Binder Blinders—Niacin of Omission?
2010; Elsevier BV; Volume: 55; Issue: 4 Linguagem: Inglês
10.1053/j.ajkd.2009.12.015
ISSN1523-6838
Autores Tópico(s)Folate and B Vitamins Research
ResumoIt is common knowledge to every schoolboy and even every Bachelor of Arts,That all sin is divided into two parts.One kind of sin is called a sin of commission, and that is very important,And it is what you are doing when you are doing something you ortant,And the other kind of sin is just the opposite and is called a sin of omissionand is equally bad in the eyes of all right-thinking people, fromBilly Sunday to Buddha,And it consists of not having done something you shuddha … .From Ogden Nash, “Portrait of the Artist as Prematurely Old Man”1Nash O. Portrait of the artist as prematurely old man.in: Smith L.N. The Best of Ogden Nash. 3rd ed. Ivan R. Dee, Chicago, IL2007: 366Google Scholar Recently, 2 clarion calls for phosphorus-lowering trials in patients with stages 3b-4 chronic kidney disease (CKD), complete with “blueprints” for their conduct, were published,2Block G.A. Persky M.S. Ketteler M. et al.A randomized double-blind pilot study of serum phosphorus normalization in chronic kidney disease: a new paradigm for clinical outcomes studies in nephrology.Hemodial Int. 2009; 13: 260-262Crossref Scopus (18) Google Scholar, 3Isakova T. Gutiérrez O.M. Wolf M. A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease.Kidney Int. 2009; 76: 705-716Crossref PubMed Scopus (94) Google Scholar followed by an extensive set of clinical practice guidelines from KDIGO (Kidney Disease: Improving Global Outcomes) for the diagnosis, evaluation, prevention, and treatment of CKD–mineral and bone disorder (CKD-MBD).4KDIGO 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 (doi:10.1038/ki.2009.197): S121-S130Google Scholar Despite compilation of nearly 650 references,2Block G.A. Persky M.S. Ketteler M. et al.A randomized double-blind pilot study of serum phosphorus normalization in chronic kidney disease: a new paradigm for clinical outcomes studies in nephrology.Hemodial Int. 2009; 13: 260-262Crossref Scopus (18) Google Scholar, 3Isakova T. Gutiérrez O.M. Wolf M. A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease.Kidney Int. 2009; 76: 705-716Crossref PubMed Scopus (94) Google Scholar, 4KDIGO 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 (doi:10.1038/ki.2009.197): S121-S130Google Scholar citations of the clinical phosphorus-lowering effects of niacin compounds, reported consistently during more than a decade,5Shimoda K. Akiba T. Matsushima T. Rai T. Abe K. Hoshino M. Niceritrol decreases serum phosphate levels in chronic hemodialysis patients.Nippon Jinzo Gakkai Shi. 1998; 40: 1-7Crossref PubMed Google Scholar, 6Sampathkumar K. Sooraj Y. Mahaldar A.R. Ramakrishnan M. Comparative efficiency of low dose nicotinic acid and lanthanum in lowering the phosphorus levels in hemodialysis patients [S-PO-0327].in: World Congress of Nephrology, Rio de Janeiro, BrazilApril 21-25, 2007Google Scholar, 7Sampathkumar K. Niacin and analogs for phosphate control in dialysis—perspective from a developing country.Int Urol Nephrol. 2009; 41: 813-918Crossref Scopus (13) Google Scholar, 8Knopp R.H. Alagona P. Davidson M. et al.Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia.Metabolism. 1998; 47: 1097-1104Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 9Capuzzi D.M. Guyton J.R. Morgan J.M. et al.Efficacy and safety of an extended-release niacin (Niaspan): a long-term study.Am J Cardiol. 1998; 82: 74U-81UAbstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 10Guyton J.R. Blazing M.A. Hagar J. et al.Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol.Arch Intern Med. 2000; 160: 1177-1184Crossref PubMed Scopus (164) Google Scholar, 11Maccubbin D. Bays H.E. Olson G. et al.Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolemia or mixed dyslipidaemia.Int J Clin Pract. 2008; 62: 1959-1970Crossref PubMed Scopus (122) Google Scholar, 12Kuboyama N. Watanabe Y. Yamaguchi M. Sato K. Suzuki T. Akiba T. Effects of niceritrol on faecal and urinary phosphate excretion in normal rats.Nephrol Dial Transplant. 1999; 14: 610-614Crossref PubMed Scopus (22) Google Scholar, 13Katai K. Tanaka H. Tatsumi S. et al.Nicotinamide inhibits sodium-dependent phosphate cotransport activity in rat small intestine.Nephrol Dial Transplant. 1999; 14: 1195-1201Crossref PubMed Scopus (99) Google Scholar, 14Eto N. Miyata Y. Ohno H. Yamashita T. Nicotinamide prevents the development of hyperphosphatemia by suppressing the intestinal sodium dependent phosphate transporter in rats with adenine induced renal failure.Nephrol Dial Transplant. 