Abstract
Background: Iron support is an important component of treatment of anemia in hemodialysis (HD) patients. However, there are concerns about endovenous (EV) iron therapy that may cause endothelial dysfunction (ED) by increasing oxidative stress (OS) and lead to cardiovascular events. In this study, we aimed to evaluate the effects of high and repeated doses of EV iron sucrose on endothelial functions in acute and subacute phases. Methods: We included 15 HD patients to our study. There were 16 patients with iron deficiency but normal kidney functions in control group. We also evaluated endothelium-dependent vasodilatation (EDV) and nitroglycerin-induced vasodilatation (NIV) from the brachial artery by ultrasonography at the beginning of the study, and then 200 mg EV iron sucrose was given initially to both groups for 1 h in 250 cc 0.9% saline and 4 h after the end of the infusion (acute phase) sonographic vasodilatation parameters were measured from brachial artery. These measurements and laboratory tests were repeated 1 week after the end of a total 1000 mg EV iron sucrose replacement (200 mg/week). Results: There was a statistically significant increase in hemoglobin and ferritin levels after the EV iron sucrose therapy in both control and patient groups. EDV values in the HD group were significantly lower than that in the control group before therapy (6.25% vs. 10.53%, p < 0.05). EV iron sucrose therapy did not alter EDV and NIV values at the 4th hour and 6th week in both control and patient groups. Conclusion: According to our study, compared with the control group with normal kidney functions, HD patients had impaired endothelial functions. However, in HD patients, high and repeated doses of EV iron sucrose do not have deleterious effects on endothelial functions at acute and subacute phases and can be used safely in that patient group.
INTRODUCTION
Anemia is a common complication and clinical symptom of acute and chronic renal failure.Citation1 The most important reason for inadequate response to erythropoiesis-stimulating agents (ESA) is iron deficiency in end-stage renal disease (ESRD) patients.Citation2 In order to achieve an optimal response to treatment with recombinant human erythropoietin therapy, having an adequate iron store is critical. Oral use of iron was found to be inadequate for the replacement of iron and maintenance of adequate serum iron levels, and therefore endovenous (EV) iron replacement has been the basic element in this patient population for the treatment of anemia.Citation3 For filling iron stores in the case of iron deficiency, a total of 1000 mg EV iron therapy can be used in certain doses for each dialysis session.Citation4 EV iron is widely used to prevent iron deficiency and to maintain adequate iron store in chronic renal failure; however, there are still some concerns about the safety of iron therapy in the long-term use.Citation5 The most important short-term side effects of EV iron therapy are allergic and anaphylactic reactions.Citation6,7 These reactions are particularly concerned with high molecular weight iron dextran.Citation7 Non-dextran iron formulations have a better safety profile.Citation8,9 Long-term concerns about EV iron are related with oxidative stress (OS), inflammation, renal, and cardiovascular damage.Citation5
How does iron cause atherosclerosis and vascular damage is still not fully understood; however, the basic mechanism for iron-mediated tissue damage is increased OS which may cause endothelial cell dysfunction.Citation10,11 EV iron may have pro-oxidant, proinflammatory, and cytotoxic effects and all forms of EV iron can cause an increase in lipid peroxidation products.Citation12 By the way, there are some studies indicating that EV iron has minimal or no effect on OS.Citation13,14 EV iron infusion causes redox-active iron, which is strongly pro-oxidant. Reactive oxygen species triggers iron-mediated lipid peroxidation and oxidized form of low-density lipoprotein (LDL) plays a role in atherogenesis. It has been shown that LDL oxidation may develop in hemodialysis (HD) patients. EV iron infusion changes the antioxidant system, and uremic patients already have some defects in their antioxidant system and thus iron toxicity may increase these defects. Chronic renal failure (CRF) can enhance the iron-mediated toxicity that targets vessel wall.Citation15
There are very few studies about the relationship between EV iron therapy and endothelial dysfunction (ED) and the result of these studies are conflicting with each other. As an example, one of these studies showed a temporary decrease in EDV in healthy subjects with normal kidney functions after 100 mg EV ferric saccharate therapy, but another study did not find any change in EDV in peritoneal dialysis (PD) patients after a single dose 200 mg EV iron sucrose therapy.Citation16,17 There is no study that evaluated the effects of high and repeated dose of EV iron therapy on acute and subacute phases of treatment in terms of ED in HD patients. In this study, using sonographic measurements of brachial artery, we aimed to evaluate whether EV iron sucrose caused ED.
