Relation between plasma homocysteine, folate, vitamin b12 levels with blood pressure, residual renal function, anemia, dialysis duration and serum albumin in maintenance hemodialysis patients

Nội dung text: Relation between plasma homocysteine, folate, vitamin b12 levels with blood pressure, residual renal function, anemia, dialysis duration and serum albumin in maintenance hemodialysis patients

1. Journal of military pharmaco-medicine n o5-2017 RELATION BETWEEN PLASMA HOMOCYSTEINE, FOLATE, VITAMIN B12 LEVELS WITH BLOOD PRESSURE, RESIDUAL RENAL FUNCTION, ANEMIA, DIALYSIS DURATION AND SERUM ALBUMIN IN MAINTENANCE HEMODIALYSIS PATIENTS Diem Thi Van*; Hoang Trung Vinh* Summary Objectives: To analyze relation between levels of plasma homocysteine (Hcy), folate, vitamin B12 with blood pressure (BP), residual renal function (RRF), anemia, dialysis duration and serum albumin in hemodialysis (HD) patients Subjects and methods: 112 HD patients were clinically and subclinically examined including measurements of plasma Hcy, folate and vitamin B12 levels. Assessments of Hcy, folate and vitamin B12 levels in HD patients were based on their levels in 56 healthy individuals. Results: Patients with unaccepted BP control had higher level of plasma Hcy and rate of hyperhomocysteinemia but a lower rate of vitamin B12 deficiency than those with accepted BP control. Patients with RRF had significantly lower rate of hyperhomocysteinemia and higher rate of vitamin B12 decrease than patients without RRF. Levels of plasma Hcy, folate and vitamin B12 in HD patients were not significantly relative to anemia. With dialysis duration, folate was negatively correlated (r = -0.47; p < 0.001) whereas vitamin B12 was positively correlated (r = 0.26; p < 0.01). Hcy was positively correlated with serum albumin (r = 0.27; p < 0.01). Conclusions: In HD patients, Hcy was significantly related to BP control, RRF and serum albumin; folate was only related to dialysis duration; vitamin B12 had significant relation to BP control, RRF and dialysis duration. * Key words: Maintenance hemodialysis; Homocysteine; Folate; Vitamin B12; Relation. INTRODUCTION diabetes, dyslipidemia, physical inactivity, obesity. HD patients also have renal Cardiovascular disease (CVD) is the disease-related risk factors such as chronic leading cause of death in HD patients, volume overload, hyperhomocysteinemia, accounting for 45 - 50% of causes of anemia, hyperparathyroidism, death [5]. Chronic kidney disease (CKD) hypoalbuminemia, oxidative stress and patients, who have the mortality rate due chronic inflammation, among them, to CVD were 16 times higher than that hyperhomocystenemia and anemia play of population [5]. There are many risk an important role in appearance and factors for CVD in HD patients. Apart progress of CVD [5]. Hcy is an from traditional risk factors known such independent risk factor for CVD. Hcy is as hypertension, age, gender, smoking, elevated in 85 - 100% of chronic kidney * 103 Hospital Corresponding author: Diem Thi Van (hoalantim1901@yahoo.com) 209
2. Journal of military pharmaco-medicine n o5-2017 disease (CKD) patients and negatively - Patients were treated by HDF online correlated with glomerular filtration rate method. (GFR) [8]. In cases of advanced CKD and - Patients with currently serious hemodialysis, Hcy level is 1.5 - 2 fold higher complications or malabsorption syndrome. than that of normal people [9]. Folate and 2. Methods. vitamin B12 are not only essential cofactors in Hcy metabolism but also * Study design: a cross-sectional important causes contributing to anemia description, in comparison with control in hemodialysis patients [8]. Therefore, group. we conducted this study for purpose: To * Study contents: analyze relation between levels of plasma - For the study group: We collected Hcy, folate, vitamin B12 with BP, residual history of disease, performed clinical renal function, anemia, dialysis duration examinations and laboratory tests. and serum albumin in HD patients. Patients were asked to provisionally stop using folate and vitamin B12-containing SUBJECTS AND METHODS drugs at least one day before taking 1. Subjects. plasma homocysteine, folate and vitamin 168 participants were enrolled in our B12 tests. Blood sample was drawn under study and divided into 2 groups: the study fasting condition and before the first group consisted of 112 hemodialysis