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A Randomized, Double-Blind, Placebo-Controlled Trial of
Niacinamide for Reduction of Phosphorus in Hemodialysis
Patients
Steven C. Cheng, Daniel O. Young, Yihung Huang, James A. Delmez, and
Daniel W. Coyne
Division of Nephrology, Washington University School of Medicine, St. Louis, Missouri
Background and objectives: Niacinamide inhibits intestinal sodium/phosphorus transporters and reduces serum phospho-
rus in open-label studies. A prospective, randomized, double-blind, placebo-controlled crossover trial was performed for
assessment of the safety and efficacy of niacinamide.
Design, setting, participants, & measurements: Hemodialysis patients with phosphorus levels >5.0 mg/dl were randomly
assigned to 8 wk of niacinamide or placebo, titrated from 500 to 1500 mg/d. After a 2-wk washout period, patients switched
to 8 wk of the alternative therapy. Vitamin D analogs and calcimimetics were held constant; phosphorus binders were not
changed unless safety criteria were met.
Results: Thirty-three patients successfully completed the trial. Serum phosphorus fell significantly from 6.26 to 5.47 mg/dl
with niacinamide but not with placebo (5.85 to 5.98 mg/dl). A concurrent fall in calcium-phosphorus product was seen with
niacinamide, whereas serum calcium, intact parathyroid hormone, uric acid, platelet, triglyceride, LDL, and total cholesterol
levels remained stable in both arms. Serum HDL levels rose with niacinamide (50 to 61 mg/dl but not with placebo. Adverse
effects were similar between both groups. Among patients who were >80% compliant, results were similar, although the
decrease in serum phosphorus with niacinamide was more pronounced (6.45 to 5.28 mg/dl) and the increase in HDL
approached significance (49 to 58 mg/dl).
Conclusions: In hemodialysis patients, niacinamide effectively reduces serum phosphorus when co-administered with
binders and results in a potentially advantageous increase in HDL cholesterol. Further study in larger randomized trials and
other chronic kidney disease populations is indicated.
Clin J Am Soc Nephrol ●●: ●●●-●●●, 2008. doi: 10.2215/CJN.04211007
E
levated serum phosphorus contributes to the develop-
ment of secondary hyperparathyroidism and renal os-
teodystrophy. In dialysis patients, hyperphosphatemia
can lead to metastatic calcifications and is associated with in-
creased cardiovascular mortality (1,2). The majority of dialysis
patients require dietary phosphorus restrictions and phosphate
binders to control serum phosphorus. Despite these measures,
most patients fail to achieve predialysis serum phosphorus
levels ⬍5.5 mg/dl (2,3).
Niacinamide (also known as nicotinamide) and niacin are the
principle forms of vitamin B3. Despite structural similarities
and equivalent nutritional properties, niacinamide and niacin
have differing actions and adverse effect profiles. Although
niacinamide can cause gastrointestinal discomfort and report-
edly lowers platelet counts, it does not cause flushing, which is
commonly seen with niacin (4,5). In vitro studies have shown
that niacinamide decreases phosphate uptake by inhibiting so-
dium/phosphorus co-transporters in the renal proximal tubule
(Na/Pi2a) and intestine (Na/Pi2b) (6 –9). An open-label study
of niacinamide in Japanese hemodialysis patients who were not
taking phosphorus binders found that dosages up to 1750
mg/d decreased serum phosphorus from 6.9 to 5.4 mg/dl (10).
In addition, HDL cholesterol increased and LDL cholesterol
declined during the 12 wk of treatment.
Dialysis patients in the United States have poorer phospho-
rus control and might benefit from the addition of niacinamide
to their binder regimen. To evaluate further the effect of oral
niacinamide in hemodialysis patients, we performed a prospec-
tive, randomized, double-blind, placebo-controlled, crossover
study of hyperphosphatemic hemodialysis patients. For assess-
ment of the additive effects of niacinamide to binder therapy,
patients were maintained on their binder regimen throughout
the study unless safety criteria for dosage titration were met.
