Long-term effects of small doses of calcitriol in hemodialysis patients with moderate secondary hyperparathyroidism

Prevention of secondary hyperparathyroidism (SHPTH) and treatment of the moderate cases by small p.os doses of Vitamin D has not been thoroughly investigated on the long term, while large doses of Vitamin D have been successful in the short term treatment of this entity. We administered calcitriol p.os 0.5-1.0 microgram, according to iPTH levels, after each dialysis session, in 19 patients (group A) for 36 months. They were ten men and nine women, 63 years old (43-81), with iPTH levels > 4N (419 +/- 185 pg/mL). Seven adenomas were found in five of them (group A1). Serum Ca, phosphate (P) and alkaline phosphatase (AP) were measured every 15-30 days. Serum iPTH and aluminum as well as echogram or scanning of the parathyroid glands were checked every 6 months. Ten additional dialysis patients, seven men and three women, 54.5 years old (36-68), non-significantly different to group A in iPTH levels (290 +/- 225 pg/mL) with three adenomas in two of them (group B1) received no calcitriol and served as controls (group B). Calcitriol treatment significantly lowered serum iPTH levels in group A patients (from 419 +/- 185 to 173 +/- 142 pg/mL, p < 0.0001, delta iPTH: -246 +/- 161 pg/mL); iPTH remained stable in group B patients (delta iPTH: +7.9 +/- 116 pg/mL) with an intergroup significant difference at P < 0.0001. All other parameters measured did not show any significant change. No significant correlation of iPTH to Ca, P or AP was found in A. Initial iPTH levels were higher in A1 and B1 patients and decreased by calcitriol in A1 group. Adenomas in A1 patients did not change in number and size in contrast to B1 where new adenomas appeared (5 patients, 10 glands). Small doses of vitamin D lower high iPTH levels and prevent parathyroid gland hyperplasia. Existing hypertrophy is stabilized under calcitriol treatment both morphologically and biologically.     

Calcitriol metabolism in patients with chronic renal failure

We studied calcitriol metabolism in white patients with chronic renal failure and in age- and sex-matched normal subjects. The plasma levels of calcitriol (21.9 +/- 1.6 pg/mL, n = 7, v control, 37.4 +/- 2.9 pg/mL, P less than 0.001), metabolic clearance rate (MCR) of calcitriol (0.45 +/- .01 mL/min/kg v control, 0.58 +/- .02 mL/min/kg, P less than 0.001), and production rate (PR) of calcitriol (14.2 +/- 1.0 ng/kg/d v control, 31.8 +/- 3.2 ng/kg/d, P less than 0.001) were significantly lower in patients with moderate renal failure (average creatinine clearance, 0.59 +/- 0.01 mL/s [35.1 +/- 6.1 mL/min]) when compared with the respective values of normal control subjects. The MCR of calcitriol was determined again in patients with renal failure after they received calcitriol, 1 microgram/d, for 1 week. The MCR remained unchanged (0.46 +/- .04 mL/min/kg, n = 7) and plasma levels of calcitriol were increased to 34.6 +/- 2.77 pg/mL. The mechanism by which the MCR of calcitriol decreases in renal failure is partly due to the presence of inhibitory factors of degradation enzymes in uremic plasma. When the ultrafiltrates of uremic plasma obtained from hemodialysis patients were infused to normal Sprague-Dawley rats, the MCRs of calcitriol (0.20 +/- .01 mL/min/kg, n = 6) were markedly suppressed in comparison to those of rats infused with the ultrafiltrates of normal plasma (0.37 +/- .01 mL/min/kg, n = 6, P less than 0.001). The uremic plasma also contained factors that inhibit the synthesis of calcitriol. We conclude that metabolic degradation of calcitriol is decreased in patients with renal failure, and uremic plasma contains inhibitory factors that suppress the synthesis and degradation of calcitriol.     

Normalization of intraoperative parathyroid hormone does not predict normal postoperative parathyroid hormone levels

BACKGROUND: Intraoperative intact parathyroid hormone (iPTH) is being used to confirm complete excision of hyperfunctioning parathyroid tissue. It is uncertain whether normalization of intraoperative iPTH levels accurately predicts long-term postoperative iPTH values. METHODS: Fifty-two consecutive patients with primary or secondary hyperparathyroidism underwent parathyroidectomy with measurement of intraoperative iPTH. Ten patients were excluded due to incomplete laboratory follow-up. Follow-up serum calcium and iPTH levels were measured at 1- and 3-month intervals. RESULTS: Before operation, the mean serum iPTH level was 249 pg/mL (SD=208) and mean serum calcium level was 11.4 +/- 0.9 mg/dL (+/- SD). In all but 4 patients, final intraoperative iPTH levels normalized to less than 67 +/- 41 pg/mL (mean, 35 pg/mL). One week after operation, serum calcium levels had returned to normal (mean, 9.4 +/- 1.1 pg/mL), which directly correlated with the final intraoperative serum iPTH values (Pearson correlation, r = -.434; P <.01). By 1 month, all but 2 patients were normocalcemic (mean, 9.4 +/- 0.9 pg/mL) with a mean iPTH level of 74.8 +/- 82 pg/mL. There was no correlation between final intraoperative and postoperative serum iPTH values (r =.099; P <.533). Both patients with persistent hypercalcemia at 1 month had appropriate intraoperative decreases in iPTH values. CONCLUSIONS: Intraoperative serum iPTH levels significantly correlate with postoperative serum calcium levels but not with postoperative serum iPTH levels. There was a 4.8% failure rate in the correction of postoperative serum calcium levels and a 29% failure rate in the normalization of postoperative serum iPTH levels.     

