By Chang, Tzu-Yuan Chou, Kang-Ju; Tseng, Chin-Feng; Chung, Hsiao-Min; Et al
Key words: Albumin – C-reactive protein – Folic acid – Hemodialysis – Homocysteine – Vitamin B ABSTRACT
Objective: Folic acid and vitamin B coplex administration in uremic patients has been reported to lower plasma total homocysteine (tHcy) levels, but whether or not this has a beneficial effect on the inflammatory state is not clear.
Methods: We conducted a randomized open labeled study to determine the effects of folic acid (5 mg daily) and vitamin B complex administration on plasma tHcy levels as well as inflammatory (serum high-sensitivity C reactive protein, hs-CRP) and nutritional (serum markers in patients on maintenance hemodialysis. Treatment was given for 3 consecutive months to 61 patients on maintenance hemodialysis. Another 60 patients, all age-, sex-, hemodialysis duration- matched served as control group.
Main outcome measures: Plasma tHcy, serum hs-CRP, albumin, creatinine (Cr), post-dialysis body] weight (BW), and normalized protein catabolism rate (nPCR).
Results: After 3 months, levels of plasma tHcy and serum hs-CRP, Cr, and nPCR were significantly decreased while levels of serum albumin, vitamin B,;, folate, and BW were significantly increased. The dialytic dose (KTW) and dietary intake remained unchanged. However, correlations between the magnitude of reduction of tHcy & hs-CRP, tHcy & Cr, and Cr & nPCR were statistically significant,
Conclusions: Folic acid and vitamin B complex co-administration effectively lowers tHcy and hs-CRP levels and increases albumin levels in stable hemodialysis subjects, underscoring their potential benefit to attenuate the state of inflammation and possibly improve the nutritional status in patients on hemodialysis.
Introduction
Hyperhomocysteinemia is a known risk factor for cardiovascular events and mortality in the general population1,2. In uremic patients, plasma total homocysteine levels (tHcy) are remarkably elevated3. In the past, numerous prospective studies4,5 have considered hyperhomocysteinemia as a risk factor for cardiovascular disease (CVD) as well as worsening survival in uremic patients. Recent prospective studies regarding the ability of tHcy to predict cardiovascular event or death in end-stage renal disease (ESRD) have shown that a low, rather dian a high tHcy is an indicator of poor outcome in hemodialysis patients6-8. These different results might be explained by the latest atudies of Ducloux et aV and Suliman et al.10 which showed a graded increase in relative risk with high tHcy levels after adjustment for confounders including nutritional and inflammatory markers. At present, there is concern over whether lowering plasma homocysteine is beneficial for dialysis patients11.
Folic acid is known to lower tHcy concentration in the general population and uremic patients1-3. However, several large prospective atudies revealed that folic acid and vitamin B supplement do not lower the risk of CVD12-14 in the high risk population for CVD. Until now there are only a few studies addressing this dilemma in uremic patients. Wrone et al.1 found no significant difference in the incidence of cardiovascular events and the mortality rate in patients on hemodialysis given varying doses of folic acid. On the contrary, Righetti et al.15 reported that homocysteine-lowering vitamin B (including folic acid) treatment decreases cardiovascular events in hemodialysis patients.
Since the presence of malnutrition and inflammation may confound the association between tHcy and clinical outcome in ESRD patients6, study designs to evaluate the homocysteine-lowering effect of the combination therapy with folic acid and vitamin B should consider the influence of underlying nutritional and inflammatory status. To date, no study has investigated how combined folic acid and vitamin B complex administration for the treatment of hyperhomocysteinemia may affect levels of serum inflammatory markers and nutritional status in uremic patients. Our study aims to examine the changes in the levels of tHcy, the inflammatory and the nutritional markers on stable hemodialysis patients who were given folic acid and vitamin B complex.
