Effect of calcitriol treatment and withdrawal on hyperparathyroidism in haemodialysis patients with hypocalcaemia.

BACKGROUND: Calcitriol is used to treat secondary hyperparathyroidism in dialysis patients. For similarly elevated parathyroid hormone (PTH) levels, the PTH response to calcitriol treatment is believed to be better in hypocalcaemic dialysis patients than in dialysis patients with higher serum calcium values. Furthermore, few studies have evaluated the rapidity of the rebound in serum PTH values after prolonged treatment with calcitriol. Our goal was to evaluate (i) the PTH response to calcitriol treatment in hypocalcaemic haemodialysis patients, (ii) the rapidity of rebound in PTH after calcitriol treatment was stopped, and (iii) whether the effect of calcitriol treatment on PTH levels could be separated from those produced by changes in serum calcium and phosphate values. METHODS: Eight haemodialysis patients (29+/-3 years) with hypocalcaemia and hyperparathyroidism were treated thrice weekly with 2 microg of intravenous calcitriol and were dialysed with a 3.5 mEq/l calcium dialysate. Parathyroid function (PTH-calcium curve) was determined before and after 30 weeks of calcitriol treatment and 15 weeks after calcitriol treatment was stopped. RESULTS: Pretreatment PTH and ionized calcium values were 907+/-127 pg/ml and 3.89+/-0.12 mg/dl (normal, 4.52+/-0.07 mg/dl). During calcitriol treatment, one patient did not respond, but basal (predialysis) PTH values in the other seven patients decreased from 846+/-129 to 72+/-12 pg/ml, P<0.001 and in all seven patients, the decrease exceeded 85%. During the 15 weeks after calcitriol treatment was stopped, a slow rebound in basal PTH values in the seven patients was observed, 72+/-12 to 375+/-44 pg/ml. Covariance analysis was used to evaluate the three tests of parathyroid function (0, 30, and 45 weeks), and showed that calcitriol treatment was associated with reductions in maximal PTH values while reductions in basal PTH were affected by ionized calcium and serum phosphate. The basal/maximal PTH ratio and the set point of calcium were associated with changes in ionized calcium. CONCLUSIONS: In haemodialysis patients with hypocalcaemia, (i) moderate to severe hyperparathyroidism responded well to treatment with calcitriol, (ii) reductions in maximal PTH were calcitriol dependent while reductions in basal PTH were affected by the ionized calcium and serum phosphate concentrations, (iii) changes in the basal/maximal PTH ratio and the set point of calcium were calcium dependent, and (iv) the delayed rebound in basal PTH levels after withdrawal of calcitriol treatment may have been due to the long duration of treatment and the marked PTH suppression during treatment.     

Sevelamer controls parathyroid hormone-induced bone disease as efficiently as calcium carbonate without increasing serum calcium levels during therapy with active vitamin D sterols

Little is known about the impact of various phosphate binders on the skeletal lesions of secondary hyperparathyroidism (2 degrees HPT). The effects of calcium carbonate (CaCO3) and sevelamer were compared in pediatric peritoneal dialysis patients with bone biopsy-proven 2 degrees HPT. Twenty-nine patients were randomly assigned to CaCO3 (n = 14) or sevelamer (n = 15), concomitant with either intermittent doses of oral calcitriol or doxercalciferol for 8 mo, when bone biopsies were repeated. Serum phosphorus, calcium, parathyroid hormone (PTH), and alkaline phosphatase were measured monthly. The skeletal lesions of 2 degrees HPT improved with both binders, and bone formation rates reached the normal range in approximately 75% of the patients. Overall, serum phosphorus levels were 5.5 +/- 0.1 and 5.6 +/- 0.3 mg/dl (NS) with CaCO3 and sevelamer, respectively. Serum calcium levels and the Ca x P ion product increased with CaCO3; in contrast, values remained unchanged with sevelamer (9.6 +/- 01 versus 8.9 +/- 0.2 mg/dl; P < 0.001, respectively). Hypercalcemic episodes (>10.2 mg/dl) occurred more frequently with CaCO3 (P < 0.01). Baseline PTH levels were 980 +/- 112 and 975 +/- 174 pg/ml (NS); these values decreased to 369 +/- 92 (P < 0.01) and 562 +/- 164 pg/ml (P < 0.01) in the CaCO3 and the sevelamer groups, respectively (NS between groups). Serum alkaline phosphatase levels also diminished in both groups (P < 0.01). Thus, treatment with either CaCO3 or sevelamer resulted in equivalent control of the biochemical and skeletal lesions of 2 degrees HPT. Sevelamer, however, maintained serum calcium concentrations closer to the lower end of the normal physiologic range, thereby increasing the safety of treatment with active vitamin D sterols.     

