Clin Exp Nephrol DOI 10.1007/s10157-014-1074-y

ORIGINAL ARTICLE

Serum ferritin is associated with progression of peripheral arterial disease in hemodialysis patients Chen-Tung Lien • Kao-Chang Lin • Yueh-Feng Tsai • Lai-King Yu • Li-Hsueh Huang Chien-An Chen



Received: 17 September 2014 / Accepted: 14 December 2014 Ó Japanese Society of Nephrology 2014

Abstract Background Dialysis patients received intravenous iron to treat anemia and had high prevalence of peripheral artery disease (PAD). We hypothesized that high iron status might associate with the progression of PAD among hemodialysis patients. Therefore, we evaluated the relationship between iron status and progression of PAD. Methods We measured iron status in 74 hemodialysis patients and studied the association with clinical, biochemical, and vascular parameters including progression of PAD measured by ankle-brachial index (ABI) over 3 years. Results Mean baseline ABI was 1.03 ± 0.18. Mean ABI at 3 years was 0.95 ± 0.20. Mean DABI (change in ABI after 3 years) was -0.08 ± 0.14. Serum ferritin was negatively correlated with baseline ABI (r = -0.232, p = 0.046). After 3 years, DABI was negatively associated with 3-year averaged serum ferritin, phosphorus, and calcium–phosphate product (Ca 9 P) (r = -0.253, p = 0.029; r = -0.278,

C.-T. Lien and K.-C. Lin contributed equally to this work.

p = 0.016; r = -0.288, p = 0.013; respectively). After an adjusted model, 3-year averaged serum ferritin and Ca 9 P remained the significant determinants of DABI (b = -0.234, p = 0.038; b = -0.271, p = 0.017; respectively). DABI was significantly different between 3-year averaged serum ferritin level C600 and\600 ng/mL (p = 0.032). Conclusions In hemodialysis patients, high serum ferritin associates with progression of PAD, especially among those with high Ca x P level. Keywords Peripheral artery disease  Ankle-brachial index  Ferritin  Calcium–phosphate product Abbreviations ABI Ankle-brachial index DABI Difference between 3-year ABI and baseline ABI Ca x P Calcium–phosphate product CVD Cardiovascular disease DM Diabetes mellitus PAD Peripheral artery disease PTH Parathyroid hormone

C.-T. Lien Department of Diagnostic Radiology, Tainan Sinlau Hospital, No. 57, 1 Sec., Dongmen Rd., Tainan, Taiwan K.-C. Lin Department of Biotechnology, Southern Taiwan University, No. 1, Nan-Tai Street, Yung-Kung, Tainan, Taiwan K.-C. Lin Department of Neurology, Chi-Mei Medical Center, No. 901, Zhonghua Rd., Yonykang, Tainan, Taiwan Y.-F. Tsai  L.-K. Yu  L.-H. Huang  C.-A. Chen (&) Division of Nephrology, Tainan Sinlau Hospital, No. 57, 1 Sec., Dongmen Rd., Tainan, Taiwan e-mail: [email protected]

Introduction Peripheral artery disease (PAD) is highly prevalent in hemodialysis patients [1]. PAD refers to thrombotic vascular disease of lower extremities and results in poorer quality of life among patients with end-stage renal disease (ESRD) [2]. The ankle-brachial index (ABI) is a non-invasive method to screen PAD and ABI \0.9 is defined to have PAD [3]. ABI has the other prediction function. A study by Kitahara and associates [3] showed that ABI is a powerful