Materials and Methods
Enrollment
This study was approved by the Human Studies Committee at Wash-
ington University School of Medicine and registered in a clinical trials
database (NCT00316472, http://www.clintrials.gov). Patients were re-
cruited at two urban dialysis units operated by Washington University
School of Medicine, Division of Nephrology, from February 2006
Received October 5, 2007. Accepted March 5, 2008.
Published online ahead of print. Publication date available at www.cjasn.org.
Correspondence: Dr. Steven Cheng, Washington University School of Medicine,
660 S. Euclid Avenue, Campus Box 8129, St. Louis, MO 63110. Phone: 314-362-
7211; Fax: 314-747-3743; E-mail: stcheng@im.wustl.edu
Copyright © 2008 by the American Society of Nephrology ISSN: 1555-9041/●●●●–0001
. Published on April 2, 2008 as doi: 10.2215/CJN.04211007CJASN ePress
through December 2006. Inclusion criteria were (1) age ⬎18 yr, (2)
capacity for informed consent, (3) on long-term hemodialysis ⬎90 d, (4)
stable dosage of phosphorus binder(s) during the previous 2-wk pe-
riod, and (5) serum phosphorus level ⱖ5.0 mg/dl on the most recent
monthly laboratory data. The criteria of a serum phosphorus ⱖ5.0
mg/dl was used to enroll patients who were within the acceptable
range of the current Kidney Disease Outcomes Quality Initiative
(KDOQI) recommendations (serum phosphorus ⬍5.5 mg/dl) but still
above the goal of normalizing serum phosphorus levels. Patients were
excluded for any of the following criteria: Pregnancy, history of liver
disease, active peptic ulcer disease, treatment with carbamazepine, on
niacin therapy, more than one missed hemodialysis session in the past
30 d, planned or expected surgical procedure in the ensuing 4 mo, or
residency at a nursing home or extended care facility where adminis-
tration of the study drug may not be appropriately given.
For exclusion of patients with isolated elevations in serum phospho-
rus, a 2-wk screening phase followed consent. Serum phosphorus was
measured before the first dialysis of both weeks. Patients were ran-
domly assigned when the average screening phosphorus was ⱖ5.0
mg/dl.
Study Medication and Randomization
Niacinamide powder was purchased from Spectrum Chemical Man-
ufacturing Corporation (New Brunswick, NJ). Identical capsules con-
taining 250 mg of niacinamide or placebo were manufactured by a
research pharmacist (Stephanie Porto, RPharm, Barnes-Jewish Hospi-
tal, St. Louis, MO). The research pharmacist also randomly assigned
patients and provided blinded bottles to the research staff for distribu-
tion. Bottles contained sufficient capsules for the next 2 wk on the basis
of the patient’s randomization order.
Study Design
The study was a crossover design (Figure 1). After successful screen-
ing, patients were randomly assigned to either placebo or niacinamide.
After 8 wk with forced dosage titration (described in the next section),
there was a 2-wk washout period, then 8 wk on the alternative therapy.
Serum calcium and phosphorus levels were measured weekly. Serum
albumin, intact parathyroid hormone (iPTH), uric acid, and complete
blood count were obtained at weeks 1, 9, 11, and 19. Additional com-
plete blood counts were drawn weeks 5 and 15 to monitor for throm-
bocytopenia. Lipid panels were drawn at weeks 1, 9, and 19. All
laboratory values were drawn before dialysis on the first dialysis
treatment of each week. Phosphorus binders, vitamin D, paricalcitol,
and cinacalcet were continued at the same dosage throughout the study
unless changes were necessary for patient safety.
Dosage Titration
Niacinamide or placebo was administered at a starting dosage of one
capsule (250 mg) twice daily. The dosage was increased to 500 mg (two
capsules) twice daily at week 3 and 750 mg (three capsules) twice daily
at week 5. When hypophosphatemia (⬍3.5 mg/dl) was present, the
previous dosage was continued. Titration resumed once the serum
phosphorus rose above 3.5 mg/dl. When consecutive serum phospho-
rus levels were ⬍3.0 mg/dl, study drug was decreased by two capsules
per day. Study drug dosage could also be decreased if patients had
adverse effects attributable to the study drug. The same dosage titration
occurred after washout, beginning in week 11. Pill counts were per-
formed at each dosage titration and at the completion of each study
arm.
