Secondary Hyperparathyroidism In Dialysis Patients Research Articles

Continuation of cinacalcet immediately after renal transplantation: a prospective cohort study

Cinacalcet is used for treating secondary hyperparathyroidism in dialysis patients, but it is currently unknown whether it can safely be continued immediately after renal transplantation. We prospectively studied renal transplant recipients with secondary hyperparathyroidism who were receiving cinacalcet before transplantation and continued treatment afterwards (n = 29) at a dose of 30 mg/day. Cinacalcet dose was titrated to serum calcium. Patients were followed for 6 months. Incidence of hypercalcemia, serum calcium and intact PTH (iPTH) were analyzed. Tacrolimus levels, acute rejection rate and renal function were compared with an age and sex matched control group. In 16 patients hypercalcemia was observed after transplantation. Severe hypercalcemia (>= 2.87 mmol/l) (n = 4) and hypocalcemia (n = 2) were infrequent. No difference in acute rejection rate or renal function between the cinacalcet and the control group was found. There also was no clinically relevant influence of cinacalcet on tacrolimus levels. Our study shows that cinacalcet can safely be continued immediately after renal transplantation. Studies are needed to determine if continuation of cinacalcet is better than early withdrawal. Also, the optimum dose of cinacalcet and the long-term effects of cinacalcet after renal transplantation must be defined.

Economic Evaluation of Cinacalcet in the Treatment of Secondary Hyperparathyroidism in Italy

Imbalanced levels of parathyroid hormone (PTH), serum calcium (Ca) and phosphorous (P) are associated with an increased risk of cardiovascular (CV) death and fracture in dialysis patients with secondary hyperparathyroidism (SHPT). The calcimimetic agent cinacalcet can attenuate the mineral and hormonal imbalances characteristic of SHPT and may improve outcomes in such patients. Here we describe a cost-utility analysis of cinacalcet for SHPT in dialysis patients in Italy. We developed a probabilistic Markov model to simulate the effect of cinacalcet on Ca, P and PTH levels in dialysis patients with SHPT, based on data from a European, multicentre, open-label study. The model then correlated these levels with mortality and morbidity (CV events, fractures and parathyroidectomies) using data from the literature, and incorporated Italian data for dialysis, drugs and management of events according to the national cost structure. The simulation horizon was patient lifetime; simulated treatment alternatives were standard treatment (mainly vitamin D sterols and phosphate binders) and cinacalcet + standard treatment. A 3.5% discount rate was applied to life expectancy (LE), quality-adjusted life-expectancy (QALE), costs and times below the upper ranges (time in range [TiR]) recommended by the National Kidney Foundation - Kidney Disease Outcomes Quality initiative for PTH, Ca, P and Ca × P. Utilities were derived from the published literature and took into account dialysis and the impairment of quality of life due to the occurrence of CV events and fractures. Costs were evaluated in year 2009 values from the perspective of the Italian National Healthcare System. Baseline results were calculated with 10,000 iterations. Compared with standard treatment alone, addition of cinacalcet was associated with a mean (SD) increase in TiR of 5.26 (6.59), 3.63 (6.87), 1.70 (6.66) and 2.68 (5.55) discounted patient-years for PTH, Ca and P, respectively, and combined PTH, Ca, P and Ca × P. Cinacalcet increased LE by 1.20 (3.75) life-years (LYs) and QALE by 0.89 (2.59) QALYs. When including the cost for dialysis, the incremental cost-effectiveness ratio (ICER) was €50,012 per LY and €67,361 per QALY, while, if dialysis costs were not included, the ICER was €23,473 per LY and €31,616 per QALY. The results suggest that cinacalcet treatment could be considered cost effective for treatment of SHPT in the Italian healthcare setting, but further investigations are needed to confirm these findings.

