Parathyroid hyperplasia in uremic rats precedes down-regulation of the calcium receptor.

BACKGROUND: Recent evidence points to a relationship between the down-regulation of the calcium-sensing receptor (CaR) and parathyroid cell hyperplasia that is associated with chronic renal failure. It is not known, however, if down-regulation of the CaR precedes, and perhaps initiates, parathyroid cell proliferation, or if a decrease in the expression of the CaR occurs subsequently to hyperplasia or the conditions promoting it. The current study examined the temporal relationship of these two events. METHODS: Rats were made uremic by subtotal nephrectomy and were (1) placed immediately on a high phosphate (HP) diet that promotes parathyroid gland hyperplasia, or (2) maintained on a low phosphate (LP) diet that inhibits development of secondary hyperparathyroidism before being switched to the HP diet. Serum chemistries and parathyroid gland (PTG) weights were examined; CaR content and parathyroid cell proliferation (PCNA/Ki-67) were analyzed by immunohistochemistry. RESULTS: When rats were nephrectomized and placed immediately on a HP diet, parathyroid cell proliferation was significantly increased by day 2 and continued to increase at day 4. CaR content was unchanged at 1 and 2 days post-nephrectomy, but fell by day 4. When nephrectomized rats were maintained for 1 week on a LP diet, then switched to a HP diet, an increase in parathyroid cell proliferation was again seen at day 2; down-regulation of the CaR did not occur until after 7 days of uremia and the HP diet. CONCLUSION: These data indicate that parathyroid cell hyperplasia precedes down-regulation of CaR expression in the uremic rat model.

Decreased calcium-sensing receptor expression in hyperplastic parathyroid glands of uremic rats: role of dietary phosphate.

BACKGROUND: The abnormal control of parathyroid hormone secretion in chronic renal failure is attributed, in part, to down-regulation of the calcium-sensing receptor (CaR) in hyperplastic parathyroid tissue. The cause of this down-regulation is unknown. Here we examined the roles of uremia and parathyroid hyperplasia on parathyroid gland (PTG) CaR expression in the rat model of renal failure. METHODS: Rats made uremic by 5/6 nephrectomy were maintained for one month on diets containing 0.2% P (low phosphate), 0.5% P (normal phosphate) or 1.2% P (high phosphate); intact rats (controls) were maintained on the normal-phosphate diet. RESULTS: CaR mRNA was reduced only in uremic rats fed the high-phosphate diet (55% less than in controls, P < 0.05). Immunohistochemical staining revealed decreased CaR protein expression in uremic high-phosphate rat PTG compared with controls (41% decrease as determined by computer-assisted quantitation, P < 0.01). PTG size was increased in uremic rats fed the high-phosphate diet compared with controls (2.77 +/- 0.95 vs. 0.77 +/- 0.16 microgram/g body wt, P < 0.0001). There was no increase in PTG size in uremic rats fed the low-phosphate and normal-phosphate diets (0.92 +/- 0.31 and 1.01 +/- 0.31 micrograms/g) compared with controls (0.77 +/- 0.16 microgram/g body wt). Immunohistochemical staining for proliferating cell nuclear antigen in hyperplastic PTG from uremic rats showed that CaR was decreased primarily in areas of active cell proliferation. CONCLUSION: These results suggest that CaR down-regulation cannot be attributed to uremia per se, but rather, is associated with parathyroid cell proliferation. Furthermore, dietary phosphate restriction prevents both the parathyroid hyperplasia and decreased CaR expression in renal failure.

RenaGel, a nonabsorbed calcium- and aluminum-free phosphate binder, lowers serum phosphorus and parathyroid hormone. The RenaGel Study Group.