Early initiation of cinacalcet for the treatment of secondary hyperparathyroidism in hemodialysis patients: a three-year clinical experience

Despite the availability of standard therapy (vitamin D sterols and phosphate binders) for the treatment of secondary hyperparathyroidism (SHPT) in hemodialyzed (HD) patients, a significant percentage of patients still fail to achieve targets recommended by the Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation for parathyroid hormone (PTH), calcium, and phosphorus. The calcimimetic cinacalcet (CN) has been shown to be an effective treatment for SHPT, significantly reducing serum PTH while simultaneously lowering calcium, phosphorus, and calcium-phosphorus product levels, thus increasing the proportion of patients achieving the K/DOQI targets for bone mineral parameters. The aim of this study was to evaluate if early treatment with CN had beneficial effects in HD patients with mild-to-moderate SHPT in whom conventional treatments had failed to achieve NKF-K/DOQI targets for PTH, serum-corrected calcium, and phosphorus while minimizing the risk of paradoxical hypercalcemia and/or hyperphosphatemia. Clinical practice data were collected monthly, starting from 6 months prior to, and up to 36 months after, the start of CN therapy. CN was started at a dose of 30 mg daily or every other day, and titrated thereafter to achieve intact PTH (iPTH) <300 pg/mL. The dose of concomitant vitamin D and phosphate binders were also adjusted in order to achieve K/DOQI targets. Data from 32 patients were collected, 28 of whom had been treated with CN for at least 36 months at the time of data analysis. At baseline, patients had serum iPTH >300 pg/mL (570 ± 295 pg/mL) and/or serum-corrected calcium >9.5 mg/dL. CN induced significant decreases in iPTH, calcium, and calcium-phosphorus product with respect to baseline levels. The percentage of patients within K/DOQI target levels at baseline, 12, 24, and 36 months was 0, 81.2, 83.3, and 86.2% for iPTH; 34.4, 65.6, 86.6, and 89.6% for serum-corrected calcium; 40.6, 56.2, 69.6, and 72.4% for phosphorus; and 37.5, 62.5, 80, and 82.7% for calcium-phosphorus product. The mean dose of CN at the end of the observation period was 38 mg/day. The mean dose of concomitant medication (calcitriol, Al-containing phosphate binders, and sevelamer) decreased from baseline to 36 months. Early treatment with CN in HD patients with SHPT increases the proportion of patients achieving and maintaining K/DOQI targets with a low dose of CN (38 mg/day). These results suggest that the metabolic control obtained with low-dose CN administered early in the course of SHPT can be maintained or increased over time.     

Usefulness of pamidronate in severe secondary hyperparathyroidism in patients undergoing hemodialysis

BACKGROUND: Although bisphosphonates have been widely used to treat bone diseases characterized by increased bone resorption, there are limited data showing their possible usefulness in patients on hemodialysis (HD) with secondary hyperparathyroidism. METHODS: The aim of this study was to evaluate the efficacy and safety of pamidronate in HD patients affected by severe secondary hyperparathyroidism and moderate hypercalcemia who were receiving intravenous calcitriol (Calcijex). RESULTS: In this prospective one-year, open-labeled study, 13 patients (9 women/4 men) with a mean age of 64 +/- 9 years and a mean time on dialysis of 94 +/- 61 months were evaluated. The inclusion criteria were: iPTH>500 pg/mL, Ca>11 mg/dL, P <6 mg/dL, and osteopenia (T-score <-1 SD). Blood levels of Ca, P, alkaline phosphatase (AP), and iPTH were assessed at the beginning of the study and every month. Radiographs of the vertebral spine and bone mineral density (BMD) (lumbar spine and femoral neck) were assessed basal and every 6 months. All patients received 60 mg of pamidronate intravenously every two months throughout the study period. Calcitriol and phosphate binders were adjusted according to iPTH, Ca, and P blood levels. BMD increased in both the lumbar and femoral neck scans (mean increase of 33%) at 6 and 12 months. iPTH increased at 3 months in all patients, and decreased more than 50% in 10 patients after increasing the calcitriol doses. Three patients had no response. A slight decrease in Ca and P was observed in all patients with no significant changes in AP. There were no adverse events. CONCLUSION: Pamidronate is effective in controlling hypercalcemia in patients on HD with secondary hyperparathyroidism and allows for a more aggressive use of intravenous calcitriol.     

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.     

