Treatment of secondary hyperparathyroidism in ESRD: a 2-year, single-center crossover study Neal Mittman 1 , Brinda Desiraju 1 , Kevin B. Meyer 1 , Jyoti Chattopadhyay 1 and Morrell M. Avram 1 1 Avram Division of Nephrology, Long Island College Hospital, Brooklyn, New York, USA Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease. The management of SHPT commonly involves vitamin D, either calcitriol or newer analogs (paricalcitol or doxercalciferol), along with dietary phosphorus restriction and phosphate binding agents. Published reports have suggested that treatment with paricalcitol in hemodialyzed (HD) patients offers a morbidity or mortality advantage in comparison with treatment with calcitriol. We have recently reported that switching from calcitriol to paricalcitol resulted in a lower serum calcium and calcium–phosphorus product (Ca P product), as well as lower parathyroid hormone (PTH) and alkaline phosphatase during 6 months of serial treatment. We converted all HD patients in our large urban dialysis center from calcitriol to paricalcitol using a 1:3 conversion ratio, on the basis of published data. Comparisons of individual patient mean biochemical values, as well as episodes of hypercalcemia and elevated Ca P product, were made after adjusting for equivalent doses. In addition, we recorded the number of missed doses during two years of therapy. No patient in this study had received a calcimimetic before or during the study period. Fifty-nine patients were treated with calcitriol for at least 12 months and then completed 12 months of paricalcitol. Conversion from calcitriol to paricalcitol resulted in lower serum calcium (P ¼ 0.0003), lower serum phosphorus (P ¼ 0.027), lower Ca P product ( P ¼ 0.003), reduced PTH ( P ¼ 0.001) and reduced serum alkaline phosphatase (P ¼ 0.0005). Most dramatically, there was a highly significant difference in the number of missed doses ( Po0.0001) during the treatments. This 2-year single-center study, comparing long-term calcitriol with paricalcitol treatment in the same HD patients, extends our previous findings, offers new information regarding single episodes of potentially adverse biochemical effects related to vitamin D therapy, and provides several clues that may explain the outcome advantages suggested by previously published retrospective analyses of large dialysis provider-pooled databases. Kidney International (2010) 78 (Suppl 117), S33–S36; doi:10.1038/ki.2010.191 KEYWORDS: calcitriol; hemodialysis; paricalcitol; secondary hyperparathyroidism; vitamin D TO CITE THIS ARTICLE: Mittman N, Desiraju B, Meyer KB, Chattopadhyay J, Avram MM. Treatment of secondary hyperparathyroidism in ESRD: a 2-year, single-center crossover study. Kidney Int 2010; 78 (Suppl 117): S33–S36. Patients with chronic kidney disease are commonly affected by secondary hyperparathyroidism (SHPT), characterized by parathyroid gland hyperplasia and elevated levels of para- thyroid hormone (PTH), and resulting in substantial morbidity. 1,2 During progressive renal insufficiency, PTH level rises inversely with reductions in glomerular filtration rate. The pathogenesis of SHPT is attributed to three factors that result from decreased functional renal mass: calcitriol deficiency, phosphate retention, and hypocalcemia. SHPT may be associated with bone disease, neuromuscular disorder, and with soft tissue and vascular calcification, and potentially with accelerated atherosclerosis in chronic kidney disease patients. 3,4 Standard therapies for SHPT include reducing dietary phosphate intake, use of phosphate-binding agents (most commonly calcium carbonate or acetate, sevelamer hydrochloride or carbonate, and lanthanum carbonate), and treatment with vitamin D sterols. More recently, cinacalcet hydrochloride, a calcimimetic agent that activates the calcium-sensing receptor on the surface of parathyroid cells and inhibits PTH secretion, has been added to the therapeutic armamentarium. 5 In hemodialyzed (HD) patients, treatment with calcitriol effectively reduces PTH levels, and also stimulates vitamin D receptors that increase intestinal absorption of calcium and phosphorus, leading to the elevation of serum calcium and phosphorus levels, thereby potentially increasing the risk of ectopic vascular calcification and cardiovascular mortality. 6 The limitations of calcitriol therapy, especially the potentially adverse calcemic and hyperphosphatemic effects, have spurred the development of newer vitamin D analogs with lesser effect on serum calcium and phosphorus than calcitriol. 7–10 One of these analogs, which is approved for use in the United States, is 19-nor-1,25(OH)2D2 (paricalcitol), 11 which was shown in rats to suppress PTH and calcitriol, but with smaller changes in serum calcium and phosphorus. 12–14 Little data exist regarding these biochemical differences in humans. We have previously reported a comparison of serial treatment for 6 months of calcitriol and paricalcitol in our HD patients. 15 Converting from calcitriol to paricalcitol http://www.kidney-international.org original article & 2010 International Society of Nephrology A portion of this work was presented as a poster at the American Society of Nephrology meeting, San Diego, CA, November 2006. Correspondence: Neal Mittman, Avram Division of Nephrology, The Long Island College Hospital, 339 Hicks Street, Brooklyn, New York 11201, USA. E-mail: [email protected] Kidney International (2010) 78 (Suppl 117), S33–S36 S33
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Treatment of secondary hyperparathyroidism in ESRD: a 2-year, single-center crossover studyTreatment of secondary hyperparathyroidism in ESRD: a 2-year, single-center crossover study Neal Mittman1, Brinda Desiraju1, Kevin B. Meyer1, Jyoti Chattopadhyay1 and Morrell M. Avram1
1Avram Division of Nephrology, Long Island College Hospital, Brooklyn, New York, USA
Secondary hyperparathyroidism (SHPT) is a common
complication of chronic kidney disease. The management of
SHPT commonly involves vitamin D, either calcitriol or newer
analogs (paricalcitol or doxercalciferol), along with dietary
phosphorus restriction and phosphate binding agents.