BACKGROUND: This multicenter, open-label, dose-titration study assessed the safety and efficacy of RenaGel(R), a nonabsorbed calcium- and aluminum-free phosphate binder, in lowering serum phosphorus. Secondary outcomes were its effects on serum intact parathyroid hormone (iPTH) and serum lipids. METHODS: Phosphate binders were discontinued during a two-week washout period. Patients whose serum phosphorus was more than 6.0 mg/dl during washout were eligible for treatment. RenaGel(R), at starting doses of two, three, or four 440 mg capsules three times per day with meals, was administered to 172 hemodialysis patients for eight weeks. RenaGel(R) could be increased by one capsule per meal every two weeks as necessary to achieve serum phosphorus control. A second two-week washout period followed. RESULTS: Mean serum phosphorus rose from 6.8 +/- 2.0 mg/dl at prewashout to 9.1 +/- 2.4 mg/dl at the end of the washout period. It then declined to 6.6 +/- 1.9 mg/dl by the end of the eight-week RenaGel(R) treatment period (P < 0. 0001). Serum phosphorus increased to 8.0 +/- 2.2 mg/dl at the end of the second washout period. The mean dose at the end of RenaGel(R) treatment was 5.4 g per day. Eighty-four percent of the patients previously used calcium-based phosphate binders. As expected, calcium declined during the initial washout period when calcium-based phosphate binders were discontinued. Mean serum calcium declined from 9.6 +/- 1.0 mg/dl at prewashout to 9.1 +/- 0.8 mg/dl after washout. It then increased to 9.4 +/- 0.9 mg/dl by the end of RenaGel(R) treatment. Median serum iPTH increased during the two-week washout from 208 pg/ml to 316 pg/ml and then declined to 224 pg/ml at the end of the eight-week treatment period (P < 0.0001 vs. end of initial washout). After eight weeks of treatment, RenaGel(R) reduced mean serum total cholesterol from 171.0 +/- 43.1 mg/dl to 145.0 +/- 38.7 mg/dl (P < 0.0001) and mean serum low-density lipoprotein cholesterol from 102.0 +/- 34.9 mg/dl to 75. 6 +/- 29.4 mg/dl (P < 0.0001). High-density lipoprotein cholesterol, triglycerides, and serum albumin did not change. CONCLUSIONS: RenaGel(R), a novel and calcium- plus aluminum-free effective phosphate binder, can control serum phosphorus and reduce the levels of PTH and cholesterol without inducing hypercalcemia or other side effects. Thus, this new phosphate binder may be effective in the treatment of renal osteodystrophy in uremic patients.

Effect of RenaGel, a non-absorbed, calcium- and aluminium-free phosphate binder, on serum phosphorus, calcium, and intact parathyroid hormone in end-stage renal disease patients.

BACKGROUND: Control of dietary phosphate absorption in end-stage renal disease patients is essential to prevent the deleterious sequelae of phosphorus retention. Efficacy of currently available calcium- and aluminium-containing phosphate binders is constrained by the side-effects associated with the absorption of calcium and aluminium. The current study examined the efficacy of RenaGel, a calcium- and aluminium-free, polymeric phosphate binder, in end-stage renal disease patients. METHODS: Administration of calcium- or aluminium-containing phosphate binders ceased during a 2-week washout period. RenaGel, at starting doses of one, two, or three 500-mg capsules three times per day with meals, was administered for 8 weeks. RenaGel dose was titrated up 1 capsule per meal at the end of each 2-week period if necessary to achieve phosphorus control. A second 2-week washout period followed the end of RenaGel treatment. RESULTS: Mean serum phosphorus rose from a pre-washout level of 6.9 mg/dl (2.23 mmol/l) to 8.1 mg/dl (2.62 mmol/l) at the end of the initial 2-week washout. With RenaGel treatment, serum phosphorus declined and returned to pre-washout levels after 4 weeks. Serum phosphorus reached a nadir of 6.5 mg/dl (2.10 mmol/l) after 7 weeks of RenaGel treatment. Serum phosphorus rose to 8.2 mg/dl (2.65 mmol/l) 2 weeks after cessation of RenaGel treatment. As anticipated, calcium declined during the initial washout period when calcium-based phosphate binders were stopped for the majority of patients. The rise in serum phosphorus and decline in serum calcium during washout resulted in an increase in median intact parathyroid hormone (iPTH) levels from 292 pg/ml to 395 pg/ml. iPTH fell to 283 pg/ml after 6 weeks of RenaGel treatment despite a persistently lower serum calcium. RenaGel treatment also reduced serum total and LDL cholesterol by 25 mg/dl (0.65 mmol/l) and 23 mg/dl (0.59 mmol/l) respectively. CONCLUSIONS: RenaGel appears to be an effective phosphate binder free of calcium and aluminium. Phosphorus control with two to four RenaGel capsules per meal appears to result in comparable phosphorus lowering seen with calcium- or aluminium-based phosphate binders. RenaGel may offer an alternative for the control of phosphorus retention in end-stage renal disease patients.