Intravenous calcitriol versus paricalcitol in haemodialysis patients with severe secondary hyperparathyroidism

Aim:   Secondary hyperparathyroidism (SHPT) is common among haemodialysis patients. Intensive treatment with calcitriol is often complicated by hypercalcaemia, hyperphosphataemia and elevated calcium phosphorus (Ca X PO₄) product. Paricalcitol is a vitamin D analogue developed to overcome some of the limitations of calcitriol therapy. The study objectives were to compare the response of intact parathyroid hormone (iPTH) and the incidence of hypercalcaemia, hyperphosphataemia and elevated Ca X PO₄ product in patients with severe SHPT treated with either i.v. calcitriol or i.v. paricalcitol.
Methods:   This was a single centre randomized open label study. Patients with serum intact iPTH of 50 pmol/L or more were randomized to receive either i.v. calcitriol (0.01 ug/kg) or i.v. paricalcitol (0.04 ug/kg) during every haemodialysis treatment. Serum iPTH, calcium, phosphorus and alkaline phosphatase were measured at the beginning of the study and every 3 weeks for 12 weeks.
Results:   Twenty-five patients were enrolled into the study – 12 were randomized into the calcitriol group and 13 into the paricalcitol group. There were no differences in the baseline study parameters between both groups. Serum iPTH levels were significantly reduced ( P  = 0.003) only in the paricalcitol group but not in the calcitriol group ( P  = 0.101). On the other hand, serum calcium levels were significantly increased only in the calcitriol group ( P  = 0.004 vs P  = 0.242). Serum phosphorus, alkaline phosphatase and Ca X PO₄ product were not different.
Conclusion:   Intravenous paricalcitol may be superior to i.v. calcitriol for the treatment of severe SHPT in our chronic haemodialysis population. A larger randomized controlled trial is indicated to confirm these initial findings.     

VDRA therapy is associated with improved survival in dialysis patients with serum intact PTH <=150 pg/mL: results of the Italian FARO Survey

Background Chronic kidney disease (CKD) patients affected by mineral bone disorders (MBD) have higher rates of all-cause and cardiovascular-related mortality. Approximately, one-third of dialysis patients have low serum parathyroid hormone (PTH) levels (≤150 pg/mL). However, the reason why these patients have higher mortality compared to patients with normal PTH levels has not yet been fully elucidated. Methods The FARO study was performed on 2453 Italian patients followed prospectively from 28 dialysis centres over a 2-year period. Data were collected every 6 months and end points included time-to-death cumulative probability in patients with serum intact PTH (iPTH) ≤150 pg/mL and the effect of vitamin D receptor activation (VDRA) therapy. Kaplan-Meier curves and proportional hazards regression models stratified by PTH levels (i.e. ≤150 and >150 pg/mL) were used to determine cumulative probability of time-to-death and adjusted hazard ratios (HRs) for demographic, clinical and CKD-MBD treatment characteristics. Results The cumulative probability of death was higher (P < 0.01) for patients with serum iPTH levels ≤150 pg/mL [25.1%, 95% confidence interval (CI): 22.1-28.5 at 18 months] versus those with serum iPTH levels within the normal range (18.0%, 95% CI: 16.1-20.1). In a model with time-dependent covariates restricted to time periods when patients had iPTH levels ≤150 pg/mL, lower mortality was observed in patients treated with VDRA [i.e. HR = 0.62, 95% CI: 0.42-0.92 for oral or intravenous (IV) calcitriol; HR = 0.18, 95% CI: 0.04-0.8 for IV paricalcitol] versus those not receiving any VDRA (P < 0.01) independently of other variables. Patients who received IV paricalcitol, compared with either oral or IV calcitriol, showed reduced mortality, but this was not statistically significant (HR = 0.3, 95% CI: 0.07-1.31, P = 0.11). Conclusion Results from this observational study suggest that VDRA therapy was associated with improved survival in dialysis patients, even with low serum iPTH levels.     

An association between inflammatory state and left ventricular hypertrophy in hemodialysis patients

This study was performed to investigate the potential relationship between left ventricular hypertrophy (LVH) and proinflammatory cytokines in hemodialysis (HD) patients and the effect of HD on cytokine production. Serum interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) measurements and echocardiographic studies were performed in 35 stable HD patients. A variety of probable risk factors for LVH including age, HD duration, blood pressure (BP), body mass index, lipid profile, hemoglobin, albumin, parathormone and homocysteine levels were also investigated. Additionally, the effect of HD procedure on cytokine levels was evaluated. Predialysis serum levels of IL-1beta, IL-6, TNF-alpha, and homocysteine in HD patients were compared with 12 healthy subjects. Left ventricular hypertrophy was demonstrated in 20 (57%) of HD patients by echocardiography. Left ventricular mass index (LVMI) was correlated positively with systolic BP (r=0.556, p=0.001), diastolic BP (r=0.474, p=0.004), and serum levels of TNF-alpha (r=0.446, p=0.009). Multiple regression analysis showed that systolic BP and TNF-alpha levels were significant independent predictors of LVH. No relationship was observed between LVH and other parameters. The mean predialysis serum level of IL-6 was significantly higher in HD patients compared to healthy controls (15.7 +/- 8.7 vs. 7.3 +/- 0.7 pg/ mL, p=0.001). Predialysis serum levels of TNF-alpha in HD patients were higher when compared to healthy subjects, but the difference was not statistically significant (8.3 +/- 3 vs. 7 +/- 1.45 pg/mL, respectively, p>0.05). However, serum levels of IL-6 and TNF-alpha significantly elevated after HD, when compared to predialysis levels (from 15.7 +/- 8.7 to 17.8 +/- 9.5 pg/mL, p=0.001 and from 8.3 +/- 3.0 to 9.9 +/- 3.5 pg/mL p=0.004, respectively). As a conclusion, in addition to BP, proinflammatory cytokines, TNF-alpha in particular, seem to be associated with LVH in ESRD patients.     