Patients and methods
Study design
Because of the inconclusive evidence regarding the role of hyperhomocysteinemia in uremia, most of the patients in our hemodialysis center had not been prescribed folic acid and vitamin B supplements in the 2 years prior to this study. This study included stable hemodialysis patients who were not taking folic acid and vitamin B complex in the past 6 months prior to the investigation. The same patients were on hemodialysis three times per week for more than 6 months using low-flux polysulfone membranes with surface areas ranging from 1.1 to 1.9 m^sup 2^. The criteria for exclusion were chronic infections such as tuberculosis and osteomyelitis, malignancy, liver disease (cirrhosis diagnosed by sonography and acute hepatitis diagnosed by elevated liver enzyme and symptoms/ signs) and drug intake (statins, fibrate, nonsteroidal anti- inflammatory drugs, steroids16, phenytoin, methotrexate, theophylline, estrogen”). The trial was designed as a randomized, controlled open-label study. A total of 136 patients were eligible and agreed to participate. Group matching with gender, age (within 5 years), and duration of hemodialysis (within 1 year) was conducted for every pair group and they were then randomly assigned to either active treatment or control group. A total of 72 patients were randomized to a treatment group who were given folic acid (5 mg daily) and vitamin B complex (B1: 5 mg, B2: 3 mg, nicotinamide: 20mg, B6: 0.5 mg, B12: 1 [mu]g, calcium pantothenate: 3 mg three times daily) for 3 consecutive mondis. A total of 64 patients were assigned to the control group who continued taking their usual prescription which did not include folic acid and vitamin B supplement. This study was approved by the medical ethics committee of our institution and all participants gave their informed written consent.
Since recording of food intake is the only method available to estimate dietary energy intake in dialysis patients in clinical practice, these patients were encouraged not to change their usual dietary habits, as supervised by a skilled dietitian18. Body weight (post-dialysis weight), body mass index (BMI), mean blood pressure, plasma tHcy, serum hs-CRP, IL-6, albumin, creatinine (Cr), total cholesterol, hematocrit, vitamin B12, folate, ALT level, clearance of urea per dialysis (KT/V) and normalized protein catabolism rate (nPCR) were recorded at baseline and after 3 months.
Pre- and postdialysis levels of serum urea were recorded for evaluation of single-pool KT/V (Daugirda method)19. nPCR was calculated from monthly kinetic modeling sessions by applying the two-blood urea nitrogen (2-BUN) method20 to predialysis BUN level, and an estimate of equilibrated postdialysis BUN level obtained using the Daugirdas-Schniditz equation. Body mass index (BMI in kg/ m^sup 2^) was calculated from patient height obtained at study entry and postdialysis weight measurements obtained at monthly kinetic modeling sessions.
Some of the participating subjects had a history of diabetic mellitus and CVD. Diabetic mellitus (DM) was defined as a past DM history or two measurements of fasting blood sugar above 126mg/dL. CVD was defined by history with cerebrovascular disease, peripheral artery disease, and coronary heart disease.
Blood measurements
A total of 6 ml of pre-dialysis fasting blood sample was drawn from each patient, 2 ml of which were added to ethylenediaminetetraacetic acid (EDTA), centrifuged within 15 min of collection, and the plasma stored at -7O0C until analysis. The remaining 4 ml of blood was centrifuged and the serum stored at – 70[degrees]C. Routine monthly blood testing was continued for all the patients studied.
Levels of fasting plasma tHcy (Immulite, DPC Cirrus Inc. Los Angeles, CA, USA), serum hs-CRP (Immulite, DPC Cirrus Inc., Los Angeles, CA, USA) and the proinflammatory cytokine, IL-6 (Immulite, Euro/ DPC Ltd, UK) were measured by enzyme-amplified chemiluminescence. The normal range for tHcy was 5-13.5 [mu]mol/L. Serum hs-CRP and IL-6 levels were monitored as indices of the degree of inflammation, with normal limits below 0.6 mg/dL and 9.7 pg/ml, respectively.
Serum folate and vitamin B12 levels were determined using a radioassay kit (MP Vitamin B12/folate Simul TRAC-SNB, MP Biomedicals Inc., NY, USA). The normal limit for serum folic acid was above 1.5 ng/ml, and the normal range for vitamin B12 was 160-970 pg/ml.
Levels of serum total cholesterol, albumin, Cr, urea and ALT, which are included in the routine monthly blood tests, were studied as a homogenous assay in a liquid phase on a Hitachi 7600 (Hitachi Ltd, Tokyo, Japan). Hematocrit was measured by automated hematology analyzer K-4500 (Sysmex Corporation, Japan).