2005; 20: 1378-1384Crossref PubMed Scopus (116) Google Scholar, 15Sabbagh Y. O'Brien S.P. Song W. et al.Intestinal Npt2b plays a major role in phosphate absorption and homeostasis.J Am Soc Nephrol. 2009; 20: 2348-2358Crossref PubMed Scopus (262) Google Scholar, 16Shahapuni I. Rahmouni K. Arrar B. Harbouche L. Esper N. Fournier A. Greater cost effectiveness of nicotinamide compared with that of sevelamer for controlling hyperphosphatemia in dialysis patients [S-PO-0311].in: World Congress of Nephrology, Rio de Janeiro, BrazilApril 22, 2007Google Scholar were omitted. A January 1998 report described the hypophosphatemic impact of niceritrol, the esterified niacin pro-drug.5Shimoda K. Akiba T. Matsushima T. Rai T. Abe K. Hoshino M. Niceritrol decreases serum phosphate levels in chronic hemodialysis patients.Nippon Jinzo Gakkai Shi. 1998; 40: 1-7Crossref PubMed Google Scholar Niceritrol administered at 250 mg 3 times daily to 10 hemodialysis patients for 8 weeks decreased mean serum phosphorus concentrations from a baseline of 6.2 ± 0.4 (standard error) to 4.4 ± 0.3 mg/dL. Serum calcium concentrations did not change. Between September and December 1998, two dyslipidemia treatment efficacy and safety studies of an extended-release niacin preparation administered at 1.5-3.0 g/d reported 7%-8% decreases in serum phosphorus concentrations (within the normative range) in a total of 301 patients actively treated.8Knopp R.H. Alagona P. Davidson M. et al.Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia.Metabolism. 1998; 47: 1097-1104Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 9Capuzzi D.M. Guyton J.R. Morgan J.M. et al.Efficacy and safety of an extended-release niacin (Niaspan): a long-term study.Am J Cardiol. 1998; 82: 74U-81UAbstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar One of these trials8Knopp R.H. Alagona P. Davidson M. et al.Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia.Metabolism. 1998; 47: 1097-1104Abstract Full Text PDF PubMed Scopus (209) Google Scholar also included data from 74 patients receiving crystalline (instant release) niacin at up to a total of 3 g/d (in 3 divided doses), and these individuals evidenced the same mean percentage of decrease (−7.6%) in serum phosphorus levels as those treated with extended-release niacin. Patients with stages 4 and 5 CKD (ie, estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) were excluded from these8Knopp R.H. Alagona P. Davidson M. et al.Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia.Metabolism. 1998; 47: 1097-1104Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 9Capuzzi D.M. Guyton J.R. Morgan J.M. et al.Efficacy and safety of an extended-release niacin (Niaspan): a long-term study.Am J Cardiol. 1998; 82: 74U-81UAbstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar and subsequent10Guyton J.R. Blazing M.A. Hagar J. et al.Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol.Arch Intern Med. 2000; 160: 1177-1184Crossref PubMed Scopus (164) Google Scholar, 11Maccubbin D. Bays H.E. Olson G. et al.Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolemia or mixed dyslipidaemia.Int J Clin Pract. 2008; 62: 1959-1970Crossref PubMed Scopus (122) Google Scholar extended-release niacin trials, consistently showing that niacin's hypophosphatemic effect8Knopp R.H. Alagona P. Davidson M. et al.Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia.Metabolism. 1998; 47: 1097-1104Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 9Capuzzi D.M. Guyton J.R. Morgan J.M. et al.Efficacy and safety of an extended-release niacin (Niaspan): a long-term study.Am J Cardiol. 1998; 82: 74U-81UAbstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 10Guyton J.R. Blazing M.A. Hagar J. et al.Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol.Arch Intern Med. 2000; 160: 1177-1184Crossref PubMed Scopus (164) Google Scholar, 11Maccubbin D. Bays H.E. Olson G. et al.Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolemia or mixed dyslipidaemia.Int J Clin Pract. 2008; 62: 1959-1970Crossref PubMed Scopus (122) Google Scholar was not confined to end-stage renal disease (ESRD) and occurred across the entire range of GFRs, including CKD stages 3-1 (30 to ≥ 90 mL/min/1.73 m2). Animal model data highlight a plausible mechanism for the observed phosphate-lowering effects of niacin preparations.12Kuboyama N. Watanabe Y. Yamaguchi M. Sato K. Suzuki T. Akiba T. Effects of niceritrol on faecal and urinary phosphate excretion in normal rats.Nephrol Dial Transplant. 