Safety Stop Points
A decrease in phosphorus binders was permitted when serum phos-
phorus remained ⬍3.0 mg/dl despite a decrease in the dosage of study
drug. An increase in binders, in conjunction with dietary counseling,
was permitted when two consecutive phosphorus levels were ⬎7.0
mg/dl or the calcium-phosphorus product was ⬎70 mg
2
/dl
2
. When
phosphorus binder dosage was changed during the first arm of the
study, the new regimen was continued through the remainder of the
study.
Statistical Analyses
Statistical analysis was performed using two-sample paired-group t
test. The primary end point was the change in serum phosphorus from
the first to the last week of each arm. Predefined secondary end points
were the change in iPTH, calcium, calcium-phosphorus products, uric
acid, platelets, and lipid profile parameters (HDL, LDL, triglycerides).
An a priori power analysis, assuming an expected phosphorus differ-
ence of 1.0 mg/dl with an expected SD of 1.0 mg/dl, showed that 24
patients were needed to achieve 90% power at the 5% significance level.
For accounting for dropout and noncompliance, planned recruitment
was 40 patients. Upon completion of the study, primary and secondary
end points were evaluated for all patients, then repeated among com-
pliant patients, defined by ⱖ80% use of study pills during each arm.
Data Reporting
The results of this randomized, controlled trial are reported in com-
pliance with the guidelines established by the CONSORT statement
(11).
Results
Patient Population
A total of 42 patients underwent screening, and 33 were ran-
domly assigned into the trial. All 33 completed the 20-wk
study, and 25 of 33 were ⱖ80% compliant with medications by
pill counts (Figure 2). Patient characteristics are shown in Table
1, and baseline data are displayed in Table 2. Laboratory results
at the start and completion of placebo and niacinamide arms
are summarized in Table 3.
Dosing Characteristics
In accordance with our protocol, the dosages of vitamin D
analogs and calcimimetics were not changed for any patient
Figure 1. After a 2-wk screening phase, patients were randomly
assigned to 8 wk of niacinamide or placebo with titration from
250 to 750 mg twice daily. A 2-wk washout preceded the switch
from niacinamide to placebo or vice versa.
2 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol ●●: ●●●-●●●, 2008
during the study. All patients on vitamin D analogs were
treated with paricalcitol. Three patients had a change in phos-
phorus binders required by our safety stop points. Binders
were increased for one patient during placebo (lanthanum car-
bonate 1000 mg three times daily to 1500 mg three times daily)
and one patient during niacinamide (calcium acetate 1334 mg
three times daily to 2001 mg three times daily). One patient
required a decrease in binder at week 5 of the niacinamide arm
(sevelamer 2400 mg three times daily to 1600 mg three times
daily). Mean dosages of paricalcitol, calcimimetics, and phos-
phorus binders are contained in Table 1.
Changes in dialysis prescription were permitted to achieve
targets for dialysis adequacy as reflected by monthly KT/V.
Among the 31 patients on thrice-weekly hemodialysis, there
was no significant difference between KT/V during placebo
and niacinamide (1.60 versus 1.56, respectively; P ⫽ 0.44).
The two patients on hemodialysis four times per week had
an average KT/V of 1.1 during placebo and 1.06 during
niacinamide, also NS (P ⫽ 0.89).
Serum Phosphorus
Among all patients, treatment with placebo resulted in an
insignificant rise in serum phosphorus from 5.85 to 5.98 mg/dl
(P ⫽ 0.73). Treatment with niacinamide resulted in a significant
fall in serum phosphorus from 6.26 to 5.47 mg/dl (P ⫽ 0.02).