Effect of paricalcitol and cinacalcet on serum phosphate, FGF-23, and bone in rats with chronic kidney disease

Calcimimetics activate the calcium-sensing receptor (CaR) and reduce parathyroid hormone (PTH) by increasing the sensitivity of the parathyroid CaR to ambient calcium. The calcimimetic, cinacalcet, is effective in treating secondary hyperparathyroidism in dialysis patients [chronic kidney disease (CKD 5)], but little is known about its effects on stage 3-4 CKD patients. We compared cinacalcet and paricalcitol in uremic rats with creatinine clearances "equivalent" to patients with CKD 3-4. Uremia was induced in anesthetized rats using the 5/6th nephrectomy model. Groups were 1) uremic control, 2) uremic + cinacalcet (U+Cin; 15 mg x kg(-1) x day(-1) po for 6 wk), 3) uremic + paricalcitol (U+Par; 0.16 microg/kg, 3 x wk, ip for 6 wk), and 4) normal. Unlike U+Par animals, cinacalcet promoted hypocalcemia and marked hyperphosphatemia. The Ca x P in U+Cin rats was twice that of U+Par rats. Both compounds suppressed PTH. Serum 1,25-(OH)(2)D(3) was decreased in both U+Par and U+Cin rats. Serum FGF-23 was increased in U+Par but not in U+Cin, where it tended to decrease. Analysis of tibiae showed that U+Cin, but not U+Par, rats had reduced bone volume. U+Cin rats had similar bone formation and reduced osteoid surface, but higher bone resorption. Hypocalcemia, hyperphosphatemia, low 1,25-(OH)(2)D(3), and cinacalcet itself may play a role in the detrimental effects on bone seen in U+Cin rats. This requires further investigation. In conclusion, due to its effects on bone and to the hypocalcemia and severe hyperphosphatemia it induces, we believe that cinacalcet should not be used in patients with CKD without further detailed studies.

Synergistic effect of cinacalcet and active vitamin D in a dialysis patient with secondary hyperparathyroidism

AbstractWhile treating a long‐term dialysis patient for secondary hyperparathyroidism (SHPT), indications of a synergistic effect between cinacalcet HCl and active vitamin D were observed. After 2.5 years, high initial cinacalcet doses of 180 mg/day could be significantly reduced to only 30 mg/non‐dialysis day without losing control over the intact parathyroid hormone. Calcium‐phosphorus product improved over time. The combination of cinacalcet and active vitamin D may improve the treatment of SHPT in dialysis patients. Dial. Transplant. © 2010 Wiley Periodicals, Inc.

Assessment of adherence to cinacalcet by prescription refill rates in hemodialysis patients

Secondary hyperparathyroidism is common among dialysis patients and leads to numerous complications including cardiovascular disease and renal osteodystrophy. Cinacalcet, an oral daily calcimimetic agent that sensitizes the calcium receptor to serum calcium, is approved for treatment of secondary hyperparathyroidism in dialysis patients. We identified 101 patients who received their first cinacalcet prescription between November 2004 and April 2005. All patients were participating in a Missouri state-funded pharmacy program providing free or low cost medications. We tracked the cinacalcet refill rate and refills for another control medication prescribed to each patient. The average cinacalcet refill rate over the first 12 months was 56% vs. 64% for the control medication (P=0.02). Good adherence, defined as >80% medication possession ratio over the 12 months, was 29% for cinacalcet and 33% for the control medication (P=0.68). Additionally, the refill rate for cinacalcet fell significantly over five quarterly periods from 53% in the first quarter to 37% in the 5th quarter. We conclude that dialysis patients' adherence to medications, including cinacalcet, is poor even when medications are provided at a nominal cost. Poor cinacalcet adherence would be expected to impair long-term control of SHPT. In a reimbursement system where injectable, but not oral medications, are bundled with dialysis payments there may be pressure to move patients to oral medications. The poor compliance found in this study highlights the potential adverse effects of movement toward self-administered oral therapy.