Efficacy and tolerability of intravenous paricalcitol in calcitriol-resistant hemodialysis patients with secondary hyperparathyroidism: 12-month prospective study

RATIONALE/OBJECTIVES: Data are limited regarding the use of paricalcitol in calcitriol-resistant patients with secondary hyperparathyroidism (SHPT). We aimed to evaluate the effects of paricalcitol in calcitriol-resistant hemodialysis patients with SHPT. METHODS: This is a 12-month, open-label, prospective study. Forty patients with calcitriol-resistant and/or calcitriol-intolerant SHPT were included. After a washout period, all patients converted to paricalcitol with a 1:3 conversion ratio. Serum calcium and phosphorus were monitored monthly, while serum intact parathyroid hormone (iPTH) once in every 3 months. Paricalcitol dose was reduced or discontinued in case of hypercalcemia and/or hyperphosphatemia. Pre- and posttreatment electrolyte and iPTH values were compared with Student's t-test and Wilcoxon signed-rank test, respectively. MAIN FINDINGS: Forty patients completed the study. Mean initiation dose of paricalcitol was 23 ± 7 μg/week. Mean serum calcium was 8.9 ± 0.8 mg/dL at baseline and 9.4 ± 0.7 mg/dL at study end (p = 0.07). Mean monthly serum phosphorus levels stayed stable. Paricalcitol was effective in reducing iPTH levels when compared with pretreatment values (747.9 ± 497.2 pg/mL, 307.3 ± 417.1 pg/mL, respectively; p < 0.001). Thirty-two patients had to discontinue intravenous (IV) paricalcitol at some time during their treatment. Main reasons for discontinuation were as follows: hyperphosphatemia (58%), hypercalcemia (25%), and iPTH < 150 pg/mL (17%). PRINCIPLE CONCLUSIONS: Paricalcitol was found to be effective in reducing iPTH levels in calcitriol-resistant patients with SHPT despite relatively frequent drug discontinuation rates.     

Pharmacokinetics of calcitriol in continuous ambulatory and cycling peritoneal dialysis patients

Oral calcitriol is commonly used for the treatment of secondary hyperparathyroidism in patients undergoing long-term dialysis, but it has been suggested that intravenous (IV) or intraperitoneal (IP) administration enhances the therapeutic efficacy of the sterol. To examine potential mechanisms for this difference, the bioavailability of calcitriol was evaluated after single oral (PO), IV, and IP doses of 60 ng/kg in each of six adolescent patients with osteitis fibrosa undergoing continuous ambulatory peritoneal dialysis (CAPD) or continuous cycling peritoneal dialysis (CCPD). Serum calcitriol levels were 3.6 +/- 4.3, 8.2 +/- 7.5, and 2.5 +/- 3.0 pg/mL, respectively, before IV, PO, and IP doses of the sterol; these values increased to similar levels at 24 hours: 55.6 +/- 14.6 pg/mL after PO, 56.4 +/- 17.6 pg/mL after IV, and 53.8 +/- 20.1 pg/mL after IP. Serum calcitriol levels were higher 1, 3, and 6 hours after IV injections than after PO or IP doses; values thereafter did not differ among groups. The bioavailability of calcitriol, determined from the 24-hour area under the curve (AUC0-24) for the increase in serum calcitriol concentration above baseline values was 50% to 60% greater after IV, 2,340 +/- 523 pg.mL-1.h-1, than after PO, 1,442 +/- 467 pg.mL-1.h-1, or IP, 1,562 +/- 477 pg.mL-1.h1, dosages, P less than 0.05. These differences were due to higher values for AUC during the first 6 hours after calcitriol administration. Although IP calcitriol did not increase sterol bioavailability, radioisotope tracer studies indicated that 35% to 40% of the hormone adheres to plastic components of the peritoneal dialysate delivery system.(ABSTRACT TRUNCATED AT 250 WORDS)     

No difference in intestinal strontium absorption after oral or IV calcitriol in children with secondary hyperparathyroidism. The European Study Group on Vitamin D in Children with Renal Failure