Published reports have suggested that treatment with
paricalcitol in hemodialyzed (HD) patients offers a morbidity or
mortality advantage in comparison with treatment with
calcitriol. We have recently reported that switching from
calcitriol to paricalcitol resulted in a lower serum calcium and
calcium–phosphorus product (CaP product), as well as lower
parathyroid hormone (PTH) and alkaline phosphatase during
6 months of serial treatment. We converted all HD patients in
our large urban dialysis center from calcitriol to paricalcitol
using a 1:3 conversion ratio, on the basis of published data.
Comparisons of individual patient mean biochemical values, as
well as episodes of hypercalcemia and elevated Ca P product,
were made after adjusting for equivalent doses. In addition, we
recorded the number of missed doses during two years of
therapy. No patient in this study had received a calcimimetic
before or during the study period. Fifty-nine patients were
treated with calcitriol for at least 12 months and then
completed 12 months of paricalcitol. Conversion from calcitriol
to paricalcitol resulted in lower serum calcium (P¼ 0.0003),
lower serum phosphorus (P¼ 0.027), lower CaP product
(P¼ 0.003), reduced PTH (P¼ 0.001) and reduced serum alkaline
phosphatase (P¼ 0.0005). Most dramatically, there was a
highly significant difference in the number of missed doses
(Po0.0001) during the treatments. This 2-year single-center
study, comparing long-term calcitriol with paricalcitol treatment
in the same HD patients, extends our previous findings, offers
new information regarding single episodes of potentially
adverse biochemical effects related to vitamin D therapy,
and provides several clues that may explain the outcome
advantages suggested by previously published retrospective
analyses of large dialysis provider-pooled databases.
Kidney International (2010) 78 (Suppl 117), S33–S36; doi:10.1038/ki.2010.191
KEYWORDS: calcitriol; hemodialysis; paricalcitol; secondary
hyperparathyroidism; vitamin D
TO CITE THIS ARTICLE:
Mittman N, Desiraju B, Meyer KB, Chattopadhyay J, Avram MM. Treatment of
secondary hyperparathyroidism in ESRD: a 2-year, single-center crossover
study. Kidney Int 2010; 78 (Suppl 117): S33–S36.
Patients with chronic kidney disease are commonly affected by secondary hyperparathyroidism (SHPT), characterized by parathyroid gland hyperplasia and elevated levels of para- thyroid hormone (PTH), and resulting in substantial morbidity.1,2 During progressive renal insufficiency, PTH level rises inversely with reductions in glomerular filtration rate. The pathogenesis of SHPT is attributed to three factors that result from decreased functional renal mass: calcitriol deficiency, phosphate retention, and hypocalcemia. SHPT may be associated with bone disease, neuromuscular disorder, and with soft tissue and vascular calcification, and potentially with accelerated atherosclerosis in chronic kidney disease patients.3,4 Standard therapies for SHPT include reducing dietary phosphate intake, use of phosphate-binding agents (most commonly calcium carbonate or acetate, sevelamer hydrochloride or carbonate, and lanthanum carbonate), and treatment with vitamin D sterols. More recently, cinacalcet hydrochloride, a calcimimetic agent that activates the calcium-sensing receptor on the surface of parathyroid cells and inhibits PTH secretion, has been added to the therapeutic armamentarium.5 In hemodialyzed (HD) patients, treatment with calcitriol effectively reduces PTH levels, and also stimulates vitamin D receptors that increase intestinal absorption of calcium and phosphorus, leading to the elevation of serum calcium and phosphorus levels, thereby potentially increasing the risk of ectopic vascular calcification and cardiovascular mortality.6
The limitations of calcitriol therapy, especially the potentially adverse calcemic and hyperphosphatemic effects, have spurred the development of newer vitamin D analogs with lesser effect on serum calcium and phosphorus than calcitriol.7–10 One of these analogs, which is approved for use in the United States, is 19-nor-1,25(OH)2D2 (paricalcitol),11
which was shown in rats to suppress PTH and calcitriol, but with smaller changes in serum calcium and phosphorus.12–14
Little data exist regarding these biochemical differences in humans. We have previously reported a comparison of serial treatment for 6 months of calcitriol and paricalcitol in our HD patients.15 Converting from calcitriol to paricalcitol
http://www.kidney-international.org o r i g i n a l a r t i c l e
& 2010 International Society of Nephrology
A portion of this work was presented as a poster at the American Society of
Nephrology meeting, San Diego, CA, November 2006.
Correspondence: Neal Mittman, Avram Division of Nephrology, The Long
Island College Hospital, 339 Hicks Street, Brooklyn, New York 11201, USA.
E-mail: [email protected]
RESULTS
The mean age of the study population was 63±12 (s.d.) years. Sixty percent were female. The majority were African Americans (79%). In all, 44% of patients had diabetes. Mean months of dialysis at enrollment was 67±61, with a wide range (Table 1).