Phosphorus control in peritoneal dialysis patients

Hyperphosphatemia is independently associated with an increased risk of death among dialysis patients. In this study, we have assessed the status of phosphate control and its clinical and laboratory associations in a large international group of patients on chronic peritoneal dialysis (PD) treatment. This cross-sectional multicenter study was carried out in 24 centers in three different countries (Canada, Greece, and Turkey) among 530 PD patients (235 women, 295 men) with a mean+/-s.d. age of 55+/-16 years and mean duration of PD of 33+/-25 months. Serum calcium (Ca(2+)), ionized Ca(2+), phosphate, intact parathyroid hormone (iPTH), 25-hydroxy vitamin D(3), 1,25-dihydroxy vitamin D(3), total alkaline phosphatase, and bone alkaline phosphatase concentrations were investigated, along with adequacy parameters such as Kt/V, weekly creatinine clearance, and daily urine output. Mean Kt/V was 2.3+/-0.65, weekly creatinine clearance 78.5+/-76.6 l, and daily urine output 550+/-603 ml day(-1). Fifty-five percent of patients had a urine volume of <400 ml day(-1). Mean serum phosphorus level was 4.9+/-1.3 mg per 100 ml, serum Ca(2+) 9.4+/-1.07 mg per 100 ml, iPTH 267+/-356 pg ml(-1), ionized Ca(2+) 1.08+/-0.32 mg per 100 ml, calcium phosphorus (Ca x P) product 39+/-19 mg(2)dl(-2), 25(OH)D(3) 8.3+/-9.3 ng ml(-1), 1,25(OH)(2)D(3) 9.7+/-6.7 pg ml(-1), total alkaline phosphatase 170+/-178 U l(-1), and bone alkaline phosphatase 71+/-108 U l(-1). While 14% of patients were hypophosphatemic, with a serum phosphorus level lower than 3.5 mg per 100 ml, most patients (307 patients, 58%) had a serum phosphate level between 3.5 and 5.5 mg per 100 ml. Serum phosphorus level was 5.5 mg per 100 ml or greater in 28% (149) of patients. Serum Ca(2+) level was > or =9.5 mg per 100 ml in 250 patients (49%), between 8.5 and 9.5 mg per 100 ml in 214 patients (40%), and lower than 8.5 mg per 100 ml in 66 patients (12%). Ca x P product was >55 mg(2)dl(-2) in 136 patients (26%) and lower than 55 mg(2)dl(-2) in 394 patients (74%). Serum phosphorus levels were positively correlated with serum albumin (P<0.027) and iPTH (P=0.001), and negatively correlated with age (P<0.033). Serum phosphorus was also statistically different (P = 0.013) in the older age group (>65 years) compared to younger patients; mean levels were 5.1+/-1.4 and 4.5+/-1.1 mg per 100 ml, respectively, in the two groups. In our study, among 530 PD patients, accepted uremic-normal limits of serum phosphorus control was achieved in 58%, Ca x P in 73%, serum Ca(2+) in 53%, and iPTH levels in 24% of subjects. Our results show that chronic PD, when combined with dietary measures and use of phosphate binders, is associated with satisfactory serum phosphorus control in the majority of patients.     

Cinacalcet HCl, an oral calcimimetic agent for the treatment of secondary hyperparathyroidism in hemodialysis and peritoneal dialysis: a randomized, double-blind, multicenter study

Management of secondary hyperparathyroidism is challenging with traditional therapy. The calcimimetic cinacalcet HCl acts on the calcium-sensing receptor to increase its sensitivity to calcium, thereby reducing parathyroid hormone (PTH) secretion. This phase 3, multicenter, randomized, placebo-controlled, double-blind study evaluated the efficacy and safety of cinacalcet in hemodialysis (HD) and peritoneal dialysis (PD) patients with PTH > or =300 pg/ml despite traditional therapy. A total of 395 patients received once-daily oral cinacalcet (260 HD, 34 PD) or placebo (89 HD, 12 PD) titrated from 30 to 180 mg to achieve a target intact PTH (iPTH) level of < or =250 pg/ml. During a 10-wk efficacy assessment phase, cinacalcet was more effective than control for PTH reduction outcomes, including proportion of patients with mean iPTH levels < or =300 pg/ml (46 versus 9%), proportion of patients with > or =30% reduction in iPTH from baseline (65 versus 13%), and proportion of patients with > or =20, > or =40, or > or =50% reduction from baseline. Cinacalcet had comparable efficacy in HD and PD patients; 50% of PD patients achieved a mean iPTH < or =300 pg/ml. Cinacalcet also significantly reduced serum calcium, phosphorus, and Ca x P levels compared with control treatment. The most common side effects, nausea and vomiting, were usually mild to moderate in severity and transient. Once-daily oral cinacalcet was effective in rapidly and safely reducing PTH, Ca x P, calcium, and phosphorus levels in patients who received HD or PD. Cinacalcet offers a new therapeutic option for controlling secondary hyperparathyroidism in patients with chronic kidney disease on dialysis.     