The change in serum phosphorus was significantly different
between the two groups: The mean change on placebo was
⫹0.13 mg/dl (95% confidence interval [CI] ⫺0.53 to 0.79 mg/
dl), whereas the mean change on niacinamide was ⫺0.79 mg/dl
(95% CI ⫺0.12 to ⫺1.46 mg/dl; P ⫽ 0.05; Figure 3). The largest
change in serum phosphorus occurred during the first 2 wk on
niacinamide, at a dosage of 250 mg twice daily. Phosphorus
levels fell from 6.26 to 5.76 mg/dl during this period but did
not reach statistical significance (P ⫽ 0.14). Dosage titration to
the maximum of 750 mg twice daily further reduced serum
phosphorus, with levels falling from 5.9 to 5.47 mg/dl during
the final 4 wk of the active arm.
Secondary End Points
The calcium-phosphorus product decreased significantly (59 to
52 mg
2
/dl
2
; P ⫽ 0.03) with niacinamide while increasing insig-
nificantly during placebo treatment (54 to 57 mg
2
/dl
2
; P ⫽
0.52). There were no significant changes in serum calcium
during either treatment arm. Calcium, iPTH, and uric acid
levels did not change in either arm, and there were no signifi-
cant differences in total cholesterol, triglycerides, or LDL cho-
lesterol between arms. HDL cholesterol rose from 50 to 61
mg/dl (P ⫽ 0.035) on niacinamide while remaining unchanged
on placebo (Figure 4).
Thrombocytopenia has been reported as an adverse effect
of niacinamide (4). In our study, the platelet count tended to
rise on placebo and fall on niacinamide (⫹9000 on placebo
versus ⫺17,000/mm
3
on niacinamide; P ⫽ 0.07). Although no
patients developed bleeding complications during the study,
nine had thrombocytopenia (platelet count ⬍150,000/mm
3
)
with niacinamide and five had thrombocytopenia on pla-
cebo. A platelet count of ⬍100,000/mm
3
was seen in one
patient on niacinamide and two patients on placebo. The
trend in platelet counts among patients with thrombocyto-
penia on niacinamide is shown in Table 4.
Adverse Effects
Two patients complained of diarrhea while receiving niacinamide,
one of whom had diarrhea before use of the study drug. This
patient had spontaneous resolution of his symptoms without a
reduction in dosage. The other had a dosage reduction from 750 to
Table 1. Patient characteristics (N ⫽ 33)
Characteristics % (n) Average Dosage
Gender
male 70 (23)
female 30 (10)
Ethnicity
black 85 (28)
white 15 (5)
Medications
acetylsalicylic acid 45 (15) 211 mg/d
clopidogrel bisulfate 6 (2) 75 mg/d
active vitamin D
(paricalcitol)
67 (22) 5.5
g/dialysis
calcimimetics 27 (9) 53 mg/d
Binder regimen
sevelamer
hydrochloride
76 (25) 7624 mg/d
lanthanum
carbonate
12 (4) 3000 mg/d
calcium carbonate 18 (6) 1775 mg/d
calcium acetate 27 (9) 5225 mg/d
Figure 2. After the 2-wk screening period, 33 patients were
enrolled in the study. All patients completed the study; 25
demonstrated compliance with the study regimen and were
included in the per-protocol analysis.
Clin J Am Soc Nephrol ●●: ●●●-●●●, 2008 Niacinamide for Hyperphosphatemia 3
500 mg twice daily with subsequent symptomatic improvement.
No diarrhea was reported during placebo therapy. One patient
complained of a rash on his abdomen during week 8 of nia-
cinamide, which resolved after 4 d. There were no reports of
flushing.
During the course of the study, eight patients were admitted
to the hospital. Four were admitted during the placebo arm
with diagnoses of osteoarthritis, septic arthritis, and volume
overload (two patients). On niacinamide, three patients were
admitted with diagnoses of volume overload, a nonhealing foot
ulcer, and osteomyelitis. The last patient was excluded in the
per-protocol analysis. One patient developed pneumonia dur-
ing the washout period. There were no deaths.