A comparison of dose-adjusted mean biochemical para- meters during 1 year of calcitriol versus 1 year of paricalcitol treatment is shown in Table 2. Changing from calcitriol to equivalent doses of paricalcitol resulted in lower levels of serum calcium (9.53±0.67 mg/dl versus 9.71±0.55, P¼ 0.0003), lower serum phosphorus (4.79±0.9 mg/dl versus 4.98±0.93, P¼ 0.027), a lower serum Ca P product (45.9±9.8 versus 48.3±10, P¼ 0.003), lower biointact PTH levels (190±123 pg/ml versus 247±224, P¼ 0.001), and lower serum alkaline phosphatase (107±55 versus 137±108, P¼ 0.0005). Figure 1 compares the number of episodes of hypercalcemia (410.5 mg/dl), hyperphosphatemia (45.5 mg/dl), and elevated Ca P product (470 and 455) during 12 months of calcitriol and paricalcitol treatment. Paricalcitol therapy was associated with fewer episodes of hypercalcemia (69 versus 111, P¼ 0.0005), hyperphosphatemia (186 versus 225, P¼ 0.03), and elevated Ca P product (455; 164 versus 211, P¼ 0.002 and 470; 39 versus 55, P¼ 0.046).
Most dramatically, there was a highly significant difference in the number of all-cause missed doses during 12 months of treatment with calcitriol and paricalcitol (18.9 during calcitriol treatment versus 8.1 doses during paricalcitol treatment, Po0.0001) (Figure 2).
DISCUSSION
We report the first study comparing long-term serial treatment of SHPT with calcitriol and paricalcitol in a large number of patients receiving maintenance HD in a single outpatient center, evaluating potential biochemical and outcome differences using individual patients as their own control. This experimental design, although using only a single arm and retrospective data collection, obviates the need for the polyvariable adjustments required in larger
Table 1 | Demographics of study population (n=59)
Age (years) (mean±s.d.) 63±12 (range 30–88)
Gender (%) Female 60
Race (%) African Americans 79 White 5 Hispanic 11 Other 5
Diabetes (%) 44 Months on dialysis at enrollment (mean±s.d.) 67±61
(range 5.8–259)
Calcitriol Paricalcitol P-value
Corrected calcium (mg/dl) 9.71±0.55 9.53±0.67 0.0003 Phosphorus (mg/dl) 4.98±0.93 4.79±0.90 0.027 Ca P product 48.3±10 45.9±9.8 0.003 Alkaline phosphatase (U/l) 137±108 107±55 0.0005 Biointact PTH (pg/ml) 247±224 190±123 0.001
Abbreviations: Ca P product, calcium–phosphorus product; PTH, parathyroid hormone. Values are expressed as mean ±s.d.
69
186
164
39
111
225
211
55
0 2 4 6 8
10 12 14 16 18 20
N um
be r
of m
is se
d do
se s
Calcitriol Paricalcitol
P< 0.0001
Figure 2 | All-cause missed doses during 12 months of calcitriol and paricalcitol treatment (Po0.0001).
S34 Kidney International (2010) 78 (Suppl 117), S33–S36
o r i g i n a l a r t i c l e N Mittman et al.: Treatment of hyperparathyroidism in HD
treatment comparisons reported, the only difference being age ±12 months. We found that equivalent doses of paricalcitol resulted in lower levels of serum calcium, Ca P product, serum alkaline phosphatase, and serum biointact PTH, which is in agreement with the results of our recently published paper.15 In addition, we found that, over 12 months of treatment, paricalcitol was also associated with lower serum phosphorus levels, fewer episodes of hypercal- cemia, fewer episodes of hyperphosphatemia, and fewer episodes of elevated Ca P product compared with calcitriol treatment in the same patients. This is consistent with a recent report in pediatric dialysis patients finding more episodes of elevated Ca P product with calcitriol than with paricalcitol.19 There are very few reports in literature directly comparing safety and efficacy of calcitriol and paricalcitol in humans. In a single-center subset extracted from a randomized, double-blind, multicenter study, Sprague et al.20 reported that paricalcitol reduced PTH levels more rapidly, and with fewer episodes of hyperphosphatemia, than did calcitriol. In a later report, however, using results from all participating centers, the same author found no difference in hyperphosphatemia between paricalcitol and calcitriol treat- ment, but reported that paricalcitol-treated patients had significantly fewer ‘sustained episodes of hypercalcemia and/ or increased Ca P product than calcitriol patients.’ It has been reported that paricalcitol provides greater PTH suppression with lesser elevation of serum phosphorus and Ca P product compared with doxercalciferol.21 Ross et al.22
has reported that paricalcitol provides a rapid and sustained reduction of PTH in both HD and PD patients, with minimal effect on serum calcium and phosphorus compared with placebo, and Capuano et al.23 recently reported that paricalcitol efficiently suppresses PTH secretion with a moderate calcemic, but not a phosphatemic, effect.