1999; 14: 610-614Crossref PubMed Scopus (22) Google Scholar, 13Katai K. Tanaka H. Tatsumi S. et al.Nicotinamide inhibits sodium-dependent phosphate cotransport activity in rat small intestine.Nephrol Dial Transplant. 1999; 14: 1195-1201Crossref PubMed Scopus (99) Google Scholar, 14Eto N. Miyata Y. Ohno H. Yamashita T. Nicotinamide prevents the development of hyperphosphatemia by suppressing the intestinal sodium dependent phosphate transporter in rats with adenine induced renal failure.Nephrol Dial Transplant. 2005; 20: 1378-1384Crossref PubMed Scopus (116) Google Scholar, 15Sabbagh Y. O'Brien S.P. Song W. et al.Intestinal Npt2b plays a major role in phosphate absorption and homeostasis.J Am Soc Nephrol. 2009; 20: 2348-2358Crossref PubMed Scopus (262) Google Scholar About 50% of net phosphate absorption occurs in the duodenum and jejunum through an active transport pathway through the epithelial sodium-phosphate (Na-Pi) cotransporters contained in abundantly expressed “ready to use” vesicles located within the small-intestinal brush border.7Sampathkumar K. Niacin and analogs for phosphate control in dialysis—perspective from a developing country.Int Urol Nephrol. 2009; 41: 813-918Crossref Scopus (13) Google Scholar, 13Katai K. Tanaka H. Tatsumi S. et al.Nicotinamide inhibits sodium-dependent phosphate cotransport activity in rat small intestine.Nephrol Dial Transplant. 1999; 14: 1195-1201Crossref PubMed Scopus (99) Google Scholar The energy required for this active phosphate transport is provided by the basolateral adenosine triphosphatase sodium-potassium pump (Na+-K+-ATPase).7Sampathkumar K. Niacin and analogs for phosphate control in dialysis—perspective from a developing country.Int Urol Nephrol. 2009; 41: 813-918Crossref Scopus (13) Google Scholar, 14Eto N. Miyata Y. Ohno H. Yamashita T. Nicotinamide prevents the development of hyperphosphatemia by suppressing the intestinal sodium dependent phosphate transporter in rats with adenine induced renal failure.Nephrol Dial Transplant. 2005; 20: 1378-1384Crossref PubMed Scopus (116) Google Scholar Eto et al14Eto N. Miyata Y. Ohno H. Yamashita T. Nicotinamide prevents the development of hyperphosphatemia by suppressing the intestinal sodium dependent phosphate transporter in rats with adenine induced renal failure.Nephrol Dial Transplant. 2005; 20: 1378-1384Crossref PubMed Scopus (116) Google Scholar showed in a rat model of ESRD that nicotinamide inhibits expression of the type IIb sodium-dependent phosphate cotransporter (NaPi-2b; also known as Npt2b and encoded by the Slc34a2 gene), which decreased phosphate absorption and prevented the progressive increase in serum phosphate levels associated with renal failure. Previous studies of healthy rats had shown independently that nicotinamide inhibited sodium-dependent intestinal phosphate cotransport,13Katai K. Tanaka H. Tatsumi S. et al.Nicotinamide inhibits sodium-dependent phosphate cotransport activity in rat small intestine.Nephrol Dial Transplant. 1999; 14: 1195-1201Crossref PubMed Scopus (99) Google Scholar whereas niceritrol increased fecal (but not urinary) phosphate excretion.12Kuboyama N. Watanabe Y. Yamaguchi M. Sato K. Suzuki T. Akiba T. Effects of niceritrol on faecal and urinary phosphate excretion in normal rats.Nephrol Dial Transplant. 1999; 14: 610-614Crossref PubMed Scopus (22) Google Scholar Very recently, Sabbagh et al15Sabbagh Y. O'Brien S.P. Song W. et al.Intestinal Npt2b plays a major role in phosphate absorption and homeostasis.J Am Soc Nephrol. 2009; 20: 2348-2358Crossref PubMed Scopus (262) Google Scholar further elucidated the role of gut phosphate active transport and showed its comparable inhibition with an inducible conditional mouse active phosphate transporter knockout model, or intraperitoneal nicotinamide (niacinamide) administration to wild-type animals. The normal increase in serum phosphorus levels observed 30 minutes after a phosphorus gavage bolus was diminished by ∼50% in wild-type animals treated with niacinamide compared with that in untreated mice.15Sabbagh Y. O'Brien S.P. Song W. et al.Intestinal Npt2b plays a major role in phosphate absorption and homeostasis.J Am Soc Nephrol. 2009; 20: 2348-2358Crossref PubMed Scopus (262) Google Scholar In contrast, niacinamide had no effect on Npt2b−/− (active phosphate transporter knockout) animals. Moreover, niacinamide administration decreased the serum phosphorus surge in wild-type animals to the same degree as that observed by deleting Npt2b. These data support the hypothesis that niacinamide mediates (acute) inhibition of intestinal phosphate transport through Npt2b.15Sabbagh Y. O'Brien S.P. Song W. et al.Intestinal Npt2b plays a major role in phosphate absorption and homeostasis.J Am Soc Nephrol. 