Đang tải... (xem toàn văn)
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.
Journal of military pharmaco-medicine no5-2017 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 Cardiovascular disease (CVD) is the leading cause of death in HD patients, accounting for 45 - 50% of causes of death [5] Chronic kidney disease (CKD) patients, who have the mortality rate due to CVD were 16 times higher than that of population [5] There are many risk factors for CVD in HD patients Apart from traditional risk factors known such as hypertension, age, gender, smoking, diabetes, dyslipidemia, physical inactivity, obesity HD patients also have renal disease-related risk factors such as chronic volume overload, hyperhomocysteinemia, anemia, hyperparathyroidism, hypoalbuminemia, oxidative stress and chronic inflammation, among them, hyperhomocystenemia and anemia play an important role in appearance and progress of CVD [5] Hcy is an independent risk factor for CVD Hcy is elevated in 85 - 100% of chronic kidney * 103 Hospital Corresponding author: Diem Thi Van (hoalantim1901@yahoo.com) 209 Journal of military pharmaco-medicine no5-2017 disease (CKD) patients and negatively correlated with glomerular filtration rate (GFR) [8] In cases of advanced CKD and hemodialysis, Hcy level is 1.5 - fold higher than that of normal people [9] Folate and vitamin B12 are not only essential cofactors in Hcy metabolism but also important causes contributing to anemia in hemodialysis patients [8] Therefore, we conducted this study for purpose: To analyze relation between levels of plasma Hcy, folate, vitamin B12 with BP, residual renal function, anemia, dialysis duration and serum albumin in HD patients SUBJECTS AND METHODS Subjects 168 participants were enrolled in our study and divided into groups: the study group consisted of 112 hemodialysis patients at the Department of Nephrology and Hemodialysis, 103 Hospital, from June to October, 2016 The control group consisted of 56 healthy individuals who age, gender matched with those of the study group * Selected criteria for the study group: - Patients with hemodialysis sessions per week - Using the same dialyzers with lowflux membranes - Using hypertensive drugs, erythropoietin, tardyferol B9 in treatment - ESRD patients with different age and gender and dialysis duration > month * Excluded criteria for the study group: 210 - Patients were treated by HDF online method - Patients with currently serious complications or malabsorption syndrome Methods * Study design: a cross-sectional description, in comparison with control group * Study contents: - For the study group: We collected history of disease, performed clinical examinations and laboratory tests Patients were asked to provisionally stop using folate and vitamin B12-containing drugs at least one day before taking plasma homocysteine, folate and vitamin B12 tests Blood sample was drawn under fasting condition and before the first dialysis session of the week Plasma Hcy, folate and vitamin B12 levels were measured by microparticle chemiluminescent immunoassay in the Department of Biochemistry, 103 Military Hospital - For the control group: We also asked for history of health and performed clinical examinations of organs After assessing heatlthy individuals, they also measured plasma Hcy, folate and vitamin B12 levels by the same method as in the study group * Statistical analysis: Stata 12.0 were used to analyse data Mean Hcy, folate and vitamin B12 levels of the study group were considered as increases when > X + SD and decreases when < X - SD of the control group Journal of military pharmaco-medicine no5-2017 RESULTS Table 1: General characteristics of the study group (n = 112) Mean age (year) Uncontrolled BP (n, %) Urine conservation (n, %) 49.93 ± 14.74 Mean dialysis duration (months) Anemia 71 (63.4) 48.62 ± 47.26 106 (94.6) (n, %) Serum albumin < 35 g/L 27 (24.1) 28 (25.2) (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 23.5 635.70 ± 297.52 235 1500 Vitamin B12 (pg/mL) Table 3: Relation between Hcy, folate, vitamin B12, and blood pressure control (n = 112) Unaccepted control Accepted controlled (n = 71) (n = 41) X ± SD 27.39 ± 9.75 22.04 ± 10.04 < 0.01 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 (%) (2.8) (22.0) < 0.01 Variable Hcy (µmol/L) p + 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 Journal of military pharmaco-medicine no5-2017 Table 4: Relation between Hcy, folate, vitamin B12 and residual kidney function (n = 112) Variable Hcy (µmol/L) Folate (ng/mL) Vit B12 (pg/mL) Yes (n = 27) No (n = 85) p X ± SD 22.89 ± 9.41 