Oral vitamin D supplementation reduces the incidence of eucalcemic PTH elevation after surgery for primary hyperparathyroidism

BACKGROUND: As many as 43% of patients will have normocalcemic intact parathyroid hormone (PTH) elevation after undergoing curative parathyroidectomy for primary hyperparathyroidism. This phenomenon may be due in part to an absolute or relative deficiency of vitamin D, which is under-recognized in patients with primary hyperparathyroidism. METHODS: From September 1, 2004, to September 30, 2005, 86 consecutive patients underwent parathyroidectomy for primary sporadic hyperparathyroidism (psHPT). The patients were segregated into 2 groups based on postoperative management. Group 1 was composed of 26 patients who received routine oral calcitriol and calcium carbonate postoperatively. The 60 patients in the second group (group 2) received calcium carbonate postoperatively at the discretion of the primary surgeon. RESULTS: A total of 85 patients (99%) achieved postoperative cure with sustained reduction in serum calcium. Within 30 days postoperatively, mean serum PTH levels normalized in both groups (41 +/- 31 vs 39 +/- 31 pg/ml; P = .91). However, at 1 to 3 months postoperatively, mean serum calcium levels remained similar (9.5 +/- 0.7 vs 9.3 +/- 0.5 mg/dl; P = .39) whereas mean serum PTH levels in groups 1 and 2 were 43 +/- 25 pg/ml and 67 +/- 45 pg/ml (P = .02), respectively. At 4 to 6 months postoperatively, mean PTH was again higher in group 2 (36 +/- 22 vs 67 +/- 35; P = .03), whereas mean serum calcium levels were normal (9.2 +/- 0.8 vs 9.6 +/- 0.4 mg/dl; P = .18). The incidence of postoperative normocalcemic PTH elevation was significantly higher in group 2 at 1 to 3 months (14% vs 39%; P = .04) and at 7 to 12 months (22% vs 83%; P = .04). CONCLUSIONS: Vitamin D supplementation following parathyroidectomy for primary hyperparathyroidism reduces the incidence of postoperative eucalcemic PTH elevation.     

Assessment of phosphorus and calcium metabolism and its clinical management in hemodialysis patients in the community of Valencia

AIM: The objective of the study was to determine the situation concerning mineral metabolism and bone disease in hemodialysis (HD) patients living in the community of Valencia (Spain), as well as the clinical practices for bone disease control in relation to the laboratory targets recommended in the National Kidney Foundation Dialysis Outcomes Quality Initiative (K/DOQI) guidelines. METHODS: In December 2003, a cross-sectional study was performed including 2392 patients (1485 males and 907 females) from 43 different centers in the council of Valencia (the entire HD population). Mean age was 65.8 +/- 14 yrs. Cut-off levels for the study of calcium, phosphorus, calcium-phosphorus product (Ca x P) and parathyroid hormone (PTH) were performed following the recommendations of the K/DOQI guidelines. RESULTS: The mean values for calcium were 9.57 +/- 0.7 mg/dL, phosphorus 4.97 +/- 1.5 mg/dL, intact PTH (iPTH) 297 +/- 353 pg/mL, Ca x P 47.5 +/- 15 mg2/dL2. Hypocalcemia (<8.4 mg/dL) was present in 5% of patients, whereas 17.8% of patients presented hypercalcemia (>10.2 mg/dL), 60.3% of whom received vitamin D. Hypophosphoremia (<3.5 mg/dL) was present in 16% of patients, and 29% of patients presented hyperphosphoremia (>5.5 mg/dL). Ca x P was <55 mg2/dL2 in 73% of patients. Thirty one percent of patients presented secondary hyperparathyroidism (HPTH >300 pg/mL), being severe in 12% (>600 pg/mL); 43% of patients presented iPTH <150 pg/mL. Only 7.3% of patients achieved the four recommendations provided in the K/DOQI guidelines. Vitamin D treatment was administered in 48% of patients. CONCLUSIONS: The population undergoing dialysis in the community of Valencia achieved targets based on the clinical recommendations of the K/DOQI guidelines as follows: 45% of patients achieved targets for calcium, 55% for phosphorus, 73% for Ca x P and 26% for iPTH levels. Surprisingly, only 7.3% of patients achieved all four targets.     

