|Year : 2020 | Volume
| Issue : 5 | Page : 883-897
|Nicotinamide Therapy in Dialysis Patients: A Systematic Review of Randomized Controlled Trials
Salman Hussain1, Ambrish Singh2, Thamir M Alshammari3, Anwar Habib4, Md. Sarfaraj Hussain5, Robin Jha6, Mohd. Akhtar7, Abul Kalam Najmi7
1 Department of Pharmaceutical Medicine (Division of Pharmacology), School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
2 Menzies Institute for Medical Research University of Tasmania, Tasmania, Australia
3 Medication Safety Research Chair, King Saud University; Saudi Food and Drug Authority, Riyadh, Saudi Arabia
4 Department of Medicine, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi, India
5 Department of Pharmacognosy & Phytochemistry, R.V Northland Institute of Pharmacy, Uttar Pradesh, India
6 Health Outcome Researcher, Independent, New Delhi, India
7 Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
Click here for correspondence address and email
|Date of Web Publication||21-Nov-2020|
| Abstract|| |
Randomized controlled trials (RCTs) have presented variable findings concerning the reduction of phosphorous level by nicotinamide. This systematic review is aimed to explore the safety and efficacy of nicotinamide in hemodialysis patients and was conducted by adhering to the PRISMA guidelines. Studies for inclusion were identified by running the suitable keywords in PubMed, Embase, and Cochrane Central till June 13, 2018. Cochrane risk of bias tool was used to judge the quality of the included RCTs. The primary outcome was change in serum phosphorus, calcium, and calcium–phosphorus product levels. Change in other biochemical parameters including serum calcium, parathormone, platelets, lipid profile parameters, and the safety profile was considered under secondary outcomes. Review Manager (RevMan v5.3) was used for the risk of bias estimate. A total of 12 articles were qualified for inclusion in this study. All the included RCTs showed a statistically significant reduction in mean serum phosphorous and calcium–phosphorus product levels in the treatment arm as compared to the placebo group. Among several biochemical parameters analyzed, only high-density lipoprotein (HDL) was found to be significantly increased from baseline to the endpoint of the study in the nicotinamide group, while the placebo group showed no significant difference. Flushing and diarrhea, followed by thrombocytopenia, were the most commonly reported adverse events in the treatment group. Nicotinamide was found to be effective in reducing the phosphorous level and calcium–phosphorus product level and increasing the HDL cholesterol level in dialysis patients. The safety profile was found to be satisfactory.
|How to cite this article:|
Hussain S, Singh A, Alshammari TM, Habib A, Hussain MS, Jha R, Akhtar M, Najmi AK. Nicotinamide Therapy in Dialysis Patients: A Systematic Review of Randomized Controlled Trials. Saudi J Kidney Dis Transpl 2020;31:883-97
|How to cite this URL:|
Hussain S, Singh A, Alshammari TM, Habib A, Hussain MS, Jha R, Akhtar M, Najmi AK. Nicotinamide Therapy in Dialysis Patients: A Systematic Review of Randomized Controlled Trials. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2021 Mar 1];31:883-97. Available from: https://www.sjkdt.org/text.asp?2020/31/5/883/301195
| Introduction|| |
Chronic kidney disease (CKD) is a condition characterized by a gradual reduction of renal functions. Mineral disorders such as hyperphosphatemia and hypocalcemia are among the severe comorbidities observed commonly in CKD patients. Hyperphosphatemia, which is marked by an abnormally elevated level of phosphates, particularly affects CKD patients receiving hemodialysis (HD) therapy.,, The conventional thrice-weekly HD modalities remove approximately 900 mg of phosphorus each cycle while intermittent HD provides modestly improved but inadequate removal of phosphorus at 1030–1700 mg each cycle. Besides, peritoneal dialysis is also comparable or inferior to that of conventional HD for clearance of serum phosphorus. The poorly managed hyperphosphatemia may lead to the development of other metabolic conditions such as secondary hyperparathyroidism, renal osteodystrophy, and soft-tissue calcifications. Studies have shown hyperphosphatemia and its resulting complications to impart a substantial mortality and morbidity burden in CKD patients.,, Hence, the need for drugs to manage the serum phosphate levels in patients with CKD is predictable.
