Changes in 3-month mineral and bone disorder patterns were associated with all-cause mortality in prevalent hemodialysis patients with secondary hyperparathyroidism.

BACKGROUND: There is limited evidence on the association between short-term changes in mineral and bone disorder parameters and survival in maintenance hemodialysis patients. METHODS: We investigated the association between changing patterns of phosphorus, calcium and intact parathyroid hormone levels and all-cause mortality in hemodialysis patients with secondary hyperparathyroidism. Each parameter was divided into three categories (low [L], middle [M] and high [H]), and the changing patterns between two consecutive visits at 3-month intervals were categorized into nine groups (e.g., L-L and M-H). The middle category was defined as 4.0-7.0 mg/dL for phosphorous, 8.5-9.5 mg/dL for calcium and 200-500 pg/mL for intact parathyroid hormone. Adjusted incidence rates and rate ratios were analyzed by weighted Poisson regression models accounting for time-dependent exposures. RESULTS: For phosphorus, shifts from low/high to middle category (L-M/H-M) were associated with a lower mortality compared with the L-L and H-H groups, whereas shifts from middle to low/high category (M-L/M-H) were associated with a higher mortality compared with the M-M group. For calcium, shifts from low/middle to high category (L-H/M-H) were associated with a higher mortality compared with the L-L and M-M groups, whereas shifts from high to middle category (H-M) were associated with a lower mortality compared with the H-H group. For intact parathyroid hormone, shifts from low to middle category (L-M) were associated with a lower mortality compared with the L-L group. CONCLUSIONS: Changes in the 3-month patterns of phosphorus and calcium toward the middle category were associated with lower mortality. Our study also suggests the importance of avoiding hypercalcemia.

Effectiveness of cinacalcet treatment for secondary hyperparathyroidism on hospitalization: Results from the MBD-5D study.

OBJECTIVES: To elucidate the effect of cinacalcet use on all-cause and cause-specific hospitalization outcomes using a prospective cohort of maintenance hemodialysis patients. METHODS: We used data from a prospective cohort of Japanese hemodialysis patients with secondary hyperparathyroidism and examined baseline characteristics as well as longitudinal changes. All patients were cinacalcet-naïve at study enrollment. Further, we used a marginal structural model to account for time-varying confounders on cinacalcet initiation and hospitalization outcomes, and an Andersen-Gill-type recurrent event model to account for any recurring events of hospitalization in the outcome analysis using the weighted dataset. RESULTS: Among the 3,276 patients, cinacalcet treatment was initiated in 1,384 patients during the entire follow-up. Cinacalcet users were slightly younger, included more patients with chronic glomerulonephritis and fewer patients with diabetes, were more likely to have a history of parathyroidectomy, and were more often used receiving vitamin D receptor activator, phosphate binders, and iron supplements. The overall hospitalization analysis yielded a hazard ratio (HR) of 0.97 (95% confidence interval [CI]: 0.80, 1.18). A trend toward a mild protective association was observed for cardiovascular-related hospitalizations (HR: 0.85; 95% CI: 0.64, 1.14). In the subgroup analysis, a protective association was seen due to cinacalcet use for infection-related hospitalizations in the lowest intact parathyroid hormone group (HR: 0.36; 95% CI: 0.14, 0.95). CONCLUSIONS: Cinacalcet initiation in patients on maintenance hemodialysis had no effect on all-cause and cause-specific hospitalizations. Although the overall association was statistically not significant, cinacalcet may have a protective association on cardiovascular-related hospitalization in all patients and infection-related hospitalization in patient with low intact parathyroid hormone.

A novel calcimimetic agent, evocalcet (MT-4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro.

Cinacalcet hydrochloride (cinacalcet), an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). In sharp contrast to vitamin D receptor activators, cinacalcet suppresses SHPT without inducing hypercalcemia or hyperphosphatemia. Nevertheless, some patients remain refractory to SHPT with this agent, as the dose cannot be sufficiently increased due to gastrointestinal symptoms. In order to resolve this issue, we have developed a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of CKD induced by 5/6 nephrectomy, oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone (PTH). With regard to the gastro-intestinal effects, cinacalcet induced a significant delay in gastric emptying in rats, while evocalcet did no marked effects on it. Evocalcet also demonstrated the less induction of emesis compared to cinacalcet in common marmosets. The pharmacological effects of evocalcet were observed at lower doses because of its higher bioavailability than cinacalcet, which may have contributed to the reduced GI tract symptoms. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro liver microsome assay, suggesting a better profile in drug interactions than cinacalcet that inhibits cytochrome P450 (CYP) 2D6. These findings suggest that evocalcet can be a better alternative to cinacalcet, an oral calcimimetic agent, with a wider safety margin.

Sevelamer hydrochloride reverses parathyroid gland enlargement via regression of cell hypertrophy but not apoptosis in rats with chronic renal insufficiency.

