| Abstract|| |
Hyperphosphatemia is a significant risk factor for the development of ectopic calcification and coronary artery diseases in patients on hemodialysis (HD), and must be controlled with the use of phosphate binders. Studies comparing the effects of sevelamer and nicotinic acid, both similar non-calcium and non-aluminum phosphate binders, are not available. In this study, 40 patients on HD with a serum phosphorus level of more than 6 mg/dL were enrolled. After a two week washout period without phosphate binders, the patients were randomly divided into two equal groups (n = 20) and were started on nicotinic acid or sevelamer for a period of four weeks. The dose of nicotinic acid used was 500 mg and that of sevelamer was 1600 mg daily. Blood samples were drawn for the measurement of the total calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), triglyceride (TG), total cholesterol (Chol), high-density lipoprotein (HDL), low-density lipoprotein (LDL), uric acid and parathyroid hormone (PTH). Patients receiving sevelamer showed a significant reduction in serum P level (2.2 ± 0.69 mg/dL; P <0.0001) in comparison with the nicotinic acid group (1.7 ± 1.06 mg/dL; P = 0.004). Reduction in the Ca-P product was significantly different in the two groups; in the sevelamer group, it was 21 ± 7; (P <0.0001) while in the nicotinic acid group, it was 16 ± 11 (P = 0.007). Also, patients on sevelamer showed greater reduction in the mean TG level (38.9 ± 92 mg/dL; P = 0.005). No significant changes were observed in the mean serum Ca, total Chol, HDL, LDL, ALP and iPTH levels in the two study groups. Our short-term study suggests that although nicotinic acid reduced hyperphosphatemia, sevelamer showed higher efficacy in controlling hyperphosphatemia as well as the Ca-P product.
|How to cite this article:|
Ahmadi F, Shamekhi F, Lessan-Pezeshki M, Khatami MR. Comparison of efficacy of the phosphate binders nicotinic acid and sevelamer hydrochloride in hemodialysis patients. Saudi J Kidney Dis Transpl 2012;23:934-8
|How to cite this URL:|
Ahmadi F, Shamekhi F, Lessan-Pezeshki M, Khatami MR. Comparison of efficacy of the phosphate binders nicotinic acid and sevelamer hydrochloride in hemodialysis patients. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2013 May 25];23:934-8. Available from: http://www.sjkdt.org/text.asp?2012/23/5/934/100865
| Introduction|| |
End-stage renal disease (ESRD) is associated with abnormalities of calcium (Ca) and phosphate (P) metabolism that can result in severe bone disease and ectopic calcification, particularly in the cardiovascular tissues.  Hyperphosphatemia and high calcium-phosphorus (Ca- P) product are independently associated with decreased survival in dialysis patients and, therefore, the treatment of hyperphosphatemia is of crucial importance.  The two principles for reversing hyperphosphatemia in patients with renal failure include restricting dietary phosphate intake and administering different agents to bind the ingested phosphate in the gut. Common phosphate binders contain aluminum or Ca. Aluminum increases the risk of aluminum intoxication with the development of major clinical manifestations in the bone, skeletal muscles and central nervous system (CNS), leading to osteomalacia, refractory microcytic anemia, bone-muscle pain and dementia.
Ca-based phosphate binders are effective. However, one potential complication of these agents is the absorption of some administered calcium, which may promote the development of coronary arterial calcification, postulated to be associated with coronary atherosclerosis. , Sevelamer (RenaGel) is a Ca- and aluminum-free P binder that binds P through ion exchange. The absence of an absorbable cation makes this agent extremely useful without the risk of Ca supplementation. Additionally, this agent is known to reduce the levels of low-density lipoprotein (LDL) through bile salt binding.  The main side-effects of sevelamer include gastro-intestinal (GI) discomfort, mild metabolic acidosis and hypocalcemia.
Nicotinamide is a metabolite of nicotinic acid that inhibits sodium-dependent P co-transporter in the small intestine and proximal renal tubule, and may be effective in lowering the P level in dialysis patients by reducing its absorption from the GI tract.  Because nicotinamide is not available in Iran, we used nicotinic acid (niacin) instead. It is a water-soluble vitamin B that lowers lipid levels and augments the control of blood glucose; it also reduces cardiovascular risk by increasing the highdensity lipoprotein (HDL) while lowering the LDL and triglyceride (TG) levels. Its main side-effects are GI discomfort, flushing and pruritis.  All available studies are on the effect of nicotinamide on P levels only; comparative studies with other P binders are very few. The aim of this study is to compare the efficacy of nicotinic acid as a P binder with sevelamer in patients on hemodialysis (HD).
| Materials and Methods|| |
One-hundred-fifty patients on HD at the Imam Khomeni Hospital were randomly selected for the present study. All patients received HD three-times a week with bicarbonate dialysate and polysulfone dialyzer. The dialysate calcium concentration was 2.5 meq/L. Of them, 40 patients with serum P levels of more than 6 mg/dL were studied. Patients with liver disease, peptic ulcer, malignancy and history of having undergone total parathyroidectomy were excluded.