MATERIALS AND METHODS
Patients and Methods
Our study consisted of 15 ESRD patients who did not take EV iron therapy for at least 3 months and having a hemoglobin level less than 11 g/dL and ferritin level less than 300 pg/mL. All the patients were in HD treatment for at least 6 months. We also had 16 patients with iron deficiency anemia as control group who did not have any chronic disease. When we examined the causes of ESRD in our patients, we saw that 7 of them have hypertension (HT), 2 with diabetes mellitus (DM), 1 with polycystic kidney disease, 1 with AA amyloidosis secondary to familial Mediterranean fever, 1 with ureteral stricture, and 1 with renal artery stenosis. We did not know the etiology of ESRD in two patients. Patients with ESRD were treated thrice a week with standard bicarbonate HD for 4 h. of 15 patients, 8 were using antihypertensive medication (4 patients were using beta-blockers and 4 patients were using calcium channel blockers). Kt/V values were higher than 1.2 (mean 1.37 ± 0.03). Twelve patients were receiving recombinant erythropoietin therapy for maintaining the Hb values between 10 and 11 g/dL (6 were using erythropoietin alpha and 6 were using darbepoetin alpha). Patients with acute or chronic infection, systemic disease, active liver disease, acute myocardial infection, cerebrovascular disease, congestive heart failure (NHYA Class III–IV), and peripheral artery disease were excluded. Patients using drugs that might affect the endothelial functions were also excluded. Ethical Research Committee approval was obtained for our study and after giving information about the study a written informed consent was obtained from the patients. Blood samples for laboratory tests were taken in the morning after a 12 h fasting. Blood samples and sonographic measurements of patient group were done in the days without dialysis session at the beginning of the study, and then 200 mg EV iron sucrose was given initially to both groups for 1 h in 250 cc 0.9% saline and 4 h after the end of the infusion (acute phase) sonographic vasodilatation parameters were measured from brachial artery. These measurements and laboratory tests were repeated 1 week after the end of a total 1000 mg EV iron sucrose replacement (200 mg/week).
Laboratory Analyses and Brachial Artery Studies
Hemoglobin, serum iron, total iron-binding capacity, transferrin, transferrin saturation, ferritin, triglyceride, total cholesterol, high-density lipoprotein (HDL), LDL, blood urea nitrogen (BUN), creatinine, calcium, phosphorus, parathormone, and albumin were all evaluated in both the patients and the control group. In all participants, using high-resolution ultrasound (Toshiba SSA – 240, Toshiba, Tokyo, Japan; ultrasound device with 7.5 MHz’lik linear transducer) endothelium-dependent vasodilatation (EDV) and nitroglycerin-induced vasodilatation (NIV) (endothelium-independent) were measured in the brachial artery according to the guidelines described by Corretti et.al.Citation18 For the assessment of EDV, the right arm was placed in extension in the elbow and the hand was placed in supination. In HD patients, EDV and NIV measurements were performed from the arm that did not have a fistula. An optimal longitudinal image of the brachial artery just above the elbow with clear anterior and posterior intimal interfaces between the lumen and vessel wall was established and kept stable. A sphygmomanometric cuff was placed distally from the elbow. A baseline rest image was obtained; thereafter, arterial occlusion was created by cuff inflation to 50 mmHg above the systolic blood pressure for 4 min. After deflation, the longitudinal image of the artery was recorded continuously from 30 s before to 2 min after deflation and the lumen diameter was measured at about 60 s. Lumen diameter was defined as the distance between media–adventitia interfaces of the vessel wall. After a 10 min resting interval, a 0.4 mg nitroglycerine spray was administered sublingually and vascular relaxation was measured on the 5th minute. EDV was defined as the percent change in brachial artery diameter within 1 min after ischemia compared to baseline. NIV was defined as the percent change within 5 min after nitroglycerine administration.
Statistics
All data analyses were performed using PASW 18 (Polar Engineering and Consulting, IBM, New York, NY, USA). Continuous variables were summarized with n (sample size), mean, and standard deviation, and categorical variables were summarized with n (sample size), median, and 25th and 75th percentiles. Normally distributed continuous variables were compared between groups with Student’s t-test, and the correlations among variables were determined using Pearson correlation analysis. Normally distributed continuous-dependent variables were analyzed using paired t-test. Nonnormally distributed variables were compared with Mann–Whitney U test for independent groups, Wilcoxon test for dependent two groups, and Friedman analysis for repeated measures. Spearman correlations analysis was applied to determine the correlations among nonnormally distributed variables. Chi-square analyses were used for categorical variables. p-Value less than 0.05 was accepted significant.
Results
shows the characteristic properties of the patient and control groups. Hematological and biochemical results of the patient and control groups are shown in . The rate of increase in EDV before treatment was significantly lower in patient group than controls (6.25% vs. 10.53%, p < 0.05), but there was no difference in NIV values between the two groups (14.29 vs. 21.11, p > 0.05) (). There were statistically significant improvements in hemoglobin and ferritin levels after iron therapy in both patient and control groups (Hb: 10.5 ± 1.4 vs. 11.53 ± 0.42 g/dL, p < 0.05, 9.9 ± 2.2 vs. 11.9 ± 1 g/dL, p < 0.001; ferritin: 143 ± 84 vs. 460 ± 263 g/dL, p < 0.001, 5.3 ± 3 vs. 165 ± 100 g/dL, p < 0.001). There was no difference between HD patients and control subjects according to their EDV response after a basal ischemic stimulus, 200 mg EV iron sucrose (acute phase), and 1 g EV iron sucrose (subacute phase) (). There was also no change in NIV between HD patients and control subjects in the initial, acute, and subacute phases (). CBC and iron status of HD patients and control subjects before and after 1 g EV iron sucrose therapy are shown in and , respectively.
