Saudi Journal of Kidney Diseases and Transplantation

ORIGINAL ARTICLE
Year
: 2008  |  Volume : 19  |  Issue : 2  |  Page : 183--188

Effect of Sevelamer on Mineral and Lipid Abnormalities in Hemodialysis Patients


Fethi Ben Hamida, Lilia Ben Fatma, Samia Barbouch, Hayet Kaaroud, Imed Helal, Hafedh Hedri, Taieb Ben Abdallah, Hedi Ben Maiz, Adel Kheder 
 Department of Nephrology, Charles Nicolle Hospital, Tunis, Tunisia

Correspondence Address:
Fethi Ben Hamida
Department of Nephrology, Charles Nicolle Hospital, Tunis
Tunisia

Abstract

We conducted a prospective study in hemodialysis patients to assess the safety and efficacy of sevelamer, a non-absorbable phosphate binding polymer free of calcium and aluminum, in lowering serum phosphorus, serum intact parathyroid hormone, and serum lipids. Phosphate binders were discontinued during a two-week washout period. We considered the patients with serum phosphorus levels more than 1.8 mmol/l during the washout period eligible for treatment. Sevelamer was administered to 29 hemodialysis patients for eight weeks. Sevelamer reduced the mean serum phosphorus levels to 1.8 mmol/l by the end of the eight-week treatment period (p < 0.0001). Two weeks after the completion of the sevelamer study the mean serum phosphorus levels increased to 2.09 mmol/l (p < 0.02). Mean serum calcium levels did not significantly change during sevelamer trial. Mean serum intact parathyroid hormone declined from 501 pg/ml at the start of the study to 425 pg/l at the end of the eight week treatment period (p = 0.05). In addition, sevelamer reduced the mean serum total cholesterol levels from 5.22 mmol/l to 4.26 mmol/l (p < 0.0001), and the mean serum low density lipoprotein cholesterol from 3.56 mmol/l to 2.79 mmol/l (p < 0.0001) at the end of the study. However, the mean serum levels of high density lipoprotein and triglycerides did not change during the study period. We conclude that sevelamer can control serum phosphorus and reduce the level of intact parathyroid hormone and cholesterol without inducing hypercalcemia or other side effects.



How to cite this article:
Hamida FB, Fatma LB, Barbouch S, Kaaroud H, Helal I, Hedri H, Abdallah TB, Maiz HB, Kheder A. Effect of Sevelamer on Mineral and Lipid Abnormalities in Hemodialysis Patients.Saudi J Kidney Dis Transpl 2008;19:183-188


How to cite this URL:
Hamida FB, Fatma LB, Barbouch S, Kaaroud H, Helal I, Hedri H, Abdallah TB, Maiz HB, Kheder A. Effect of Sevelamer on Mineral and Lipid Abnormalities in Hemodialysis Patients. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2021 Mar 8 ];19:183-188
Available from: https://www.sjkdt.org/text.asp?2008/19/2/183/39027


Full Text

 Introduction



Patients with advanced Chronic Kidney Disease (CKD) usually develop hyperphos­phatemia, which is associated with severe complications such as secondary hyperpara­thyroidism and metastatic calcifications. [1]

To decrease the absorption of the dietary phosphorus load, patients with advanced CKD are prescribed phosphorus-restricted diets, which is usually insufficient and most patients require phosphate binders to control the serum phosphorus levels. [1],[2]

Aluminum salts are effective phosphate binders, however, aluminum accumulates in the tissues of CKD patients, and it is asso­ciated with significant toxicity. [3],[4] Calcium salts are also effective as phosphate binders, however, calcium can lead to hypercalcemia as well as soft tissue calcification in some patients. [5],[6]

Sevelamer, a cross-linked poly allylamine hydrochloride, is a non-absorbable calcium­and aluminum-free phosphate binder. Seve­lamer binds preferentially to trivalent anions, such as phosphate and citrate. It also binds bile acids, which results in improved fecal bile acid excretion and lower low density lipo­protein (LDL) cholesterol serum levels. [7],[8]

In this study, we evaluate the safety and efficacy of sevelamer to decrease serum phosphorus (sPho) and serum intact para­thyroid hormone (PTH), and improve the serum lipid profile in hemodialysis patients.