RenaGel, a novel calcium- and aluminium-free phosphate binder, inhibits phosphate absorption in normal volunteers.

BACKGROUND: Available phosphate binders contain aluminium or calcium which can be associated with undesirable effects. RenaGel, cross-linked poly (allylamine hydrochloride), is a non-absorbed phosphate-binding polymer, free of calcium and aluminium. We conducted this study to examine the safety and phosphate binding efficacy of RenaGel in volunteers. METHODS: During 18 days (days 0-17) at the clinical study unit, 24 subjects consumed a phosphate-controlled diet designed to provide 37.5 mmol (1200 mg) elemental phosphorus per day. From the morning of day 5 to the morning of day 9, urine and faeces were collected. Average baseline urine and faecal phosphorus contents were determined. On days 9-16, the subjects received either RenaGel 1 g, 2.5 g, or 5 g or placebo three times per day immediately prior to the meals. From the morning of day 13 to the morning of day 17, urine and faeces were again collected and phosphorus contents on treatment were determined. RESULTS: RenaGel inhibited dietary phosphate absorption as measured by a decline in average daily urinary phosphorus excretion and an increase in average daily fecal phosphorus excretion. Average urine phosphorus contents on treatment were 27.2 mmol (870 mg) per day in the placebo group vs 23.8 mmol (762 mg), 19.5 mmol (625 mg), and 16.6 mmol (530 mg) per day in the RenaGel 1-g, 2.5-g, and 5-g groups. Average daily faecal phosphorus content on treatment was markedly higher in the RenaGel 5-g group, 19.1 mmol (611 mg) per day vs 10.7 mmol (342 mg) per day for the placebo group. RenaGel also decreased total serum cholesterol by 0.71 mmol/L (27.5 mg/dl), 0.55 mmol/l (21.3 mg/dl), and 1.08 mmol/l (41.8 mg/dl) for the RenaGel 1-g, 2.5-g, and 5-g groups. RenaGel was well tolerated with adverse events similar to placebo. CONCLUSIONS: RenaGel is a safe, effective, and well tolerated phosphate binder in normal volunteers. The degree of phosphate binding consistent with its potential use as a phosphate binder in renal failure patients.

Intravenous calcitriol in the treatment of refractory osteitis fibrosa of chronic renal failure.