The clinical significance of these biochemical differences remains unclear. In a historical cohort study of long-term HD patients utilizing a large dialysis provider’s database, Teng et al.16 reported that patients who received paricalcitol seem to have a survival advantage over those who receive calcitriol, in association with lesser increases in serum calcium and serum phosphorus. Recently, Shinaberger et al.24 reported that a higher weekly paricalcitol dosage per unit of serum PTH seems to have an incremental association with greater survival in maintenance HD patients. The results of our study, indicating lower levels of serum calcium, serum phosphorus, Ca P product, and serum biointact PTH during paricalcitol treatment, as well as fewer episodes of hypercalcemia, hyperphosphatemia, and elevated Ca P product, may explain a survival advantage in paricalcitol- treated patients. Recently, there has been increasing concern regarding calcification in major vessels and organs, and a potential contribution to the high cardiovascular mortality seen in this population.25 Higher serum phosphorus and Ca P product have been associated with higher mortality in dialyzed patients,26 and higher Ca P product has been linked to coronary artery calcification, cardiovascular disease,
and poorer survival.27 In some animal models of chronic kidney disease, unlike other vitamin D receptor activators, paricalcitol does not cause vascular calcification.12 In addition, SHPT has long been considered a morbid uremic toxin, associated with uremic neuropathy,28 abnormalities of carbohydrate, and lipid metabolism,29,30 as well as debilitat- ing bone disease and extraskeletal calcification.31,32
Serum alkaline phosphatase activity is inversely correlated with bone mineral density in chronic renal failure patients.33
Elevated serum alkaline phosphatase has been recently associated with higher risks of hospitalization and death in HD patients, independent of calcium, phosphorus, and PTH levels.34 Our results, showing a lower alkaline phosphatase activity during paricalcitol treatment, are also consistent with a possible morbidity and mortality advantage with paricalci- tol treatment.
We found a striking difference in all-cause missed doses over 12 months of therapy in the same patients, confirming that paricalcitol treatment resulted in significantly fewer missed doses compared with calcitriol (Figure 2). Whereas the greater number of total doses administered during 12 months of paricalcitol administration may explain the greater therapeutic activity, that is, reduced biointact PTH and reduced total alkaline phosphatase, the lower serum calcium levels and Ca P product with paricalcitol would imply lesser gastrointestinal absorption or more favorable bone turnover. Although we were unable to accurately obtain the reason for each missed dose, these were most commonly due to hospitalization, missed treatments, or held doses due to elevated serum calcium (410.5 mg/dl) or elevated Ca P product (470). The number of missed doses, therefore, may indirectly imply adverse therapeutic response, morbidity, and hospitalization. This is in agreement with another large dialysis provider report that paricalcitol-treated HD patients experienced fewer hospitalizations and hospital stays per year compared with calcitriol-treated patients.17
The major strength of this study is its unique ability to compare biochemical differences between long-term calcitriol and paricalcitol therapy without requiring multivariable adjustments for potential confounders. We are unaware of any study of a similar scale in publication. In addition, there was no support or involvement by industry. The limitations of this study include its retrospective data collection and use of a unidirectional crossover (single arm). The study design did not permit any mortality comparison, nor do we have any data regarding the use of doxercalciferol. Although our findings need to be confirmed in a large prospective bidirectional crossover study, the predominant use of newer vitamin D analogs and the widespread use of calcimimetics make a confirmatory study very difficult in the United States.
MATERIALS AND METHODS This is a single center, retrospective single-arm crossover study. HD patients undergoing maintenance HD therapy at the Avram Center for Kidney Diseases at Long Island College Hospital were enrolled in
Kidney International (2010) 78 (Suppl 117), S33–S36 S35
N Mittman et al.: Treatment of hyperparathyroidism in HD o r i g i n a l a r t i c l e
this study. Patients who received calcitriol for at least 1 year before conversion to paricalcitol (1:3 unit conversion) were included in this study. Patients who received a calcimimetic agent at any time before or during the study period were excluded from the study. All patients underwent HD three times weekly using a standard bicarbonate bath (Ca2þ 2.5 mEq/l) and received proper nutritional counseling. Data were collected by retrospective chart review, and entered into an anonymized database. Demographic and clinical data included age, race, gender, diabetic status, and presence of hypertension. Results of monthly evaluation of biochemical parameters were recorded for the preceding 12 months of calcitriol treatment and then with paricalcitol treatment for 1 year. Biochemical parameters included corrected serum calcium, serum phosphorus, serum albumin, serum alkaline phosphatase, and biointact PTH drawn before dialysis during a midweek dialysis treatment as part of usual care (Spectra Laboratories, Rockleigh, NJ, USA). Corrected calcium was calculated as (4serum albumin) 0.8þmeasured serum calcium. Biointact PTH was assayed (Nichols Institute diagnostics) by Spectra Laboratories (reference range: 12.6–53.5 pg/ml). In addition, data were collected regarding missed vitamin D doses (irrespective of reason) during 1 year of treatment with calcitriol and with paricalcitol.
Statistical analysis Data were expressed as means±s.d. Comparison of mean values of biochemical parameters, number of episodes of hypercalcemia, hyperphosphatemia, elevated CaP product, and number of missed doses between calcitriol and paricalcitol was made after adjusting for equivalent doses using a mixed model regression analysis. Correlations between the different parameters were estimated by the use of Spearman’s rank correlation. Calculations were made using SPSS for Windows 12.0.1 (SPSS, Chicago, IL, USA) and SAS software, version 9.0 (SAS Institute, Cary, NC, USA). P- values o0.05 were considered significant.
DISCLOSURE NM and MMA have served as site PI in clinical trials sponsored by Amgen. None of the authors have a financial relationship with companies that may have an interest in the information contained in this article.
ACKNOWLEDGMENTS This study was supported, in part, by the Kidney and Urology Foundation of America and by the Nephrology Foundation of Brooklyn. There was no pharmaceutical industry support or involvement.