Per-Protocol Analysis
A total of 25 of the 33 patients were ⱖ80% compliant with the
study on the basis of pill counts and were assessed in the
per-protocol analysis. The results parallel the findings de-
scribed among the total study population (Table 5). Serum
phosphorus rose insignificantly (from 5.59 to 5.96 mg/dl; P ⫽
0.40) on placebo but decreased significantly from 6.45 to 5.28
Figure 3. Serum phosphorus levels rose during the 8 wk of the
placebo arm (solid line) but decreased significantly during
treatment with niacinamide (dotted line). Placebo n ⫽ 33;
niacinamide n ⫽ 33.
Table 2. Baseline data
Parameter Week 1 Placebo Week 1 Niacinamide P
Age (yr) 52.6 52.6
Duration on hemodialysis (yr) 4.4 4.4
Calcium (mg/dl) 9.35 9.39 0.81
Phosphorus (mg/dl) 5.85 6.26 0.27
iPTH (pg/ml) 288 291 0.96
Uric acid (mg/dl) 7.15 7.25 0.80
Platelet count (1000/mm
3
) 216 216 0.97
Total cholesterol (mg/dl) 142 142 0.92
LDL (mg/dl) 57 63 0.46
HDL (mg/dl) 55 50 0.30
Triglycerides (mg/dl) 145 146 0.96
Table 3. Summary of laboratory findings
Parameter
Placebo Arm Niacinamide Arm
Week 1 Week 9 P Week 1 Week 9 P
Phosphorus (mg/dl) 5.85 ⫾ 1.67 5.98 ⫾ 1.40 NS 6.26 ⫾ 1.28
a
5.47 ⫾ 1.49
a
0.02
a
Calcium (mg/dl) 9.35 ⫾ 0.57 9.52 ⫾ 0.76 NS 9.39 ⫾ 0.72 9.45 ⫾ 0.70 NS
Calcium-phosphorus product
(mg
2
/dl
2
)
54.47 ⫾ 14.80 56.73 ⫾ 13.22 NS 58.72 ⫾ 12.42
a
51.56 ⫾ 13.48
a
0.02
a
iPTH (pg/ml) 288 ⫾ 240 280 ⫾ 222 NS 291 ⫾ 240 296 ⫾ 195 NS
Uric acid (mg/dl) 7.15 ⫾ 1.67 6.88 ⫾ 1.56 NS 7.25 ⫾ 1.56 6.81 ⫾ 1.50 NS
Total cholesterol (mg/dl) 142 ⫾ 30 141 ⫾ 32 NS 142 ⫾ 30 150 ⫾ 28 NS
LDL (mg/dl) 57 ⫾ 21 59 ⫾ 29 NS 63 ⫾ 29 60 ⫾ 25 NS
HDL (mg/dl) 55 ⫾ 19 53 ⫾ 20 NS 50 ⫾ 17
a
61 ⫾ 21
a
0.04
a
TG (mg/dl) 145 ⫾ 74 145 ⫾ 86 NS 146 ⫾ 70 150 ⫾ 84 NS
Platelet (1000/mm
3
) 216 ⫾ 68 225 ⫾ 57 NS 216 ⫾ 53 199 ⫾ 55 NS
a
Values changed significantly.
4 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol ●●: ●●●-●●●, 2008
mg/dl (P ⫽ 0.002) with niacinamide. There was a statistically
significant difference between the mean change in serum phos-
phorus on placebo (⫹0.37 mg/dl; 95% CI ⫺0.37 to 1.11 mg/dl)
and the mean change on niacinamide (⫺1.17 mg/dl; 95% CI
⫺0.52 to ⫺1.82 mg/dl; P ⫽ 0.002; Figure 5). As expected, there
was a concomitant fall in the calcium phosphorus product with
niacinamide, from 61 to 51 mg
2
/dl
2
(P ⫽ 0.003); serum calcium
remained stable. Neither serum calcium nor calcium-phospho-
rus product changed significantly during placebo therapy.
iPTH and uric acid levels remained the same in both arms.
