INTRODUCTION:

Hyperphosphatemia is a serious and common biochemical abnormality that affected almost patients undergoing maintenance hemodialysis (HD)¹, it defined as an abnormally high serum phosphate concentration of >1.46 mmol/L².

Kidneys have a major role in maintaining phosphate homoeostasis through urinary excretion of excess phosphate³. However, the phosphatehomeostasis is lost in hemodialysis patients with the continues decline in the functional nephrons leading to persistence hyperphosphatemia⁴. Hyperphosphatemia has independent association with high risk of mortality in HD patients⁵. Studies had shown that relative risk of death increased by 27% with serum phosphorus >2 mmol/L among chronic dialysis patients⁶. This high mortality rate is mainly related to CVD that have an incremental risk associated with elevated serum phosphorus ranging from 10- 200-fold in those populations^7,8. The mechanism linking hyperphosphatemia to cardiovascular mortality is vascular calcificationthat it is promoted by elevated serum phosphorus level⁹. The role of hyperphosphatemia in the pathogenesis of vascular calcification includethe association in the osteogenic genes expression, apoptosis induction of endothelial cells and formation of calcium X phosphate product in the presence of high calcium (Ca2+) concentration that deposited in the vessels during calcification process^10,11. It was indicated that for every 10 units increase in the Ca X P product, there was 7% increase in the relative risk of death in dialysis patients¹².

The control of hyperphosphatemia remains a major challenge in spite of new phosphate binder introduction and improvements in the quality of dialysis¹³. All currently available phosphate binders have requirement for dosing with each meals, therefore they are contributed to high pill burden that may reduce patient compliance¹⁴. Calcium-based binders preferred to be avoided at present time due to high risk of vascular classification associated with their use¹⁵. However the expensiveness and relative high treatment cost of non-calcium based binder represent the major drawbacks in their use mainly in developing countries¹⁴. Thus, new therapies or adjunctive compounds that increase the effectiveness of treatment and/or minimize associated side effects, well-tolerated, and cost-effective is of particular attention¹³.

Niacin also known as vitamin B3, is a naturally occurring water-soluble vitamin that is essential in different biological activities and redox reactions¹⁶, also it is the first antidyslipidemic drug used since more than 50 years ago^17,18. Niacin has been demonstrated to show therapeutic potential in the treatment of hyperphosphatemia in HD patients. However, it decreases phosphorus absorption in the GIT, thereby lowering serum phosphorus level¹⁸.The potential advantages of niacin over others phosphate binders in that it is typically administered once or twice/ day with no need to be taken at the meal time, offering a more flexible dosing regimen with a low pill burden that may increase patient compliance¹⁹. Furthermore, its availability in many generic formulations that provides a cost-effective treatment compared to the expensive non-calcium based binders¹⁹. Thus, niacin appears to be a promising agent for treating hyperphosphatemia in HD patients with distinct mechanism of action²⁰.

This study is designed to evaluate the effect of adding niacin to one of the phosphate binder, sevelamer carbonate, for treating hyperphosphatemia in HD patients.

PATIENTS AND METHODS:

A prospective, randomized clinical trial was conducted to evaluate the effect of adding niacin to sevelamer in hemodialytic patients with hyperphosphatemia. A total of 55 patients were selected from the dialysis center of Al- Karama teaching hospital and only 39 enrolled in the study. A written informed consent was obtained from all subjects before participation. Patients were eligible to study if they were aged 18-60 years on a constant program of maintenance HD (thrice weekly ) for more than six months, who had serum phosphorus levels >5mg/dL, and receiving a stable dosage of phosphate binder (sevelamer carbonate) during the previous two weeks prior to study. The exclusion criteria were patients with +ve hepatitis C virus or active liver disease, patients with DM, patients with diagnosed peptic ulcer disease, also pregnant and lactating women, and patients with active malignancy, as well as patients allergic to any of the study medications.

Eligible patients were allocated randomly into two groups: group (1); 19 patients treated with 800mg sevelamer carbonate tablets (as a phosphate binder), thrice daily²¹, and group (2); 20 patients treated with 800mg sevelamer carbonate tablets (as a phosphate binder), thrice daily plus 500 mg niacin (extend release tablet) once daily²², both for 2 months duration.