dialysis session of the week. Plasma Hcy, patients at the Department of Nephrology folate and vitamin B12 levels were and Hemodialysis, 103 Hospital, from measured by microparticle chemiluminescent June to October, 2016. The control group immunoassay in the Department of consisted of 56 healthy individuals who Biochemistry, 103 Military Hospital. age, gender matched with those of the - For the control group: We also asked study group. for history of health and performed clinical * Selected criteria for the study group: examinations of organs. After assessing - Patients with 3 hemodialysis sessions heatlthy individuals, they also measured per week. plasma Hcy, folate and vitamin B12 levels by the same method as in the study - Using the same dialyzers with low- group. flux membranes. * Statistical analysis : Stata 12.0 were - Using hypertensive drugs, erythropoietin, used to analyse data. Mean Hcy, folate tardyferol B9 in treatment. and vitamin B12 levels of the study group - ESRD patients with different age and were considered as increases when > X + gender and dialysis duration > 1 month. SD and decreases when < X - SD of the * Excluded criteria for the study group: control group. 210
3. Journal of military pharmaco-medicine n o5-2017 RESULTS Table 1: General characteristics of the study group (n = 112). Mean age (year) 49.93 ± 14.74 Mean dialysis duration (months) 48.62 ± 47.26 Uncontrolled BP Anemia 71 (63.4) 106 (94.6) (n, %) (n, %) Urine conservation Serum albumin < 35 g/L 27 (24.1) 28 (25.2) (n, %) (n, %) Table 2: Features of Hcy, folate, vitamin B12 levels in HD patients. Variable X ± SD Min Max Hcy (µmol/L) 25.43 ± 10.15 3.91 50 Folate (ng/mL) 12.61 ± 6.74 3.63 23.5 Vitamin B12 (pg/mL) 635.70 ± 297.52 235 1500 Table 3: Relation between Hcy, folate, vitamin B12, and blood pressure control (n = 112). Unaccepted control Accepted controlled Variable p (n = 71) (n = 41) X ± SD 27.39 ± 9.75 22.04 ± 10.04 < 0.01 Hcy (µmol/L) High n (%) 71 (100) 38 (92.7) < 0.05 Folate X ± SD 12.17 ± 6.44 13.36 ± 7.24 > 0.05 (ng/mL) Low n (%) 20 (28.2) 12 (29.3) > 0.05 Vit B12 X ± SD 668.77 ± 290.57 578.44 ± 304.28 > 0.05 (pg/mL) Low n (%) 2 (2.8) 9 (22.0) < 0.01 + Mean Hcy level and rate of hyperhomocysteinemia of group with unaccepted BP control were significantly higher than those of the other group. + Unaccepted BP control group had a lower folate level and a higher rate of folate deficiency than the other group, but these differences had no satistical significance. + There were no significant differences in mean vitamin B12 levels between two groups (p > 0.05). + Rate of vitamin B12 deficiency in unaccepted BP control group was lower than that in the other group (p < 0.01). 211
4. Journal of military pharmaco-medicine n o5-2017 Table 4: Relation between Hcy, folate, vitamin B12 and residual kidney function (n = 112). Variable Yes (n = 27) No (n = 85) p X ± SD 22.89 ± 9.41 26.23 ± 10.29 > 0.05 Hcy (µmol/L) High n (%) 24 (88.9) 85 (100) < 0.05 Folate X ± SD 14.85 ± 7.17 11.89 ± 6.48 > 0.05 (ng/mL) Low n (%) 6 (22.2) 26 (30.6) > 0.05 Vit B12 X ± SD 463.63 ± 171.12 690.36 ± 308.82 < 0.001 (pg/mL) Low n (%) 7 (25.9) 4 (4.7) < 0.01 + Mean Hcy level of patients with RRF was lower than that of patients without RRF but had no statistical significance (p > 0.05). + Rate of hyperhomocysteinemia of RRF group was significantly higher than that of the other group (p < 0.05). + Mean folate level and rate of folate deficiency were not different between the two groups. + RRF group had a lower mean vitamin B12 level and a higher rate of vitamin B12 deficiency than the other group. Table 5: Relation between Hcy, folate, vitamin B12 and anemia (n = 112). Variable Anemia (n = 106) Non-anemia (n = 6) p Hcy X ± SD 25.45 ± 9.98 24.98 ± 14.02 > 0.05 (µmol/L) High n (%) 103 (97.2) 6 (100) > 0.05 Folate X ± SD 12.74 ± 6.72 10.18 ± 7.14 > 0.05 (ng/mL) Low n (%) 29 (27.4) 3 (50.0) > 0.05 Vit B12 X ± SD 628.41 ± 291.73 764.50 ± 396.10 > 0.05 (pg/mL) Low n (%) 10 (9.4) 1 (16.7) > 0.05 Mean Hcy, folate, vitamin B12 levels, rates of high Hcy, low folate and low vitamin B12 were not different between two groups of anemia (p > 0.05). Table 6: Correlation between Hcy, folate, vitamin B12 and dialysis duration, serum albumin. Hcy (µmol/L) Folate (ng/mL) Vitamin B12 (pg/mL) Variable r p r p r p Dialysis duration (month) (n = 112) 0.11 > 0.05 -0.47 < 0.001 0.26 < 0.01 Serum albumin (g/L) (n = 111) 0.27 0.05 -0.06 > 0.05 + With dialysis duration: folate had moderately negative correlation (r = -0.47, p < 0.001), vitamin B12 had slightly positive correlation (r = 0.26, p < 0.01), Hcy had no correlation. + With serum albumin: plasma Hcy level had slightly positive correlation (r = 0.27; p < 0.01), plasma folate and vitamin B12 levels had no correlation. 212