All the study patients had a washout period of two weeks, following which they were randomly assigned to two equal groups that were administered sevelamer or nicotinic acid (n = 20) on a random basis. The starting dose of nicotinic acid tablet was 500 mg (Tab Sobhan Darou 100 mg), three tablets in the morning and two in the evening. The dose of sevelamer was 1600 mg (Cap 800 mg Genzym), once in the morning and repeated in the evening; all drugs were given with meals. After four weeks of treatment, the patients were taken off nicotinic acid and sevelamer. Five patients from the nicotinic acid-treated group and one patient from the sevelamer group were removed from the study because of the development of complications. The five patients from the nicotinic acid group were excluded because they developed flushing, pruritis and vomiting, while the single patient from the sevelamer group was excluded due to diarrhea and nausea. Blood samples were collected from all the study patients before and after the treatment; all samples were collected before a HD session.
Blood tests including serum alkaline phosphatase (ALP), lipids, P, total Ca and uric acid were determined by standard clinical laboratory methods. The serum intact parathormone (iPTH) concentration was determined using an immunochemilumetric assay (upper limit of normal, 65 pg/mL). Compliance was confirmed by conducting a face to face interview.
| Statistical Analysis|| |
The data are expressed as mean ± standard deviation (SD).They were based on the two-tailed student t test and cross-tabs. P-value of less than 0.05 was considered statistically significant. All statistical analyses were performed using SPSS-11.5.
| Results|| |
The study included 27 males (67.5%) and 13 females (32.5%). Their mean age was 50 ± 15 years (range 21-81 years) and the mean duration on HD of the study patients was 5.8 ± 4.8 years [Table 1]. The mean serum P level before the commencement of the study was 6.9 ± 1.05 mg/dL in the sevelamer group (S) and 7.3 ± 1.19 mg/dL in the nicotinic acid group (N).
Drug administration for four weeks resulted in a statistically significant reduction of the mean serum level of P from 6.9 ± 1.05 mg/dL to 4.7 ± 1.1 mg/dL; P <0.0001, in the S group and from 7.3 ± 1.19 mg/dL to 5.6 ± 1.6 mg/dL in the N group. The serum P level was normalized in seven patients (46.7%) from the N group, while in eight others (53.5%) the P levels were higher than normal at the end of the study. In the S group, the P levels were normalized after the study period in 11 patients (57.9%), while it remained above normal in eight others (42.1%).
The mean serum Ca-P product showed a similar reduction. It reduced from 65.7 ± 1.09 to 44.1 ± 12.5 (P < 0.0001) in the S group and from 68.5 ± 15 to 52.1 ± 15 (P = 0.007) in the N group.
There was a significant reduction in the levels of serum TG in both groups after the study period. In the S group, the mean TG level came down from 148 ± 112 to 109.4 ± 92.7 mg/dL (P = 0.0005), while in the N group, it came down from 109.8 ± 52.7 to 77.47 ± 36.6 mg/dL (P = 0.0008). Similarly, the mean serum uric acid level reduced from 6.5 ± 1.7 to 4.7 ± 1 mg/dL (P <0.0001) in the S group, and from 6.5 ± 1.1 to 4.6 ± 1.5 mg/dL (P <0.00001) in the N group. The serum Ca level remained unchanged in both groups after the study. Similarly, no significant changes were noted in the other laboratory parameters measured during the study period [Table 2].
| Discussion|| |
Non-Ca and non-aluminum-containing phosphate binders such as sevelamer may be the first-line therapy in patients with ESRD.  It was noted that the use of nicotinamide for the purpose of correcting hyperlipidemia led to a reduction of phosphorus levels as well in patients on HD.  Nicotinamide is not really a phosphate binder but is an inhibitor of sodium-dependent phosphate co-transporter in both small intestine and renal tubules. It has been found to be more effective in reducing hyperphosphatemia (at a mean dose of 1000 mg) in comparison with calcium carbonate. 
In the present study, nicotinic acid and sevelamer hydrochloride reduced the serum P levels after four weeks. This study proves the P-lowering capability of nicotinic acid, but with a lesser potency in comparison with sevelamer. Takahashi et al have shown that nicotinamide significantly reduced the serum P level after 12 weeks of treatment without causing significant changes in the serum Ca level.  Mullers et al have shown that niacin effectively lowers serum P levels and considerably increases the levels of HDL-c.  In our study, neither nicotinic acid nor sevelamer caused any change in the serum Ca levels during the four weeks of treatment; however, both drugs reduced the Ca-P product. Sevelamer was found to be more effective in controlling hyperphosphatemia and the Ca-P product than nicotinic acid, which is probably related to the higher dose of sevelamer used. Sampath Kumar et al showed a significant decrease of serum P and Ca-P product in patients on maintenance HD after eight weeks of treatment with extended release nicotinic acid; however, the serum Ca levels also increased.  The comparison of sevelamer with colestimide has shown similar effects on hyper phosphatemia without any significant change of the Ca-P product. 
