has been shown to directly stimulate parathyroid hormone (PTH) secretion in a normal calcium concentration and to reduce PTH suppression in a high calcium concentration. In hemodialysis patients during dialysis-induced hypercalcemia, the effect of hyperphosphatemia on PTH secretion was less than in vitro studies. Our goal was to determine whether hyperphosphatemia retards PTH suppression during calcitriol-induced hypercalcemia in azotemic rats with hyperparathyroidism. METHODS: Rats underwent a two-stage 5/6 nephrectomy or sham operations. After surgery, rats received a high phosphate diet (P 1.2%, Ca 0.6%) for 4 weeks to induce hyperparathyroidism and then were placed on a normal diet (P 0.6%, Ca 0.6%) for two additional weeks to normalize serum calcium values in azotemic rats. At week 7, rats were divided into five groups and before sacrifice received at 24-hour intervals, three doses of calcitriol (CTR) or its vehicle. The five groups and dietary phosphate content were: group 1--normal renal function (NRF) + 0.6% P + vehicle; group 2--NRF + 0.6% P + CTR; group 3--renal failure (RF) + 0.6% P + vehicle; group 4--RF + 1.2% P + CTR; and group 5--RF + 0.6% P + CTR. RESULTS: In the two CTR-treated groups with marked hypercalcemia (groups 2 and 5), 15.52 +/- 0.26 and 15.12 +/- 0.13 mg/dl, respectively, stepwise regression showed that hyperphosphatemia retarded PTH suppression. When the two azotemic groups treated with CTR (groups 4 and 5) were combined to expand the range of serum calcium values, stepwise regression showed that hypercalcemia suppressed and hyperphosphatemia modestly retarded PTH suppression. Similarly, in groups 4 and 5 combined, correlations were present between PTH and both serum calcium (r = -0.70, p < 0.001) and serum phosphate (r = 0.64, p = 0.001). CONCLUSIONS: Hypercalcemia and high doses of calcitriol markedly reduced PTH secretion in azotemic rats despite severe hyperphosphatemia. Even though hyperphosphatemia did retard PTH suppression during hypercalcemia, its effect was small.

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BACKGROUND: The effect of hyperphosphataemia on serum calcium regulation in renal failure has not been well studied in a setting in which hypercalcaemia is not parathyroid hormone (PTH) mediated. In azotemic rats with a normal serum calcium concentration, an increased dietary phosphate burden affects serum calcium regulation because of its effects on skeletal resistance to PTH, calcitriol production, and possibly intestinal calcium absorption. Our goal was to determine how hyperphosphataemia affected the development of hypercalcaemia during calcitriol-induced hypercalcaemia and PTH suppression in azotemic rats with established hyperparathyroidism. METHODS: Rats underwent a two-stage 5/6 nephrectomy or corresponding sham operations. After surgery, rats were given a high phosphate diet (P 1.2%) for 4 weeks to exacerbate hyperparathyroidism and were then changed to a normal diet (P 0.6%) for 2 weeks to normalize serum calcium values in the azotemic rats. At week 7, rats were divided into five groups and sacrificed after receiving three intraperitoneal doses of calcitriol (CTR, 500 pmol/100 g) or vehicle at 24 h intervals. The five groups and dietary phosphate content were: group 1, normal renal function (NRF)+0.6% P+vehicle; group 2, NRF+0.6% P+CTR; group 3, renal failure (RF)+0.6% P+vehicle; group 4, RF+1.2% P+CTR; and group 5, RF+0.6% P+CTR. Both the 0.6% and 1.2% phosphate diets contained 0.6% calcium. RESULTS: Serum creatinine values were increased (P<0.05) in 5/6 nephrectomized rats (groups 3, 4 and 5), as were serum calcium values (P<0.05) in CTR-treated rats (groups 2, 4 and 5) and serum phosphate values (P<0.05) in CTR-treated azotemic rats (groups 4 and 5). Serum PTH values were suppressed (P<0.05) in CTR-treated hypercalcemic rats (groups 2, 4 and 5) and increased (P<0.05) in azotemic rats not given CTR (group 3). In the azotemic groups (groups 3, 4 and 5), an inverse correlation was present between serum calcium and phosphate in each group, despite a wide variation in serum calcium values. The slope of the inverse relationship between serum calcium and phosphate was steeper in CTR-treated azotemic rats on a 1.2% phosphate (group 4) diet than on a 0.6% phosphate (group 5) diet (P=0.02). Thus, for a similar increase in the serum phosphate concentration, serum calcium values decreased more in group 4 than in group 5. The independent effect of dietary phosphate on serum calcium values was also confirmed by analysis of covariance. Finally, the serum calcium concentration was shown to be greater for any given serum phosphate value in CTR-treated rats than in those not on CTR. CONCLUSIONS: In azotemic rats with calcitriol-induced hypercalcaemia, the magnitude of hypercalcaemia is affected by: (i) the serum phosphate concentration; and (ii) differences in dietary phosphate content. Calcitriol administration also acts to shift upwards the relationship between serum calcium and phosphate so that a higher serum calcium concentration can be maintained for any given serum phosphate value.

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