Niacin was administered at a starting dose of 500mg once daily at night for one week, at week 2 it was increased to be 1000mg at bedtime and continued till the end of the study to ensure tolerance²². Patients were advised to take 100mg aspirin 30 minutes before niacin in case of flush symptom, and sevelamer carbonate were administered with meals^23,21. Clinical outcomes were evaluated by measuring serum levels of the study parameters (inorganic phosphorus (Pi), calcium (Ca), calcium-phosphorus product (Ca x P) at baseline, after 1 month and at the end of treatment after 2 months^24-26. The study was approved by the scientific and ethical committee at college of pharmacy/Mustansiriyah University. The agreement of Al-karama teaching hospital was achieved according to the Iraqi ministry of health’s' ethical committee.

RESULTS:

Fifty five patients were initially enrolled this trial but only 39 patients completed the 2 months of study and were included in the final analysis. The mean values of gender, age, BMI, and duration of symptoms between the study group's patients were statistically non-significant differences.

Table 1: Patient’s demographic data and disease characteristics

Variable	Group 1	Group 2	P value
Gender	n (%)	n (%)
Male	8 (42.1)	11 (55)
Female	11 (57.9)	9 (45)	0.42^NS
Total	19 (100)	20 (100)
Age (year)	48.2 (12.77)	49.1 (14.11)	0.85^NS
BMI(kg/m²)	24.16 (2.88)	25.98 (3.94)	0.17^NS
Duration (years)
<1	4 (21.1)	5 (25)
1-5	15 (78.9)	14 (70)	0.57^NS
>1	0 0	1 (5)

Number of patients (n), Percentage (%), NS: No significant differences (P>0.05). One way anova is used for statistical analysis of (age, BMI). Chi-square test is used for statistical analysis of (gender, duration of symptoms).

Study results showed that there was a statistically high significant difference in the level of Pi between both groups throughout the study period after 1 and 2 months (P˂0.01), andhigh significant reduction within each group after two months of treatment (P˂0.01) in respect to the baseline levels. Table (2), figure (1).

A non-significant change in serum Ca levels was demonstrated after each period interval of treatment between the study groups (P˃0.05) compared to pre-treatment level. While after 2 months of treatment, there was a notable difference in serum Ca level in both groups compared to baseline, nevertheless, was not significant (P ˃0.05). Table (3), figure (2).

The changes in serum (Ca x P) level showed a significant difference between groups 1 and 2 patients throughout the whole study intervals (P˂0.05) compared to the pre-treatment level. Treatment with combination of sevelamer and niacin resulted in higher significant reduction in serum (Ca x P) product level after 2 months of treatment than with sevelamer alone compared to baseline as showed in table (4), figure (3).

Table (2): Effect of phosphate binder alone and in combination with niacin on serum inorganic phosphorus level.

Variable	Study groups
Pi (mmol/L)	Group 1	Group 2	P value
Adjusted baseline	2.66	2.66
After 1 month	2.32±0.042	2.12±0.041	0.001^**
After 2 month	2.20±0.058	1.86±0.057	0.001^**
P-value	0.001^**	0.001^**

Data expressed as mean ±SEM (standard error of mean). ** Highly Significant difference (P<0.01). One way ANCOVA test used to compare pre or post treatment between group 1 and group 2 patients. Paired t-test used to compare between pre- and post-treatment results in same group.

Table (3): Effect of phosphate binder alone and in combination with niacin on serum calcium level

Variable	Study groups
Ca (mmol/L)	Group 1	Group 2	P value
Adjusted baseline mean	2.09	2.09
After 1 month	2.07±0.044	2.08±0.036	0.7^NS
After 2 mounth	2.1±0.072	2.07±0.059	0.6^NS
P-value	0.09^NS	0.07^NS

Data expressed as mean ±SEM (standard error of mean), Ca: serum calcium level. NS: Not significant (P>0.05), one way ANCOVA test used to compare pre or post treatment between group 1 and group 2 patients. Paired t-test used to compare between pre- and post-treatment results in same group.

Table (4): Effect of phosphate binder alone and in combination with niacin on serum calcium-phosphorus product level

Variable	Study groups
Pi (mmol/L)	Group 1	Group 2	P value
Adjusted baseline mean	5.6	5.6
After 1 month	4.62±0.133	4.27±0.136	0.04*
After 2 mounth	4.15±0. 264	3.49±0.270	0.05*
P-value	0.02*	0.001**

Data expressed as mean ±SEM. * Significant difference (P≤0.05). ** Highly Significant difference (P<0.01). One way ANCOVA test used to compare pre or post treatment between group 1 and group 2 patients. Paired t-test used to compare between pre- and post-treatment results in same group.

Figure (1): Effect of phosphate binder alone and in combination with niacin on serum inorganic phosphorus Level.

Figure (2): Effect of phosphate binder alone and in combination with niacin on serum calcium level.