Statistical analysis
Continuous variables are expressed as mean +- SD and categorical values are expressed in frequency and percentage. The normality test was performed initially. If the data were normally distributed, the chi-square or Fisher exact test and Student t-test were used to compare the difference between control and experimental groups. Paired f-test was applied to compare the values obtained at baseline and after 3 months. Pearson correlation coefficients were applied to evaluate the correlations between the baseline levels of plasma tHcy, serum albumin, hs-CRP, and nPCR. It was also used to evaluate the correlations between the magnitude of increase/reduction levels of plasma tHcy, serum hs-CRP, albumin, Cr and nPCR after 3 months’ treatment. The Mann-Whitney U-test or Wilcoxon test was used if the normality test failed. The p-value
In the experimental group, 61 of the 72 subjects completed the study. The remaining 11 subjects failed for various reasons, including hospitalization due to acute illness (four), poor ‘compliance (three), nausea and abdominal discomfort due to medications (two), transfer to another hemodialysis center (one), and death (one). In the control group, 60 of the 64 subjects completed the study. The remaining four subjects failed because of hospitalization due to acute illness (three) and withdrawal of consent for blood extraction at the end of the study (one). Patient compliance with folic acid and vitamin B complex intake in the experimental group was verified by two mediods: daily record- keeping of actual pill intake and monitoring of vitamin B12, folate and tHcy levels. Dietary intake was also monitored.
Table 1 shows the baseline demographic, clinical characteristics and biochemistry profile (values are expressed as mean +- standard deviation) of all the subjects. There was no remarkable difference between the two groups except albumin level (p = 0.045). The baseline median (range) of serum hs-CRP were 0.60 (0.21-1.11) and 0.51 (0.37-0.63) mg/dL in the experimental and control group, respectively, and tHcy were 31.9 (22.33-40.16) and 33.3 (29.60- 38.89) [mu]mol/L. The causes of ESRD in the experimental group are: diabetic nephropathy (16), chronic interstitial nephropathy (13), chronic glomerular nephropathy (9), lupus nephritis (2), polycystic kidney disease (2), gouty nephropathy (1), trauma-related nephrectomy (1), and unknown (1 7). In the control group, the causes of uremia were: diabetic nephropathy (16), chronic interstitial nephropathy (14), chronic glomerular nephropathy (10), lupus nephritis (3), polycystic kidney disease (1), and unknown (16).
Table 2 compares the clinical features and the biochemistry findings before and after treatment. In the experimental group, levels of plasma tHcy (mean +- standard deviation 34.01 +- 14.89 vs. 22.01 +- 10.55 [mu]mol/L, p
Table 1. Clinical characteristics and biochemistry data, at inclusion, for hemodialysis subjects with or without folic acid and vitamin B therapy
In the baseline data (Table 3) only Cr and albumin showed a positive significant correlation [r = 0.282, p = 0.0276). However, we observed positive correlated trends between nPCR & albumin (p = 0.0521), tHcy & hs-CRP (p = 0.065), and tHcy & Cr (p = 0.0695), but a negative correlated trend between hs-CRP & albumin (p = 0.0553). In comparing the correlation (Table 4) between the magnitude of increase [(final level – initial level)/initial level] of serum albumin , and the magnitude of reduction [(initial level – final level)/ initial level] of serum hs-CRP, Cr, plasma tHcy or nPCR in the experimental group, only the magnitude of reduction of tHcy and hs-CRP, the magnitude of reduction of serum Cr and nPCR and the magnitude of reduction of Cr and tHcy were significantly correlated (r = 0.527, p
Figure 1. Pearson correlation of reduction rates of tHcy (X axis) and hs-CRP (Y axis) after 3 months of treatment in experimental subjects (r = 0.527, p
Discussion
This study showed that folic acid and vitamin B complex administration for 3 months significantly decreased plasma tHcy and serum hs-CRP levels and increased serum albumin levels in stable hemodialysis patients. The present study suggests that folic acid and vitamin B treatment on hemodialysis patients without previous intake may (1) lower the tHcy level, (2) decrease the inflammation marker hs-CRP, and (3) increase the nutritional marker albumin.