Typical strategy for management of hyperphosphatemia requires maintenance of serum phosphate levels in CKD patients to prevent hyperparathyroidism, renal osteodystrophy, vascular calcification, and cardiovascular complications. The guideline by the Kidney Disease Improving Global Outcomes (KDIGO) recommends the control of serum phosphorus concentrations in CKD patients using phosphate binder agents. The available options for lowering the serum phosphorus levels are (1) limiting phosphorus intake and (2) increasing the duration and frequency HD and use of phosphate-binding agents such as carbonate salts of calcium, magnesium or lanthanum, aluminum hydroxide, and sevelamer.,,, Although used commonly in current clinical settings, these strategies have some associated disadvantages. Limiting phosphorus intake is of limited efficacy in CKD and often results in a positive phosphorus balance., The magnesium- and calcium-based binders are associated with hypermagnesemia related gastrointestinal disorders, and hypercalcemia related soft-tissue calcification, respectively., The aluminum salt binders are associated with clinical toxicity, while clinical application of sevelamer is limited by its large pill burden and associated high cost.
Nicotinamide, also known as niacinamide, is a derivative of Vitamin B3 and has the property to inhibit sodium-dependent phosphate co-transport in the renal proximal tubule and intestine., This pharmacological property of niacinamide makes it a good candidate to reduce hyperphosphatemia in patients with CKD. Numerous studies have evaluated the efficacy and safety of niacinamide in reducing hyperphosphatemia. Although numerous randomized controlled trials (RCTs) have evaluated the efficacy and safety of niacinamide in reducing the hyperphosphatemia, the findings are variable concerning the reduction of serum phosphorous level. Hence, in this systematic review, we aim to assess the evidence from RCTs evaluating the safety and efficacy of nicotinamide in reducing the hyperphosphatemia in patients with CKD receiving HD.
| Methods|| |
This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The protocol of this systematic review was prospectively registered at PROSPERO (a database of systematic reviews).
Search strategy and study selection
We searched PubMed, Embase, and Cochrane Central databases, bibliography of the included studies as well as previous reviews for articles assessing the efficacy and safety of nicotinamide for the management of hyperphosphatemia in HD patients. Search period was from inception to June 13, 2018. Search was restricted to the English language only.
Interventional studies assessing the safety and efficacy of nicotinamide in HD or peritoneal dialysis patients were included. We included studies that examined nicotinamide vs. placebo or any active drug. All the articles were judged for inclusion based on the screening of title and abstract followed by full-text screening. Participants were required to have been receiving HD or peritoneal dialysis for at least two months, two to three times in a week, and belonging to any age group. Study screening and selection were made independently by two of the authors (SH and AS). All studies other than RCTs were excluded from the study. We excluded case–control, cohort, cross-sectional, case report, case series, letter to the editor, and commentary.
Data extraction and quality assessment
Two independent investigators (SH and AS) extracted and tabulated the data in a predesigned standard data extraction template. Any discrepancy on the data in reference to original studies was resolved by group discussion or, if necessary, by consulting with an arbitrator (AKN). Information which was similar across the majority of the studies was abstracted, which included: author and year, country, study identifier, type of RCTs (single-blind or double-blind), inclusion criteria, number of participants in the treatment and the placebo group, dose and duration of intervention, primary and secondary outcomes, duration of follow-up, and number of withdrawals. Any differences in opinion were resolved by consensus; if not resolved, then the decision was made by consultation with the third investigator (AKN).
Quality of the included RCTs was assessed by two independent reviewers using the Cochrane Risk of Bias Tool (CRBT) as per the points mention in the Cochrane Handbook for Systematic Reviews of Interventions. Discrepancies were resolved by discussion.
Efficacy and safety outcomes
Primary outcomes of this study were to assess the change in serum phosphorus level, serum calcium, calcium–phosphorus product level while the change in other biochemical parameters including serum 25-hydroxyvitamin D, intact PTH, platelets, lipid profile parameters, hemoglobin level, platelet count, blood glucose, uric acid, aspartate aminotransferase, alanine aminotransferase, and the safety profile was considered under secondary outcomes.
| Statistical Analysis|| |
This study was restricted to systematic review only. Due to the presence of heterogeneity in terms of doses, treatment modalities, randomization, participant's inclusion criteria, duration of intervention, and follow-up, a meta-analysis was not feasible. Hence, this study is presented in the form of narrative synthesis. Review Manager (RevMan) v 5.3 was used for the risk of bias estimate.
| Results|| |
The search identified 531 articles, while three additional articles were identified through bibliographic searches for the initial screening. After removing the duplicates, 505 articles were screened based on the title and abstract, of which only 22 articles were assessed for eligibility based on full text. Finally, 12 articles were found eligible for inclusion in the analysis. [Figure 1] shows the study selection process.
| Study Description|| |
[Table 1] summarizes the characteristics of the 12 included RCTs: 10 studies,,,,,,,,, published as a full text and two studies, as an abstract. The studies were conducted between 2008 and 2017. Majority of the studies (7 studies) were single-center studies. The included studies were from Iran (6), the United States (2), Egypt (2), France (1), and Thailand (1).