5. Journal of military pharmaco-medicine n o5-2017 DISCUSSION were significantly lower than those in hypertensive patients (30.76 ± 7.36 µmol/L 1. Relation with blood pressure and 81.9%, respectively) [1]. control. * Folate and vitamin B12: folate and * Hcy: Lim and Cassano (2002) explored vitamin B12 are the main nutrition factors the relationship between Hcy and blood affecting Hcy levels and have a protective pressure by analyzing data in the NHANES role against cardiovascular disease. Protective III study from 1988 to 1994. The results effect of these B vitamins are not only due indicated that the average diastolic and to their ability of lowering Hcy level but systolic blood pressure measurements also due to the ability to act as an increased by 3.7 and 9.3 mmHg, antioxidant, to increase the concentration of respectively, from the lowest to the NO - a vasodilator of endothelial cells. highest quintile of Hcy, unadjusted for Many studies have shown that treatment age. An increase of 5 µmol/L in Hcy was with B vitamins may reduce BP and associated with increases in diastolic and cardiovascular events. A study by Scazzone systolic blood pressure of 0.5 and 0.7 (2014) in 116 hypertensive patients and mmHg, respectively, in men and of 0.7 81 healthy individuals reported that average and 1.2 mmHg in women [6]. Mechanisms level of folate in the hypertensive group that could explain the relationship between (6.7 ± 5.0 ng/mL) was significantly lower homocysteine and blood pressure are than that of the group control (9.0 ± homocysteine-induced arteriolarconstriction, 4.4 ng/mL), while vitamin B12 level was renal dysfunction and increased sodium not different between the two groups (440 reabsorption, and increased arterial stiffness ± 223 pg/mL in the hypertensive group [10]. Because of relation between Hcy and versus 491 ± 185 pg/mL in the control blood pressure, blood pressure control is group) [9]. Our study indicated that no affected by plasma Hcy level. Our study differences in folate and vitamin B12 demonstrated that patients with unaccepted levels were observed between the group BP control had higher level of plasma Hcy with accepted BP control and the group and rate of hyperhomocysteinemia than with unaccepted BP control (table 3) . We patients with accepted BP control (table 3). believe that our results could not find out In hemodialysis patients, Huynh Van the relation between folate, vitamin B12 Nhuan (2009) also showed that plasma and blood pressure because in HD Hcy level in patients without hypertension patients, blood pressure was influenced was 18.04 ± 8.47 µmol/L, significantly lower by many factors, in which folate and than that of patients with hypertension vitamin B12 play only a small role. (27.63 ± 12.70 µmol/L, p < 0.05) [2]. Ha Van Hung (2016) indicated that non- 2. Relation with residual renal hypertensive patients had mean plasma function (or urine conservation). Hcy level of 23.76 ± 8.10 µmol/L and rate Residual renal function is assessed by of elevated homocystein of 18.1%, which volume of 24-hour urine while patients still 213
6. Journal of military pharmaco-medicine n o5-2017 remain dialysis. If 24-hour urine output 3. Relation to anemia. < 500 mL is considered to have no residual * Hcy: Anemia is a common manifestation renal function or no urine conservation. In in hemodialysis patients and has multifactorial contrast, 24-hour urine output ≥ 500 mL is etiology, in which lack of materials for considered as having residual renal hematopoiesis such as folic acid and function or urine conservation. RRF plays vitamin B12 also significantly contributed an important role for patients on dialysis, to appearance and progression of anemia. especially peritoneal dialysis patients. Hcy level is affected by folate and vitamin RRF contributes significantly to the overall B12 because they act as cofactors in the health and well-being of dialysis patients. It process of Hcy re-methylation into does not only provide small solute methionine. Thus