Table 2. Comparison of clinical characteristics and biochemistry data in hemodialysis subjects before and after 3 months of treatment
Table 3. Pearson correlation coefficient data between the baseline of tHcy, hs-CRP, albumin, Cr, and nPCR in the experimental group
Chronic inflammation, with increased levels of various acute phase reactants such as hs-CRP, has recently been shown to be a common feature which increases cardiovascular risk and predicts a worse outcome in patients with ESRD3,21,22. The relationship between hyperhomocysteinemia and inflammation has long been the goal of research23-25. Several studies have proved that Hcy itself may serve as an inflammatory marker26-28. Thus, the reduction in tHcy levels achieved after vitamin supplementation may lead to patients presenting very similar reductions in CRP concentrations. In our study, both the control and experimental groups had baseline high- normal levels of hs-CRP, indicating that all of our study subjects have modest inflammation before treatment. After 3 months of treatment, hs-CRP levels significantly decreased in the experimental group. Our study also found significant correlations between the magnitude of reduction of hs-CRP and tHcy levels after treatment. Since the liver is considered the most likely major organ for Hey metabolism in renal patients29 and that CRP is produced predominantly by hepatocytes, therefore, it would not be unexpected that Hcy-lowering treatment would lower CRP levels as well. Our data strongly suggested that folic acid and vitamin B treatment induced a decrease in serum hs-CRP as a consequence of the decrease in the plasma tHcy26-28. Thus, combination therapy with folic and vitamin B complex in stable hemodialysis patients not only lessens plasma tHcy but also attenuates modest inflammation.
Table 4. Pearson correlation coefficient data between the rates of increase of serum albumin and the rates of reduction of hs-CRP, tHcy, Cr, nPCR levels in the experimental group
Elevation of serum IL-6 levels may be an important predictor of outcome in patients on dialysis30. Kimmel et al.31 have reported that higher levels of circulating pro-inflammatory cytokines, such as IL-6, are associated with increased mortality. The cytokine IL-6 is a 2OkDa polypeptide secreted by fibroblasts, adipocytes, monocytes and endothelial cells31. Dialysis-related uremia or an oxidative state may increase IL-6 levels, since IL-6 levels are positively correlated with time on hemodialysis, an observation which is not apparent with CRP32. Serum IL-6 levels were not changed signifkantiy in our subjects after 3 months of treatment. However, it should be noted that most of our patients had relatively low levels of baseline IL-6, which underscores the fact that our subjects did not have obvious inflammation. On the other hand, IL-6 analysis was done with enzyme-amplified chemiluminescence assay which is much less sensitive for values in the lower range as our data showed.
Stenvinkel et al.33 have proposed the existence of a syndrome consisting of malnutrition, inflammation and atherosclerosis (the MIA syndrome) in some patients with chronic renal failure. The MIA syndrome involves a chain of events triggered by inflammatory agents stimulating the hepatic secretion of proinflammatory cytokines and CRP. It is generally accepted that inflammation exerts an effect on albumin level34. Inflammation acting through nuclear factor kappa B (NF-kappaB) causes decreased albumin gene expression, with resultant decreased rate of albumin synthesis27,35, consequently leading to a reduced serum albumin concentration. Our study found significant decrease in the levels of hs-CRP after 3 months of treatment. During the same period, albumin levels were increased significantly. These findings may indicate that attenuation of the degree of inflammation as a result of folic acid and vitamin B complex supplementation may lead to the improvement of the nutritional status36.
Both CRP and albumin are produced in the liver. Hepatic synthesis of albumin is lower in dialysis patients with elevated CRP levels37. Aldiough different stimuli may govern their production, any change in liver function will have considerable effects on bodi CRP and albumin production. Our study showed no significant changes in serum ALT levels during the study period. Likewise, the dialysis dosage, KT/V, during the study period also showed no obvious change. Thus, these two variables could not have played a significant role in the modulation of the inflammatory and nutritional status in our study subjects. Our result is similar to a study by Vernaglione et al.38 which showed that atorvastatin, a lipid-lowering agent, decreases serum CRP levels in hemodialysis patients after 6 months of treatment, with a corresponding increase in serum albumin levels.