Several investigators have shown that increased serum P levels increase the synthesis and secretion of PTH. Evidence exists for a direct role of serum P as a regulator of parathyroid gland function. In the present study, the PTH concentration showed an increase after treatment initiation, although we do not have a proper explanation to account for this paradox.
Takahashi et al also showed a significant reduction of serum iPTH, in association with a reduction in serum P levels after 12 weeks of treatment in a group of patients on maintenance HD. The decline in the serum PTH level was in parallel with the decline in the serum phosphorus. Nicotinamide is widely used as an anti-hyperlipidemic agent due to its ability to increase HDL and decrease the total cholesterol levels. Similarly, sevelamer can also reduce the total cholesterol and LDL. ,,
In our study, there were no significant changes in the lipid profile except the triglyceride levels. Sevelamer is known to reduce the serum uric acid levels in contrast to nicotinamide. In our study, both drugs were found to cause a similar reduction in the mean serum uric acid levels
In conclusion, in this short-term study, although nicotinic acid ameliorated hyperphosphatemia, sevelamer was more effective in controlling hyperphosphatemia as well as the Ca-P product. Further studies on the long-term effects of administering higher dose of nicotinic acid are needed to study the efficacy and complications with this treatment.
| References|| |
|1.||Foley RN, Parfery PS, sarnak MJ. clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998; 32:S112-9. |
|2.||Block GA, Hulbert Shearson TE, Levin NW, port FK. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: A national study. Am J kidney Dis 1998;31:607-17. |
|3.||Block GA, Port FK. Re-evaluation of risk associated with Hyperphosphatemia and hyperparathyroidism in dialysis patients: Recommendations for a change in management. Am J Kidney Dis 2000;35:1229-37. |
|4.||Goodman WG, Golden J, Kuizon BD, et al. Coronary artery Calcification in young adults with end stage renal disease who are undergoing dialysis. N Engl J Med 2000;342:1473-83. |
|5.||Block GA, Spiegel DM, Ehrlich J, et al. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. kidney Int 2005;68:1815-24. |
|6.||Takahashi Y, Tanaka A, Nakumura T, et al. Nicotinamide suppresses hyperphosphatemia in hemodialysis patients. Kidney Int 2004;65:1099-104. |
|7.||Alderman JD, Pasternak RD, Sacks FM, Smith HS, Monrad ES, Grossman W. Effect of a modified, well tolerated niacin regimen on serum total cholesterol, high density lipoprotein cholesterol and the cholesterol to high density lipoprotein ratio. Am J Cardiol 1989;64:725-9. |
|8.||Wheeler DC. Should hyperlipidemia in dialysis patients be treated? Nephrol Dial Transplant 1997; 12:19-21. |
|9.||Shimoda K, Akiba T, Matsushima T, et al. Nicerittrol reduces serum phosphate in chronic hemodialysis patients. Nippon Jinzo Gakkai Shi 1998; 40:1-7. |
|10.||Gulliaume J, Charles C, Bernard C. Hyperphosphatemia and related mortality. Nephrol Dial Transplant 2006;21:273-28. |
|11.||Muller D, Mehling H, Otto B, et al. Niacin lowers serum phosphate and increases HDL cholesterol in dialysis patients. Clin J Am Soc Nephrol 2007; 1249-54. |
|12.||Sampathkumar K, Selvam M, Santhakumari Y, Gowthaman S, Ajeshkumar R. Extended release nicotinic acid - a novel agent for phosphate control. Int Urol Nephrol 2006;38:171-4. |
|13.||Itoh K, Tanaka M, Hashiguchi J, et al. Comparison of sevelamer hydrochloride with colestimide administered alone or in combination with calcium carbonate in patients on hemodialysis. Ther Apher Dial 2008;12:126-32. |
|14.||Chertow GM, Burk SK, Lazarus JM, et al. poly [allylamine hydrochloride] (RenaGel): A noncalcemic phosphate binder for the treatment of hyperphosphatemia in chronic renal failure. Am J kidney Dis 1997;29:66-71. |
|15.||Goldberg DI, Dillon MA, Slatopolsky EA, et al. Effect of Renagel, a non-absorbed, calcium and aluminium- free phosphate binder on serum phosphorus, calcium and intact parathyroid hormone in end-stage renal disease patients. Nephrol Dial Transplant 1998;13:2303-10. |
|16.||Slatopolsky EA, Bruke SK, Dillon MA. RenaGel, a nonabsorbed calcium and aluminum free phosphate binder, lower serum phosphorus and parathyroid hormone. The RenaGel Study Group. Kidney Int 1999;55:299-307. |
Associate Professor, Department of Nephrology Research Center, Tehran University of Medical Science, Imam Khomeni Hospital, Tehran
[Table 1], [Table 2]