 Patients and Methods



The study included chronic hemodialysis patients, 18 years of age or older, and on therapy for a minimum of three months with adequate dialysis prescription. Inclusion crite­ria required stable dosage of calcium-based phosphate binder and vitamin D supple­mentation for at least one month. Over the course of the study, patients were strongly advised not to consume antacids that contained aluminum or magnesium and to avoid inten­tional changes in diet. After initial screening of the patients, we discontinued the calcium phosphate binders, vitamin D, fibrates, and statins followed by a two-week washout period (week 1 and 2 of the study). Patients who increased their serum phosphorus levels to > 1.8 mmol/l during this washout period were eligible to receive sevelamer for eight weeks (weeks 3 to 10 of the study). To establish that serum phosphorus control was due to sevelamer treatment, the levels of the phosphorus and calcium were checked after discontinuation of the drug (week 11 to 12 of the study).

Sevelamer was administered as 800 mg tablets. The starting dose was two, three, or four tablets three times per day with meals based on the washout serum phosphorus levels (WSPL): two tablets if WSPL ranged from 1.8-2.2 mmol/l, three tablets if WSPL ranged from 2.3- 2.7 mmol/l, and four tablets if WSPL was > 2.8 mmol/l. The sevelamer dose could be increased one tablet per meal (three tablets per day) every two weeks as necessary to achieve serum phosphorus level demographic charac­teristics of the study patients. No serious adverse events occurred during the study. Only 1 patient discontinued sevelamer because a complaint of weakness. There was no evidence that sevelamer treatment was associated with any adverse effects.

[Figure 1] displays the mean sPho throughout the study. The mean sPho levels increased from 2.15 ± 0.51 mmol/l at pre-washout to 2.35 ± 0.49 mmol/l after washout. Upon initia­tion of sevelamer treatment, the mean sPho levels declined immediately to 1.8 ± 0.38 mmol/l, and maintained this effect until the discontinuation of the drug at week 10 (p phosphorus product decreased from 5.45 mmol 2 /L 2 after the initial washout period to 4.14 mmol 2 /L 2 after eight weeks of sevelamer treatment.

The mean serum intact PTH levels over the course of the study are displayed in [Figure 2]. Mean serum intact PTH levels increased during the washout period from 442 pg/ml to 501 pg/ml (p [9] Second, lowering serum phosphorus might have improved the calcemic response to PTH. [10] Third, intestinal phosphate binding by sevelamer could have increased the intestinal absorption of calcium.

Because sevelamer is a calcium-free drug, physicians should be able to prescribe calci­triol with less frequent episodes of hyper­calcemia, which is a hindering adverse effect during the treatment of hyperpara­thyroid CKD patients with a combination of calcium based phosphate binder and calcitriol. [11] Furthermore, the recent treatment of secondary hyperparathyroidism with calcimimetics decreased serum calcium levels, which may decrease the incidence of hypercalcemia secondary to the use of calcium based binders. [12],[13]

Serum intact PTH levels significantly decreased during sevelamer treatment. This decline was anticipated because serum calcium and phosphorus are known to regulate PTH secretion. [14] As expected, the increase in serum phosphorus during the washout period prompted a corresponding increase of intact PTH.

The currently pharmaceutical form of seve­lamer, sevelamer hydrochloride, is accom­panied by a reduction in serum levels of bicarbonate in some patients. [15],[16] To minimize the possibility of this effect, a new salt form of sevelamer has been developed in which carbonate replaces the chloride ion. [17]

Sevelamer treatment reduced both serum total cholesterol and LDL cholesterol. [18] How­ever, sevelamer treatment did not affect HDL cholesterol and triglycerides. The cholesterol­ lowering effect of sevelamer is probably caused by bile acid binding. Increased fecal excretion of bile acids leads to LDL receptor up-regulation in the liver similar to the mechanism of action of the lipid-lowering drugs cholestyramine and colestipol. This side-effect may prove to be beneficial in dialysis patients, who may have atherogenic lipid profiles and/or may suffer from athero­sclerosis, a major cause of morbidity and mortality in this population. [19],[20],[21]

We conclude that sevelamer, a non absor­bable aluminum and calcium-free phosphate binder, safely and effectively reduced serum phosphorus in dialysis patients. Sevelamer was well tolerated without hypercalcemia episodes. In addition, it significantly decreased serum intact PTH, and reduced total and LDL cholesterol. This phosphate binder may great potential in the management of CKD patients.