Table 1. Demographic data of HD patients and controls.
Table 2. Comparison of pretreatment values of patients and controls.
Table 3. Percent changes of EDV and NIV in HD patients and control subjects.
Table 4. Hb and iron status of HD patients before and after 1 g EV iron therapy.
Table 5. Hb and iron status of control subjects before and after 1 g EV iron therapy.
DISCUSSION
Cardiovascular mortality and morbidity increased in HD patients because of an abnormal level of OS and inflammation that led to ED, which is the first step of atherosclerosis. The exact cause of these changes is not fully understood, but it is thought to contain multi numbers of factors such as itself of HD procedure.Citation13 The imbalance between pro-oxidant reactions and antioxidant defense mechanisms begins in the early phase of the CRF and deteriorates with the progression of renal failure. As a result, OS becomes most obvious in dialysis patients.Citation19 It is very hard to evaluate the endothelial damage in vivo because of the multifunctional nature of endothelial cells. Endothelial activation which can be demonstrated with impaired EDV is a response against damage, and it is considered to be the first step of atherogenesis. Vasomotor functions of endothelial cells can be evaluated with EDV which can be measured by ultrasonographically.Citation20 In our study basal EDV values of HD patients were significantly decreased when compared with the control group and this result was consistent with the literature.Citation21
In our study, we found a statistically significant improvement in hemoglobin and ferritin levels of HD patients and control group after EV iron therapy. This result supports the efficiency of EV iron therapy in the partial recovery of renal anemia.Citation3 However, there is some controversial information in the literature about the effects of high-dose EV iron therapy and treatment of renal anemia with erythropoietin in chronic renal failure.Citation16,22–25 Recently, it has been shown that the HD process itself causes an increase in inflammation, OS, and ED, but EV iron sucrose therapy with 50 and 100 mg had minimal effects on inflammation and OS with no effects on endothelial functions in acute period.Citation13 In another study, there has been no increase in the markers of ED in CRF patients after EV high-dose iron sucrose therapy.Citation11
In our study there was no significant change in EDV and NIV measurements after 4 h from the EV iron sucrose infusion (acute phase) in HD patients and healthy control subjects. There was also no change in EDV and NIV measurements which was done 1 week later from the end of an administration of a total 1000 mg EV iron sucrose with a dosing of 200 mg/week (subacute phase).
Balanos et al.Citation17 reported no change in flow mediated dilatation (FMD) and non-EDV in PD patients measured 3 h after a 200 mg EV iron sucrose infusion. Similarly, Schaller et al.Citation26 reported that a 300 mg EV iron sucrose infusion in PD patients did not impair forearm blood flow as measured by strain-gauge plethysmography in PD patients, despite a marked elevation of total iron and nontransferrin-bound iron, as well as a significant increase of redox-active iron. These results suggest our data; however, Rooyakers et al. reported that iron infusion at a currently used therapeutic dose (100 mg ferric saccharate) for intravenous iron supplementation in healthy subjects leads to increased oxygen radical stress and acute ED. Impairment in FMD was found statistically significant but this continued only up to 4 h.Citation16 The cause of the contradiction between Rooyakers’ and our study can be explained by the difference between design, such as the type of EV iron (iron sucrose vs. ferric saccharate) and the time of the evaluation of endothelial functions (4th hour and 6th week measurements vs. 10th min after EV infusion).
Our study is important because this is the first study that compares the ED parameters after high and repeated dose of EV iron therapy in HD patients and healthy control subjects in acute and subacute periods. However, there are some limitations in our study: first, we did not evaluate the endothelial functions during or immediately after the EV iron infusion, so we could miss an early or transient deterioration of vasodilatation property of the vessel. Second, we did not evaluate the biochemical markers of ED. We also did not evaluate the long-term effects of EV iron therapy. Third, there was a significant difference in age between dialysis patients and control groups. This is because most of the control patients with iron deficiency anemia were young females with hypermenorrhea and this might lead to the difference in basal FMD values between two groups.
In conclusion, HD patients have high mortality and morbidity rates due to impaired endothelial functions and cardiovascular events. Successful treatment of anemia in HD patients improves cardiovascular and hemodynamic disorders and makes a positive impact on the quality of life. There are still some concerns about EV iron therapy but in HD patients this treatment modality is highly effective in the treatment of renal anemia. According to our findings high and repeated doses of EV iron therapy did not have any side effects on endothelial functions in HD patients and healthy control subjects in acute and subacute periods and can be used safely.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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