The dose of nicotinamide varied across studies, with the majority of the studies using 500 mg/day as the initial dose. The duration of interventions varied from 4-24 weeks.
The 12 included RCTs,,,,,,,,,,, included 636 patients consisting of 318 patients in the nicotinamide group and 318 patients in the control group. The mean age of the included population was 47.72 ± 11.50 years. The mean calcium level was 6.60 ± 1.10 mg/dL and 9.084 ± 0.79 mg/dL, respectively, in the nicotinamide and the placebo groups. [Table 2] summarizes the baseline characteristics of the included studies.
| Assessment of Risk of Bias|| |
The risk of bias graph and summary is presented in [Figure 2]a and [Figure 2]b. Risk of bias assessment based on Cochrane risk of bias tool showed a low risk of bias in random sequence generation, allocation concealment, blinding of personnel and participants, blinding of outcome assessment, attrition bias, and selective reporting in the majority of the included studies.
| Evaluation of Efficacy|| |
Serum phosphorus In the nicotinamide-treated group, serum phosphorus level was significantly lower in all the included studies, while no significant change was observed in the control groups in all the studies except that of Lenglet et al (P <0.001) and Borolossy et al (P = 0.0001).
Serum calcium levels were significantly increased in only two of the studies in the nicotinamide-treated group, while no significant change was noticed in the control group except in the study of Lenglet et al (P = 0.014).
Serum Ca × P product
It was significantly lower in the nicotinamide-treated group as compared to the placebo group [Table 2].
Lipid profile such as LDL cholesterol was investigated in a total of 397 HD patients, of which 198 patients were in the treatment group, and 200 patients were in the control group at the end of the treatment period. No significant difference in LDL cholesterol level was noticed at the endpoint of the study in both the treatment group and in the control group except in the study by Lenglet et al, which showed a significant increase in LDL level in the treatment group. Similarly, for total cholesterol and triglycerides, no significant change was noticed at the endpoint of the study in the treatment group as well as in the control group. However, the HDL cholesterol level was significantly increased in the treatment group (P >0.05), while a non-significant effect was observed in the control group. Among other biochemical parameters such as intact PTH and platelet count, no significant change was noticed in the treatment group as well as in the placebo group (P >0.05).
| Evaluation of Safety|| |
Safety profile was assessed in all the studies except the study by Ahmadi et al. Flushing was the most common adverse event in the nicotinamide group as reported by Aramwit et al (1 patient), Nejad et al (3 patients), and Borolossyet et al (7 patients). Diarrhea as an adverse event was reported by a total of 20 patients in the included studies. Thrombocytopenia was reported by only two studies in the treatment group. Overall, the safety profile was tolerable and satisfactory.
| Discussion|| |
Nicotinamide (niacinamide or nicotinic amide) and nicotinic acid (or niacin) are the two forms of Vitamin B3. Through the process of amidation, niacin is converted to nicotinamide which is a key component of coenzyme nicotinamide adenine dinucleotide (NAD). Nicotinamide has been demonstrated as an alternative that can reduce the serum phosphate level in patients undergoing dialysis by lowering the absorption of phosphate from the GI tract. Preclinical studies in animals have demonstrated that nicotinamide inhibits the co-transporter NaPi2a in the renal proximal tubule and inhibits the expression of co-transporter NaPi2b in the intestine, causing a decreased serum phosphate levels.,,,
In this systematic review, we found that for patients undergoing HD, nicotinamide was effective in reducing the serum phosphate level with a tolerable safety profile.
Nicotinamide offers some unique advantages over other commonly used phosphate binders. It reduces the serum phosphate levels without inducing hypercalcemia in patients undergoing HD, is a relatively low cost, and does not necessitate the need to be administered with a meal. Hence, nicotinamide-mediated modulation of serum phosphate levels presents a new approach to control serum phosphate levels.