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tool in predicting mortality in hemodialysis patients. Tanaka and associates [4] also demonstrated that ABI is a strong predictor of both cardiovascular disease and cardiovascular mortality in hemodialysis patients. Dialysis patients may have unique factors associated either with the dialysis process or with ESRD itself for cardiovascular disease. Such processes may include oxidative stress, chronic inflammation, vascular calcification, or exposure to atherogenic factors associated with dialysis or uremia. Cheung et al. and O’Hare et al. observed that smoking, DM, aging, duration of dialysis, serum albumin level, parathyroid hormone (PTH), and Kt/V may be associated with PAD in hemodialysis patients [5, 6]. Iron is essential for heme constituent, cellular metabolism, and enzymes involved in DNA synthesis, electron transport, and ATP synthesis [7]. Iron homeostasis needs to be tightly regulated, because high iron status can induce oxidative stress. In 1981, Sullivan [8] proposed the iron hypothesis that there is a correlation between iron status and cardiovascular disease. Kiechl’s study also showed that serum ferritin is a significant indicator of carotid artery disease in 847 subjects aged in the range of 40–79 years old [9]. Drueke [10] and colleagues reported that serum ferritin associates with levels of advanced oxidation protein products, carotid artery intima-media thickness, and carotid artery wall-to-lumen ratio in hemodialysis patients. Other authors also found that high level of iron status is a risk factor for cardiovascular disease [11, 12]. However, some studies failed to document the correlation between iron status and cardiovascular disease [13, 14]. Anemia in dialysis patients is treated by erythropoiesisstimulating agents and intravenous iron administration. We hypothesized that high iron status might associate with the progression of PAD among hemodialysis patients. We, therefore, evaluated the relationship between iron status and change in ABI over 3 years in hemodialysis patients.

Methods Study design This was a retrospective, observational, single-center study of a cohort of hemodialysis patients from a regional hospital in Tainan, Taiwan. Data collection included chart reviews, assessments of laboratory records, and analyses of outcomes and other clinical data. The ABI measurements were routinely performed per year from 2008 to 2010. The ABI at study entry was defined as baseline ABI. The change in ABI after 3 years was defined as DABI (difference between 3-year and baseline ABI). We investigated initially the correlations of iron status with clinical parameters at the study entry. Then, we re-evaluated the

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correlations of 3-year averaged iron status and other parameters with DABI. This study was approved by our Institutional Ethics Committee (Tainan Sinlau Hospital, SLH919-101-05). Patient samples We studied patients undergoing hemodialysis 3 times a week for 3 months or longer at the Division of Nephrology and Dialysis of Tainan Sinlau Hospital. All patients included in this study were that their condition had been stable for least one month. The following patients were excluded: chronic or serious infection, malignancy, severe disease of liver, drug abuse, ABI more than 1.3, or serum ferritin C1,500 ng/mL. The patients with ABI more than 1.3 were excluded, because ABI values are elevated among patients with extensive medial artery calcification of the lower extremities, which prevents occlusion of blood flow by the blood pressure cuff [2]. This artery calcification leads to an unusually high ABI reading. Patients with serum ferritin C1,500 ng/mL were also excluded from this study, because serum ferritin C1,500 ng/mL was not accurately measured at our laboratory department. Dialysis time was 4 h. Monthly blood samples were collected immediately before of each dialysis session directly from the fistula. The complete blood count (CBC) and laboratory blood test including calcium (Ca), phosphorus (P), calcium–phosphate product (Ca 9 P), total cholesterol (TC), triglyceride (TG), and albumin were routinely assessed, using standard laboratory techniques. The iron, ferritin, and total iron binding capacity (TIBC) routinely assessed per 3 months. The percentage of transferrin saturation (TS) was calculated as follows: TS % = serum iron/ TIBC 9 100 %. The intact parathyroid hormone (PTH) routinely assessed per 6 months. The initial hemodialysis patients with serum ferritin \200 ng/mL and TS \20 % received intravenous ferrichydroxide–sucrose (Nang Kung, Taiwan) at a dose of 100 mg per dialysis session to total 1,000 mg. Sufficient intravenous iron was administered to maintain serum ferritin [300 ng/mL and TS [30 % [15, 16]. When serum ferritin [800 ng/mL or TS [50 %, intravenous iron supplementation was avoided [15, 16]. The Hct level was kept between 33 and 36 %. The initial dose of darbepoetin alfa (Taiyo for Kyowa Hakao Kirin, Japan) was 20 mcg/week and the maintenance dose 20–60 mcg/week. The maintenance dose was decreased by 25 % when a patient’s Hct exceeded 36 % and restarted the maintenance dose when it was below 33 %. Ankle-brachial index (ABI) measurement The ABI measurement was performed according to Ono et al. description and our previous report [17, 18]. In brief,