26.23 ± 10.29 > 0.05 High n (%) 24 (88.9) 85 (100) < 0.05 X ± SD 14.85 ± 7.17 11.89 ± 6.48 > 0.05 Low n (%) (22.2) 26 (30.6) X ± SD 463.63 ± 171.12 690.36 ± 308.82 < 0.001 Low n (%) (25.9) (4.7) < 0.01 > 0.05 + 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 Hcy (µmol/L) Folate (ng/mL) Vit B12 (pg/mL) X ± SD Anemia (n = 106) Non-anemia (n = 6) p 25.45 ± 9.98 24.98 ± 14.02 > 0.05 High n (%) 103 (97.2) (100) > 0.05 X ± SD 12.74 ± 6.72 10.18 ± 7.14 > 0.05 Low n (%) 29 (27.4) (50.0) > 0.05 X ± SD 628.41 ± 291.73 764.50 ± 396.10 > 0.05 Low n (%) 10 (9.4) (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 Variable Hcy (µmol/L) Folate (ng/mL) Vitamin B12 (pg/mL) 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 < 0.01 0.04 > 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 Journal of military pharmaco-medicine no5-2017 DISCUSSION Relation with blood pressure control * Hcy: Lim and Cassano (2002) explored the relationship between Hcy and blood pressure by analyzing data in the NHANES III study from 1988 to 1994 The results indicated that the average diastolic and systolic blood pressure measurements increased by 3.7 and 9.3 mmHg, respectively, from the lowest to the highest quintile of Hcy, unadjusted for age An increase of µmol/L in Hcy was associated with increases in diastolic and systolic blood pressure of 0.5 and 0.7 mmHg, respectively, in men and of 0.7 and 1.2 mmHg in women [6] Mechanisms that could explain the relationship between homocysteine and blood pressure are homocysteine-induced arteriolarconstriction, renal dysfunction and increased sodium reabsorption, and increased arterial stiffness [10] Because of relation between Hcy and blood pressure, blood pressure control is affected by plasma Hcy level Our study demonstrated that patients with unaccepted BP control had higher level of plasma Hcy and rate of hyperhomocysteinemia than patients with accepted BP control (table 3) In hemodialysis patients, Huynh Van Nhuan (2009) also showed that plasma Hcy level in patients without hypertension was 18.04 ± 8.47 µmol/L, significantly lower than that of patients with hypertension (27.63 ± 12.70 µmol/L, p < 0.05) [2] Ha Van Hung (2016) indicated that nonhypertensive patients had mean plasma Hcy level of 23.76 ± 8.10 µmol/L and rate of elevated homocystein of 18.1%, which were significantly lower than those in hypertensive patients (30.76 ± 7.36 µmol/L and 81.9%, respectively) [1] * Folate and vitamin B12: folate and vitamin B12 are the main nutrition factors affecting Hcy levels and have a protective role against cardiovascular disease Protective effect of these B vitamins are not only due to their ability of lowering Hcy level but also due to the ability to act as an antioxidant, to increase the concentration of NO - a vasodilator of endothelial cells Many studies have shown that treatment with B vitamins may reduce BP and cardiovascular events A study by Scazzone (2014) in 116 hypertensive patients and 81 healthy individuals reported that average level of folate in the hypertensive group (6.7 ± 5.0 ng/mL) was significantly lower than that of the group control (9.0 ± 4.4 ng/mL), while vitamin B12 level was not different between the two groups (440 ± 223 pg/mL in the hypertensive group versus 491 ± 185 pg/mL in the control group) [9] Our study indicated that no differences in folate and vitamin B12 levels were observed between the group with accepted BP control and the group with unaccepted BP control (table 3) We believe that our results could not find out the relation between folate, vitamin B12 and blood pressure because in HD patients, blood pressure was influenced by many factors, in which folate and vitamin B12 play only a small role Relation with residual renal function (or urine conservation) Residual renal function is assessed by volume of 24-hour urine while patients still 213 Journal of military pharmaco-medicine no5-2017 remain dialysis If 24-hour urine output < 500 mL is considered to have no residual renal function or no urine conservation In contrast, 24-hour urine output ≥ 500 mL is considered as having residual renal function or urine conservation RRF plays an important role for patients on dialysis, especially peritoneal dialysis patients RRF contributes significantly to the overall health and well-being of dialysis patients It does not only provide small solute clearance but also plays an important role in maintaining fluid balance, phosphorus control, and removal of middle molecular uremic toxins such as beta microglobulin Decline of RRF also contributes significantly to anemia, inflammation, and