In this systematic review, the nicotinamide arm demonstrated a statistically significant reduction in mean serum phosphorous levels compared to the baseline, while no such reduction was observed in the placebo arm. Safety was also found to be satisfactory. Flushing and diarrhea were the most common adverse events observed in the nicotinamide group. Although we included 12 studies, considering the differences in the intervention (nicotinamide, niacin, calcium-based phosphate binder + nicotinamide, and nicotinic acid) and comparator (placebo, sevelamer, and calcium carbonate), variable treatment doses (25 mg daily to 1500 mg/day), duration (4–24 weeks), and study follow-up duration (4–24 weeks), we restricted our analysis to narrative synthesis only. However, similar findings were reported by a few recent meta-analyses assessing the efficacy of nicotinamide to control hyperphosphatemia in patients undergoing HD.,
This systematic review has a few limitations that should be considered. The first limitation is restricting the inclusion of English language studies only; second, two of the included studies were abstract only, and limited information was available to make any inference. Finally, a meta-analysis was not feasible because of the different doses and forms of nicotinamide and different forms of the drug in the comparator arm. The present study has several strengths; first, exhaustive literature search, including major conferences proceedings. Second, quality evaluation of the included studies was transparent, and the included studies were of low risk of bias.
| Conclusion|| |
Nicotinamide was found to be effective in reducing the phosphorous level and calcium–phosphorus product level and increasing the HDL cholesterol level in the HD patients. The safety profile was found to be satisfactory. Further research in the form of sufficiently powered RCTs to obtain conclusive evidence with a higher statistical power is welcome in this area.
Conflict of interest: None declared.
| References|| |
Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 2004; 15:2208-18.
Palmer SC, Hayen A, Macaskill P, 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.
Tentori F, Blayney MJ, Albert JM, Gillespie BW, Kerr PG, Bommer J, et al. Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: The Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2008;52:519-30.
Gotch FA, Panlilio F, Sergeyeva O, Rosales L, Folden T, Kaysen G, et al. A kinetic model of inorganic phosphorus mass balance in hemo-dialysis therapy. Blood Purif 2003;21:51-7.
Minutolo R, Bellizzi V, Cioffi M, Iodice C, Giannattasio P, Andreucci M, et al. Postdialytic rebound of serum phosphorus: Pathogenetic and clinical insights. J Am Soc Nephrol 2002;13:1046-54.
Delmez JA, Slatopolsky E, Martin KJ, Gearing BN, Harter HR. Minerals, vitamin D, and parathyroid hormone in continuous ambulatory peritoneal dialysis. Kidney Int 1982;21:862-7.
Ganesh SK, Stack AG, Levin NW, Hulbert-Shearon T, Port FK. Association of elevated serum PO4, Ca× PO4 product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol 2001;12:2131-8.
Mathew S, Tustison KS, Sugatani T, Chaudhary LR, Rifas L, Hruska KA. The mechanism of phosphorus as a cardiovascular risk factor in CKD. J Am Soc Nephrol 2008;19:1092-105.
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl 2009;(113):S1-130.
Bellasi A, Kooienga L, Block GA. Phosphate binders: New products and challenges. Hemodial Int 2006;10:225-34.
Coladonato JA. Control of hyperphosphatemia among patients with ESRD. J Am Soc Nephrol 2005;16 Suppl 2:S107-14.
Hutchison AJ, Smith CP, Brenchley PE. Pharmacology, efficacy and safety of oral phosphate binders. Nat Rev Nephrol 2011;7:578-89.
Tonelli M, Pannu N, Manns B. Oral phosphate binders in patients with kidney failure. N Engl J Med 2010;362:1312-24.
Hsu CH. Are we mismanaging calcium and phosphate metabolism in renal failure? Am J Kidney Dis 1997;29:641-9.
Ramirez JA, Emmett M, White MG, Fathi N, Santa Ana CA, Morawski SG, et al. The absorption of dietary phosphorus and calcium in hemodialysis patients. Kidney Int 1986;30:753-9.
Tzanakis IP, Papadaki AN, Wei M, Kagia S, Spadidakis VV, Kallivretakis NE, et al. Magnesium carbonate for phosphate control in patients on hemodialysis. A randomized controlled trial. Int Urol Nephrol 2008;40:193- 201.
Goodman WG. Vascular calcification in chronic renal failure. Lancet 2001;358:1115-6.
Schaefer K, Umlauf E, von Herrath D. Reduced risk of hypercalcemia for hemo-dialysis patients by administering calcitriol at night. Am J Kidney Dis 1992;19:460-4.
Malluche HH. Aluminium and bone disease in chronic renal failure. Nephrol Dial Transplant 2002;17 Suppl 2:21-4.