Cinacalcet Use Patterns and Effect on Laboratory Values and Other Medications in a Large Dialysis Organization, 2004 through 2006

Cinacalcet was introduced in mid-2004 to treat secondary hyperparathyroidism in dialysis patients. We aimed to characterize adult patients who received cinacalcet prescriptions and to determine (1) dosage titration and effects on laboratory values, active intravenous vitamin D use, and phosphate binder prescriptions and (2) percentage who achieved National Kidney Foundation Kidney Disease Outcomes Quality Initiative targets for serum parathyroid hormone, calcium, and phosphorus and experienced biochemical adverse effects. This observational study evaluated 45,487 prevalent patients from a dialysis organization database linked with the Centers for Medicare and Medicaid Services End-Stage Renal Disease database. Patient characteristics, laboratory values (albumin, parathyroid hormone, calcium, phosphorus), intravenous vitamin D, and oral medication (cinacalcet, phosphate binders) prescriptions were evaluated for cinacalcet patients. By June 2006, almost 32% of patients had received cinacalcet prescriptions. Mean baseline corrected calcium was 9.8 mg/dl and phosphorus was 6.3 mg/dl, and median parathyroid hormone was 577 pg/ml, versus 9.5 mg/dl, 5.3 mg/dl, and 215 pg/ml, respectively, for noncinacalcet patients. Patients with cinacalcet prescriptions for > or =6 mo had corrected calcium reduced by 4.2%, phosphorus by 7.0%, and parathyroid hormone by 29.9% by 12 mo. More cinacalcet patients attained Kidney Disease Outcomes Quality Initiative targets with less hyperparathyroidism, hypercalcemia, and hyperphosphatemia but more hypoparathyroidism and hypocalcemia. Over 12 mo, vitamin D use and use consistency increased, phosphate binder dosages increased, and mean cinacalcet daily dosage reached 55 mg. Patients with cinacalcet prescriptions exhibited more severe hyperparathyroidism and hyperphosphatemia than noncinacalcet patients. Positive effects were less dramatic than in Phase III clinical trials, possibly as a result of modest, slow dosage titration.

Cinacalcet HCl and Concurrent Low-dose Vitamin D Improves Treatment of Secondary Hyperparathyroidism in Dialysis Patients Compared with Vitamin D Alone

Patients with chronic kidney disease (CKD) receiving dialysis often develop secondary hyperparathyroidism with disturbed calcium and phosphorus metabolism. The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (KDOQI) was established to guide treatment practices for these disorders. The ACHIEVE study was designed to test two treatment strategies for achieving KDOQI goals. Individuals on hemodialysis treated with vitamin D sterols were enrolled in this 33-week study. Subjects were randomly assigned to treatment with either cinacalcet and low-dose vitamin D (Cinacalcet-D) or flexible vitamin D alone (Flex-D) to achieve KDOQI-recommended bone mineral targets. ACHIEVE included a 6-week screening phase, including vitamin D washout, a 16-week dose-titration phase, and an 11-week assessment phase. Of 173 subjects enrolled, 83% of Cinacalcet-D and 67% of Flex-D subjects completed the study. A greater proportion of Cinacalcet-D versus Flex-D subjects had a >30% reduction in parathyroid hormone (PTH) (68% versus 36%, P < 0.001) as well as PTH <300 pg/ml (44% versus 23%, P = 0.006). The proportion of subjects simultaneously achieving targets for intact PTH (150-300 pg/ml) and calcium-phosphorus product (Ca x P) (<55 mg2/dl2) was also greater (21% versus 14%), but this was not statistically significant. This was attributable to 19% of Cinacalcet-D subjects with a PTH value below the KDOQI target range. Achievement of KDOQI targets was difficult, especially with Flex-D. Maintaining calcium and phosphorus target values precluded the use of vitamin D doses necessary to lower PTH to within the narrow target range and highlighted limitations inherent to the KDOQI treatment algorithm.