malnutrition in patients on dialysis [12] Plasma Hcy, folate and vitamin B12 levels are all influenced by residual renal function because all of them are filtered through the glomeruli Therefore, if patients still has residual renal function, levels of these substances will be lower than those of patients without RRF Our results showed that patients with RRF had lower rate of hyperhomocysteinemia than patients without RRF We also found that patients with RRF had lower vitamin B12 levels and higher rate of vitamin B12 deficiency than patients without RRF But regarding folate, our study revealed that no differences in folate level and rate of folate deficiency were observed between the two groups (table 4) In our study, folate was not related to RRF, which can be attributable to folate level in hemodialysis patients influenced by many factors such as diet, using folate-containing drugs in treatment before 214 Relation to anemia * Hcy: Anemia is a common manifestation in hemodialysis patients and has multifactorial etiology, in which lack of materials for hematopoiesis such as folic acid and vitamin B12 also significantly contributed to appearance and progression of anemia Hcy level is affected by folate and vitamin B12 because they act as cofactors in the process of Hcy re-methylation into methionine Thus between Hcy and anemia may have a relation with each other because they are all affected by the status of folate, vitamin B12 in the body In our study, no significant differences were observed in Hcy level and the rate of hyperhomocysteinemia between anemia patients and non-anemia patients (table 5) Similar to our results, Ha Van Hung (2016) reported that Hcy levels of patients with anemia was 28.64 ± 7.65 µmol/L, which was not different from that of patients without anemia (34.02 ± 8.07 µmol/l) (p > 0.05) There were no differences in rate of elevated Hcy between group with anemia and group without anaemia [1] Tayebi (2016) showed that no significant correlation was found between Hcy level and hemoglobin [11] * Folate and vitamin B12: Folate and vitamin B12 are essential for the process of hematopoiesis so that the lack of them will cause macrocytic anemia However, in this study we did not observe any significant relations between folate, vitamin B12 levels and anemia (table 5) This could be explained by anemia in HD patients attributable to many causes such as shortened red blood cell survival, blood loss, inflammation and the deficiency of EPO and vitamin Journal of military pharmaco-medicine no5-2017 Correlation with dialysis duration * Hcy: Hcy has a molecular weight of 135 dalton within range of glomerular filtration Absorption of Hcy in renal tubular was clearly seen through kinetic studies in rat renal cortex Kidneys have an important role in the metabolism of homocysteine Total homocysteine concentration increases as impaired renal function and achieves the highest level in end-stage renal disease Many studies have demonstrated that after each hemodialysis session, Hcy levels may decrease partly but then rise again until the next session Hence the longer dialysis duration is, the more level of Hcy accumulates De Vecchi (2000) indicated that plasma Hcy level was positively correlated with dialysis duration (r = 0.32; p < 0.0001) [4] Moustapha A et al (1999) reported that there was a positive correlation between Hcy level and dialysis duration (r = 0.15; p < 0.05) [7] However, our study demonstrated that plasma Hcy level was not correlated with dialysis duration (table 6) We could not find out the correlation between Hcy level and dialysis duration, which could be explained by plasma Hcy level influenced by many factors * Folate: Folate is a water-soluble vitamin, small molecular weight of 441 dalton It exists in plasma mainly in the free form or loosely bound with non-specific proteins, so that folate may be lost through the membrane Hence, the longer dialysis duration is, the higher the risk of folate deficiency is Our study showed that plasma folate level was inversely correlated with dialysis duration (table 6) * Vitamin B12: Vitamin B12 has a greater molecular weight than folate (1,355 dalton) Moreover, in blood, vitamin B12 exists in the form bound to the carrier proteins (transcobalamin and haptocorrin), so vitamin B12 is hardly lost through low-flux dialysis membrane Our research showed that a positive correlation was observed between vitamin B12 level and dialysis duration (table 6), which may be firstly explained by vitamin B12 level not affected by hemodialysis; Moreover, patients with long dialysis duration