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patients with chronic kidney disease. Am J Med Sci 2007; 333: 201–207. 2. Slatopolsky E, Lopez-Hilker Delmez J, Dusso A. The parathyroid-calcitriol
axis in health and chronic renal failure. Kidney Int 1986; 29: S41–S47. 3. Friedman EA. Consequences and management of hyperphosphatemia
in patients with renal insufficiency. Kidney Int 2005; 67(Suppl 95): S1–S7. 4. Michael M, Garcia D. Secondary hyperparathyroidism in chronic kidney
disease: clinical consequences and challenges. Nephrol Nurs J 2004; 31: 185–194.
5. Block GA, Martin KJ, de Francisco AL et al. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 2004; 350: 1516–1525.
6. Moe SM, Drueke TB. Management of secondary hyperparathyroidism: the importance and the challenge of controlling parathyroid hormone levels without elevating calcium, phosphorus, and calcium-phosphorus product. Am J Nephrol 2003; 23: 369–379.
7. Brown AJ, Slatopolsky E. Vitamin D analogs: therapeutic applications and mechanisms for selectivity. Mol Aspects Med 2008; 29: 433–452.
8. Martin KJ, Gonzalez EA. Vitamin D analogs: actions and role in the treatment of secondary hyperparathyroidism. Semin Nephrol 2004; 24: 456–459.
9. Salusky IB. Are new vitamin D analogues in renal bone disease superior to calcitriol? Pediatr Nephrol 2005; 20: 393–398.
10. Cheng S, Coyne D. Paricalcitol capsules for the control of secondary hyperparathyroidism in chronic kidney disease. Expert Opin Pharmacother 2006; 7: 617–621.
11. Goldenberg MM. Paricalcitol, a new agent for the management of secondary hyperparathyroidism in patients undergoing chronic renal dialysis. Clin Ther 1999; 21: 432–441.
12. Cozzolino M, Brancaccio D. Emerging role for the vitamin D receptor activator (VDRA), paricalcitol, in the treatment of secondary hyperparathyroidism. Expert Opin Pharmacother 2008; 9: 947–954.
13. Slatopolsky E, Finch J, Ritter C et al. Effects of 19-nor-1,25(OH)2D2, a new analogue of calcitriol, on secondary hyperparathyroidism in uremic rats. Am J Kidney Dis 1998; 32: S40–S47.
14. Slatopolsky E, Brown AJ. Vitamin D analogs for the treatment of secondary hyperparathyroidism. Blood Purif 2002; 20: 109–112.
15. Mittman N, Khanna R, Rani S et al. Paricalcitol therapy for secondary hyperparathyroidism in patients on maintenance hemodialysis previously treated with calcitriol: a single center crossover study. Kidney Int 2006; 70: S64–S67.
16. Teng M, Wolf M, Lowrie E et al. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 2003; 349: 446–456.
17. Dobrez DG, Mathes A, Amdahl M et al. Paricalcitol-treated patients experience improved hospitalization outcomes compared with calcitriol- treated patients in real-world clinical settings. Nephrol Dial Transplant 2004; 19: 1174–1181.
18. Llach FL, Yudd M. Paricalcitol in dialysis patients with calcitriol-resistant secondary hyperparathyroidism. Am J Kidney Dis 2001; 38(suppl 5): S45–S50.
19. Seeherunvong W, Nwobi O, Abitbol CL et al. Paricalcitol versus calcitriol treatment for hyperparathyroidism in pediatric hemodialysis patients. Pediatr Nephrol 2006; 21: 1434–1439.
20. Sprague SM, Lerma E, McCormmick D et al. Suppression of parathyroid hormone secretion in hemodialysis patients: comparison of paricalcitol with calcitriol. Am J Kidney Dis 2001; 38: S51–S56.
21. Joist HE, Ahya SN, Giles K et al. Differential effects of very high doses of doxercalciferol and paricalcitol on serum phosphorus in hemodialysis patients. Clin Nephrol 2006; 65: 335–341.
22. Ross EA, Tian J, Abboud H et al. Oral paricalcitol for the treatment of secondary hyperparathyroidism in patients on hemodialysis or peritoneal dialysis. Am J Nephrol 2008; 28: 97–106.
23. Capuano A, Serio V, Pota A et al. Beneficial effects of better control of secondary hyperparathyroidism with paricalcitol in chronic dialysis patients. J Nephrol 2009; 22: 59–68.
24. Shinaberger CS, Kopple JD, Kovesdy CP et al. Ratio of paricalcitol dosage to serum parathyroid hormone level and survival in maintenance hemodialysis patients. Clin J Am Soc Nephrol 2008; 3: 1769–1776.
25. Goodman WG. The consequences of uncontrolled secondary hyperparathyroidism and its treatment in chronic kidney disease. Semin Dial 2004; 17: 209–216.
26. Block GA, Hulbert-Shearon TE, Levin NW et al. Association of serum phosphorus and calcium X phosphorus product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 1998; 31: 607–617.
27. Raggi P. Electron beam tomography to image cardiovascular calcifications in hemodialysis patients. J Nephrol 2002; 15(Suppl 6): S77–S81.
28. Avram MM, Feinfeld DA, Huatuco AH. Search for the uremic toxin. Decreased motor-nerve conduction velocity and elevated parathyroid hormone in uremia. N Engl J Med 1978; 298: 1000–1003.