2009; 20: 2348-2358Crossref PubMed Scopus (262) Google Scholar Abnormalities in calcium-phosphorus homeostasis, including significant increases in serum phosphorus concentrations, are believed to contribute to arterial stiffening, hypertension, and cardiovascular disease (CVD) risk in patients with advanced CKD and ESRD requiring maintenance dialysis therapy.2Block G.A. Persky M.S. Ketteler M. et al.A randomized double-blind pilot study of serum phosphorus normalization in chronic kidney disease: a new paradigm for clinical outcomes studies in nephrology.Hemodial Int. 2009; 13: 260-262Crossref Scopus (18) Google Scholar, 3Isakova T. Gutiérrez O.M. Wolf M. A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease.Kidney Int. 2009; 76: 705-716Crossref PubMed Scopus (94) Google Scholar, 4KDIGO 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 (doi:10.1038/ki.2009.197): S121-S130Google Scholar Marked hyperphosphatemia in ESRD and the very increased phosphorus concentrations of advanced (ie, stage 4) CKD have both been associated with the development of CVD, particularly fatal outcomes.2Block G.A. Persky M.S. Ketteler M. et al.A randomized double-blind pilot study of serum phosphorus normalization in chronic kidney disease: a new paradigm for clinical outcomes studies in nephrology.Hemodial Int. 2009; 13: 260-262Crossref Scopus (18) Google Scholar, 3Isakova T. Gutiérrez O.M. Wolf M. A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease.Kidney Int. 2009; 76: 705-716Crossref PubMed Scopus (94) Google Scholar, 4KDIGO 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 (doi:10.1038/ki.2009.197): S121-S130Google Scholar Additional reports from high-CVD-risk populations—myocardial infarction survivors2Block G.A. Persky M.S. Ketteler M. et al.A randomized double-blind pilot study of serum phosphorus normalization in chronic kidney disease: a new paradigm for clinical outcomes studies in nephrology.Hemodial Int. 2009; 13: 260-262Crossref Scopus (18) Google Scholar, 3Isakova T. Gutiérrez O.M. Wolf M. A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease.Kidney Int. 2009; 76: 705-716Crossref PubMed Scopus (94) Google Scholar and hypertensive patients with type 2 diabetes2Block G.A. Persky M.S. Ketteler M. et al.A randomized double-blind pilot study of serum phosphorus normalization in chronic kidney disease: a new paradigm for clinical outcomes studies in nephrology.Hemodial Int. 2009; 13: 260-262Crossref Scopus (18) Google Scholar—have described linear associations between serum phosphorus concentrations within the normative range and arteriosclerotic outcomes, especially recurrent fatal CVD events. Observational data from population-based studies further suggest that normative serum phosphorus concentrations are linearly associated with measures of subclinical arteriosclerosis and the development of incident CVD outcomes.2Block G.A. Persky M.S. Ketteler M. et al.A randomized double-blind pilot study of serum phosphorus normalization in chronic kidney disease: a new paradigm for clinical outcomes studies in nephrology.Hemodial Int. 2009; 13: 260-262Crossref Scopus (18) Google Scholar, 3Isakova T. Gutiérrez O.M. Wolf M. A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease.Kidney Int. 2009; 76: 705-716Crossref PubMed Scopus (94) Google Scholar, 4KDIGO 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 (doi:10.1038/ki.2009.197): S121-S130Google Scholar Such observational data2Block G.A. Persky M.S. Ketteler M. et al.A randomized double-blind pilot study of serum phosphorus normalization in chronic kidney disease: a new paradigm for clinical outcomes studies in nephrology.Hemodial Int. 2009; 13: 260-262Crossref Scopus (18) Google Scholar, 3Isakova T. Gutiérrez O.M. Wolf M. A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease.Kidney Int. 2009; 76: 705-716Crossref PubMed Scopus (94) Google Scholar, 4KDIGO 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 (doi:10.1038/ki.2009.197): S121-S130Google Scholar have engendered calls2Block G.A. Persky M.S. Ketteler M. et al.A randomized double-blind pilot study of serum phosphorus normalization in chronic kidney disease: a new paradigm for clinical outcomes studies in nephrology.Hemodial Int. 2009; 13: 260-262Crossref Scopus (18) Google Scholar, 3Isakova T. Gutiérrez O.M. Wolf M. A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease.Kidney Int. 2009; 76: 705-716Crossref PubMed Scopus (94) Google Scholar for controlled clinical trials to test the hypothesis that serum