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ABI was determined in all participants using a Waveform analyzer (VaSera VS-1,000; Fukuda Denshi, Tokyo, Japan) which simultaneously measures bilateral arm and ankle (brachial and posterior tibial arteries, respectively) blood pressure by an oscillometric method. The patients were at rest in supine position at least 15 min for the blood pressure to stabilize after completion of the dialysis treatment. The systolic pressure of the arm without dialysis access (brachial artery) and both ankles (posterior tibial arteries) was used for the calculation. ABI was calculated by the ratio of the ankle systolic pressure divided by the arm systolic pressure. Statistical analysis Descriptive values were shown as mean ± standard deviation (SD). Differences between groups were analyzed using unpaired Student’s t test for continuous variables. Correlation between two continuous variables in the study entry was analyzed by Pearson‘s correlation test. Univariate regression analysis was performed for examining the factors related to the change of ABI after 3 years. Then, variables with p \ 0.05 were entered into the stepwise multivariable regression analysis. p value \ 0.05 was considered statistically significant for all analysis. SPSS version 17.0 for Windows (SPSS Inc., Chicago, IL, USA) was used for the statistical analysis.

Table 1 Characteristics of the 74 patients Parameters

At inclusion

3-year average or after 3 years

Age (year)

60.69 ± 11.60

Gender (F/M)

47/27

Dialysis duration (months) DM history

100.31 ± 61.90

Smoking history

16/74

PAD

12/74

Albumin (g/dL)

3.93 ± 0.29

4.02 ± 0.30a

Hemoglobin (g/dL)

11.64 ± 0.90

11.70 ± 0.64a

Total cholesterol (mg/dL)

182.72 ± 40.65

188.04 ± 28.50a

Triglyceride (mg/dL)

167.93 ± 136.92

170.34 ± 93.27a

Calcium (mg/dL)

9.62 ± 0.51

9.41 ± 0.32a

Phosphorus (mg/dL)

4.85 ± 1.54

4.95 ± 0.90a

Ca 9 P

46.62 ± 14.85

45.02 ± 8.76a

Intact PTH (pg/mL)

337.09 ± 372.57

347.73 ± 327.95a

Ferritin (ng/mL)

652.94 ± 324.84

562.12 ± 186.66a

TS (%)

38.53 ± 15.42

38.66 ± 10.41a

12/74

2,151.35 ± 1,722.95a

IV iron dosage (mg) ABI a

1.03 ± 0.18

0.95 ± 0.20

3-year average values

Intact PTH intact parathyroid hormone, IV iron dosage intravenous ferrichydroxide–sucrose dosage

Table 2 Correlations of iron status with clinical parameters

Results

Parameter

Ferritin r

Baseline demographic and clinical data

Age (year) Gender (F/M)

74 patients were included. The mean age was 61 ± 1 years, female/male was 47/27, and mean duration of HD was 100 months (10–248 months). There were 12 patients with diabetes history. 16 patients were smoker. The patients with PAD (ABI\0.9) were 12. Mean baseline ABI was 1.03 ± 0.18 at the study entry. After 3 years, mean ABI was 0.95 ± 0.20. The mean value of change in ABI over 3 years (DABI) was -0.08 ± 0.14. The clinical characteristics of study patients are summarized in Table 1. Serum ferritin was negatively correlated with baseline ABI (r = -0.232, p = 0.046) (Table 2). Transferrin saturation was negatively correlated with calcium, Ca 9 P and i-PTH (r = -0.288, p = 0.013; r = -0.251, p = 0.031; r = -0.386, p = 0.001; respectively, Table 2). Determinants of change in ABI over 3 years (DABI) Univariate analysis showed that DABI was negatively related with 3-year averaged serum ferritin, phosphorus

Dialysis duration (months) DM history

TS % p

r

p

0.187

0.110

0.144

0.222

-0.091

0.439

0.013

0.910

0.125

0.290

-0.090

0.446 0.390

0.040

0.734

-0.101

Smoking history

-0.114

0.331

0.029

0.805

Albumin (g/dL)

-0.133

0.259

-0.058

0.624

0.013 0.049

0.911 0.692

-0.051 -0.054

0.668 0.645

Total cholesterol (mg/dL) Triglyceride (mg/dL) Calcium (mg/dL)

-0.186

0.113

-0.288

0.013*

Phosphorus (mg/dL)