29. Procopio M, Borretta G. Derangement of glucose metabolism in hyperparathyroidism. J Endocrinol Invest 2003; 26: 1136–1142.
30. Zanos S, Mitsopoulos E, Sakellariou G. Parathyroid hormone levels, calcium-channel blockers, and the dyslipidemia of nondiabetic hemodialysis patients. Ren…
1Avram Division of Nephrology, Long Island College Hospital, Brooklyn, New York, USA
Secondary hyperparathyroidism (SHPT) is a common
complication of chronic kidney disease. The management of
SHPT commonly involves vitamin D, either calcitriol or newer
analogs (paricalcitol or doxercalciferol), along with dietary
phosphorus restriction and phosphate binding agents.
Published reports have suggested that treatment with
paricalcitol in hemodialyzed (HD) patients offers a morbidity or
mortality advantage in comparison with treatment with
calcitriol. We have recently reported that switching from
calcitriol to paricalcitol resulted in a lower serum calcium and
calcium–phosphorus product (CaP product), as well as lower
parathyroid hormone (PTH) and alkaline phosphatase during
6 months of serial treatment. We converted all HD patients in
our large urban dialysis center from calcitriol to paricalcitol
using a 1:3 conversion ratio, on the basis of published data.
Comparisons of individual patient mean biochemical values, as
well as episodes of hypercalcemia and elevated Ca P product,
were made after adjusting for equivalent doses. In addition, we
recorded the number of missed doses during two years of
therapy. No patient in this study had received a calcimimetic
before or during the study period. Fifty-nine patients were
treated with calcitriol for at least 12 months and then
completed 12 months of paricalcitol. Conversion from calcitriol
to paricalcitol resulted in lower serum calcium (P¼ 0.0003),
lower serum phosphorus (P¼ 0.027), lower CaP product
(P¼ 0.003), reduced PTH (P¼ 0.001) and reduced serum alkaline
phosphatase (P¼ 0.0005). Most dramatically, there was a
highly significant difference in the number of missed doses
(Po0.0001) during the treatments. This 2-year single-center
study, comparing long-term calcitriol with paricalcitol treatment
in the same HD patients, extends our previous findings, offers
new information regarding single episodes of potentially
adverse biochemical effects related to vitamin D therapy,
and provides several clues that may explain the outcome
advantages suggested by previously published retrospective
analyses of large dialysis provider-pooled databases.
Kidney International (2010) 78 (Suppl 117), S33–S36; doi:10.1038/ki.2010.191
KEYWORDS: calcitriol; hemodialysis; paricalcitol; secondary
hyperparathyroidism; vitamin D
TO CITE THIS ARTICLE:
Mittman N, Desiraju B, Meyer KB, Chattopadhyay J, Avram MM. Treatment of
secondary hyperparathyroidism in ESRD: a 2-year, single-center crossover
study. Kidney Int 2010; 78 (Suppl 117): S33–S36.
Patients with chronic kidney disease are commonly affected by secondary hyperparathyroidism (SHPT), characterized by parathyroid gland hyperplasia and elevated levels of para- thyroid hormone (PTH), and resulting in substantial morbidity.1,2 During progressive renal insufficiency, PTH level rises inversely with reductions in glomerular filtration rate. The pathogenesis of SHPT is attributed to three factors that result from decreased functional renal mass: calcitriol deficiency, phosphate retention, and hypocalcemia. SHPT may be associated with bone disease, neuromuscular disorder, and with soft tissue and vascular calcification, and potentially with accelerated atherosclerosis in chronic kidney disease patients.3,4 Standard therapies for SHPT include reducing dietary phosphate intake, use of phosphate-binding agents (most commonly calcium carbonate or acetate, sevelamer hydrochloride or carbonate, and lanthanum carbonate), and treatment with vitamin D sterols. More recently, cinacalcet hydrochloride, a calcimimetic agent that activates the calcium-sensing receptor on the surface of parathyroid cells and inhibits PTH secretion, has been added to the therapeutic armamentarium.5 In hemodialyzed (HD) patients, treatment with calcitriol effectively reduces PTH levels, and also stimulates vitamin D receptors that increase intestinal absorption of calcium and phosphorus, leading to the elevation of serum calcium and phosphorus levels, thereby potentially increasing the risk of ectopic vascular calcification and cardiovascular mortality.6
The limitations of calcitriol therapy, especially the potentially adverse calcemic and hyperphosphatemic effects, have spurred the development of newer vitamin D analogs with lesser effect on serum calcium and phosphorus than calcitriol.7–10 One of these analogs, which is approved for use in the United States, is 19-nor-1,25(OH)2D2 (paricalcitol),11
which was shown in rats to suppress PTH and calcitriol, but with smaller changes in serum calcium and phosphorus.12–14
Little data exist regarding these biochemical differences in humans. We have previously reported a comparison of serial treatment for 6 months of calcitriol and paricalcitol in our HD patients.15 Converting from calcitriol to paricalcitol
http://www.kidney-international.org o r i g i n a l a r t i c l e
& 2010 International Society of Nephrology
A portion of this work was presented as a poster at the American Society of
Nephrology meeting, San Diego, CA, November 2006.
Correspondence: Neal Mittman, Avram Division of Nephrology, The Long
Island College Hospital, 339 Hicks Street, Brooklyn, New York 11201, USA.
E-mail: [email protected]
RESULTS
The mean age of the study population was 63±12 (s.d.) years. Sixty percent were female. The majority were African Americans (79%). In all, 44% of patients had diabetes. Mean months of dialysis at enrollment was 67±61, with a wide range (Table 1).