Manns B, Stevens L, Miskulin D, Owen WF Jr., Winkelmayer WC, Tonelli M. A systematic review of sevelamer in ESRD and an analysis of its potential economic impact in Canada and the United States. Kidney Int 2004;66:1239- 47.
Eto N, Miyata Y, Ohno H, Yamashita T. Nicotinamide prevents the development of hyperphosphataemia by suppressing intestinal sodium-dependent phosphate transporter in rats with adenine-induced renal failure. Nephrol Dial Transplant 2005;20:1378-84.
Katai K, Tanaka H, Tatsumi S, Fukunaga Y, Genjida K, Morita K, et al. Nicotinamide inhibits sodium-dependent phosphate cotransport activity in rat small intestine. Nephrol Dial Transplant 1999;14:1195-201.
Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Medicine 2009;6: e1000100.
Higgins JP, Altman DG, Gøtzsche PC, et al. Research methods & reporting-the Cochrane collaboration's tool for assessing risk of bias in randomised trials. Br Med J 2011;343:889.
Popay J, Roberts H, Sowden A, et al. Guidance on the conduct of narrative synthesis in systematic reviews. A product from the ESRC methods programme Version. 2006;1:b92.
Review Manager (RevMan) [Computer program]. Version 53 Copenhagen: The Nordic Cochrane Centre, The CochraneCollaboration; 2014.
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. [Full text]
Aramwit P, Srisawadwong R, Supasyndh O. Effectiveness and safety of extended-release nicotinic acid for reducing serum phosphorus in hemodialysis patients. J Nephrol 2012;25: 354-62.
Cheng SC, Young DO, Huang Y, Delmez JA, Coyne DW. A randomized, double-blind, placebo-controlled trial of niacinamide for reduction of phosphorus in hemodialysis patients. Clin J Am Soc Nephrol 2008;3:1131- 8.
Edalat-Nejad M, Zameni F, Talaiei A. The effect of niacin on serum phosphorus levels in dialysis patients. Indian J Nephrol 2012;22: 174-8.
] [Full text]
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;31:289-96.
El-Sharkawy M, El-Hamamsy M, Allam S, Ramadan A. Low dose nicotinamide as an adjunctive therapy to calcium carbonate for control of hyperphosphatemia in hemodialysis patients. Egypt J Hosp Med 2013;31:1-11.
Lenglet A, Liabeuf S, El Esper N, et al. Efficacy and safety of nicotinamide in haemodialysis patients: The NICOREN study. Nephrol Dial Transplant 2017;32:870-9.
Shahbazian H, Zafar Mohtashami A, Ghorbani A, 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.
Young DO, Cheng SC, Delmez JA, Coyne DW. The effect of oral niacinamide on plasma phosphorus levels in peritoneal dialysis patients. Perit Dial Int 2009;29:562-7.
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;26:239-43.
] [Full text]
Shahidi S, Sajjadieh S, Gholamrezaei A. Niacinamideamide for reduction of phosphorus in hemodialysis and peritoneal dialysis patients. A randomized, double-blind, placebo-controlled trial. Era Edta Congress 2011;48:84- 5.
Tayebi Kh, Etemadi J, Sephidmuy M, et al. The Effect of Nicotinamide in the Treatment of Hyperphosphatemia in Dialysis Patients; 2011.
Takahashi Y, Tanaka A, Nakamura T, et al. Nicotinamide suppresses hyperphosphatemia in hemodialysis patients. Kidney Int 2004;65: 1099-104.
Berndt TJ, Pfeifer JD, Knox FG, Kempson SA, Dousa TP. Nicotinamide restores phosphaturic effect of PTH and calcitonin in phosphate deprivation. Am J Physiol 1982;242:F447-52.
Kempson SA, Colon-Otero G, Ou SY, Turner ST, Dousa TP. Possible role of nicotinamide adenine dinucleotide as an intracellular regulator of renal transport of phosphate in the rat. J Clin Invest 1981;67:1347-60.
Zhang Y, Ma T, Zhang P. Efficacy and safety of nicotinamide on phosphorus metabolism in hemodialysis patients: A systematic review and meta-analysis. Medicine (Baltimore) 2018; 97:e12731.
Liu X, Yang R, Dai B, Zhang H, Wang J, Ma N. Nicotinic acid and related compounds: A meta-analysis of their use for hyperphosphatemia in dialysis patients. Medicine (Baltimore) 2018;97:e0117.
Department of Medicine, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi - 110 062
[Figure 1], [Figure 2]
[Table 1], [Table 2]