References

1Delmez JA, Slatopolsky E. Hyperphosphatemia: Its consequences and treatment in patients with chronic renal disease. Am J Kidney Dis 1992;19(4):303-17.
2Ross Morton, Hercz G, Coburn JW. Control of hyperphosphatemia in chronic renal failure. Semin Dial 1990;4:219-23.
3Hercz G, Goburn JW. Prevention of phosphate retention and hyperphosphatemia in uremia. Kidney Int Suppl 1987;22:S215-20.
4Alfrey AC. Aluminium toxicity in patients with chronic renal failure. Ther Drug Monit 1993;15(6):593-7.
5Ramirez JA, Emmett M, White MG, et al. The absorption of dietary phosphorus and calcium in hemodialysis patients. Kidney Int 1986;30(5):753-9.
6Sperschneider H, Gunther K, Marzoll I, Kirchner E, Stein G. Calcium carbonate (CaCO3): An efficient and safe phosphate binder in haemodialysis patients? A 3-year study. Nephrol Dial Transplant 1993;8(6):530­-4.
7Burke SK, Slatopolsky EA, Goldberg DI. Renagel®, a novel calcium-and aluminium free phosphate binder, inhibits phosphate absorption in normal volunteers. Nephrol Dial Tranplant 1997;12(8):1640-4.
8Slatopolsky EA, Burke SK, Dillon MA. Renagel®, a nonabsorbed calcium and aluminium-free phosphate binder, lowers serum phosphorus and parathyroid hormone. Kidney Int 1999;55(1):299-307.
9Katz AI, Hampers CL, Merrill JP. Secondary hyperparathyroidism and renal osteodystrophy in chronic renal failure. Medicine 1969;48 (5):333-74.
10Rodriguez M, Martin-Malo A, Martinez MD, Torres A, Felsenfeld AJ, Llac F. Calcemic response to parathyroid hormone in renal failure: Role of phosphorus and its effects on calcitriol. Kidney Int 1991;40 (6):1055-62.
11Salusky IB, Goodman WG, Sahney S, et al. Sevelamer controls parathyroid hormone­induced bone disease as efficiently as calcium carbonate without increasing serum calcium levels during therapy with active vitamin D sterols. J Am Soc Nephrol 2005; 16(8):2501-8.
12Moe SM, Chertow GM, Coburn JW, et al. Achieving NKF-K/DOQI TM bone metabolism and disease treatment goals with cinacalcet HCI. Kidney Int 2005;67(2):760-71.
13Moe SM, Cunningham J, Bommer J, et al. Long-term treatment of secondary hyper­parathyroidism with the calcimimetic cinacalcet HCI. Nephrol Dial Transplant 2005;20(10):2186-93.
14Coburn JW, Slatopolsky E. Vitamin D, parathyroid hormone and renal osteodystrophy. In the Kidney (4 th ed), edited by Brenner BM, Rector FCJ R , Philadelphia, Saunders 1991:2036-122.
15Sonikian MA, Pani IT, Iliopoulos AN, Koutala KG, Marioli SI, Vlassopoulos DA. Metabolic acidosis aggravation and hyper­kaliemia in hemodialysis patients treated by sevelamer hydrochloride. Ren Fail 2005; 27(2):143-7.
16Brezina B, Qunibi WY, Nolan CR. Acid loading during treatment with sevelamer hydrochloride: Mechanisms and clinical implications. Kidney Int 2004;66(Suppl 90):S39-45.
17Duggal A, Hanus M, Zhorov E, et al. Novel dosage forms and regimens for sevelamer­based phosphate binders. J Ren Nutr 2006; 16(3):248-52.
18Yamada K, Fujimoto S, Tokura T, et al. Effect of sevelamer on dyslipidemia and chronic inflammation in maintenance hemodialysis patients. Ren Fail 2005;27(4):361-5.
19Bomer J, Stroheck E, Goerich J, Babner M, Zuna I. Arteriosclerosis in dialysis patients. Int J Artif Organs 1996;19(11):638-44.
20United States Renal Data System: USRDS 1997 Annual Report. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease, Bethesda, MD, 1997:93.
21Ferramosca E, Burke S, Chasan-Taber S, Ratti C, Chertow GM, Raggi P. Potential antiatherogenic and anti-inflammatory properties of sevelamer in maintenance hemodialysis patients. Am Heart J 2005; 149(5):820-5.