A comparison of dose-adjusted mean biochemical para- meters during 1 year of calcitriol versus 1 year of paricalcitol treatment is shown in Table 2. Changing from calcitriol to equivalent doses of paricalcitol resulted in lower levels of serum calcium (9.53±0.67 mg/dl versus 9.71±0.55, P¼ 0.0003), lower serum phosphorus (4.79±0.9 mg/dl versus 4.98±0.93, P¼ 0.027), a lower serum Ca P product (45.9±9.8 versus 48.3±10, P¼ 0.003), lower biointact PTH levels (190±123 pg/ml versus 247±224, P¼ 0.001), and lower serum alkaline phosphatase (107±55 versus 137±108, P¼ 0.0005). Figure 1 compares the number of episodes of hypercalcemia (410.5 mg/dl), hyperphosphatemia (45.5 mg/dl), and elevated Ca P product (470 and 455) during 12 months of calcitriol and paricalcitol treatment. Paricalcitol therapy was associated with fewer episodes of hypercalcemia (69 versus 111, P¼ 0.0005), hyperphosphatemia (186 versus 225, P¼ 0.03), and elevated Ca P product (455; 164 versus 211, P¼ 0.002 and 470; 39 versus 55, P¼ 0.046).
Most dramatically, there was a highly significant difference in the number of all-cause missed doses during 12 months of treatment with calcitriol and paricalcitol (18.9 during calcitriol treatment versus 8.1 doses during paricalcitol treatment, Po0.0001) (Figure 2).
DISCUSSION
We report the first study comparing long-term serial treatment of SHPT with calcitriol and paricalcitol in a large number of patients receiving maintenance HD in a single outpatient center, evaluating potential biochemical and outcome differences using individual patients as their own control. This experimental design, although using only a single arm and retrospective data collection, obviates the need for the polyvariable adjustments required in larger
Table 1 | Demographics of study population (n=59)
Age (years) (mean±s.d.) 63±12 (range 30–88)
Gender (%) Female 60
Race (%) African Americans 79 White 5 Hispanic 11 Other 5
Diabetes (%) 44 Months on dialysis at enrollment (mean±s.d.) 67±61
(range 5.8–259)
Calcitriol Paricalcitol P-value
Corrected calcium (mg/dl) 9.71±0.55 9.53±0.67 0.0003 Phosphorus (mg/dl) 4.98±0.93 4.79±0.90 0.027 Ca P product 48.3±10 45.9±9.8 0.003 Alkaline phosphatase (U/l) 137±108 107±55 0.0005 Biointact PTH (pg/ml) 247±224 190±123 0.001
Abbreviations: Ca P product, calcium–phosphorus product; PTH, parathyroid hormone. Values are expressed as mean ±s.d.
69
186
164
39
111
225
211
55
0 2 4 6 8
10 12 14 16 18 20
N um
be r
of m
is se
d do
se s
Calcitriol Paricalcitol
P< 0.0001
Figure 2 | All-cause missed doses during 12 months of calcitriol and paricalcitol treatment (Po0.0001).
S34 Kidney International (2010) 78 (Suppl 117), S33–S36
o r i g i n a l a r t i c l e N Mittman et al.: Treatment of hyperparathyroidism in HD
treatment comparisons reported, the only difference being age ±12 months. We found that equivalent doses of paricalcitol resulted in lower levels of serum calcium, Ca P product, serum alkaline phosphatase, and serum biointact PTH, which is in agreement with the results of our recently published paper.15 In addition, we found that, over 12 months of treatment, paricalcitol was also associated with lower serum phosphorus levels, fewer episodes of hypercal- cemia, fewer episodes of hyperphosphatemia, and fewer episodes of elevated Ca P product compared with calcitriol treatment in the same patients. This is consistent with a recent report in pediatric dialysis patients finding more episodes of elevated Ca P product with calcitriol than with paricalcitol.19 There are very few reports in literature directly comparing safety and efficacy of calcitriol and paricalcitol in humans. In a single-center subset extracted from a randomized, double-blind, multicenter study, Sprague et al.20 reported that paricalcitol reduced PTH levels more rapidly, and with fewer episodes of hyperphosphatemia, than did calcitriol. In a later report, however, using results from all participating centers, the same author found no difference in hyperphosphatemia between paricalcitol and calcitriol treat- ment, but reported that paricalcitol-treated patients had significantly fewer ‘sustained episodes of hypercalcemia and/ or increased Ca P product than calcitriol patients.’ It has been reported that paricalcitol provides greater PTH suppression with lesser elevation of serum phosphorus and Ca P product compared with doxercalciferol.21 Ross et al.22
has reported that paricalcitol provides a rapid and sustained reduction of PTH in both HD and PD patients, with minimal effect on serum calcium and phosphorus compared with placebo, and Capuano et al.23 recently reported that paricalcitol efficiently suppresses PTH secretion with a moderate calcemic, but not a phosphatemic, effect.
