Clinical Evaluation of Niacin in Hemodialysis Patients with Hyperphosphatemia as Adjuvant to Calcium Carbonate
Keywords:Niacin, Calcium, Hyperphosphatemia, Hemodialysis.
Background: The complications of End Stage Renal Disease ESRD attributed to high morbidity and mortality such as hyperphosphatemia and vascular disease. Vascular smooth muscle cells (VSMCs) are sensitive to elevation in serum phosphate levels and have the ability to modify their functions in response to this
elevation through h many processes that promote calcification. Vascular calcification is highly correlated with the major events of cardiovascular mortality which are included heart failure, sudden cardiac death, and ischemic heart disease. The control of hyperphosphatemia in HD patients remains poor in spite of the effectiveness of all the available phosphate binders. However, calcium based binder may promote the aggravation of vascular calcification while Aluminum- based binder associated with osteomalacia, and encephalopathy. Calcium/aluminum free phosphate binder may cause gastrointestinal adverse effect in addition to their high cost of treatment. The active phosphate transport inhibitors are the newest interesting agents in the management of hyperphosphatemia alone or as add-on therapy to the existing phosphate binders. Niacin is one of this novel drug classes that has been demonstrated to show promising therapeutic potential in the treatment of hyperphosphatemia in HD patients.
Aim of study: This study is designed to evaluate the efficacy of niacin as adjuvant therapy to calcium carbonate (as a phosphate binder) in hemodialysis patients.
Method: In this prospective, randomized interventional study, 56 patients confirmed with end stage renal disease (ESRD) and hyperphosphatemia on regular hemodialysis were included. Only 40 patients completed the study and were classified randomly into two groups: group (1); composed of 19 patients who received 1500 mg/day of calcium carbonate tablets, and group (2); composed 21 patients who received 1500 mg/day calcium carbonate tablets plus niacin both for 2 months’ duration. Blood sample was taken thrice, at baseline, after 1 month and at the end of month 2 for measurement of serum study parameters: (inorganic phosphorus (Pi), calcium (Ca), Calcium-Phosphorus product (Ca x P) .
Results: Results of this study showed that the patients who administered orally niacin as adjuvant to calcium had the superiority over using calcium alone in the reduction of serum phosphorus level (-20.3% and -13.5%) respectively after 2 months of treatment in respect to baseline levels. Meanwhile, there was a marked increase in serum Ca level in both groups after 2 months of treatment however, it was non-significant. In addition, treatment with combination of calcium and niacin resulted in more reduction in serum (Ca x P) product level at the end of study than with calcium alone compared to baseline, nevertheless the change was non-significant.
Conclusion: Administration of niacin for hemodialysis patients is an effective strategy for reducing the serum levels of inorganic phosphorus and calcium-phosphorus product which may lead to reduce the risks of cardiovascular diseases associated with hyperphosphatemia.
- Xie Y, Bowe B, Mokdad A, Xian H, Yan Y, Li T, et al. Analysis of the Global Burden of Disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016. Kidney int. 2018; 94(3): 567-581
- Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095-2128.
- Jonathan H, Ikizler T. Chronic Kidney Disease, Dialysis, and Transplan-tation. 4th ed. Philadelphia: Brenner and Rector’s the Kidney; 2019.Chapter 21, Dialysis and End-Stage Kidney Disease: Epidemiology, Costs, and Outcomes; p 311-337.
- US Renal Data System. in: USRDS 2018 Annual Data Report: Atlas of chronic kidney disease and end-stage renal disease in the United States. Vol. 2. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA; 2018
- Thaminda L, Toshiharu N, Vivekanand J, Bruce N, Halle M, Ikechi O, et al. Worldwide access to treatment for end-stage kidney disease: a systematic review. Lancet.2015; 385: 1975–82
- Fox CS, Matsushita K, Woodward M, Bilo HJ, Chalmers J, Heerspink HJ, et al. Chronic Kidney Disease Prognosis Consortium. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet.2012;380(9854):1662-73.
- Wang Z, Jiang A, Wei F, Chen H, et al. Cardiac valve calcification and risk of cardiovascular or all-cause mortality in dialysis patients: a meta-analysis. BMC Cardiovasc Disord.2018; 18: 12
- Shaman AM, Kowalski SR. Hyperphosphatemia management in patients with chronic kidney disease. Saudi Pharm J.2016; 24:494-505
- Adeney KL, Siscovick DS, Ix JH, Seliger SL, Shlipak MG, Jenny NS, et al. Association of serum phosphate with vascular and valvular calcification in moderate CKD. J Am Soc Nephrol.2009; 20: 381-387.
- Garimella PS, Hart PD, O’Hare A, DeLoach S, Herzog CA, Hirsch AT. Peripheral artery disease and CKD: a focus on peripheral artery disease as a critical component of CKD care. Am J Kidney Dis.2012; 60: 641-654.