between Hcy and clearance but also plays an important role anemia may have a relation with each in maintaining fluid balance, phosphorus other because they are all affected by the control, and removal of middle molecular status of folate, vitamin B12 in the body. uremic toxins such as beta 2 microglobulin. In our study, no significant differences Decline of RRF also contributes significantly were observed in Hcy level and the rate of to anemia, inflammation, and malnutrition hyperhomocysteinemia between anemia patients and non-anemia patients (table 5). in patients on dialysis [12]. Plasma Hcy, Similar to our results, Ha Van Hung (2016) folate and vitamin B12 levels are all reported that Hcy levels of patients with influenced by residual renal function anemia was 28.64 ± 7.65 µmol/L, which because all of them are filtered through was not different from that of patients the glomeruli. Therefore, if patients still without anemia (34.02 ± 8.07 µmol/l) has residual renal function, levels of these (p > 0.05). There were no differences in substances will be lower than those of rate of elevated Hcy between group with patients without RRF. Our results showed anemia and group without anaemia [1]. that patients with RRF had lower rate of Tayebi (2016) showed that no significant hyperhomocysteinemia than patients correlation was found between Hcy level without RRF. We also found that patients and hemoglobin [11]. with RRF had lower vitamin B12 levels * Folate and vitamin B12: Folate and and higher rate of vitamin B12 deficiency vitamin B12 are essential for the process than patients without RRF. But regarding of hematopoiesis so that the lack of them folate, our study revealed that no differences will cause macrocytic anemia. However, in folate level and rate of folate deficiency in this study we did not observe any were observed between the two groups significant relations between folate, (table 4). In our study, folate was not vitamin B12 levels and anemia (table 5). related to RRF, which can be attributable This could be explained by anemia in HD to folate level in hemodialysis patients patients attributable to many causes such influenced by many factors such as diet, as shortened red blood cell survival, blood using folate-containing drugs in treatment loss, inflammation and the deficiency of before. EPO and vitamin. 214
7. Journal of military pharmaco-medicine n o5-2017 4. Correlation with dialysis duration. the form bound to the carrier proteins * Hcy: Hcy has a molecular weight of (transcobalamin and haptocorrin), so vitamin 135 dalton within range of glomerular B12 is hardly lost through low-flux dialysis filtration. Absorption of Hcy in renal tubular membrane. Our research showed that a was clearly seen through kinetic studies in positive correlation was observed between rat renal cortex. Kidneys have an important vitamin B12 level and dialysis duration role in the metabolism of homocysteine. (table 6) , which may be firstly explained Total homocysteine concentration increases by vitamin B12 level not affected by as impaired renal function and achieves hemodialysis; Moreover, patients with long the highest level in end-stage renal disease. dialysis duration often have more nervous Many studies have demonstrated that after complications than patients with short each hemodialysis session, Hcy levels dialysis duration, so they often use group may decrease partly but then rise again B vitamins including vitamin B12 more. until the next session. Hence the longer 5. Correlation with level of serum dialysis duration is, the more level of Hcy albumin. accumulates. De Vecchi (2000) indicated that plasma Hcy level was positively Serum albumin is an important marker correlated with dialysis duration (r = 0.32; of Hcy level because in plasma most p < 0.0001) [4]. Moustapha A et al (1999) Hcy binds with protein (mainly albumin). reported that there was a positive correlation Meanwhile, only free form of Hcy is between Hcy level and dialysis duration filtered through the glomeruli. Thus, when (r = 0.15; p < 0.05) [7]. However, our study the level of serum albumin increases, the demonstrated that plasma Hcy level was rate of albumin-bound Hcy will increase, not correlated with dialysis duration (table leading to decreased elimination of Hcy 6) . We could not find out the correlation by kidneys, which results in elevated level between Hcy