The compliant subset showed no change in total cholesterol,
triglycerides, or LDL during either arm, but HDL levels after
treatment with niacinamide approached significance (49 to
58 mg/dl; P ⫽ 0.07) while remaining unchanged in the
placebo arm. During the 8-wk study period, the platelet
count in the compliant subset fell from 214,000 to 197,000
(P ⫽ 0.10) during niacinamide. Among patients with throm-
bocytopenia described in Table 4, only patients 2 and 8 were
⬍80% compliant with the study regimen.
Discussion
The two major forms of vitamin B
3
are niacin (or nicotinic acid)
and its amide, niacinamide, also known as nicotinamide. Be-
cause niacinamide serves as a central component of nicotin-
amide adenine dinucleotide and nicotinamide adenine dinucle-
otide phosphate, it plays an important role in sustaining several
crucial metabolic processes. As such, supplementation may be
useful over a broad range of metabolic disorders. In the clinical
setting, niacinamide is used primarily for the treatment of acne
and pellagra; however, niacinamide has also been studied in
insulin-dependent diabetes, where it may preserve pancreatic

cells (12), and ischemia-reperfusion injury, where it inhibits
nitric oxide synthase (13). Niacinamide may mediate a variety
of protective mechanisms through downregulation of TNF-
␣
(14), increased free radical scavenging (15), and inhibition of
poly-ADP-ribose synthetase, an emerging target for cardiovas-
cular disease and cancer (16). Niacinamide is now known to
inhibit sodium/phosphorous transport in both renal and intes-
tinal brush borders, stimulating interest in its use for phospho-
rus reduction among patients with chronic kidney disease.
In large, multicenter studies, elevated serum phosphorus has
been associated with an increase in morbidity and mortality in
patients with ESRD (1,17,18). Hyperphosphatemia is linked to
cardiovascular risk as well as bone disease (19,20), and the
hyperphosphatemic milieu may promote vascular calcification
through cellular changes in vascular smooth muscle cells (21).
Previous open-label studies by Takahashi et al. (10) and Sam-
pathkumar et al. (22) demonstrated that niacinamide lowers
serum phosphorus levels in maintenance hemodialysis patients
when traditional binding agents are withheld. This study is the
first randomized, double-blind, placebo-controlled study to as-
sess the effectiveness of niacinamide on phosphorus reduction
in conjunction with phosphorus binders.
Table 4. Platelet counts in patients with thrombocytopenia during niacinamide
a
Patient
Niacinamide Arm
Follow-up
Week 1 Week 5 Week 9
1 145
b
297 267 Completed study
2 105
b
167 169 Completed study
3 135
b
127
b
137
b
Placebo arm counts: 135, 98, 111
4 123
b
116
b
132
b
Placebo arm counts: 99, 109, 122
5 176 106
b
185 Placebo arm counts: 288, 206, 340
6 196 106
b
61
b
Completed study
7 204 150 144
b
Completed study
8 244 229 141
b
Placebo arm counts: 240, 274, 310
9 284 250 110
b
Completed study
a
Patients 10 through 33 had no episodes of thrombocytopenia during treatment with niacinamide. Three patients (in
addition to patients 3 and 4) had thrombocytopenia during the placebo arm.
b
Platelet counts of ⬍150.
Figure 4. Effect of niacinamide on HDL cholesterol levels is
shown in both randomization schemes. Among all patients,
HDL cholesterol levels increased significantly on niacinamide
(50 to 61 mg/dl; P ⫽ 0.035). Placebo n ⫽ 33; niacinamide n ⫽ 33.