BACKGROUND: Oral and intravenous calcitriol bolus therapy are both recommended for the treatment of secondary hyperparathyroidism, but it has been claimed that the latter is less likely to induce absorptive hypercalcemia. The present study was undertaken to verify whether intravenous calcitriol actually stimulates intestinal calcium absorption less than oral calcitriol and whether it is superior in suppressing parathyroid hormone (PTH) secretion. METHODS: Twenty children (16 males, age range of 5.1 to 16.9 years, mean creatinine clearance 21.9 +/- 11.5 mL/min/1.73 m2, range of 7.4 to 52.7) with chronic renal failure (CRF) and secondary hyperparathyroidism [median intact PTH (iPTH), 327 pg/mL; range 143 to 1323] received two single calcitriol boli (1.5 mg/m2 body surface area) orally and intravenously using a randomized crossover design. iPTH and 1,25(OH)2D3 levels were measured over 72 hours, and intestinal calcium absorption was measured 24 hours after the calcitriol bolus using stable strontium (Sr) as a surrogate marker. Baseline control values for Sr absorption were obtained in a separate group of children with CRF of similar severity. RESULTS: The peak serum level of 1,25(OH)2D3 and area under the curve baseline to 72 hours (AUC0-72h) were significantly higher after intravenous (IV) calcitriol (AUC0-72h oral, 1399 +/- 979 pg/mL. hour vs. IV 2793 +/- 1102 pg/mL. hour, P < 0.01), but the mean intestinal Sr absorption was not different [SrAUC0-240min during the 4 hours after Sr administration 2867 +/- 1101 FAD% (fraction of the absorbed dose) vs. 3117 +/- 1581 FAD% with oral and IV calcitriol, respectively]. The calcitriol-stimulated Sr absorption was more then 30% higher compared with control values (2165 +/- 176 FAD%). A significant decrease in plasma iPTH was noted 12 hours after the administration of the calcitriol bolus, which was maintained for up to 72 hours without any differences regarding the two routes of administration. CONCLUSIONS: These results demonstrate that under acute conditions, intravenous and oral calcitriol boli equally stimulate calcium absorption and had a similar efficacy in suppressing PTH secretion.     

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.     

Cinacalcet is efficacious in pediatric dialysis patients

Secondary hyperparathyroidism (high-turnover bone disease, or HTBD) is manifested by elevated parathyroid hormone (PTH) levels. Control of HTBD may be achieved by maintaining low serum phosphorous levels and administering vitamin D therapy, although some patients continue to exhibit high PTH levels. We report the results of the efficacy of the calcimimetic cinacalcet in six hemodialysis (HD) and three peritoneal dialysis (PD) pediatric patients with HTBD, age 14.5 +/- 1.0 (range 7.5-17.5) years. Six patients received 30 mg/day, one required 60 mg/day, and two received 120 mg/day. Treatment with cinacalcet resulted in a 61% decline in intact PTH (iPTH) levels (1,070 +/- 171.5 pretreatment to 417.6 +/- 97.8 posttreatment pg/ml, p = 0.005). Serum alkaline phosphatase also declined (561.8 +/- 169.6 U/L pretreatment to 390.3 +/- 110.3 U/L posttreatment pg/ml). During therapy, serum calcium (p = 0.9) and phosphorous (p = 0.9) levels, calcium-phosphorous product (p = 0.8), systolic blood pressure (BP) (p = 1.0), diastolic BP (p = 0.8), and hemoglobin (p = 0.9) remained unchanged. The dose of oral calcitriol for the three patients on PD while receiving cinacalcet trended downward (0.8 +/- 0.2 pretreatment vs. 0.5 +/- 0.0 mug/day posttreatment pg/ml), as did the dose of paracalcitol for those receiving HD (6.6 +/- 2.3 pretreatment vs. 4.3 +/- 1.7 micrograms/day posttreatment pg/ml). We conclude that short-term treatment with the calcimimetic cinacalcet is efficacious in adolescent dialysis patients.     

TNF Alpha−308 Genotype and Renin–Angiotensin System in Hemodialysis Patients: An Effect on Inflammatory Cytokine Levels?

BACKGROUND: Renin-angiotensin system (RAS) was suggested to modulate inflammatory cytokine production. Angiotensin II was consistently shown to increase production of tumor necrosis factor alpha (TNF-alpha). However, inflammatory cytokines and RAS were modulated by genetic polymorphisms such as TNF-alpha-308 G > A and angiotensin-converting enzyme (ACE) I/D gene polymorphisms. The aim of this study was to investigate the effects of ACE and TNF-alpha genotypes on inflammatory cytokines in hemodialysis (HD) patients. METHODS: ACE I/D and TNF-alpha-308 G > A genotypes, pre- and postdialysis plasma renin activity (PRA), serum ACE, interleukin-1 beta (IL-1beta), and TNF-alpha levels were determined in 22 HD patients. RESULTS: Predialysis serum ACE activity is correlated with TNF-alpha (r = 0.63; P = 0.01), and PRA was correlated with IL-1beta levels (r = 0.49; P = 0.02). Pre/postdialysis IL-1beta and TNF-alpha were similar in DD and II/ID ACE genotypes. Predialysis TNF-alpha and IL-1beta (32.4 +/- 5; 35.1 +/- 4.2 vs. 28.1 +/- 3.7; 26.5 +/- 6.2 pg/mL; P < 0.05) and postdialysis TNF-alpha levels (30.4 +/- 1.4 vs. 28.4 +/- 0.82 pg/mL; P < 0.05) were significantly higher in TNF1/2 than TNF1/1 patients. CONCLUSION: ACE and TNF-alpha-308 G > A (1/2) gene polymorphisms may contribute to modulation of proinflammatory cytokine production and hence chronic inflammation in HD patients.     