The clinical significance of these biochemical differences remains unclear. In a historical cohort study of long-term HD patients utilizing a large dialysis provider’s database, Teng et al.16 reported that patients who received paricalcitol seem to have a survival advantage over those who receive calcitriol, in association with lesser increases in serum calcium and serum phosphorus. Recently, Shinaberger et al.24 reported that a higher weekly paricalcitol dosage per unit of serum PTH seems to have an incremental association with greater survival in maintenance HD patients. The results of our study, indicating lower levels of serum calcium, serum phosphorus, Ca P product, and serum biointact PTH during paricalcitol treatment, as well as fewer episodes of hypercalcemia, hyperphosphatemia, and elevated Ca P product, may explain a survival advantage in paricalcitol- treated patients. Recently, there has been increasing concern regarding calcification in major vessels and organs, and a potential contribution to the high cardiovascular mortality seen in this population.25 Higher serum phosphorus and Ca P product have been associated with higher mortality in dialyzed patients,26 and higher Ca P product has been linked to coronary artery calcification, cardiovascular disease,
and poorer survival.27 In some animal models of chronic kidney disease, unlike other vitamin D receptor activators, paricalcitol does not cause vascular calcification.12 In addition, SHPT has long been considered a morbid uremic toxin, associated with uremic neuropathy,28 abnormalities of carbohydrate, and lipid metabolism,29,30 as well as debilitat- ing bone disease and extraskeletal calcification.31,32
Serum alkaline phosphatase activity is inversely correlated with bone mineral density in chronic renal failure patients.33
Elevated serum alkaline phosphatase has been recently associated with higher risks of hospitalization and death in HD patients, independent of calcium, phosphorus, and PTH levels.34 Our results, showing a lower alkaline phosphatase activity during paricalcitol treatment, are also consistent with a possible morbidity and mortality advantage with paricalci- tol treatment.
We found a striking difference in all-cause missed doses over 12 months of therapy in the same patients, confirming that paricalcitol treatment resulted in significantly fewer missed doses compared with calcitriol (Figure 2). Whereas the greater number of total doses administered during 12 months of paricalcitol administration may explain the greater therapeutic activity, that is, reduced biointact PTH and reduced total alkaline phosphatase, the lower serum calcium levels and Ca P product with paricalcitol would imply lesser gastrointestinal absorption or more favorable bone turnover. Although we were unable to accurately obtain the reason for each missed dose, these were most commonly due to hospitalization, missed treatments, or held doses due to elevated serum calcium (410.5 mg/dl) or elevated Ca P product (470). The number of missed doses, therefore, may indirectly imply adverse therapeutic response, morbidity, and hospitalization. This is in agreement with another large dialysis provider report that paricalcitol-treated HD patients experienced fewer hospitalizations and hospital stays per year compared with calcitriol-treated patients.17
The major strength of this study is its unique ability to compare biochemical differences between long-term calcitriol and paricalcitol therapy without requiring multivariable adjustments for potential confounders. We are unaware of any study of a similar scale in publication. In addition, there was no support or involvement by industry. The limitations of this study include its retrospective data collection and use of a unidirectional crossover (single arm). The study design did not permit any mortality comparison, nor do we have any data regarding the use of doxercalciferol. Although our findings need to be confirmed in a large prospective bidirectional crossover study, the predominant use of newer vitamin D analogs and the widespread use of calcimimetics make a confirmatory study very difficult in the United States.
MATERIALS AND METHODS This is a single center, retrospective single-arm crossover study. HD patients undergoing maintenance HD therapy at the Avram Center for Kidney Diseases at Long Island College Hospital were enrolled in
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this study. Patients who received calcitriol for at least 1 year before conversion to paricalcitol (1:3 unit conversion) were included in this study. Patients who received a calcimimetic agent at any time before or during the study period were excluded from the study. All patients underwent HD three times weekly using a standard bicarbonate bath (Ca2þ 2.5 mEq/l) and received proper nutritional counseling. Data were collected by retrospective chart review, and entered into an anonymized database. Demographic and clinical data included age, race, gender, diabetic status, and presence of hypertension. Results of monthly evaluation of biochemical parameters were recorded for the preceding 12 months of calcitriol treatment and then with paricalcitol treatment for 1 year. Biochemical parameters included corrected serum calcium, serum phosphorus, serum albumin, serum alkaline phosphatase, and biointact PTH drawn before dialysis during a midweek dialysis treatment as part of usual care (Spectra Laboratories, Rockleigh, NJ, USA). Corrected calcium was calculated as (4serum albumin) 0.8þmeasured serum calcium. Biointact PTH was assayed (Nichols Institute diagnostics) by Spectra Laboratories (reference range: 12.6–53.5 pg/ml). In addition, data were collected regarding missed vitamin D doses (irrespective of reason) during 1 year of treatment with calcitriol and with paricalcitol.
Statistical analysis Data were expressed as means±s.d. Comparison of mean values of biochemical parameters, number of episodes of hypercalcemia, hyperphosphatemia, elevated CaP product, and number of missed doses between calcitriol and paricalcitol was made after adjusting for equivalent doses using a mixed model regression analysis. Correlations between the different parameters were estimated by the use of Spearman’s rank correlation. Calculations were made using SPSS for Windows 12.0.1 (SPSS, Chicago, IL, USA) and SAS software, version 9.0 (SAS Institute, Cary, NC, USA). P- values o0.05 were considered significant.
DISCLOSURE NM and MMA have served as site PI in clinical trials sponsored by Amgen. None of the authors have a financial relationship with companies that may have an interest in the information contained in this article.
ACKNOWLEDGMENTS This study was supported, in part, by the Kidney and Urology Foundation of America and by the Nephrology Foundation of Brooklyn. There was no pharmaceutical industry support or involvement.
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