often have more nervous complications than patients with short dialysis duration, so they often use group B vitamins including vitamin B12 more Correlation with level of serum albumin Serum albumin is an important marker of Hcy level because in plasma most Hcy binds with protein (mainly albumin) Meanwhile, only free form of Hcy is filtered through the glomeruli Thus, when the level of serum albumin increases, the rate of albumin-bound Hcy will increase, leading to decreased elimination of Hcy by kidneys, which results in elevated level of plasma Hcy Our study indicated that there was a positive correlation between Hcy level and serum albumin (table 6) Similar to our result, many other researchers also reported a positive correlation between Hcy and serum albumin such as Huynh Van Nhuan (2009) (r = 0.353; p < 0.01) [2]; Arnadottir (1999) (r = 0.28; p < 0.05) [3] We did not find any correlation between folate, vitamin B12 and serum albumin (table 6), which may be also suitable because folate in plasma exists mainly in the free form and vitamin B12 is bound with two transport proteins (not albumin) (transcobalamin and haptocorrin), so that the level of folate and vitamin B12 are not affected by serum albumin 215 Journal of military pharmaco-medicine no5-2017 CONCLUSIONS - Patients with unaccepted BP control had higher level of plasma Hcy and rate of hyperhomocysteinemia whereas a lower rate of vitamin B12 decrease 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 relate to anemia - Folate was negatively correlated with dialysis duration (r = -0.47; p < 0.001) whereas vitamin B12 was positively correlated with dialysis duration (r = 0.26; p < 0.01) - Hcy was positively correlated with serum albumin (r = 0.27; p < 0.01) REFERENCES Ha Van Hung Researching on change in serum hs-CRP and homocysteine levels before and after HDF online in chronic renal failure patients on hemodialysis Specialist level thesis VietNam Military Medical University Ha Noi 2016 Huynh Van Nhuan Research on change of blood homocysteine levels and effect of treatment in patients with chronic renal failure on hemodialysis Medical doctoral thesis, Hue University of Medicine and Pharmacy 2009 dialysis and hemodialysis patients Perit Dial Int 2000, 20 (2), pp.169-173 Herzog C.A, Asinger RW, Berger A.K et al Cardiovascular disease in chronic kidney disease A clinical update from kidney disease: Improving Global Outcomes (KDIGO) Kidney Int 2011, 80 (6), pp.572-586 Lim U, Cassano P.A Homocysteine and blood pressure in the Third National Health and Nutrition Examination Survey, 1988 1994 American Journal of Epidemiology 2002, 156, pp.1105-1113 Moustapha A, Gupta A, Robinson K et al Prevalence and determinants of hyperhomocysteinemia in hemodialysis and peritoneal dialysis Kidney Int 1999, 55 (4), pp.1470-1475 Nand N, Sharma M, Mittal N Prevalence of hyperhomocysteinaemia in chronic kidney disease and effect of supplementation of folic acid and vitamin B12 on cardiovascular mortality JIACM 2013, 14 (1), pp.33-36 Scazzone C, Bono A, Tornese F et al Correlation between low folate levels and hyperhomocysteinemia, but not with vitamin B12 in hypertensive patients Annals of Clinical & Laboratory Science 2014, 44 (3), pp.286-290 10 Stehouwer C.D, Van G.C Does homocysteine cause hypertension? Clin Chem Lab Med 2003, 41 (11), pp.1408-1411 Arnadottir M, Berg A.L, Hegbrant J et al Influence of haemodialysis on plasma total homocysteine concentration, Nephrol Dial Transplant 1999, 14 (1), pp.142-146 11 Tayebi A, Biniaz V, Savari S et al Effect of vitamin B12 supplementation on serum homocysteine in patients undergoing hemodialysis: A Randomized Controlled Trial Saudi Journal of Kidney Diseases and Transplantation 2016, 27 (2), pp.256-262 De Vecchi A.F, Bamonti-Catena F, Finazzi S et al Homocysteine, vitamin B12, and serum and erythrocyte folate in peritoneal 12 Wang A.Y, Lai K.N The importance of residual renal function in dialysis patients Kidney Int 2016, 69 (10), pp.1726-1732 216 ... purpose: To analyze relation between levels of plasma Hcy, folate, vitamin B12 with BP, residual renal function, anemia, dialysis duration and serum albumin in HD patients SUBJECTS AND METHODS Subjects... not find any correlation between folate, vitamin B12 and serum albumin (table 6), which may be also suitable because folate in plasma exists mainly in the free form and vitamin B12 is bound with. .. with short dialysis duration, so they often use group B vitamins including vitamin B12 more Correlation with level of serum albumin Serum albumin is an important marker of Hcy level because in