Secondary hyperparathyroidism and anemia. Effects of a calcimimetic on the control of anemia in chronic hemodialysed patients. Pilot Study

The main cause of resistance to erythropoiesis-stimulating agents (ESA) used for treatment of anemia in chronic hemodialysed patients (CHP) is the iron deficiency, absolute or functional. Secondary hyperparathyroidism (SHPT) is a secondary factor of resistance. Indeed, it has been reported in the literature an improvement of anemia parameters after surgical parathyroidectomy (PTX). The objective of this study is to assess in CHP, the impact of the correction of SHPT by a calcimimetic, cinacalcet (CI), (which is considered as a pharmacological PTX) on the response to ESA, measured by the erythropoietin resistance index (ERI). Twenty-two CHP with severe SHPT documented by an intact parathyroid hormone (iPTH) above 800pg/mL were included in this prospective pilot study. Mineral bone metabolism, anemia and nutritional parameters were measured baseline and after 6 months of treatment by CI. The effect on anemia was assessed at the end of study by the ERI, the change in Hb concentration, and the proportion of patients with Hb levels above 11g/dL. RESULTS: At the end of study there was a significant decrease (M6 vs M0) in iPTH (1302 vs 674pg/mL or -48%, p=0.006), serum calcium (2.39 vs 2.15mmol/L or -10%), serum phosphate (2 vs 1.7mmol/L or -15%), serum calcium-phosphorus product (CaxP) (4.8 vs 3.8mmol(2)/L(2) or - 20% (p<0.05), and the number of patients with CaxP>4.4mmol(2)/L(2) (64 vs 32%, p<0.05). The level of bone alkaline phosphatase remained stable during the study (28 vs 27?IU/L). The Hb levels increased from 11 to 11.4g/dL, as did the proportion of patients whose Hb concentration reached 11g/dL or higher (50 vs 70%, p<0.05) without important change of the median weekly ESA dosis in the majority of patients, 18?cases (81%) vs four (19%). Two subgroups were identified from the median decreases in iPTH (delta iPTH) between M0 and M6, Group?1 (delta iPTH≥400pg/mL, n=10) and group?2 (delta iPTH<400pg/mL, n=12): in group?1, we found a correlation between the decrease in iPTH by CI and the stability or decrease in ERI (group?1), at comparable dose of dialysis, nutritional and iron intakes and inflammatory profiles; in group?2 without a significant effect of CI on PTH reduction the levels of ERI and ESA dosis were more elevated. CONCLUSION: A treatment by calcimimetic improves the control of anemia by ESA in CHP and interferes positively on a cause of secondary resistance to ESA represented by SHPT. The mechanism of these effects could be linked to the decreased of bone marrow fibrosis and inflammation and to the triptych formed by the reduction in iPTH, CaxP and phosphate.     

Metabolic acidosis aggravation and hyperkaliemia in hemodialysis patients treated by sevelamer hydrochloride

Reports on acid-base side effects of sevelamer hydrochloride (SH), a new aluminum (Al)- and calcium (Ca)-free phosphate binder are rare and conflicting. In a retrospective analysis, we evaluated SH impact on metabolic acidosis and serum potassium (K) in hemodialysis (HD) patients. Two groups of stable HD patients were studied. Group A included 17 patients, M/F=15/2, 64 (42-80) years old, dialyzed since 130 (34-253) months, under SH for 24 months. Group B serving as controls was made of 7 patients, M/F=4/3, 67 (48-91) years old, dialyzed since 67 (27-174) months, under CaCO3 and/or Al(OH)3 as phosphate binders also for 24 months. Bicarbonate (BIC), K, Ca, phosphorus (P), Ca x P, alkaline phosphatase (ALP), and intact parathyroid hormone (iPTH) were recorded before (MO) and at the end (M24) of 24-month SH or CaCO3-Al(OH)3 treatment in group A and B patients. In group A, BIC fell from 20.02 +/- 1.43 to 17.89 +/- 2.30 mEq/ L, P=.002; and K rose from 5.45 +/- 0.51 to 5.75 +/- 0.49 mEq/L, P=0.02. In group B, BIC (19.8 +/- 3.03 to 19.0 +/- 3.3 mEq/L) and K (5.01 +/- 0.8 to 4.9 +/- 1.1 mEq/L) had nonsignificant changes. In group A, iPTH rose from 132.82 +/- 124.08 to 326.89 +/- 283.91 pg/mL, P=.0008; P fell from 5.92 +/- 1.48 to 4.9 +/- 1.01, P=.02; and Ca x P decreased from 52.04 +/- 9.7 to 45.58 +/- 10.42 mg2/dL2, P=.04. In group B, changes in iPTH from 240.71 +/- 174.7 to 318.57 +/- 260.2 pg/mL, P from 4.9 +/- 0.5 to 4.8 +/- 1.3 mg/dL, and CaxP product from 44.3 +/- 6.6 to 44 +/- 11.2 mg2/dL2 were nonsignificant. The changes observed in Ca and ALP in both groups were nonsignificant. Correlations in group A between metabolic acidosis (BIC) and SH doses, or iPTH and BIC, Ca, or P changes, were also found to be nonsignificant. Long-term use of SH, effectively controlling serum P levels and Ca x P values, is associated with acidosis aggravation and hyperkaliemia. Worsening of secondary hyperparathyroidism, also noted, needs to be confirmed and could be related to Ca/Al salt discontinuation and to metabolic acidosis aggravation itself.     