BACKGROUND: Dietary phosphate restriction suppresses parathyroid hormone (PTH) secretion, synthesis, and parathyroid cell proliferation in experimental animals with chronic renal insufficiency (CRI), independently of serum calcium and 1,25(OH)2D3 levels. This study was conducted to examine whether sevelamer hydrochloride (sevelamer), a metal-free phosphate binder, could regress an advanced parathyroid gland (PTG) hyperplasia and enlargement in rats with CRI. METHODS: Male Sprague-Dawley rats were fed a diet containing adenine for 6 weeks to establish CRI. Normal rats and adenine-treated rats were sacrificed to obtain the PTG (baseline group). The adenine diet was changed to a normal diet or diet containing 1 or 3% sevelamer for another 4 weeks. Time course changes of serum levels of calcium, phosphorus, and PTH were measured. At the end of the study, the PTG was weighed and examined histologically. RESULTS: Adenine-treated rats developed severe CRI with marked elevation of serum phosphorus and PTH. The PTG weight markedly increased with enlarged cell volume (i.e. cell hypertrophy) at baseline. Sevelamer treatment rapidly lowered serum phosphorus and PTH levels within 6 days, and after 4 weeks, reduced the PTG weight by 38% compared to adenine-treated rats at baseline. The reduction in PTG weight was due to regression of cell hypertrophy, but not to decreased cell number by apoptosis. Decreased expression of calcium receptor in the PTG at baseline was partially recovered by the sevelamer treatment. CONCLUSIONS: The sevelamer treatment can reduce the PTG weight with a reduction in serum PTH levels via regression of cell hypertrophy but not apoptosis in rats with CRI. Reduced PTG function might contribute to the regression of cell hypertrophy.

[Effects of intermittent treatment with sevelamer hydrochloride on parathyroid hyperplasia and vascular calcification in rats with chronic kidney disease].

Phosphorus directly controls parathyroid hormone (PTH) synthesis and secretion. Serum levels of the novel phosphate-regulating hormone, fibroblast growth factor 23 (FGF23), are positively correlated with hyperphosphatemia in patients with chronic kidney disease (CKD). Rats were fed a diet containing adenine for 4 weeks to establish CKD. Animals were then offered a diet containing sevelamer hydrochloride (sevelamer) or a normal diet for alternating 2 week periods over 8 weeks. Adenine-treated rats showed marked elevations of serum phosphorus, PTH and FGF23 levels associated with parathyroid hyperplasia and aortic calcification. Serum phosphorus, PTH and FGF23 levels decreased rapidly when sevelamer treatments commenced and recovered rapidly once they were discontinued. However, intermittent treatment with sevelamer successfully inhibited parathyroid hyperplasia and aortic calcification. In conclusion, phosphate-binder treatment can effectively inhibit the elevation of serum FGF23 levels, as well as PTH levels, under conditions of CKD. Setting up a period of reduced serum phosphorus levels, even if it is intermittent, is worthwhile for the inhibition of the development of parathyroid hyperplasia and aortic calcification.

Sevelamer hydrochloride, a phosphate binder, protects against deterioration of renal function in rats with progressive chronic renal insufficiency.

BACKGROUND: Dietary phosphate restriction prevents renal function deterioration in animal models. This study examined whether sevelamer hydrochloride (Renagel(R); 'sevelamer' hereafter), a non-calcaemic phosphate binder could slow deterioration of renal function in rats with progressive renal insufficiency. METHODS: Wistar Kyoto male rats were singly injected with normal rabbit serum or rabbit anti-rat glomerular basement membrane serum. Three days later, rats were fed a powder diet containing 0, 1 or 3% sevelamer for 58 days. Time course changes of serum levels of blood urea nitrogen (BUN), creatinine, calcium, phosphorus and parathyroid hormone (PTH) were measured throughout, and creatinine clearance (CCr), kidney calcium content and renal histology examined at the end of the study. RESULTS: Sevelamer partially inhibited elevation of BUN and serum creatinine, and completely inhibited increases in serum phosphorus, PTH and calcium xphosphorus product. Sevelamer significantly prevented the decrease in CCr and kidney calcium content elevation. Kidney calcium content and BUN and serum creatinine were strongly positively correlated, and kidney calcium content and CCr strongly negatively correlated. Kidney calcium content correlated well with serum phosphorus, serum calcium x phosphorus product and PTH, but not serum calcium. Sevelamer treatment partly prevented histological deterioration of both glomerular and tubulointerstitial lesions of the kidney. CONCLUSIONS: The results suggest that sevelamer protects against renal function deterioration by maintaining kidney calcium at a low level as a result of reducing serum phosphorus and PTH.

Sevelamer hydrochloride, a calcium-free phosphate binder, inhibits parathyroid cell proliferation in partially nephrectomized rats.

BACKGROUND: Secondary hyperparathyroidism characterized by hyperplasia of the parathyroid gland (PTG) is a consequence of chronic renal insufficiency (CRI). Dietary phosphate restriction and sevelamer hydrochloride, a calcium-free phosphate binder, suppress parathyroid hormone (PTH) secretion and PTG hyperplasia in experimental animals with CRI, independently of serum calcium and 1,25(OH)(2)D(3) concentrations. In the present study, the effect of sevelamer on PTG cell proliferation in rats with CRI was investigated. METHODS: Seven weeks after a 5/6 nephrectomy, rats were fed a diet containing 0, 1 or 3% sevelamer for 4 weeks, and sham-operated rats were fed a normal diet. Serum calcium, phosphorus, PTH and 1,25(OH)(2)D(3) concentrations were measured. The number of cells positive for proliferating cell nuclear antigen (PCNA) in the maximal two-dimensional PTG area was counted at the end of study. RESULTS: Sevelamer inhibited increases in serum phosphorus, calcium-phosphorus product and PTH concentrations without affecting serum calcium or 1,25(OH)(2)D(3). Sevelamer also suppressed the maximal PTG area and PCNA-positive cells. There was also a strong correlation between the maximal PTG area and serum PTH concentration, and between PCNA-positive cells and the maximal PTG area, as well as between serum phosphorus concentration and PCNA-positive cells. CONCLUSIONS: These results indicate that sevelamer treatment reduces serum phosphorus concentration and could inhibit PTG cell proliferation and prevent PTG hyperplasia.