- O’Neill WC. Understanding the pathogenesis of vascular calcification: timing is everything. Kidney Int. 2017; 92:1316-1318.
- Da J, Xie X, Wolf M, Disthabanchong S, Wang J, Yan Zha Y, et al. Serum Phosphorus and Progression of CKD and Mortality: A Meta-analysis of Cohort Studies. Am J Kidney Dis.2015; 66:258-265.
- Frazão JM, Adragão T. Non-calcium-containing phosphate binders: comparing efficacy, safety, and other clinical effects. Nephron Clin Pract.2012;120(2):108-119.
- Shanahan CM, Crouthamel MH, Kapustin A, Giachelli CM. Arterial calcification in chronic kidney disease: key roles for calcium and phosphate. Circ Res.2011:109697–109711.
- Mudge DW, Johnson DW, Hawley CM, Campbell SB, Isbel NM, van Eps CL, et al. Do aluminium-based phosphate binders continue to have a role in contemporary nephrology practice? BMC Nephrol.2011; 13:12-20.
- Wang S, Alfieri T, Ramakrishnan K, Braunhofer P, Newsome BA. Serum phosphorus levels and pill burden are inversely associated with adherence in patients on hemodialysis. Nephrol Dial Transplant.2014;29(11):2092-9.
- Fouque D, Vervloet M, Ketteler M. Targeting Gastrointestinal Transport Proteins to Control Hyperphospha-temia in Chronic Kidney Disease. Drugs.2018 ;78(12):1171–1186
- Kirkland JB. Niacin status, NAD distribution and ADP-ribose metabolism. Curr Pharm Des.2009;15:3-11.
- Carfagna F, Del Vecchio L, Pontoriero G, Locatelli F. Current and potential treatment options for hyperphosphatemia. Expert Opin Drug Saf.2018;17(6):597-
- Yasmeen G, Dawani ML, Mahboob T. Hypophosphatemic effect of niacin extended release in ischemic kidney disease. EXCLI J. 2015; 14:1095-1103
- Sampathkumar K, Selvam M, Sooraj YS, Gowthaman S, Ajeshkumar RN. Extended release nicotinic acid_a novel oral agent for phosphate control. Int Urol Nephrol.2006; 38:171-174.
- Shin S, Lee S. Niacin as a drug repositioning candidate for hyper-phosphatemia management
- in dialysis patients. Ther Clin Risk Manag .2014;10:875-883.
- Shahbazian H, Zafar Mohtashami A, Ghorbani A, Abbaspour MR, Belladi Musavi SS, Hayati F, et al. Oral nicotinamide reduces serum phosphorus, increases HDL, and induces thrombocytopenia in hemodialysis patients: a double-blind randomized clinical trial. Nefrologia.2011;31:58–65.
- Rabbani S, Sathvik BS, Rao P, Kurian M, EL essawy B H. Hyperphosphatemia End stage renal disease: prevelance and patients characteristics of multiethnic population of United Arab Emirates. Int J Pharm Pharm Sci.2017;9(12): 283-287.
- Abdu A, Abdu A, Arogundade FA. Prevalence and pattern of chronic kidney disease-mineral bone disorders among hemodialysis patients in kano, northwest Nigeria. Ann Afr Med 2019;18(4): 191-195.
- Salhab N, Alrukhaimi M, Kooman J, Fiaccadori E, Aljubori H, Rizk R, Karavetian M. Effect of Intradialytic Exercise on Hyperphosphatemia and Malnu-trition. Nutrients.2019, 11, 2464.
- Mohamed Koya SNM. Management of phosphate abnormalities in hemodialysis patients: Findings from Malaysia. Saudi J Kidney Dis Transpl. 2019;30(3):670–677.
- Nafar M, Sabaghian T, Khoshdel A, Alipour B, Samavat S. Serum Calcium and Phosphorus Levels in Hemodialysis Patients: A Large Population-Based Multicenter Study, Iran Red Crescent Med J.2019; 21(1):1-9
- Gray K, Ficociello LH, Hunt AE, Mullon C, Brunelli SM. Phosphate binder pill burden, adherence, and serum phosphorus control among hemodialysis patients converting to sucroferric oxyhydroxide. Int J Nephrol Renovasc Dis. 2019; 12:1-8
- Amann K, Gross ML, London GM, Ritz E. Hyperphosphataemia-a silent killer of patients with renal failure? Nephrol Dial Transplant. 1999;14(9):2085-2087.
- Palmer SC, Hayen A, Macaskill P, Pellegrini F, Craig JC, Elder GJ, et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis. JAMA. 2011; 305:1119–27.
- Alattiya TN, Mohammed MM, Jaleel NA, Jamil NS, Al-Sabbag MS. Effect of Oral L-carnitine Supplementation on the Mortality Markers in Hemodialysis Patients. Int. J. Pharm. Sci. Rev. Res.41(1), November - December 2016; Article No. 14, Pages: 64-69.