Serum fibroblast growth factor-23 levels in chronic haemodialysis patients

Fibroblast growth factor-23 (FGF23) is a circulating factor that regulates renal reabsorption of inorganic phosphate. Serum FGF23 level is increased in chronic kidney disease (CKD) patients as a compensatory mechanism to hyperphosphataemia. FGF23 directly signals in the parathyroid glands and can be used to predict future secondary hyperparathyroidism in dialysis patients. We examined the relationship between FGF23 and serum calcium, phosphate, 1,25(OH)(2)D(3), and PTH levels in haemodialysis patients. FGF23 and the above mentioned characteristics were measured in 50 chronic haemodialysis patients. We analysed the correlation between FGF23 and the other characteristics by using the Pearson correlation coefficient and multiple regression analysis. FGF23 was significantly increased in haemodialysis patients compared with healthy controls (1525 +/- 373 vs. 37 +/- 9 pg/ml, P < 0.0001). There was a significant negative correlation between log FGF23 and 1,25(OH)(2)D(3) (R = -0.375, P = 0.009) and a significant positive correlation between log FGF23 and log PTH values (R = 0.287, P = 0.041). In multiple regression analysis log PTH and 1,25(OH)(2)D(3) values were independent predictors of log FGF23 (P = 0.037 and 0.009, respectively). Our results revealed a marked increase in FGF23 levels in haemodialysis patients. PTH and vitamin D3 were independent predictors of FGF23 in the study group. Serum phosphate did not correlate with or predict FGF23 level despite the high prevalence of hyperphosphataemia in the study group.

Cinacalcet Treatment in Dialysis Patients with Secondary Hyperparathyroidism: Effects and Open Issues

The recent introduction of calcimimetics, a novel class of therapeutic agents, has led to a change in the treatment strategy of secondary hyperparathyroidism in patients with end-stage renal disease. In initial acute studies in chronic hemodialysis patients, the calcimimetic cinacalcet was shown to reduce plasma intact parathyroid hormone within hours, followed by a rapid, profound decrease in plasma calcium and a minor decrease in plasma phosphorus. Subsequent reports showed that the long-term administration of cinacalcet to such patients proved to be superior to standard therapy in controlling secondary uremic hyperparathyroidism, in that it was able to induce a decrease in both plasma intact parathyroid hormone and the calcium x phosphorus product, in contrast to the effects of active vitamin D sterols. This allowed the achievement of the guideline treatment targets proposed by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative in a much larger proportion of dialysis patients than standard therapy did. Moreover, the effect of cinacalcet is long-lasting. An important question is that of cinacalcet's effects on patient outcomes, which is still lacking. A similar lack of information exists for most other treatment modalities given to correct the mineral and bone disorder of chronic kidney disease. A post-hoc analysis of four clinical trials combined done in hemodialysis patients showed that randomization to cinacalcet led to significant reductions in the risk of parathyroidectomy, fracture, and cardiovascular hospitalization. To obtain a definitive answer to this question, including patient survival, we will have to wait for the results of prospective, randomized controlled trials. In pre-clinical studies performed in rats with chronic renal failure, the administration of the calcimimetic NPS R-568 at the time of uremia induction allowed the prevention of parathyroid hyperplasia, and the reversal of already established hyperplasia as well. Perhaps more important from the clinical point of view, NPS R-568 also appeared to allow reversal of osteitis fibrosa in uremic rats and reduction of aortic calcification and atherosclerosis in uremic rats and mice. In conclusion, the clinical introduction of cinacalcet allows for better control of secondary hyperparathyroidism in dialysis patients as compared to standard therapy, based on surrogate biochemical markers. Hopefully, in the future, this improvement will be shown to be associated with better patient outcomes for the treatment of fractures and cardiovascular morbidity and mortality.

Pathophysiology of parathyroid hyperplasia in chronic kidney disease: preclinical and clinical basis for parathyroid intervention.