Direct inhibitory effect of calcitriol on parathyroid function (sigmoidal curve) in dialysis

The effect of intravenous calcitriol on parathyroid function was evaluated in nine chronic hemodialysis patients with secondary hyperparathyroidism. Two micrograms of calcitriol were administered intravenously after dialysis thrice weekly for ten weeks. Parathyroid function was assessed by inducing hypo- and hypercalcemia with low calcium (1.0 mEq/liter) and high calcium (4.0 mEq/liter) dialyses before and after ten weeks of intravenous calcitriol therapy. To avoid hypercalcemia during calcitriol administration, the dialysate calcium was reduced to 2.5 mEq/liter. Parathyroid hormone (PTH) values (pg/ml) from dialysis-induced hypo- and hypercalcemia were plotted against serum ionized calcium, and the sigmoidal relationship between PTH and calcium was evaluated. Basal PTH levels fell from 902 +/- 126 pg/ml to 466 +/- 152 pg/ml (P less than 0.01) after therapy without a significant change in the serum total calcium concentration. The ionized calcium-PTH sigmoidal curve shifted to the left and downward after calcitriol therapy. The maximal PTH response during hypocalcemia decreased after calcitriol from 1661 +/- 485 pg/ml before calcitriol to 1031 +/- 280 pg/ml afterward (P less than 0.05). The PTH level at maximal inhibition due to hypercalcemia decreased from 281 +/- 76 pg/ml before calcitriol to 192 +/- 48 pg/ml afterward (P less than 0.05). The slope of the sigmoidal curve changed from -2125 +/- 487 to -1563 +/- 385 (P less than 0.05). The set point of ionized calcium (4.60 +/- .11 mg/dl before vs. 4.44 +/- .07 mg/dl after) did not change significantly with calcitriol therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

The clinical evaluation of maxacalcitol on therapy for secondary hyperparathyroidism of chronic hemodialysis patients

The spectrum of bone disease in end-stage renal failure is changing, but secondary hyperparathyroidism is still a troublesome complication. The vitamin D3 analog, maxacalcitol, has reduced calcemic action compared to vitamin D3, but show equivalent suppression of parathyroid hormone(PTH) secretion. In the first step of the study, we investigated the severity of secondary hyperparathyroidism in 670 chronic hemodialysis patients, whose age, sex(male/female), and duration on dialysis were 63.5 +/- 12.4 years, 383/287, and 7.3 +/- 6.0 years, respectively. The number of patients with serum intact-PTH concentrations over 300 pg/ml was 118. Most patients in this group(87.3%) were already being prescribed oral vitamin D3 analog. In the second step, maxacalcitol was administered intravenously, instead of the oral vitamin D3 analog, to 92 patients selected from the above-described group. The age, sex(male/female), and duration of dialysis were 59.4 +/- 11.5 years, 56/36, and 7.3 +/- 6.0 years, respectively. Serum intact-PTH concentration and alkaline phosphatase activity decreased significantly, from 612.3 +/- 32.7 to 414.2 +/- 26.8 pg/ml, and from 329.3 +/- 17.3 to 277.0 +/- 12.5 IU/l, respectively. Serum calcium phosphorous concentration increased significantly, and maxacalcitol administration was interrupted because of hypercalcemia in 17 patients(18.5%). Serum intact-PTH concentration did not decrease in patients with serum Ca concentrations of 10.5 mg/dl or more before maxacalcitol therapy. In conclusion, maxacalcitol suppressed PTH secretion more effectively in hemodialysis patients with secondary hyperparathyroidism than did oral active vitamin D3 therapy, especially in patients with serum Ca concentrations lower than 10.5 mg/dl.     

Parathyroid function as a determinant of the response to calcitriol treatment in the hemodialysis patient.