Clin J Am Soc Nephrol ●●: ●●●-●●●, 2008 Niacinamide for Hyperphosphatemia 5
After 8 wk of therapy, patients in our study had a statistically
and clinically significant drop in serum phosphorus and calci-
um-phosphorus product, whereas serum calcium and uric acid
levels remained unchanged. The reduction in serum phospho-
rus and calcium-phosphorus product was more pronounced in
the compliant subgroup analysis. The fall in phosphorus was
most notable during the initial 2-wk period, which was associ-
ated with highest serum phosphorus levels and the lowest
dosage (250 mg twice daily) of niacinamide; however, levels
continued to decrease through the titration to 750 mg twice
daily. Phosphorus levels may have continued to fall without
titration to higher dosages, and further studies comparing dif-
ferent dosages for longer time periods are needed to address
this issue.
The effect of niacinamide on HDL levels was somewhat
surprising. Although niacin is known to increase serum HDL,
previous reports suggested that in normal and hyperlipidemic
individuals, niacinamide does not have similar effects on lipid
metabolism (23,24). Although a detailed mechanism for their
distinctive actions has yet to be understood, a nicotinic acid
(niacin) receptor that binds niacin but not the nutritionally
equivalent amide form, niacinamide, has been characterized
(25,26). The effects of these compounds in uremic individuals is
even less well studied; however, Takahashi et al. (10) reported
that niacinamide raised HDL from 47 to 67 mg/dl (P ⬍ 0.0001)
and lowered LDL from 79 to 70 mg/dl (P ⬍ 0.01) in Japanese
patients on hemodialysis. Our study demonstrated an increase
in HDL of 11 mg/dl (a 21.5% increase) with niacinamide,
although no LDL-lowering effect was seen. The kinetics of the
HDL changes could not be characterized because lipid panels
were drawn only at the start and completion of the treatment
arms. Of note, most patients in our study were concomitantly
treated with sevelamer, which lowers LDL via bile acid binding
(27,28). This may obscure further lipid lowering by niacinamide.
The cumulative effect of niacinamide on lipid metabolism
observed in our study may have important benefits in
chronic kidney disease and dialysis patients and warrants
further investigation.
Niacinamide seems to be well tolerated in the general pop-
ulation (29). Even at our maximum daily dosage of 1500 mg,
there were no major adverse effects. Only one patient (of 33)
required a dosage adjustment because of diarrhea, which re-
solved when niacinamide was decreased from 1500 to 1000
mg/d. This is in marked contrast to a report by Delanaye et al.
(5) that noted the occurrence of diarrhea in five of six patients
enrolled in an open-label trial of the safety and efficacy of
niacinamide. The symptoms from that report began at a mean
niacinamide dosage of 1050 ⫾ 447 mg and resolved after drug
cessation. Patients in that study were on calcium-based and/or
sevelamer-based binder regimens. The authors speculated that
co-administration of phosphorus binders with niacinamide
may have contributed to the severe diarrhea, because a much
lower percentage of patients (7.8%) in Takahashi’s cohort de-
Table 5. Per-protocol analysis
Parameter
Placebo Arm Niacinamide Arm
Week 1 Week 9 P Week 1 Week 9 P
Phosphorus (mg/dl) 5.59 ⫾ 1.53 5.96 ⫾ 1.54 NS 6.45 ⫾ 1.33 5.28 ⫾ 1.22 0.002
Calcium (mg/dl) 9.41 ⫾ 0.58 9.60 ⫾ 0.73 NS 9.47 ⫾ 0.71 9.58 ⫾ 0.64 NS
Calcium-phosphorus product
(mg
2
/dl
2
)
52.47 ⫾ 14.26 57.02 ⫾ 14.88 NS 61.00 ⫾ 12.88 50.54 ⫾ 11.46 0.003
iPTH (pg/ml) 296 ⫾ 182 277 ⫾ 219 NS 305 ⫾ 254 311 ⫾ 194 NS
Uric acid (mg/dl) 6.95 ⫾ 1.77 6.67 ⫾ 1.67 NS 7.01 ⫾ 1.67 6.70 ⫾ 1.56 NS
Total cholesterol (mg/dl) 139 ⫾ 29 134 ⫾ 27 NS 137 ⫾ 27 143 ⫾ 26 NS
LDL (mg/dl) 56 ⫾ 21 54 ⫾ 28 NS 58 ⫾ 27 55 ⫾ 22 NS
HDL (mg/dl) 52 ⫾ 17 50 ⫾ 17 NS 49 ⫾ 16 58 ⫾ 20 0.070
TG (mg/dl) 153 ⫾ 73 148 ⫾ 80 NS 150 ⫾ 73 157 ⫾ 84 NS
Platelet (1000/mm
3
) 214 ⫾ 72 224 ⫾ 59 NS 214 ⫾ 52 197 ⫾ 56 NS
Figure 5. Serum phosphorus is represented by the solid line
during the placebo arm and the dotted line during niaci-
namide. Among compliant patients, a more pronounced dif-
ference was noted in the change in serum phosphorus be-
tween placebo and niacinamide (⫹0.37 on placebo versus
⫺1.17 mg/dl on niacinamide; P ⫽ 0.002). Placebo n ⫽ 25;
niacinamide n ⫽ 25.