- Zahed NS, Zamanifar N, Nikbakht H. Effect of low dose nicotinic acid on hyperphosphatemia in patients with end stage renal disease. Indian J Nephrol 2016;26(4):239-243
- Ahmadi F, Shamekhi F, Lessan-Pezeshki M, Khatami MR.Coparison of efficacy of the phosphate binders nicotinicacid and sevelamerhydrochloride in hemodialysis patients. Saudi J Kidney Dis Transpl .2012;23(5):934-938.
- Khalid SA, Inayat F, Tahir MK, Younus A, Ahmad HI, Bokhari SRA, Yaqoob U. Nicotinic acid as a Phosphate-lowering Agent in Patients with End-stage Renal Disease on Maintenance Hemodialysis: A Single-center Prospective Study. Cureus. 2019 30;11(4): e4566
- Sampathkumar K. Niacin and analogs for phosphate control in dialysis–perspective from a developing country. Int Urol Nephrol.2009; 41:913–918.
- Sabbagh Y, O’Brien SP, Song W, Boulanger JH, Stockmann A, Arbeeny C, et al. Intestinal npt2b plays a major role in phosphate absorption and homeostasis. J Am Soc Nephrol.2009;20(11):2348–58.
- El Borolossy R, El Wakeel LM, El Hakim I, Sabri N. Efficacy and safety of nicotinamide in the management of hyperphosphatemia in pediatric patients on regular hemodialysis. Pediatr Nephrol.2016;31(2):289–96.
- Ikuta K, Segawa H, Sasaki S, Hanazaki A, Fujii T, Kushi A, etal.Effect of Npt2b deletion on intestinal and renal inorganic phosphate (Pi) handling. Clin Exp Nephrol 2018 ;22(3):517-528.
- Nomura K, Tatsumi S, Miyagawa A, Shiozaki Y, Sasaki S, Kaneko I, et al. Hepatectomy-related hypophosphatemia: a novel phosphaturic factor in the liver-kidney axis. J Am Soc Nephrol.2014;25(4):761–72.
- Wu KI, Bacon RA, Al-Mahrouq HA, Kempson SA. Nicotinamide as a rapid-acting inhibitor of renal brush-border phosphate transport. Am J Physiol. 1988; 255(1): 15–21.
- Block GA, Wheeler DC, Persky MS, Kestenbaum B, Ketteler M, Spiegel DM, et al. Effects of phosphate binders in moderate CKD. J Am Soc Nephrol. 2012;23(8):1407-1415.
- Ketteler M, Liangos O, Biggar PH. Treating hyperphosphatemia-current and advancing drugs. Expert Opin Pharmacother 2016 ;17(14):1873-1879
- Spiegel DM, Brady K. Calcium balance in normal individuals and in patients with chronic kidney disease on low-and high-calcium diets. Kidney Int.2012; 81: 1116-1122.
- Wang Y, Xie G, Huang Y, Zhang H, Yang B, Mao Z. Calcium acetate or calcium carbonate
- for hyperphosphatemia of hemodialysis patients, a meta-analysis. PLoSOne.2015;10(3): e0121376
- Rivara MB, Ravel V, Kalantar-Zadeh K, Streja E, Lau WL, Nissenson AR, et al.Uncorrected and Albumin-Corrected Calcium, Phosphorus, and Mortality in Patients Undergoing Maintenance Dialysis. J Am Soc Nephrol. 2015;26(7):1671-81.
- Moe SM. Calcium as a cardiovascular toxin in CKD-MBD. Bone. 2017;100: 94–99.
- Palit S, Kendrick J. Vascular calcification in chronic kidney disease: role of disordered mineral metabolism. Curr Pharm Des.2014 ;20(37):5829-33.
- Elder GJ .Calcium-based phosphate binders; down, but not out.Nephrol Dial Translant .2017;32:5-8.
- Moshar S, Bayesh S, Mohsenikia M, Najibpour R. The Association of Calcium-Phosphorus Product with the Severity of Cardiac Valves Failure in Patients under Chronic Hemodialysis. Cardiol Res.2016;7(2):80-83.
- Kahnooj M, Masoomi M, Naderinasab A, Zaeem A, Sheikhvatan M. Relationship between Calcium-Phosphorus Product and Severity of Valvular Heart Insufficiency in Patients Undergoing Chronic Hemodialysis. J Tehran Heart Cent.2010;5(2):78-82.
- Cheema UK, Ahmed A, Junaid Nazar CMJ, Butt GU, Cheema A, Bilal M, et al. Effectiveness and tolerability of sevelamer in the treatment of hyperphosphatemia in hemodialysis patients. J parathyr dis.2017;5(1): 17-24.