BACKGROUND: Bolus calcitriol (CTR) is used for the treatment of secondary hyperparathyroidism in dialysis patients. Although CTR treatment reduces parathyroid hormone (PTH) levels in many dialysis patients, a significant number fail to respond. METHODS: To learn whether or not an analysis of parathyroid function could further illuminate the response to CTR, a PTH-calcium curve was performed before and after at least two months of CTR treatment in 50 hemodialysis patients with a predialysis intact PTH of greater than 300 pg/ml. RESULTS: For the entire group (N = 50), CTR treatment resulted in a 24% reduction in predialysis (basal) PTH from 773 +/- 54 to 583 +/- 71 pg/ml (P < 0.001), whereas ionized calcium increased from 1.10 +/- 0.02 to 1.22 +/- 0.02 mM (P < 0.001); however, maximal and minimal PTH did not change from pre-CTR values. Based on whether or not the basal PTH decreased by 40% or more during CTR treatment, patients were divided into responders (Rs, N = 25) and nonresponders (NRs, N = 25). Before CTR, the NR group was characterized by a greater basal (959 +/- 80 vs. 586 +/- 51 pg/ml, P < 0.001) and maximal (1899 +/- 170 vs. 1172 +/- 108 pg/ml, P < 0. 001) PTH and serum phosphorus (6.14 +/- 0.25 vs. 5.14 +/- 0.34 mg/dl, P < 0.01). Logistical regression analysis showed that the pre-CTR basal PTH was the most important predictor of the post-CTR basal PTH, and a pre-CTR basal PTH of 750 pg/ml represented a 50% probability of a response. Basal PTH correlated with the ionized calcium in the NR group (r = 0.59, P = 0.002) but not in the R group (r = 0.06, P = NS). In the R group, an inverse correlation was present between ionized calcium and the basal/maximal PTH ratio, an indicator of whether calcium is suppressing basal PTH secretion relative to the maximal secretory capacity (maximal PTH) r = -0.55, P = 0.004; in the NR group, this correlation approached significance but was positive (r = 0.34, P = 0.09). After CTR treatment, serum calcium increased in both groups, and despite marked differences in basal PTH (Rs, 197 +/- 25 vs. NRs, 969 +/- 85 pg/ml), an inverse correlation between ionized calcium and basal/maximal PTH was present in both groups (Rs, r = -0.61, P = 0.001, and NRs, r = -0.60, P = 0.001). CONCLUSIONS: (a) Dynamic testing of parathyroid function provided insights into the pathophysiology of PTH secretion in hemodialysis patients. (b) The magnitude of hyperparathyroidism was the most important predictor of the response to CTR. (c) Before CTR treatment, PTH was sensitive to calcium in Rs, and serum calcium was PTH driven in NRs, and (d) after the CTR-induced increase in serum calcium, calcium suppressed basal PTH relative to maximal PTH in both groups.     

The effects of intraperitoneal calcitriol on calcium and parathyroid hormone

Parathyroid suppression by intraperitoneal calcitriol (1,25(OH)2D3) during peritoneal dialysis. The purpose of this study was to determine if parathyroid hormone (PTH) suppression could be achieved by increasing calcium mass transfer (Ca MT) with high dialysate Ca (4 mEq/liter) or via intraperitoneal (i.p.) 1,25(OH)2D3 in patients undergoing continuous ambulatory peritoneal dialysis. Eleven patients were dialyzed for two months with standard Ca dialysate (3.5 mEq/liter) followed by two months with 4.0 mEq/liter Ca, then by three months of i.p. 1,25(OH)2D3. During the latter period, patients were randomized to groups whose dialysate contained either 3.5 mEq/liter or 4.0 mEq/liter Ca. We found that 4.0 mEq/liter Ca dialysate more than doubled Ca MT (37 +/- 17 mg/day to 84 +/- 6 mg/day) leading to a modest fall (P less than 0.05) in PTH levels (84 +/- 5.5% of controls). Ionized calcium levels did not change. With i.p. 1,25(OH)2D3, however, ionized calcium rose significantly (P less than 0.001) leading to a decline in PTH levels to 53.9 +/- 7.9% of control values. Serum 1,25(OH)2D3 levels rose from undetectable to 47.7 +/- 7.2 pg/dl (normal range 20 to 35). These studies indicate that increasing Ca MT using a 4.0 mEq/liter Ca dialysate leads to a small reduction in PTH concentrations. On the other hand, i.p. 1,25(OH)2D3 is well absorbed into the systemic circulation, raises ionized calcium levels, and leads to a marked suppression of PTH. Thus, i.p. 1,25(OH)2D3 may be a simple and effective means to suppress secondary hyperparathyroidism in patients undergoing CAPD.     

Long-term outcomes of cinacalcet and paricalcitol titration protocol for treatment of secondary hyperparathyroidism

Long-term outcomes of combined cinacalcet and paricalcitol therapy for secondary hyperparathyroidism (SHPT) in patients failing traditional therapies with phosphate binders and active vitamin D compound analogs are not well described. We implemented a titration protocol for cinacalcet and paricalcitol and assessed its long-term effects on bone metabolism and disease in hemodialysis (HD) patients. Thirty-five patients were started on 30 mg of cinacalcet daily. After 12 months, median cinacalcet dose was 60 mg. There was a 33% increase in number of patients receiving paricalcitol. Average corrected serum calcium (Ca) decreased from 9.5 to 8.8 mg/dl (p = 0.003, 95% CI 0.34-1.04); phosphorus (P) from 6.2 to 5.5 mg/dl (p = 0.047, 95% CI 0.01-1.34); Ca x P product from 58 to 48 (p = 0.001, 95% CI 4.2-15.7); and intact PTH (iPTH) from 426 +/- 274 to 300 +/- 228 pg/ml (p = 0.03, 95% CI 19.3-401.7). Number of patients achieving three or more K/DOQI criteria increased by 29% (p = 0.009).     