phosphorus-lowering treatment primarily will decrease CVD mortality. Two very prominent blueprints for such trials recently were published,2Block G.A. Persky M.S. Ketteler M. et al.A randomized double-blind pilot study of serum phosphorus normalization in chronic kidney disease: a new paradigm for clinical outcomes studies in nephrology.Hemodial Int. 2009; 13: 260-262Crossref Scopus (18) Google Scholar, 3Isakova T. Gutiérrez O.M. Wolf M. A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease.Kidney Int. 2009; 76: 705-716Crossref PubMed Scopus (94) Google Scholar targeting patients within specific eGFR ranges of stages 3-4 CKD (15-44 and 20-45 mL/min/1.73 m2). Both these communications referenced the major commercial phosphorus binders sevelamer, calcium acetate, and lanthanum. One communication2Block G.A. Persky M.S. Ketteler M. et al.A randomized double-blind pilot study of serum phosphorus normalization in chronic kidney disease: a new paradigm for clinical outcomes studies in nephrology.Hemodial Int. 2009; 13: 260-262Crossref Scopus (18) Google Scholar included the description of a pilot intervention study using each binder as a prelude to an outcome intervention, and the other3Isakova T. Gutiérrez O.M. Wolf M. A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease.Kidney Int. 2009; 76: 705-716Crossref PubMed Scopus (94) Google Scholar provided a formal sample size and power calculation for a placebo-controlled phosphate-binder study, dependent on as yet undetermined entry concentrations of the phosphatonin fibroblast growth factor 23 (FGF-23)3Isakova T. Gutiérrez O.M. Wolf M. A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease.Kidney Int. 2009; 76: 705-716Crossref PubMed Scopus (94) Google Scholar and assuming a 20% decrease in mortality with active treatment. However, as noted at the outset, neither trial rationalization blueprint2Block G.A. Persky M.S. Ketteler M. et al.A randomized double-blind pilot study of serum phosphorus normalization in chronic kidney disease: a new paradigm for clinical outcomes studies in nephrology.Hemodial Int. 2009; 13: 260-262Crossref Scopus (18) Google Scholar, 3Isakova T. Gutiérrez O.M. Wolf M. A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease.Kidney Int. 2009; 76: 705-716Crossref PubMed Scopus (94) Google Scholar referenced any of the published literature5Shimoda K. Akiba T. Matsushima T. Rai T. Abe K. Hoshino M. Niceritrol decreases serum phosphate levels in chronic hemodialysis patients.Nippon Jinzo Gakkai Shi. 1998; 40: 1-7Crossref PubMed Google Scholar, 6Sampathkumar K. Sooraj Y. Mahaldar A.R. Ramakrishnan M. Comparative efficiency of low dose nicotinic acid and lanthanum in lowering the phosphorus levels in hemodialysis patients [S-PO-0327].in: World Congress of Nephrology, Rio de Janeiro, BrazilApril 21-25, 2007Google Scholar, 7Sampathkumar K. Niacin and analogs for phosphate control in dialysis—perspective from a developing country.Int Urol Nephrol. 2009; 41: 813-918Crossref Scopus (13) Google Scholar, 8Knopp R.H. Alagona P. Davidson M. et al.Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia.Metabolism. 1998; 47: 1097-1104Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 9Capuzzi D.M. Guyton J.R. Morgan J.M. et al.Efficacy and safety of an extended-release niacin (Niaspan): a long-term study.Am J Cardiol. 1998; 82: 74U-81UAbstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 10Guyton J.R. Blazing M.A. Hagar J. et al.Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol.Arch Intern Med. 2000; 160: 1177-1184Crossref PubMed Scopus (164) Google Scholar, 11Maccubbin D. Bays H.E. Olson G. et al.Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolemia or mixed dyslipidaemia.Int J Clin Pract. 2008; 62: 1959-1970Crossref PubMed Scopus (122) Google Scholar, 12Kuboyama N. Watanabe Y. Yamaguchi M. Sato K. Suzuki T. Akiba T. Effects of niceritrol on faecal and urinary phosphate excretion in normal rats.Nephrol Dial Transplant. 1999; 14: 610-614Crossref PubMed Scopus (22) Google Scholar, 13Katai K. Tanaka H. Tatsumi S. et al.Nicotinamide inhibits sodium-dependent phosphate cotransport activity in rat small intestine.Nephrol Dial Transplant. 1999; 14: 1195-1201Crossref PubMed Scopus (99) Google Scholar, 14Eto N. Miyata Y. Ohno H. Yamashita T. Nicotinamide prevents the development of hyperphosphatemia by suppressing the intestinal sodium dependent phosphate transporter in rats with adenine induced renal failure.Nephrol Dial Transplant. 2005; 20: 1378-1384Crossref PubMed Scopus (116) Google Scholar, 15Sabbagh Y. O'Brien S.P. Song W. et al.Intestinal Npt2b plays a major role in phosphate absorption and homeostasis.J Am Soc Nephrol. 