\0.001

0.996

-0.205

0.080

Ca 9 P

-0.032

0.785

-0.251

0.031*

Intact PTH (pg/mL)

-0.038

0.747

-0.386

0.001*

ABI

-0.233

0.046*

0.089

0.449

r Pearson’s correlation coefficient * p value \ 0.05 was considered statistically significant

and Ca x P (r = -0.278, p = 0.016; r = -0.288, p = 0.013; r = -0.253, p = 0.029; respectively, Table 3 and Fig. 1 A–C), but not to the other variables. The relationship between 3-year averaged intravenous iron dosages

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Clin Exp Nephrol Table 3 Univariate analysis of determinants of change in ABI over 3 years (DABI) Dependent variable: DABI

Parameter

r

p

Age

-0.029

0.809

Dialysis duration (months)

-0.160

0.174

DM history Smoking history

-0.159 0.038

0.176 0.748

-0.027

0.817

0.213

0.068

0.023

0.848

Triglyceride (mg/dL)a

-0.109

0.356

Calcium (mg/dL)a

-0.039

0.741

Phosphorus (mg/dL)a

-0.278

0.016*

Albumina Hemoglobin (g/dL)

a

Total cholesterol (mg/dL)a

Ca 9 P

a

-0.288

0.013*

Intact PTH (pg/mL)a

-0.151

0.200

Ferritin (ng/mL)a

-0.253

TS (%)a IV iron dosage (mg)a

0.029*

0.136

0.248

-0.144

0.220

r: Pearson’s correlation coefficient; * p value \ 0.05 was considered statistically significant. a3 year time-average values DABI difference between 3-year ABI and baseline ABI IV iron dosage intravenous ferrichydroxide–sucrose dosage

and the change of ABI after 3 years was also evaluated. The result showed that 3-year averaged intravenous iron dosages did not associate with DABI (r = -0.144, p = 0.220; Table 3). Then, 3-year averaged serum ferritin, phosphorus and Ca 9 P were entered into a multivariate stepwise model where 3-year averaged serum ferritin and Ca 9 P remained significant determinants of DABI (b = -0.271, p = 0.017; b = -0.234, p = 0.038; respectively, Table 4), but 3-year averaged serum phosphorus was not significant to DABI (b = -0.038, p = 0.932; Table 4). Kletzmayr et al. found that ferritin [600 ng/mL has an increased overall 4-year mortality in hemodialysis patients [19]. We also found that DABI was a significantly different between 3-year averaged serum ferritin C600 ng/mL and \600 ng/mL (ferritin C600 ng/mL: -0.13 ± 0.03, ferritin \600 ng/mL: -0.05 ± 0.02, p = 0.032) (Fig. 1 D).

Discussion The biomarkers of progressive PAD are clinical significance. In analyzing the effect of iron status on baseline ABI at study entry, serum ferritin was negatively correlated to baseline ABI. The rate of change in ABI over 3 years (DABI) was affected to a greater extent by 3-year averaged serum ferritin. However, DABI was not affected by transferrin saturation, age, and DM history. We considered that