Secondary hyperparathyroidism is characterised by excessive secretion of parathyroid hormone and parathyroid hyperplasia, resulting in both skeletal and extraskeletal consequences. Recent basic and clinical studies have brought considerable advances in our understanding of the pathophysiology of parathyroid hyperplasia and have also provided practical therapeutic approaches, especially with regard to indications for parathyroid intervention. In this context, it is quite important to recognize the development of nodular hyperplasia, because the cells in nodular hyperplasia are usually resistant to calcitriol treatment. Patients with nodular hyperplasia should undergo parathyroid intervention including percutaneous ethanol injection therapy (PEIT). Selective PEIT of the parathyroid gland is an effective approach in which the enlarged parathyroid gland with nodular hyperplasia is ‘selectively’ destroyed by ethanol injection, and other glands with diffuse hyperplasia are then managed by medical therapy. With a more focused attention to applying parathyroid intervention, we can expect significant improvement in the management of secondary hyperparathyroidism in dialysis patients.

Pathogenesis and Treatment of Secondary Hyperparathyroidism in Dialysis Patients: The Role of Paricalcitol

Hemodialysis (HD) patients are commonly affected by secondary hyperparathyroidism (SHPT), in which 3 well-known factors are usually involved: hypocalcemia, hyperphosphatemia and calcitriol deficiency. Classically, high parathyroid hormone (PTH) levels cause bone-associated diseases, such as osteitis fibrosa and renal osteodystrophy, but more recently it has been demonstrated the link between SHPT and a systemic toxicity, with a major role in determining cardio-vascular disease, including arterial calcification, endocrine disturbances, compromised immune system, neurobehavioral changes, and altered erythropoiesis. Treatment with calcitriol (CT), the active form of vitamin D, reduces parathyroid hormone (PTH) levels, but may result in elevations in serum calcium (Ca) and phosphorus (P), increasing the risk of cardio-vascular calcification in the HD population. Several new vitamin D analogs have been developed and investigated with the rationale to treat SHPT with a reduced risk of hypercalcemia and hyperphosphatemia in HD patients. Paricalcitol (1,25-dihydroxy-19-nor-vitamin D(2), 19-Nor-D(2)) is a vitamin D analog that suppresses PTH secretion with minimal increases on serum calcium and phosphate levels. It was demonstrated that paricalcitol prevents vascular calcification in experimental models of renal failure, compared with calcitriol. Furthermore, 19-Nor-D(2) is the first analog approved for use in HD patients and is available for i.v. and oral administration, commonly 3 times weekly after HD. The purpose of the present review is to analyze the pathogenesis and treatment of SHPT in HD patients, and the role of paricalcitol in the prevention of arterial calcification.

Effect of Cinacalcet Hydrochloride, a New Calcimimetic Agent, on the Pharmacokinetics of Dextromethorphan: In Vitro and Clinical Studies

Cinacalcet hydrochloride (cinacalcet) is a positive allosteric modulator of the calcium-sensing receptor indicated for the treatment of secondary hyperparathyroidism in dialysis patients. In vitro study has demonstrated that cinacalcet is a potent inhibitor of cytochrome P450 (CYP) 2D6 with a K(i) value of 0.087 micromol/L, which is comparable to the well-known potent CYP2D6 inhibitor, quinidine (0.064 micromol/L). A clinical study was conducted to assess the inhibitory effect of cinacalcet on CYP2D6 substrates in healthy volunteers. Each subject received 50 mg of cinacalcet or a matched placebo orally once daily for 8 days with 30 mg of dextromethorphan coadministered on day 8. The mean AUC(0-infinity) and C(max) of dextromethorphan increased 11- and 7-fold, respectively, in extensive metabolizers when coadministered with cinacalcet versus placebo. Therefore, during concomitant treatment with cinacalcet, it may be necessary to consider making dose adjustments for drugs with a narrow therapeutic index that are mainly metabolized by CYP2D6.