2009; 20: 2348-2358Crossref PubMed Scopus (262) Google Scholar, 16Shahapuni I. Rahmouni K. Arrar B. Harbouche L. Esper N. Fournier A. Greater cost effectiveness of nicotinamide compared with that of sevelamer for controlling hyperphosphatemia in dialysis patients [S-PO-0311].in: World Congress of Nephrology, Rio de Janeiro, BrazilApril 22, 2007Google Scholar for the phosphorus-lowering efficacy of niacin compounds. Extant publications of the phosphorus-lowering impact of niacin compounds on patients with ESRD5Shimoda K. Akiba T. Matsushima T. Rai T. Abe K. Hoshino M. Niceritrol decreases serum phosphate levels in chronic hemodialysis patients.Nippon Jinzo Gakkai Shi. 1998; 40: 1-7Crossref PubMed Google Scholar, 6Sampathkumar K. Sooraj Y. Mahaldar A.R. Ramakrishnan M. Comparative efficiency of low dose nicotinic acid and lanthanum in lowering the phosphorus levels in hemodialysis patients [S-PO-0327].in: World Congress of Nephrology, Rio de Janeiro, BrazilApril 21-25, 2007Google Scholar, 7Sampathkumar K. Niacin and analogs for phosphate control in dialysis—perspective from a developing country.Int Urol Nephrol. 2009; 41: 813-918Crossref Scopus (13) Google Scholar, 16Shahapuni I. Rahmouni K. Arrar B. Harbouche L. Esper N. Fournier A. Greater cost effectiveness of nicotinamide compared with that of sevelamer for controlling hyperphosphatemia in dialysis patients [S-PO-0311].in: World Congress of Nephrology, Rio de Janeiro, BrazilApril 22, 2007Google Scholar (7Sampathkumar K. Niacin and analogs for phosphate control in dialysis—perspective from a developing country.Int Urol Nephrol. 2009; 41: 813-918Crossref Scopus (13) Google Scholar reviews 7 independent reports from 1998-2008) including once-daily extended-release niacin6Sampathkumar K. Sooraj Y. Mahaldar A.R. Ramakrishnan M. Comparative efficiency of low dose nicotinic acid and lanthanum in lowering the phosphorus levels in hemodialysis patients [S-PO-0327].in: World Congress of Nephrology, Rio de Janeiro, BrazilApril 21-25, 2007Google Scholar, 7Sampathkumar K. Niacin and analogs for phosphate control in dialysis—perspective from a developing country.Int Urol Nephrol. 2009; 41: 813-918Crossref Scopus (13) Google Scholar show niacin's hypophosphatemic effects to be of the same magnitude achieved using calcium acetate, sevelamer, or lanthanum when these agents are administered thrice daily and timed requisitely to meals.2Block G.A. Persky M.S. Ketteler M. et al.A randomized double-blind pilot study of serum phosphorus normalization in chronic kidney disease: a new paradigm for clinical outcomes studies in nephrology.Hemodial Int. 2009; 13: 260-262Crossref Scopus (18) Google Scholar, 3Isakova T. Gutiérrez O.M. Wolf M. A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease.Kidney Int. 2009; 76: 705-716Crossref PubMed Scopus (94) Google Scholar, 4KDIGO 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 (doi:10.1038/ki.2009.197): S121-S130Google Scholar These data include a pilot 4-week comparison study of low-dose extended-release niacin versus lanthanum.6Sampathkumar K. Sooraj Y. Mahaldar A.R. Ramakrishnan M. Comparative efficiency of low dose nicotinic acid and lanthanum in lowering the phosphorus levels in hemodialysis patients [S-PO-0327].in: World Congress of Nephrology, Rio de Janeiro, BrazilApril 21-25, 2007Google Scholar As reported by Sampathkumar et al,6Sampathkumar K. Sooraj Y. Mahaldar A.R. Ramakrishnan M. Comparative efficiency of low dose nicotinic acid and lanthanum in lowering the phosphorus levels in hemodialysis patients [S-PO-0327].in: World Congress of Nephrology, Rio de Janeiro, BrazilApril 21-25, 2007Google Scholar age- and sex-matched Indian patients with ESRD undergoing twice-weekly hemodialysis achieved at least the same phosphorus lowering as that attained using lanthanum treatment in the only direct comparison study available. Similar findings were reported from the only direct comparison of niacin (administered as nicotinamide, a major circulating niacin metabolite) and the binder sevelamer in patients with ESRD.16Shahapuni I. Rahmouni K. Arrar B. Harbouche L. Esper N. Fournier A. Greater cost effectiveness of nicotinamide compared with that of sevelamer for controlling hyperphosphatemia in dialysis patients [S-PO-0311].in: World Congress of Nephrology, Rio de Janeiro, BrazilApril 22, 2007Google Scholar During a 6-month open-label crossover study, mean doses of 720 mg/d of nicotinamide versus 3,200 mg/d of sevelamer afforded the same phosphorus control in hemodialysis patients.16Shahapuni I. Rahmouni K. Arrar B. Harbouche L. Esper N. Fournier A. Greater cost effectiveness of nicotinamide compared with that of sevelamer for controlling hyperphosphatemia in dialysis patients [S-PO-0311].in: World Congress of Nephrology, Rio de Janeiro, BrazilApril 22, 2007Google Scholar Other published findings from sizable clinical trials using once-daily extended-release niacin8Knopp R.H. Alagona P. Davidson M. et al.Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia.Metabolism. 1998; 47: 1097-1104Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 9Capuzzi D.M. Guyton J.R. Morgan J.M. et al.Efficacy and safety of an extended-release niacin (Niaspan): a long-term study.Am J Cardiol. 1998; 82: 74U-81UAbstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 10Guyton J.R. Blazing M.A. Hagar J. et al.Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol.Arch Intern Med. 2000; 160: 1177-1184Crossref PubMed Scopus (164) Google Scholar, 11Maccubbin D. Bays H.E. Olson G. et al.Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolemia or mixed dyslipidaemia.Int J Clin Pract. 2008; 62: 1959-1970Crossref PubMed Scopus (122) Google Scholar are germane to the design of phosphorus-lowering interventions in patients with CKD, notably those that might focus on patients with stages 3-4 CKD (eGFRs of 15-59 mL/min/1.73 m2) before the development of ESRD (stage 5 CKD; eGFR < 15 mL/min/1.73 m2) and imminent or ongoing dialysis dependence. In stark contrast, very limited data are available from small brief studies of lanthanum, sevelamer, or calcium acetate administered to patients with stages 3 and 4 CKD.2Block G.A. Persky M.S. Ketteler M. et al.A randomized double-blind pilot study of serum phosphorus normalization in chronic kidney disease: a new paradigm for clinical outcomes studies in nephrology.Hemodial Int. 2009; 13: 260-262Crossref Scopus (18) Google Scholar, 3Isakova T. Gutiérrez O.M. Wolf M. A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease.Kidney Int. 2009; 76: 705-716Crossref PubMed Scopus (94) Google Scholar, 4KDIGO 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 (doi:10.1038/ki.2009.197): S121-S130Google Scholar Although thrice-daily lanthanum treatment3Isakova T. Gutiérrez O.M. Wolf M. A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease.Kidney Int. 2009; 76: 705-716Crossref PubMed Scopus (94) Google Scholar, 4KDIGO 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 (doi:10.1038/ki.2009.197): S121-S130Google Scholar may achieve phosphorus lowering similar to that shown for once-daily extended-release niacin,8Knopp R.H. Alagona P. Davidson M. et al.Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia.Metabolism. 1998; 47: 1097-1104Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 9Capuzzi D.M. Guyton J.R. Morgan J.M. et al.Efficacy and safety of an extended-release niacin (Niaspan): a long-term study.Am J Cardiol. 1998; 82: 74U-81UAbstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 10Guyton J.R. Blazing M.A. Hagar J. et al.Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol.Arch Intern Med. 2000; 160: 1177-1184Crossref PubMed Scopus (164) Google Scholar, 11Maccubbin D. Bays H.E. Olson G. et al.Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolemia or mixed dyslipidaemia.Int J Clin Pract. 2008; 62: 1959-1970Crossref PubMed Scopus (122) Google Scholar both sevelamer (up to 6.4 g/d) and calcium acetate (up to 5.28 g/d) failed to decrease serum phosphorus levels in a pilot study of 19 patients with CKD with a mean creatinine clearance of 36.8 mL/min and baseline serum phosphorus concentrations of 3.3-3.4 mg/dL.3Isakova T. Gutiérrez O.M. Wolf M. A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease.Kidney Int. 2009; 76: 705-716Crossref PubMed Scopus (94) Google Scholar Moreover, given the onerous pill burden thrice-daily phosphorus-binder treatment imposes on patients with ESRD,17Chiu Y.W. Teitelbaum I. Misra M. de Leon E.M. Adzize T. Mehrotra R. Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients.Clin J Am Soc Nephrol. 2009; 4: 1089-1096Crossref PubMed Scopus (407) Google Scholar severely limiting their treatment adherence,17Chiu Y.W. Teitelbaum I. Misra M. de Leon E.M. Adzize T. Mehrotra R. Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients.Clin J Am Soc Nephrol. 2009; 4: 1089-1096Crossref PubMed Scopus (407) Google Scholar it is an uncertain proposition that patients with less advanced asymptomatic stages 3-4 CKD will comply adequately with binders. Finally, in light of the secondary CVD prevention data from the crystalline niacin arm of the Coronary Drug Project,18Canner P.L. Berge K.G. Wenger N.K. et al.Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin.J Am Coll Cardiol. 1986; 8: 1245-1255Abstract Full Text PDF PubMed Scopus (1594) Google Scholar, 19Canner P.L. Furberg C.D. Terrin M.L. McGovern M.E. Benefits of niacin by glycemic status in patients with healed myocardial infarction (from the Coronary Drug Project).Am J Cardiol. 2005; 95: 254-257Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar the established ameliorative effects of extended-release niacin on lipoprotein metabolism8Knopp R.H. Alagona P. Davidson M. et al.Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia.Metabolism. 1998; 47: 1097-1104Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 9Capuzzi D.M. Guyton J.R. Morgan J.M. et al.Efficacy and safety of an extended-release niacin (Niaspan): a long-term study.Am J Cardiol. 1998; 82: 74U-81UAbstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 10Guyton J.R. Blazing M.A. Hagar J. et al.Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol.Arch Intern Med. 2000; 160: 1177-1184Crossref PubMed Scopus (164) Google Scholar, 11Maccubbin D. Bays H.E. Olson G. et al.Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolemia or mixed dyslipidaemia.Int J Clin Pract. 2008; 62: 1959-1970Crossref PubMed Scopus (122) Google Scholar and the systematic under-representation of patients with eGFR < 60 mL/min in randomized controlled trials to decrease CVD outcomes,20Coca S.G. Krumholz H.M. Garg A.X. Parikh C.R. Under-representation of renal disease in randomized controlled trials of cardiovascular disease.JAMA. 2006; 296: 1377-1384Crossref PubMed Scopus (342) Google Scholar the data for niacin presented here5Shimoda K. Akiba T. Matsushima T. Rai T. Abe K. Hoshino M. Niceritrol decreases serum phosphate levels in chronic hemodialysis patients.Nippon Jinzo Gakkai Shi. 1998; 40: 1-7Crossref PubMed Google Scholar, 6Sampathkumar K. Sooraj Y. Mahaldar A.R. Ramakrishnan M. Comparative efficiency of low dose nicotinic acid and lanthanum in lowering the phosphorus levels in hemodialysis patients [S-PO-0327].in: World Congress of Nephrology, Rio de Janeiro, BrazilApril 21-25, 2007Google Scholar, 7Sampathkumar K. Niacin and analogs for phosphate control in dialysis—perspective from a developing country.Int Urol Nephrol. 2009; 41: 813-918Crossref Scopus (13) Google Scholar, 8Knopp R.H. Alagona P. Davidson M. et al.Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia.Metabolism. 1998; 47: 1097-1104Abstract Full Text PDF PubMed Scopus (209) Google Scholar, 9Capuzzi D.M. Guyton J.R. Morgan J.M. et al.Efficacy and safety of an extended-release niacin (Niaspan): a long-term study.Am J Cardiol. 1998; 82: 74U-81UAbstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 10Guyton J.R. Blazing M.A. Hagar J. et al.Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol.Arch Intern Med. 2000; 160: 1177-1184Crossref PubMed Scopus (164) Google Scholar, 11Maccubbin D. Bays H.E. Olson G. et al.Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolemia or mixed dyslipidaemia.Int J Clin Pract. 2008; 62: 1959-1970Crossref PubMed Scopus (122) Google Scholar, 16Shahapuni I. Rahmouni K. Arrar B. Harbouche L. Esper N. Fournier A. Greater cost effectiveness of nicotinamide compared with that of sevelamer for controlling hyperphosphatemia in dialysis patients [S-PO-0311].in: World Congress of Nephrology, Rio de Janeiro, BrazilApril 22, 2007Google Scholar suggest that an extended-release niacin treatment arm deserves the utmost consideration for any future CVD prevention trials targeting patients with stages 3-5 CKD. Financial Disclosure: The author declares that he has no relevant financial interests. New Evidence for the Phosphorus-Lowering Effects of NiacinAmerican Journal of Kidney DiseasesVol. 56Issue 1PreviewThe April issue of the American Journal of Kidney Diseases included 2 editorials on niacin: my contention that niacin's omission from the recent KDIGO (Kidney Disease: Improving Global Outcomes) bone guideline was unjustified,1 and a rejoinder from Moorthi et al2 arguing that the evidence for its inclusion was inadequate. I have 2 brief comments regarding the points raised by Moorthi et al. First, niacin compounds—niacin (short or long acting), niceritrol, and niacinamide—are not “phosphate binders.” Indeed, their elegant phosphorus-lowering mechanism does not require multiple dosing, high pill burden regimens timed requisitely to meal ingestion, precisely because niacin compounds do not simply trap food-bound phosphorus liberated in the gut. Full-Text PDF
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