level and dialysis duration, of plasma Hcy. Our study indicated that which could be explained by plasma Hcy there was a positive correlation between level influenced by many factors. Hcy level and serum albumin (table 6). Similar to our result, many other researchers * Folate: Folate is a water-soluble vitamin, also reported a positive correlation between small molecular weight of 441 dalton. It Hcy and serum albumin such as Huynh exists in plasma mainly in the free form or Van Nhuan (2009) (r = 0.353; p < 0.01) loosely bound with non-specific proteins, [2]; Arnadottir (1999) (r = 0.28; p < 0.05) so that folate may be lost through the [3]. We did not find any correlation between membrane. Hence, the longer dialysis folate, vitamin B12 and serum albumin duration is, the higher the risk of folate (table 6), which may be also suitable deficiency is. Our study showed that because folate in plasma exists mainly in plasma folate level was inversely correlated the free form and vitamin B12 is bound with dialysis duration (table 6). with two transport proteins (not albumin) * Vitamin B12: Vitamin B12 has a greater (transcobalamin and haptocorrin), so that molecular weight than folate (1,355 dalton). the level of folate and vitamin B12 are not Moreover, in blood, vitamin B12 exists in affected by serum albumin. 215
8. Journal of military pharmaco-medicine n o5-2017 CONCLUSIONS dialysis and hemodialysis patients. Perit Dial Int. 2000, 20 (2), pp.169-173. - Patients with unaccepted BP control 5. Herzog C.A, Asinger RW, Berger A.K et had higher level of plasma Hcy and rate al . Cardiovascular disease in chronic kidney of hyperhomocysteinemia whereas a lower disease. A clinical update from kidney disease: rate of vitamin B12 decrease than those Improving Global Outcomes (KDIGO). Kidney with accepted BP control. Int. 2011, 80 (6), pp.572-586. - Patients with RRF had significantly 6. Lim U, Cassano P.A . Homocysteine and lower rate of hyperhomocysteinemia and blood pressure in the Third National Health higher rate of vitamin B12 decrease than and Nutrition Examination Survey, 1988 - patients without RRF. 1994. American Journal of Epidemiology. - Levels of plasma Hcy, folate and 2002, 156, pp.1105-1113. vitamin B12 in HD patients were not 7. Moustapha A, Gupta A, Robinson K et significantly relate to anemia. al. Prevalence and determinants of - Folate was negatively correlated with hyperhomocysteinemia in hemodialysis and dialysis duration (r = -0.47; p < 0.001) peritoneal dialysis. Kidney Int. 1999, 55 (4), whereas vitamin B12 was positively pp.1470-1475. correlated with dialysis duration (r = 0.26; 8. Nand N, Sharma M, Mittal N . p < 0.01). Prevalence of hyperhomocysteinaemia in chronic kidney disease and effect of - Hcy was positively correlated with supplementation of folic acid and vitamin B12 serum albumin (r = 0.27; p < 0.01). on cardiovascular mortality. JIACM. 2013, 14 (1), pp.33-36. REFERENCES 9. Scazzone C, Bono A, Tornese F et al . 1. Ha Van Hung. Researching on change Correlation between low folate levels and in serum hs-CRP and homocysteine levels hyperhomocysteinemia, but not with vitamin before and after HDF online in chronic renal B12 in hypertensive patients. Annals of failure patients on hemodialysis. Specialist Clinical & Laboratory Science. 2014, 44 (3), level 2 thesis. VietNam Military Medical pp.286-290. University. Ha Noi. 2016. 10. Stehouwer C.D, Van G.C. Does 2. Huynh Van Nhuan. Research on change of blood homocysteine levels and effect of homocysteine cause hypertension?. Clin treatment in patients with chronic renal failure Chem Lab Med. 2003, 41 (11), pp.1408-1411. on hemodialysis . Medical doctoral thesis, Hue 11. Tayebi A, Biniaz V, Savari S et al. University of Medicine and Pharmacy. 2009. Effect of vitamin B12 supplementation on 3. Arnadottir M, Berg A.L, Hegbrant J et al. serum homocysteine in patients undergoing Influence of haemodialysis on plasma total hemodialysis: A Randomized Controlled Trial. homocysteine concentration, Nephrol Dial Saudi Journal of Kidney Diseases and Transplant. 1999, 14 (1), pp.142-146. Transplantation. 2016, 27 (2), pp.256-262. 4. De Vecchi A.F, Bamonti-Catena F, 12. Wang A.Y, Lai K.N. The importance of Finazzi S et al. Homocysteine, vitamin B12, residual renal function in dialysis patients. and serum and erythrocyte folate in peritoneal Kidney Int. 2016, 69 (10), pp.1726-1732. 216