Normocalcemia without hyperparathyroidism in vitamin D-deficient rats

Despite numerous attempts, no reliable dietary regimen exists to achieve vitamin D deficiency (-D) in rats without attendant changes in plasma parathyroid hormone (PTH), Ca, or phosphate. This represents an important obstacle to proper investigations of the physiologic role(s) of vitamin D metabolites in the function of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] target tissues. This paper describes the successful development of such a diet, which uses a combination of high Ca content, properly controlled Ca/P ratio, and lactose. Normal weanling rats were fed diets containing A, 0.8% Ca, 0.5% P, +D3, or -D diets containing B, 0.8% Ca and 0.5% P; C, 2.0% Ca and 1.25% P; or D, 2.0% Ca, 1.25% P, and 20% lactose. After 6 diet weeks group D rats remained normocalcemic and normophosphatemic, but diet groups B and C became hypocalcemic (6.9 +/- 0.8 and 7.2 +/- 0.4 mg/dl, respectively). Thus high dietary Ca and P was incapable of maintaining normal plasma Ca levels in the absence of dietary lactose. The normocalcemia in group D was not maintained by elevated PTH secretion because N-terminal PTH levels were also normal (14 +/- 3 versus 20 +/- 5 pg/ml). In contrast, PTH levels were markedly elevated in hypocalcemic groups B and C (47 +/- 7 and 48 +/- 10 pg/ml, respectively). Plasma 25-OHD3 and 1,25-(OH)2D3 levels were reduced to less than 120 and less than 12 pg/ml, respectively, in all -D groups. Thus the high-Ca diet and the use of normal weanlings did not impede the development of vitamin D deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy of cinacalcet administered with the first meal after dialysis: the SENSOR Study

BACKGROUND: Cinacalcet, a novel calcimimetic, simultaneously lowers parathyroid hormone (PTH), phosphorus (P), calcium (Ca) and Ca x P in patients who are on dialysis with secondary hyperparathyroidism (sHPT) associated with CKD. Previous studies have required cinacalcet to be administered during the dialysis session and at the same time on non-dialysis days. The aim of the SENSOR study was to demonstrate that cinacalcet given in a more clinically practical manner with the first major meal after dialysis is noninferior to cinacalcet given with food during the dialysis session. METHODS: In this open-label study dialysis patients with poorly controlled sHPT (intact PTH (iPTH) (3) 300 pg/ml) were randomized to receive cinacalcet either daily with their post-dialysis meal (n = 337) or with food during the dialysis session (n = 336). The primary endpoint was the proportions of patients with mean iPTH pound 300 pg/ml ( pound 31.8 pmol/l) at Weeks 11 and 13 of a 21-week treatment period. Secondary endpoints included the proportion of patients with Ca x P < 55 mg2/dl2 (< 4.44 mmol2/l2) at Weeks 11 and 13 and patients who discontinued the study due to nausea or vomiting. RESULTS: Comparable proportions of patients in the cinacalcet "during dialysis" and "post-dialysis meal" groups had a mean iPTH pound 300 pg/ml (54 vs. 57%, respectively, 95% confidence interval (CI) difference -4, +10%) and Ca x P < 55 mg2/dl2 (78 vs. 73%, respectively, 95% CI difference -11, +2%) at Weeks 11 and 13. The groups were also comparable at Week 21. Cinacalcet was well tolerated, with < 3% of patients in both groups discontinuing due to nausea or vomiting. A combined post-hoc analysis of both groups showed the incidence of nausea and vomiting was lower if cinacalcet was administered during the evening. CONCLUSIONS: Administering cinacalcet with the first main meal after dialysis was as effective as administration with food during the dialysis session. Cinacalcet was well tolerated. The incidence of gastrointestinal adverse events appeared to be lower when cinacalcet was administered in the evening.     

Relationship between parathyroid gland size and responsiveness to maxacalcitol therapy in patients with secondary hyperparathyroidism.

