Hyperparathyroidism In Dialysis Patients Research Articles

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.

Control of severe hyperparathyroidism in dialysis patients with nodular hyperplasia.

Secondary hyperparathyroidism is one of the most important abnormalities in chronic kidney disease-mineral and bone disorder (CKD-MBD). Despite the recent development of therapeutic modalities including new phosphate binders, new vitamin D analogues and cinacalcet, manypatientswithveryseverehyperparathyroidismstillremainuncontrollable.Severalstudieshavedemonstratedthat such refractory patients have markedly enlarged parathyroid glands with nodular hyperplasia composed of cells with decreased numbers of vitamin D and calcium-sensing receptors [1]. Percutaneous ethanol injection therapy (PEIT) of parathyroid glands was originally developed as an alternative to conventional surgical parathyroidectomy in Europe during the 1980s. Together with the advances in imaging techniques allowing identification of the glands to be destroyed, this therapy became a more sophisticated and practical therapeutic modality to control severe hyperparathyroidism during the early 1990s in Japan [2]. In this ‘selective PEIT’, glands with nodular hyperplasia are destroyed by ethanol injection, and remaining glands with diffuse hyperplasia are controlled by subsequent medical therapy. Analysis of the prognosis of parathyroid function following these procedures clearly suggests that patients with one nodular gland were best suited to selective PEIT [3]. The Japanese Society for Parathyroid Intervention, originally named as the Japanese Society for PEIT of Parathyroid, was established in 1996. The initial purpose of this society was to standardize the indication and protocol of PEIT. As a result, we published clinical guidelines for

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.

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

Active vitamin D agents and refractory hyperparathyroidism in dialysis patients

Active vitamin D agents and refractory hyperparathyroidism in dialysis patients

Active vitamin D agents and refractory hyperparathyroidism in dialysis patients

Active vitamin D agents and refractory hyperparathyroidism in dialysis patients

Serum fibroblast growth factor-23 levels predict the future refractory hyperparathyroidism in dialysis patients

Secondary hyperparathyroidism is a common complication among long-term dialysis patients. The method of predicting future parathyroid function has not yet been established. Fibroblast growth factor-23 (FGF-23) is a newly found humoral phosphaturic factor. One hundred and three nondiabetic dialysis patients whose plasma intact parathyroid hormone (PTH) levels were below 300 pg/mL were included in the study. Blood samples were stored at -80 degrees C for 2 years. Meanwhile, each physician in charge decided upon the strategy of medical therapy for maintaining intact PTH levels between 150 and 300 pg/mL. Patients were judged 2 years after the sample collection with regard to whether the hyperparathyroidism responded to the medical therapy. The definition of refractory secondary hyperparathyroidism was either (1) retaining intact PTH levels greater than 300 pg/mL 2 years after sample collection, or (2) having received the parathyroid intervention therapy during the observation period. Serum FGF-23 levels were determined with a sandwich enzyme-linked immunosorbent assay system that detects biologically active human FGF-23. Seventeen patients with intact PTH levels greater than 300 pg/mL were judged as having secondary hyperparathyroidism refractory to medical therapy. A stepwise regression analysis revealed that only serum levels of FGF-23 were significantly related to the prognosis of parathyroid function. A receiver-operated characteristic analysis demonstrated that the area under the curves obtained from FGF-23 (7099.9) was significantly greater than that obtained from intact PTH (6306.4, P < .01) and Ca x Pi (5670.3, P <.0001). Although the plasma intact PTH levels at the beginning of the observation period were comparable to each other, the intact PTH levels at 2 years after the sample collection were significantly higher in the patients with FGF-23 >/=7500 ng/L than in those with FGF-23 <7500 ng/L (P < .0001). Serum FGF-23 level was found to be the most useful factor in predicting future development of refractory secondary hyperparathyroidism in long-term dialysis patients with mild secondary hyperparathyroidism. The measurement of serum FGF-23 levels is a promising laboratory examination that can be applied in the clinical practice of uremic secondary hyperparathyroidism.

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

Intravenous versus oral vitamin D therapy in dialysis patients: What is the question?

The debate regarding the administration of vitamin D (parenteral versus pulse oral) in dialysis patients has centered on the efficacy of parathyroid hormone (PTH) suppression while ignoring other questions related to complications and compliance. Past studies looking at efficacy showed no differences during short-term treatment, although the small number of patients studied reduces the significance of these findings. Long-term studies with larger populations have shown that parenteral calcitriol is more effective than pulse oral calcitriol in suppressing PTH. When considering the questions of complications and compliance the current literature demonstrates that parenteral vitamin D therapy is associated with fewer episodes of hypercalcemia and hyperphosphatemia and that patients receiving pulse oral calcitriol require more phosphate binders. Because of the documented high noncompliance rate with oral medications in the dialysis population, parenterally administered vitamin D is expected to more completely suppress PTH long term and result in fewer parathyroidectomies. Based on these considerations it is suggested that parenteral vitamin D analogs are superior to pulse oral calcitriol for the long-term control of hyperparathyroidism in dialysis patients.

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.

Re-evaluation of risks associated with hyperphosphatemia and hyperparathyroidism in dialysis patients: Recommendations for a change in management

Hyperphosphatemia is a predictable consequence of chronic renal failure and is present in most patients on dialysis. Traditionally, the risk associated with elevated serum phosphorus has focused on its impact on renal osteodystrophy. A growing body of evidence, however, suggests that abnormalities in serum phosphorus, calcium-phosphorus product (CaxP), and parathyroid hormone (PTH) levels are resulting in vascular and visceral calcification, thereby contributing to the substantially increased risk of cardiovascular death in this population. In this analysis, we review in detail the literature that describes these associations. We show that the current treatment paradigm for serum phosphorus and secondary hyperparathyroidism is ineffective for a large segment of dialysis patients. Currently, 60% of hemodialysis patients have phosphorus greater than 5.5 mg/dL, and 40% have CaxP greater than 60 mg2/dL2. It is our belief that prevention of uremic calcification, cardiac death, and vascular disease should assume primary importance when evaluating the risks associated with elevated levels of phosphorus, CaxP, and PTH. We recommend that target levels should become 9.2 to 9.6 mg/dL for calcium, 2.5 to 5.5 mg/dL for phosphorus, less than 55 mg2/dL2 for CaxP product, and 100 to 200 pg/mL for intact PTH.

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.

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.