Cinacalcet HCl: A Novel Treatment for Secondary Hyperparathyroidism Caused by Chronic Kidney Disease

Secondary hyperparathyroidism (SHPT) develops as a result of impaired calcium homeostasis when the failing kidneys disturb the complicated interactions between parathyroid hormone (PTH), calcium, phosphorus, and vitamin D. Twelve years ago, the calcium-sensing receptor (CaR) of the parathyroid gland was first cloned and identified as the principal regulator of PTH secretion. The activation of the CaR by small changes in extracellular calcium (ec(Ca2+)) regulates PTH, calcitonin secretion, urinary calcium excretion, and ultimately, bone turnover. The CaR became an ideal target for the development of calcimimetics, which are able to amplify its sensitivity to ec(Ca2+) suppressing PTH secretion. Cinacalcet HCl, a first-in-class calcimimetic, approved in both the United States and the European Union, offers a new therapeutic approach to the treatment of SHPT. The efficacy of cinacalcet HCl in treating SHPT in dialysis patients (n = 1,136) was studied in three similarly designed phase III clinical trials comparing patients receiving standard SHPT therapy plus cinacalcet HCl or plus placebo. Cinacalcet HCl, dosed from 30 to 180 mg/day, significantly reduced PTH while simultaneously lowering calcium, phosphorus, and calcium-phosphorus product in each of the three studies. Respective to the National Kidney Foundation-Kidney Disease Outcomes and Quality Initiative (NKF-K/DOQI) recommended targets for bone and mineral metabolism, 41% of cinacalcet HCl-treated patients achieved both PTH and calcium-phosphorus product targets, compared with only 6% in the placebo group. Results from 2 recent phase IIIb studies (TARGET and CONTROL) conducted in the United States also showed that cinacalcet HCl can significantly reduce or maintain reduction in PTH while simultaneously lowering calcium, phosphorus, and calcium-phosphorus product. In addition, patients taking vitamin D at baseline of these 2 trials were able to see significant mean reductions in vitamin D dose. Further assessment of cinacalcet HCl trial data has shown some important effects in SHPT patient clinical outcomes. A combined post-hoc analysis of clinical events using data from 4 (n = 1,184) cinacalcet HCl phase II and III studies suggests that treatment with cinacalcet HCl has a beneficial effect on relative risks of parathyroidectomy, fracture, and hospitalization for cardiovascular complications. Nausea and vomiting occurred more often in patients taking cinacalcet HCl than in those taking a placebo. There were also transient episodes of hypocalcemia in 5% of cinacalcet HCl patients versus 1% of placebo patients. However, these episodes were rarely associated with symptoms. The development of calcimimetics has already changed the treatment of SHPT in renal patients. Its effectiveness on the control of PTH secretion, along with simultaneous reductions in calcium, phosphorus, and calcium-phosphorus product, give this agent an advantage over traditional therapies in all levels of severity of SHPT.

Drug Insight: renal indications of calcimimetics

Calcimimetics suppress the secretion of parathyroid hormone by sensitizing the parathyroid calcium receptor to serum calcium. Cinacalcet (Sensipar/Mimpara), Amgen Inc., Thousand Oaks, CA), the first-in-class calcimimetic agent approved for treatment of secondary hyperparathyroidism in dialysis patients, is, in association with higher dose of a calcium-based oral phosphate binder, a well-tolerated and effective alternative to standard treatments such as vitamin D derivatives in association with a non-calcium-based oral phosphate binder. Here, we present an overview of evidence in support of this assertion. We extend our discussion to encompass other indications for calcimimetics -- secondary hyperparathyroidism in predialysis chronic kidney disease patients, hypercalcemic hyperparathyroidism in renal transplant recipients, primary hyperparathyroidism, and hypercalcemia associated with parathyroid carcinoma -- as well as providing guidance on optimal usage of this drug.

CHAPTER 3

CHAPTER 3

The renal dietitian's role in managing hyperphosphatemia and secondary hyperparathyroidism in dialysis patients: A national survey