Figure (3): Effect of phosphate binder alone and in combination with niacin on serum calcium-phosphorus product.

DISCUSSION:

The present study and other study revealed that hemodialysis patients of both genders have higher phosphorus serum level with slight predominance towards female patients in this study and others²⁷, or towards male patients in other study²⁸. Regarding to the age, hyperphosphatemic patients tended to be younger in the current study with a mean age 48.2 years in group 1 and 49.1 years in group 2, comparable results were found in other studies where hyperphosphatemia was inversely correlated with age in dialysis population, Salhab et al. (2019), and Mohamed Koya et al. (2019), reported a mean of age 48.8 and 46 years, respectively^{29, 30}. This association can be attributed to the reduced in renal phosphate reabsorption and increased under nutrition with age²⁷. Most patients in the present study were slightly underweight among the study groups where BMI ˂25 kg/m², a similar finding has been found in other study³¹.Meanwhile,another study by Gray et al. (2019) reported a high BMI values among hyperphosphatemic patients' on maintenance hemodialysis³². Majority of patients in the current study presented with duration of hemodialysis between 1-5 years while only 1 patient presented with duration of more than 5years.

Hyperphosphatemia have been shown to be associated with increased risk of cardiovascular mortality, and considered the “silent killer” for HD patients³³. The risk of death increased by 18% with each 0.323 mmol/L increase in the phosphorus level³⁴. Cardiovascular mortality risk is mainly due to vascular calcification that promoted and induced by high serum phosphate levels, elevated (Ca x P) product, and high calcium serum level ⁸. The risk of death due to CVD in HD patients is about 10 to 30 times than general population³⁵.

In the present study, the patients who administered oral niacin as adjuvant to sevelamer had the superiority over using sevelamer alone in the reduction of both serum phosphorus level and (Ca x P) product level (-30%,-37% respectively). Meanwhile, no statistically significant difference observed in serum calcium level (P ˃0.05). In line with these results, Zahed et al. (2016), in a study on dialysis patients, reported a significant reduction in the level of serum phosphorus after 8 weeks use of niacin³⁶. Furthermore, previous study by Ahmadi et al. (2012) stated that the level of both serum phosphorus and (Ca X P) product dropped significantly in HD patients after 4-weeks treatment with niacin²¹. On the other hand, these two studies showed that the reduction of serum phosphorus level by niacin was achieved without significant change in serum calcium level^36,21, that is in consistence with the current study. More recently, a study by Khalid et al. (2019), demonstrated that serum phosphorus level decreased significantly after 4 weeks with low dose niacin therapy (100mg/day) on HD patients³⁷. While the exact mode of action remains unknown, the observed reduction in serum phosphorus level is mostly attributed to the decreasing effect of niacin to the active transport-mediated phosphorus absorption in GIT³⁸. Hence, niacin seems to have mechanistic basis distinct from the traditional phosphate binders.

In vitro and in vivo studies have indicated that niacin can suppress the sodium-dependent intestinal phosphate absorption through inhibiting the expression of phosphate co-transporter (NaPi2b) in the brush border of intestine^39,40. The intestinal NaPi2b co-transporter has been shown to be responsible for up to 50% of total phosphate uptake⁴¹. In addition numerous animal in vitro studies observed that administration of niacin (or its metabolite nicotinamide) was associated with a decrease in renal co-transporter (NaPi2a) level with noticeable increase in renal phosphate excretion^42,43. The intestinal NaPi2b found to be strongly upregulated as a compensatory mechanism in response to situations of phosphate depletion like using of phosphate binder or phosphate dietary restriction⁴⁴. Therefore inhibition of NaPi2b activities can provide greater phosphate controlling efficacy in patients when adding to phosphate binders⁴⁵. This may explain why niacin treated group appeared to be more effective in lowering serum phosphate concentrations in the current study.

CONCLUSION:

The effect of niacin to suppress the sodium-dependent intestinal phosphate absorption, and thereafter serum phosphate and calcium-phosphorus product levels was obvious in this study. Using niacin as adjuvant therapy to conventional phosphate binder for hemodialysis patients is a promising strategy to reduce the prospective risks of both hyperphosphatemia and long term use of phosphate binder.

ACKNOWLEDGEMENT:

The authors would like to thanks Mustansiriyah University (www.uomustansiriyah.edu.iq) Baghdad - Iraq for its support in the present work and for their help in providing the practical platform of this study.

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Received on 19.06.2020 Modified on 13.02.2021

Research J. Pharm. and Tech. 2022; 15(5):2158-2162.

DOI: 10.52711/0974-360X.2022.00358