An intact parathyroid hormone–based protocol for the prevention and treatment of symptomatic hypocalcemia after thyroidectomy

Background

Symptomatic (SX) hypocalcemia after thyroidectomy is a barrier to same day surgery and the cause of emergency room visits. A standard protocol of calcium and vitamin D supplementation, dependent on intact parathyroid hormone (iPTH) levels, can address this issue. How effective is it? When does it fail?

Methods

We performed a retrospective review of the prospective Thyroid database from January 2006 to December 2010. Six hundred twenty patients underwent completion thyroidectomy or total thyroidectomy and followed our postoperative protocol of calcium carbonate administration for iPTH levels ≥10 pg/mL and calcium carbonate and 0.25 μg calcitriol twice a day for iPTH <10 pg/mL. Calcium and iPTH values, pathology, and medication were compared to evaluate protocol efficacy. A P value <0.05 was considered statistically significant.

Results

Using the protocol, sixty-one (10.2%) patients were chemically hypocalcemic but never developed symptoms and 24 (3.9%) patients developed breakthrough SX hypocalcemia. The SX and asymptomatic groups were similar with regard to gender, cancer diagnosis, and preoperative calcium and iPTH. The SX group was significantly younger (39.6 ± 2.8 versus 49 ± 0.6 y, P = 0.01), with lower postoperative iPTH levels. Thirty-three percent (n = 8) of SX patients had an iPTH ≤5 pg/mL versus only 6% (n = 37) of ASX patients. Although the majority of patients with a iPTH ≤5 pg/mL were asymptomatic, 62.5% (n = 5) of SX patients with iPTH levels ≤5 pg/mL required an increase in calcitriol dose to achieve both biochemical correction and symptom relief.

Conclusions

Prophylactic calcium and vitamin D supplementation based on postoperative iPTH levels can minimize SX hypocalcemia after thyroidectomy. An iPTH ≤5 pg/mL may warrant higher initial doses of calcitriol to prevent symptoms.     

Comparisons between oral pulse alfacalcidol therapy and daily therapy in maintenance hemodialysis patients with secondary hyperparathyroidism: a randomized, controlled, and multicenter study

OBJECTIVE: To investigate the efficacy and safety of 1alpha-(OH)-D3 high-dose pulse therapy or daily low-dose therapy in secondary hyperthyroidism in maintenance hemodialysis patients in China. METHODS: Maintenance hemodialysis patients of both gender with intact parathyroid hormone (iPTH) level above 200 pg/mL were randomly divided into a pulse group and a daily group. They were treated for 20 weeks, with 2 microg oral Alfacalcidol twice weekly or thrice weekly in the pulse group, and 0.5 microg oral Alfacalcidol per day in the daily group. The therapeutic end point was parathyroid hormone level < 200 pg/ mL. The iPTH levels during the study were monitored, and parameters representative of calcium and phosphate metabolism and side effects were also observed. RESULTS: One hundred and fifty-eight patients were initially enrolled, 91 in the pulse therapy group and 67 in the daily therapy group. There was no significant difference in age, hemodialysis duration, proportion of diabetic nephropathy and systemic diseases, proportion of patients who had received active vitamin D therapy previously, mean initial iPTH level (pulse group 570.47 +/- 295.86 pg/mL; daily group 498.33 +/- 207.84 pg/mL), serum calcium, serum phosphate, alkaline phosphatase (AKP), and albumin between two groups. In the pulse therapy group there were more patients with iPTH levels of 500 to approximately 1,000 pg/mL and > 1,000 pg/mL, so stratified analysis according to iPTH level was used. In therapeutic end point, iPTH levels in both groups were significantly lower compared with those before therapy (pulse group 261.29 +/- 234.97 pg/mL, P < .01; daily group 262.17 +/- 274.82 pg/mL, P < .01). After 4 weeks, the ratio of reaching end point in the pulse group was 35.2%, which was significantly higher than that (19.4%) in the daily group (P < .05). More obvious change was seen in the 200 to approximately 500 pg/mL subgroup by stratified analysis (P < .05), whereas there was no significant difference between the 500 to approximately 1,000 pg/mL and > 1,000 pg/mL subgroup (P > .05). At therapeutic end point, the total ratio of reaching end point did not differ between the two groups, and there were no obvious differences between each subgroup. In the iPTH 200 to approximately 500 pg/mL subgroup, mean iPTH%/week in the pulse group was significantly higher than that in the daily group, and no obvious difference was seen in other subgroups. AKP levels decreased significantly in both groups at therapeutic end point (pulse group 98.42 +/- 54.52 vs. 74.21 +/- 30.68 IU/L, P < .01; daily group 103.3 +/- 68.04 vs. 75.40 +/- 34.12 IU/L, P < .01). On the 4th week, AKP level in pulse group (82.39 +/- 35.23 IU/L) was significantly lower than the initial level (98.42 +/- 54.52 IU/L, P < .05), whereas in the daily group there was no difference between each week. The mean serum calcium, phosphate, and [Ca2+] x [P3+] levels in both groups did not change greatly. Nine patients in the pulse group (9.9%) and 8 patients in the daily group (11.9%) suffered hypercalcemia at least once. Persistent hypercalcemia occurred in 8 patients in the pulse group (8.8%) and 9 patients in the daily group (13.4%), but the difference in proportion did not show statistical significance. The serum phosphate in the daily group was higher after the therapy (1.74 +/- 0.36 vs. 1.89 +/- 0.36 mmol/L, P < .05), whereas that in the pulse group remained unchanged. At therapeutic end point, [Ca2+] x [P3+] level in the daily group was higher than that before the therapy (48.04 +/- 11.71 vs. 55.46 +/- 12.66, P < .05), whereas in the pulse group there was no significant difference. Side effects for both groups were minimal and well tolerated. CONCLUSIONS: Alfacalcidol [1alpha-(OH)-D3] has good and safe effects on secondary hyperparathyroidism in maintenance hemodialysis patients. The efficacy and early effects of pulse therapy are superior to those of daily therapy in moderate hyperparathyroidism patients.     