Purpose: To survey the medical nutrition therapy practices of renal dietitians for the treatment of bone mineral metabolism. Objectives: To obtain data on phosphorus diet prescription levels. To determine allied team involvement for phosphate binder and Vitamin D therapies. To assess the frequency and target levels for monitoring serum calcium, phosphorus, -phosphorus product, intact PTH and alkaline phosphatase. Methods: Two renal dietitians from the National Kidney Foundation-Council on Renal Nutrition developed a 5-question survey. This was posted on both the RenalRD Listserv and the NKF-CRN website from January 1 through February 15, 2001. Dietitians were asked to respond using facsimile, e-mail or reply by mail. Results: One hundred and thirty-one surveys were received representing all major dialysis providers in the United States, the British Virgin Islands, and Japan. Results included information for peritoneal and hemodialysis patients. Five different methods for dosing phosphate binders were determined. Prescribed phosphate binders included calcium acetate, sevelamer hydrochloride, and calcium carbonate. 108 out of 131 dietitian respondents (82.5%) have a medical protocol in place for vitamin D therapy. Of the respondents, 47% were directly responsible for implementing the vitamin D protocol. Paricalcitol was the most widely used form of IV Vitamin D. Biochemistry results were as follows: calcium, 16 different ranges from 8.0 mg/dL to 11.5 mg/dL; phosphorus, 13 different ranges from 2.5 mg/dL to 6.5 mg/dL; calcium-phosphorus product, 13 different ranges from 55-75; iPTH, 20 different ranges from 50-300 pg/mL; alkaline phosphatase, 18 different ranges from no records being monitored to a level of 500 mg/dL. Conclusion: The survey revealed a large variability in the treatment of bone mineral metabolism. Improved clinical practice guidelines for the health care team are being developed with the National Kidney Foundation (NKF)-Kidney Disease Outcomes and Quality Initiative (KDOQI) bone disease management workgroup. © 2003 by the National Kidney Foundation, Inc.

Review: The renal dietitian's role in managing hyperphosphatemia and secondary hyperparathyroidism in dialysis patients: A national survey

Review: The renal dietitian's role in managing hyperphosphatemia and secondary hyperparathyroidism in dialysis patients: A national survey

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

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. 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. 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. 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.

Failure of high doses of calcitriol and hypercalcaemia to induce apoptosis in hyperplastic parathyroid glands of azotaemic rats.

Whether calcitriol administration, which is used to treat secondary hyperparathyroidism in dialysis patients, induces regression of parathyroid-gland hyperplasia remains a subject of interest and debate. If regression of the parathyroid gland were to occur, the presumed mechanism would be apoptosis. However, information on whether high doses of calcitriol can induce apoptosis of parathyroid cells in hyperplastic parathyroid glands is lacking. Consequently, high doses of calcitriol were given to azotaemic rats and the parathyroid glands were evaluated for apoptosis. Rats were either sham-operated (two groups) or underwent a two-stage 5/6 nephrectomy (three groups). For the first 4 weeks, all rats were given a high (1.2%) phosphorus (P) diet to stimulate parathyroid gland growth and then were changed to a normal (0.6%) P diet for 2 weeks. At week 7, three of the five groups were given high doses of calcitriol (500 pmol/100 g body weight) intraperitoneally every 24 h during 72 h before sacrifice. The five groups during week 7 were: (i) normal renal function (NRF)+0.6% P diet; (ii) NRF+0.6% P+calcitriol; (iii) renal failure (RF)+0.6% P; (iv) RF+1.2% P+calcitriol; and (v) RF+0.6% P+calcitriol. Parathyroid glands were removed at sacrifice and the TUNEL stain was performed to detect apoptosis. At sacrifice, the respective serum calcium values in calcitriol-treated groups (groups 2, 4, and 5) were 15.52+/-0.26, 13.41+/-0.39 and 15.12+/-0.32 mg/dl. In group 3, PTH was 178+/-42 pg/ml, but in calcitriol-treated groups, PTH values were suppressed, 8+/-1 (group 2), 12+/-2 (group 4), and 7+/-1 pg/ml (group 5). Despite, the severe hypercalcaemia and marked PTH suppression in calcitriol-treated groups, the percentage of apoptotic cells in the parathyroid glands was very low (range 0.08+/-0.04 to 0.25+/-0.20%) and not different among the five groups. We found no evidence in hyperplastic parathyroid glands that apoptosis could be induced in azotaemic rats by the combination of high doses of calcitriol and severe hypercalcaemia despite the marked reduction in PTH levels that was observed.

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

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. 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. 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). (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.