BACKGROUND: Although vitamin D has been reported to be useful in the treatment of patients with secondary hyperparathyroidism, it is not effective in some of them. The goal of this study was to see whether a relationship could be found between maxacalcitol responsiveness and parathyroid gland size. METHODS: Parathyroid gland size was measured by ultrasonography in 25 patients with secondary hyperparathyroidism [serum intact parathyroid hormone (PTH) >300 pg/ml, 58.1 +/- 2.8 years old, 15 males and 10 females], who were treated with maxacalcitol. Patients were divided into two groups according to the mean value of the maximum diameter of the glands: group S with a diameter <11.0 mm and group L with a diameter >or =11.0 mm. Between the two groups there were no significant differences in serum intact PTH, calcium or phosphate level or duration of haemodialysis. RESULTS: Mean (+/- SE) maximal diameter of detectable parathyroid glands was 11.0 +/- 0.7 mm before treatment. At 4-24 weeks after administration of maxacalcitol, intact PTH concentrations decreased significantly in group S (from 546 +/- 39 to 266 +/- 34 pg/ml at 24 weeks; P < 0.01), but did not significantly change in group L (from 481 +/- 39 to 403 +/- 49 pg/ml at 24 weeks). At 24 weeks after maxacalcitol administration, the number of detectable parathyroid glands was significantly decreased in group S (from 2.2 +/- 0.3 to 1.8 +/- 0.4; P < 0.05), but not in group L. Serum calcium increased significantly in group L (from 9.6 +/- 0.2 to 10.2 +/- 0.3 mg/dl; P < 0.05), but not in group S. There was a significant correlation between reduction in PTH and parathyroid gland size (r = -0.42, P < 0.05). CONCLUSIONS: These results indicate that the responsiveness to maxacalcitol therapy of secondary hyperparathyroidism is dependent on parathyroid gland size and that the simple measurement of maximum parathyroid gland diameter by ultrasonography may be useful for predicting responsiveness to maxacalcitol treatment.     

Treatment of secondary hyperparathyroidism in hemodialyzed patients with high-dose calcium carbonate without vitamin D3 supplements.

BACKGROUND: Vitamin D compounds are usually indicated for the treatment of secondary hyperparathyroidism in dialysis patients. The possibility to induce a reversal of hyperparathyroidism with calcium supplementation alone is controversial. The present study was conducted to assess if oral calcium carbonate may constitute a therapeutic option for the control of hyperparathyroidism in patients with high PTH concentrations at the beginning of the treatment with chronic hemodialysis. METHODS: Thirty-one patients with end-stage renal failure with an intact PTH concentration above 250 pg/ml at the beginning of chronic hemodialysis therapy were treated with high doses of calcium carbonate; no patient received either aluminium-containing binders or vitamin D compounds. To minimize hypercalcemia, a calcium dialysate concentration of 2.5 mEq/l was used in all patients. The goal of the study was to reduce the intact PTH concentration to 250 pg/ml with oral calcium carbonate supplements alone. RESULTS: Throughout the first year on hemodialysis treatment, the intact PTH concentration decreased from 538 +/- 256 to 251 +/- 218 pg/ml (p < 0.001). By the end of the study, the therapeutic objective was achieved in 22 patients (71%) ('responder' group). The remaining 9 patients were classified as the 'treatment failure' group. The basal intact PTH concentration was not different between both groups (508 +/- 235 vs. 612 +/- 303 pg/ml, respectively, p = n.s.), but 5 'treatment failure' patients admitted to take a dose of calcium carbonate lower than that prescribed. There were 40 episodes of hyperphosphatemia (11% of all measurements) in 7 of 31 patients, 5 of them belonged to the noncompliance 'treatment failure' patients. Only 15 episodes (4% of all measurements) of transient hypercalcemia (range 11.1 - 11.9 mg/dl) were detected in 8 patients. CONCLUSIONS: Secondary hyperparathyroidism in hemodialysis patients can often be reverted by oral calcium carbonate alone. But a good adherence to treatment is absolutely necessary.     

Cinacalcet for the treatment of hypercalcemia in renal transplanted patients with secondary hyperparathyroidism

Persistent hyperparathyroidism is the most frequent cause of hypercalcemia after renal transplantation, namely, hypercalcemia is observed in about 10% of patients at 1 year. This prospective study evaluated the effect of cinacalcet, a second-generation calcimimetic, on serum calcium and parathyroid hormone (PTH) blood levels among recipients with hypercalcemia due to persistent hyperparathyroidism. Thirteen renal transplanted patients (10 women and 3 men) were included based upon: a total serum calcium >10.5 mg/dL; intact PTH (iPTH) blood levels >65 pg/mL; graft function >6 months, and stable maintenance immunosuppressive therapy. After inclusion, patients initially received 30 mg of cinacalcet once daily. The mean time of initiation was 64 +/- 7 months after transplantation. The follow-up was 6 months. The median dose of cinacalcet was 30 mg/d (5 patients received 60 mg/d). During the study period, renal function remained stable. Serum calcium levels decreased significantly from 11.7 +/- 0.39 to 10.35 +/- 0.8 mg/dL (P < .001). Serum phosphate levels increased from 2.82 +/- 0.34 mg/dL to 3.2 +/- 0.41 mg/dL (P < .05). The mean iPTH levels significantly decreased from 308 +/- 120 to 210 +/- 80 pg/mL (P < .05). There were no significant change in 25-hydroxyvitamin D3 blood levels (from 17.7 +/- 9 to 17.4 +/- 6 ng/mL), but the 1,25-dihydroxyvitamin D3 blood levels decreased from 53.8 +/- 18.2 to 32.6 +/- 9.2 pg/mL (P < .01). There were no significant changes in blood levels of alkaline phosphatase, magnesium, bicarbonate, calciuria, phosphaturia, and immunosuppressive drugs. Cinacalcet was well tolerated in all patients except one who had gastrointestinal discomfort. In summary, cinacalcet corrected hypercalcemia and improved phosphatemia in patients with persistent hyperparathyroidism after transplantation with no negative effects on renal function.     