Osteitis fibrosa, a frequent complication of chronic renal failure, is characterized by increased rates of bone formation and bone resorption due to increased secretion of parathyroid hormone (PTH). Effective treatment with oral calcitriol is often impossible in patients with osteitis fibrosa, because low doses may cause hypercalcemia. Because short-term infusions of intravenous calcitriol are capable of suppressing the secretion of parathyroid hormone in patients with uremia without causing hypercalcemia, we evaluated the effectiveness of long-term intermittent calcitriol infusions (1.0 to 2.5 micrograms three times weekly, during dialysis) in treating severe osteitis fibrosa in 12 consecutive patients on hemodialysis whose disease was refractory to conventional therapy. After a mean (+/- SE) treatment period of 11.5 +/- 1.4 months, the mean bone-formation rate declined from 1642 +/- 277 to 676 +/- 106 microns 2 per square millimeter per day (P less than 0.01) in the 11 patients who successfully completed the study. Similar reductions occurred in the osteoblastic osteoid (18 +/- 3 to 9 +/- 2 percent; P less than 0.01) and the degree of marrow fibrosis (6.2 +/- 1.7 to 3.5 +/- 1.3 percent; P = 0.01). Concomitant serum biochemical changes included increased calcium levels (2.55 +/- 0.03 to 2.67 +/- 0.05 mmol per liter; P less than 0.01), decreased alkaline phosphatase levels (489 +/- 77 to 184 +/- 32 U per liter; P less than 0.001), and decreased levels of PTH (amino-terminal, 172 +/- 34 to 69 +/- 16 ng per liter in five patients, P less than 0.03; and carboxy-terminal, 1468 +/- 467 to 1083 +/- 402 ml-eq per liter in six patients, P not significant). Although the majority of the patients had transient episodes of asymptomatic hypercalcemia, this complication could be quickly reversed by temporarily halting treatment or decreasing the dose of calcitriol. We conclude that long-term intermittent infusions of intravenous calcitriol are effective in ameliorating osteitis fibrosa in patients on dialysis. Patients whose osteitis fibrosa is refractory to oral calcitriol and who are candidates for parathyroidectomy should be considered first for intravenous calcitriol therapy.

Bone histologic response to deferoxamine in aluminum-related bone disease.

We have examined the changes in bone histology in 28 uremic patients after long-term treatment with the aluminum chelator, deferoxamine. Marked declines in stainable bone-surface aluminum were associated with increases in bone formation rate and osteoblastic osteoid following deferoxamine. The increased bone formation resulted from increases in bone apposition and length of double-tetracycline labels, the latter being highly correlated with the increase in osteoblastic osteoid (r = 0.85). While bone surface aluminum was highly correlated with bone formation rate (r = .69, p less than .001), bone aluminum content did not correlate with bone formation (r = 0.13) and was often elevated after treatment despite an improvement in bone histology. Patients who had undergone prior parathyroidectomy were less likely to have improved bone histology than those with intact parathyroid glands. We conclude that aluminum chelation therapy with deferoxamine is effective in ameliorating the bone histology of patients with chronic renal failure and bone aluminum accumulation, and that the change in stainable bone-surface aluminum is a more sensitive indicator than the change in bone aluminum content in assessing adequacy of chelation therapy. Patients who need deferoxamine treatment but have undergone a prior parathyroidectomy will probably require a more intensive treatment schedule than those who have intact parathyroid glands.

Use of the deferoxamine infusion test in the diagnosis of aluminum-related osteodystrophy.

The accumulation of aluminum in bone can cause disabling osteodystrophy in patients with renal failure. Because the chelating agent deferoxamine can mobilize aluminum from tissues, we evaluated the effect of a standard intravenous dose of deferoxamine on plasma aluminum concentrations in 54 patients on hemodialysis. Stainable bone aluminum, bone histologic findings, and bone aluminum content were studied. Baseline plasma aluminum concentrations of greater than 200 micrograms/L were associated with aluminum-related osteodystrophy (specificity, 93%), but concentrations of less than 200 micrograms/L did not exclude the diagnosis (sensitivity, 43%). After administration of deferoxamine, the increase in plasma aluminum concentration was 534 +/- 260 (SD) and 214 +/- 92 micrograms/L in patients with and without aluminum-related bone disease, respectively (p less than 0.001), and correlated with the bone aluminum content (r = 0.64). An increment in plasma aluminum concentration of greater than 200 micrograms/L identified 35 of the 37 patients with aluminum-related osteodystrophy; sensitivity was 94% and specificity, 50%. The deferoxamine infusion test is noninvasive, well tolerated, and of value particularly in excluding the diagnosis of aluminum-related osteodystrophy.