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intravenous iron dosages may be a significant role in the change of ABI after 3 years. But, we found that 3-year averaged intravenous iron dosages did not associate with DABI. These findings indicated that progression of PAD was attributable to serum ferritin over and above the aging process and diabetic status in hemodialysis patients. The progression of PAD did not associate with intravenous iron dosages. Iron overload causes oxidative stress, lower density lipoprotein oxidation, and endothelial damage thereby stimulating atherosclerosis [10, 20]. Then, iron also plays a significant role in vascular intimal/medial calcification and promotes advanced calcific atherosclerosis [20]. Studies examining the role of iron status in PAD have several repots in general population. Menke’s study demonstrated that serum ferritin and transferrin saturation are associated with PAD in man and postmenopausal women participating in the 1999–2002 National Health and Nutrition Examination Survey (NHANES) [21]. DePalma and associates also found that serum ferritin levels correlate with inflammatory biomarkers and mortality in patient with PAD [22]. In the present study, we also found that DABI levels were significantly different between 3-year averaged serum ferritin \600 and C600 ng/mL. KDOQI anemia guidelines recommend caution about the regular administration of intravenous iron when serum ferritin level is [500 ng/mL [23]. It is also reported that bone marrow iron is higher in patients with serum ferritin [500 ng/mL than in those with serum ferritin B500 ng/mL by histomorphometry in hemodialysis patients [24]. High serum ferritin level ([800 ng/mL) is recently found to be associated with non-traditional cardiovascular risk factors in children and adolescents with hemodialysis [25]. From our results and above reports, we suggest that that serum ferritin C600 ng/ mL may cause progression of PAD in hemodialysis patients. Hyperphosphatemia, hypercalcaemia, high Ca 9 P, and high level of PTH have been associated with vascular calcification [26, 27]. Ohtake et al. [28] demonstrated that arterial calcification of lower limbs’ arteries was closely associated with the prevalence and severity of PAD and calcification score in superficial femoral artery (SFACS) had stronger negative correlation with ABI in hemodialysis patients. However, data from Rajagopalan and associates revealed that PAD is not associated with calcium, phosphorus, Ca 9 P, and PTH [1]. In the present study, only 3-year averaged Ca x P was a significant determinant of DABI in univariate and multivariate analysis. But, 3-year averaged calcium, phosphorus, and i-PTH were not determinants of DABI. Our present results indicated that Ca 9 P was a risk factor for progression of PAD. The different results in our results and other authors may be that variation in susceptibility and differential chronicity of exposure to various risk factors (e.g., calcium, phosphate, calcium–

Clin Exp Nephrol Fig. 1 The changes in ABI over 3 years (DABI) was associated with 3-year averaged phosphorus (P), calcium– phosphate product (Ca 9 P), ferritin (A \ B and C), and different between 3-year averaged serum ferritin \600 ng/mL and C600 ng/mL. aP: 3-year averaged phosphorus; aCa 9 P: 3-year averaged calcium–phosphate product; aFerritin: 3-year averaged ferritin; p value \0.05 was considered statistically significant

Table 4 Multiple stepwise regression analysis of factors associated with DABI standardized b coefficient

p

Pa

-0.038

0.932

Ca 9 Pa

-0.271

0.017*

a

-0.234

Ferritin

0.038* a

* p value \0.05 was considered statistically significant; 3 year timeaverage values; DABI: difference between 3-year ABI and baseline ABI

phosphate product, or PTH) among the different ethnic groups may have influenced these results. Older age, black race, smoking, DM, hypertension, hypercholesterolemia, coronary artery disease, and elevated C-reactive protein levels are reported to be risk factors for ABI B0.9 in a voluntary screening population [29]. In our present study, age, smoking, DM, and 3-year averaged cholesterol did not correlate with DABI. Our results indicated that non-traditional risk factors such as iron status and altered mineral metabolism associated with progressive PAD than traditional risk factors. However, the diabetes mellitus and smoking are the important risk factors for PAD in hemodialysis patients [5, 6]. The different results between our study and other authors may be that the number of smoking and DM patients is small, and the

chronicity of exposure to various risk factors (e.g., smoking, and diabetes) is differential. This study had several limitations. First, the number of patients in this study was only 74. Thus, lower statistical power may exist. Second, we chose our studying members from a group of patients who survived on the 3-year study period. This leads to miss enrolling patients died during this study. It may result in selection bias. Third, patients with serum ferritin C1,500 ng/mL were excluded from this study. It may underestimate the effect of high serum ferritin levels on ABI values. Fourth, inflammation can induce hyperferritinemia [15, 30]. But, we did not routinely check inflammatory biomarkers (such as high sensitive C-reactive protein or IL-6) in our hemodialysis patients. Hence, inflammation was the confounder in our hemodialysis patients with hyperferritinemia. In summary, we have showed that high serum ferritin associates with progression of PAD in hemodialysis patients, particularly among those with high Ca 9 P level. The serum ferritin C600 ng/mL may be a cut-off value to induce progression of PAD. Larger scaled and prospective studies were needed to investigate whether control of serum ferritin might prevent worsening PAD over time in hemodialysis patients. Conflict of interest The authors declared no conflicts of interest relevant to this manuscript.

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Serum ferritin is associated with progression of peripheral arterial disease in hemodialysis patients.

Dialysis patients received intravenous iron to treat anemia and had high prevalence of peripheral artery disease (PAD). We hypothesized that high iron...
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