Post-transplant hypophosphatemia: Tertiary 'Hyper-Phosphatoninism'?

Hypophosphatemia is a common complication of kidney transplantation. Tertiary hyperparathyroidism has long been thought to be the etiology, but hypophosphatemia can occur despite low parathyroid hormone (PTH) levels and can persist after high PTH levels normalize. Furthermore, even in the setting of normal allograft function, hypophosphatemia, and hyperparathyroidism, calcitriol levels remain inappropriately low following transplantation, suggesting that mechanisms other than PTH contribute. Fibroblast growth factor-23 (FGF-23) induces phosphaturia, inhibits calcitriol synthesis, and accumulates in chronic kidney disease. We performed a prospective, longitudinal study of 27 living donor transplant recipients to test the hypotheses that excessive FGF-23 accounts for hypophosphatemia and decreased calcitriol levels following kidney transplantation. Hypophosphatemia <2.5 mg/dl developed in 85% of subjects, including one who had previously undergone parathyroidectomy; 37% developed phosphate < or =1.5 mg/dl. The mean pre-transplant FGF-23 level was 1,218+/-542 RU/ml. Within the first week following transplantation, mean levels decreased to 557+/-579 RU/ml, which were still above normal. FGF-23 was independently associated with serum phosphate (P < 0.01), urinary excretion of phosphate (P < 0.01), and calcitriol levels (P < 0.01); PTH was not independently associated with any of these parameters. We calculated area under the curve for FGF-23 and PTH between the pre- and first post-transplant levels as a summary measure of early exposure to these phosphaturic hormones. An area under the FGF-23 curve greater than the median was associated with a relative risk of developing hypophosphatemia < or =1.5 mg/dl of 5.3 (P = 0.02) compared with lower levels. Increased area under the PTH curve was not associated with greater risk of hypophosphatemia. Excessive FGF-23 exposure in the early post-transplant period appears to be more strongly associated with post-transplant hypophosphatemia than PTH.     

The effect of long-term intravenous calcitriol administration on parathyroid function in hemodialysis patients.

Secondary hyperparathyroidism is common in dialysis patients. Intravenous calcitriol has proven to be an effective therapy for the reduction of parathyroid hormone (PTH) levels. However, the effect of i.v. calcitriol on parathyroid function, defined as the sigmoidal PTH-calcium curve developed during hypocalcemia and hypercalcemia, has not been evaluated during the prolonged administration of i.v. calcitriol. Six hemodialysis patients with marked secondary hyperparathyroidism, PTH levels greater than 500 pg/mL (normal, 10 to 65 pg/mL), were treated for 42 wk with 2 micrograms of i.v. calcitriol after each hemodialysis. Parathyroid function was evaluated before and after 10 and 42 wk of calcitriol therapy. Between baseline and 42 wk, the basal PTH level decreased from 890 +/- 107 to 346 +/- 119 pg/mL (P less than 0.02) and the maximally stimulated PTH level decreased from 1293 +/- 188 to 600 +/- 140 pg/mL (P less than 0.01). In addition, calcitriol administration significantly decreased PTH levels throughout the hypocalcemic range of the PTH-calcium curve. Although the slope of the PTH-calcium curve (with maximal PTH as 100%) decreased between baseline and 42 wk (P less than 0.05), the set point of calcium did not change. Two patients with a decrease in both basal and maximally stimulated PTH levels after 10 wk of calcitriol, developed marked hyperphosphatemia between 10 and 42 wk; this resulted in an exacerbation of hyperparathyroidism despite continued calcitriol therapy. In conclusion, prolonged i.v. calcitriol administration is an effective treatment for secondary hyperparathyroidism in hemodialysis patients provided that reasonable control of the serum phosphate is achieved. In addition, the slope of the PTH-calcium curve may be a better indicator of parathyroid cell sensitivity than the set point of calcium.