nPCR, also called the protein equivalent of nitrogen appearance (PNA), is the parameter used in most hemodialysis units to assess dietary protein intake only in patients who are in a steady state. We use nPCR in our analysis as a surrogate for nutritional intake. Clearly, there is a mismatch between nPCR and dietary nitrogen ingestion, since it frequently overestimates nitrogen intake, especially in the inflammatory situation39. Although nPCR is often viewed as a variable that can be manipulated independently, it varies directly with the Kt/V, a measure of dialysis adequacy. Our study showed that folic acid and vitamin B treatment obviously decreased nPCR which may indicate decreasing protein catabolism. The dialysis dosage and the dietary habits during the study period were unchanged in our study groups. Apparendy, Kt/V and dietary intake did not seem to play an important role in modulating protein catabolism in our patient groups. However, the inflammatory status was explicitly decreased as serum hs-CRP showed. Therefore, lessening the degree of inflammation may lower the nPCR. Strikingly similar results were observed for the serum Cr concentration. In dialysis patients, serum Cr concentration may serve as a surrogate marker of somatic protein in tiiat it is a reflection of muscle mass34. Indeed, Cr concentration is a function of production, including that contributed by diet, distribution, and removal. Clearly, dialysis intensity would be expected to affect predialysis serum Cr levels. However, our data presented here showed consistent dialytic dosage during the study period. After 3 mondis of treatment, our study group showed a marked decrease in serum Cr and a slight but significant increase in body weight. In the absence of obvious blood pressure changes during the study period, the observed minimal increments in the body weights of our subjects may be due to increased intracellular water. Meanwhile, the observed decline in levels of creatinine (Cr) is probably partly due to loss of muscle mass in the treated group. In addition, creatine synthesis and homocysteine formation are metabolically connected. Hey is derived from methionine in a multiple step metabolic cycle39. Methionine can intracellularly be converted to S-adenosyl methionine, which acts as a universal metbyl donor in numerous transmethylation reactions in vivo. On the other hand, creatine is synthesized in humans by two successive metabolic steps. First, guanidinoacetate is synthesized mainly in the kidney, then guanidinoacetate is metiiylated in the liver to creatine by guanidinoacetate-metiiyltransferase (GAMT] widi S-adenosylmediionine as metiiyl donor40. Exogenous folic acid and vitamin B supplementation can, thus, be expected to decrease endogenous Hey synthesis with parallel decrease in creatine synthesis which may then contribute to a lower serum Cr level.
In conclusion, we found tiiat treatment of hyperhomocysteinemia with folic acid and vitamin B complex significantly lowers plasma tHcy and serum hs-CRP levels, with corresponding increases in serum albumin levels. Such treatment with folic acid and vitamin B is effective and beneficial for stable maintenance in hemodialysis patients, but whether the amelioration of inflammation and improvement of the nutritional status may provide a degree of cardiovascular protection deserves further elucidation.
Acknowledgments
The research for this article was supported by Kaohsiung Veterans General Hospital grant VGHKS94-018.
We are deeply grateful to Ms. Yang YC and Mr. Chiu CC for their excellent technical and administrative help.
* This work was presented in part at the XLIII ERA-EDTA (European Renal Association – European Dialysis and Transplantation Association) annual congress, Glasgow, United Kingdom, July 15-18, 2006
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Paper CMRO-3915_3, Accepted for publication: 05 June 2007
Published Online: 29 June 2007 doi:10.1185/030079907X218077
Tzu-Yuan Chang(a), Kang-Ju Chou(a), Chin-Feng Tseng(b), Hsiao- Min Chung(a), Hua-Chang Fang(a), Yao-Min Hung(a), Ming-Jei Wu(a), Huey-Ming Tzeng(c), Chang-Chung Lind and Kuo-Cheng Lu(b)
a Division of Nephrology, Department of Medicine & Department of Nuclear Medicine, Kaohsiung Veterans General Hospital, School of Medicine, National Yang-Ming University, Taipei, Taiwan
b Division of Nephrology, Department of Medicine, Cardinal-Tien Hospital, School of Medicine, Fu-Jen Catholic University, Hsin-Tien City, Taipei, Taiwan
c Division of Nursing Business and Health Systems, the University of Michigan, School of Nursing, Ann Arbor, Ml, USA
Address for correspondence: Kuo-Cheng Lu, MD, Division of Nephrology, Department of Medicine, Cardinal-Tien Hospital, School of Medicine, Fu-Jen Catholic University, 23rd F, No 65, Min-Chiuan Road, Hsin-Tien City, Taipei, Taiwan. Tel: + 886-2-29155739; Fax: + 886-2-29107920; [email protected]
Copyright Librapharm Aug 2007
(c) 2007 Current Medical Research and Opinion. Provided by ProQuest Information and Learning. All rights Reserved.
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