6 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol ●●: ●●●-●●●, 2008
veloped diarrhea when niacinamide was administered alone
(10). In our study, 76% were on concurrent sevelamer hydro-
chloride, 12% were on lanthanum carbonate, and 45% were on
calcium-based binders, and only 6% (two of 33) of the total
study population and 8% (two of 25) of the compliant subset
complained of diarrhea. No patients were removed from the
study, and there were no deaths during the study period.
Hospitalizations were roughly equivalent between the two
groups, with all admissions related to underlying comorbidities
and not the administration of niacinamide. Hospitalization may
also transiently affect serum phosphorus levels and confound
results; however, when hospitalized patients are removed from
the per-protocol analysis, a significant change in phosphorus
during niacinamide treatment is still noted (6.6 to 5.2 mg/dl;
P ⬍ 0.05), whereas phosphorus remains unchanged during
placebo.
Thrombocytopenia has been a concern from previous stud-
ies of niacinamide, and our analysis did find a trend toward
decreasing platelet counts on niacinamide. Nevertheless, no
clinical manifestations of thrombocytopenia complicated the
administration of study drug in our study. The mechanism
by which niacinamide may decrease platelet counts is not
fully understood. Studies with nicotinic acid suggested that
thrombocytopenia may be mediated through a decrease in
thyroxin-binding globulin (4). Although clinical manifesta-
tions did not occur during our study period, further inves-
tigation is warranted to evaluate the effect of niacinamide on
platelets for a longer period of administration. For now,
monitoring for thrombocytopenia in dialysis patients on ni-
acinamide is prudent.
This study supports the usefulness of niacinamide in hemo-
dialysis patients with hyperphosphatemia. Furthermore, it
seems to be well tolerated, and its effect on serum HDL levels
is particularly appealing for a population at high risk for car-
diovascular disease. As demonstrated here, niacinamide can be
used in conjunction with phosphorus binders, although it does
not need to be administered with meals. A recent study found
that niaspan (prolonged-release niacin) also reduced phospho-
rus and raised HDL levels in dialysis patients after washout
from calcium-based binders (30). Although both forms of vita-
min B
3
have now shown favorable effects on lipid and phos-
phorus levels, they are clinically distinguished by distinct dif-
ferences in adverse effects. Flushing remains an important
limitation to the titration of niacin in some patients, whereas
further studies are needed to evaluate niacinamide’s effect on
platelet counts.
Conclusions
This randomized, double-blind, placebo-controlled, crossover
trial demonstrates that niacinamide is effective in controlling
serum phosphorus when co-administered with phosphorus
binders in patients on hemodialysis. Moreover, niacinamide
increased serum HDL levels. The combination of phosphorus
reduction with a beneficial change in lipid profiles makes ni-
acinamide an attractive agent for further investigation and use
for patients who are on maintenance hemodialysis.
Acknowledgments
D.O.Y. received support for this study through the Amgen Fellow-
ship Support Stipend during the 2006 to 2007 academic year.
Disclosures
None.
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