Hemodynamic changes during hemodialysis: role of nitric oxide and endothelin

BACKGROUND: Etiology of dialysis induced hypotension and hypertension remains speculative. There is mounting evidence that nitric oxide (NO) and endothelin (ET-1) may play a vital role in these hemodynamic changes. We examined the intradialytic dynamic changes in NO and ET-1 levels and their role in the pathogenesis of hypotension and rebound hypertension during hemodialysis (HD). METHODS: The serum nitrate + nitrite (NT), fractional exhaled NO concentration (FENO), L-arginine (L-Arg), NGNG-dimethyl-L-arginine (ADMA) and endothelin (ET-1) profiles were studied in 27 end-stage renal disease (ESRD) patients on HD and 6 matched controls. The ESRD patients were grouped according to their hemodynamic profile; Group I patients had stable BP throughout HD, Group II had dialysis-induced hypotension, and Group III had intradialytic rebound hypertension. RESULTS: Pre-dialysis FENO was significantly lower in the dialysis patients compared to controls (19.3 +/- 6.3 vs. 28.6 +/- 3.4 ppb, P < 0.002). Between the experimental groups, pre-dialysis FENO was significantly higher in Group II (24.1 +/- 6.7 ppb) compared to Group I (17.8 +/- 5.6 ppb) and Group III (16.1 +/- 4.2 ppb; P < 0.05). Post-dialysis, FENO increased significantly from the pre-dialysis values (19.3 +/- 6.3 vs. 22.6 +/- 7.9 ppb; P=0.001). Pre-dialysis NT (34.4 +/- 28.2 micromol/L/L) level was not significantly different from that of controls (30.2 +/- 12.3 micromol/L/L). Serum NT decreased from 34.4 +/- 28.2 micromol/L/L at initiation of dialysis to 10.0 +/- 7.4 micormol/L/L at end of dialysis (P < 0.001). NT concentration was comparable in all the three groups at all time points. Pre-dialysis L-Arg (105.3 +/- 25.2 vs. 93.7 +/- 6.0 micromol/L/L; P < 0.05) and ADMA levels were significantly higher in ESRD patients (4.0 +/- 1.8 vs. 0.9 +/- 0.2 micromol/L/L; P < 0.001) compared to controls. Dialysis resulted in significant reduction in L-Arg (105.3 +/- 25.2 vs. 86.8 +/- 19.8 micromol/L/L; P < 0.005) and ADMA (4.0 +/- 1.8 vs. 1.6 +/- 0.7 micromol/L/L; P < 0.001) concentrations. Pre-dialysis ET-1 levels were significantly higher in ESRD patients compared to the controls (8.0 +/- 1.9 vs. 12.7 +/- 4.1 pg/mL; P < 0.002), but were comparable in the three study groups. Post-dialysis ET-1 levels did not change significantly in Group I compared to pre-dialysis values (14.3 +/- 4.3 vs.15.0 +/- 2.4 pg/mL, P=NS). However, while the ET-1 concentration decreased significantly in Group II (12.0 +/- 4.0 vs. 8.7 +/- 1.8 pg/mL, P < 0.05), it increased in Group III from pre-dialysis levels (12.8 +/- 3.8 vs. 16.7 +/- 4.5 pg/mL, P=0.06). CONCLUSION: Pre-dialysis FENO is elevated in patients with dialysis-induced hypotension and may be a more reliable than NT as a marker for endogenous NO activity in dialysis patients. Altered NO/ET-1 balance may be involved in the pathogenesis of rebound hypertension and hypotension during dialysis.