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*
Second Department of Internal Medicine, Hiroshima University School of
Medicine, Hiroshima, Japan.
Tsuchiya General Hospital, Hiroshima, Japan.
Correspondence to Dr. Noriaki Yorioka, Second Department of Internal Medicine, Hiroshima University School of Medicine, 1-2-3 Kasumi Minami-ku Hiroshima 734-8551, Japan. Phone: + 81 82 257 5196; Fax: + 81 82 255 7360; E-mail: nyorioka{at}mcai.med.hiroshima-u.ac.jp
Abstract
Abstract. In the present study, the relationship between the blood erythropoietin level and cardiac function was investigated in 15 patients on chronic hemodialysis who developed chronic heart failure. Another 45 patients without cardiac dysfunction were selected as a control group that was matched for gender, age, and the duration of dialysis. The erythropoietin level was 256.3 ± 481.8 mU/ml in the heart failure group, which was significantly higher than that in the control group (17.0 ± 10.0 mU/ml, P <0.01). Eight of the 15 patients in the heart failure group maintained a hematocrit of more than 30% without receiving recombinant human erythropoietin therapy, whereas 29 of the 45 patients in the control group required erythropoietin. In the heart failure group, the erythropoietin level was significantly correlated with the levels of atrial natriuretic peptide and brain natriuretic peptide (P < 0.01). These results suggest that heart failure can increase the erythropoietin level in proportion to the severity of cardiac dysfunction, even in patients on long-term dialysis.
A high blood level of erythropoietin (EPO) despite the presence of end-stage renal disease (ESRD) has been reported in a patient with chronic severe hypotension on chronic dialysis (1). Acquired cystic kidney disease or renal carcinoma are also reported to be associated with increased EPO production (2, 3, 4). However, we have previously managed a few patients with heart failure who had high blood EPO levels in the absence of such conditions. This may be related to the stimulation of EPO production by circulatory insufficiency secondary to hypotension and heart failure, but the mechanism involved is uncertain. To clarify the clinical significance of an elevated blood EPO level in dialysis patients, the present study was performed to investigate the relationship between EPO and cardiac function in patients on chronic hemodialysis.
Materials and Methods
Of 363 patients on chronic hemodialysis at Tsuchiya General Hospital, echocardiography was performed in 222 who agreed to participate in this study. Informed consent was obtained from all of the subjects. Echocardiography was specifically done as part of this study. Fifteen of these 222 patients were shown to have severe heart failure, with a left ventricular ejection fraction (EF) <50% and a New York Heart Association (NYHA) class of III or IV. Abdominal computed tomography was performed in these 15 patients, but revealed no evidence of acquired cystic kidney disease or renal cancer.
The 15 patients were designated as the heart failure group. They comprised 11 men and four women, and the primary disease was chronic glomerulonephritis in eight patients, diabetic nephropathy in six patients, and systemic lupus erythematosus in one patient. The patients were 58.4 ± 12.7 yr old and had been on dialysis for 100.3 ± 111.6 mo (Table 1). Another 45 patients without cardiac dysfunction (34 male, 11 female) were also selected as a control group. There were 39 patients with chronic glomerulonephritis, one patient with nephrosclerosis, three patients with diabetic nephropathy, one patient with systemic lupus erythematosus, and one patient with gestational toxicosis. They were 56.0 ± 10.5 yr old and had been on dialysis for 131.5 ± 87.8 mo. The two groups were matched for gender, age, and duration of dialysis (Table 2).
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The need for treatment with recombinant human EPO (rhEPO) as well as the hematocrit and the blood EPO level were compared between the two groups. The levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were also measured as indices of cardiac function (5, 6, 7), and their relationship with EPO was assessed. Furthermore, we measured the cardiothoracic ratio as an index of cardiomegaly. In both groups, iron was administered intravenously to keep the ferritin level at about 100 pg/ml, and rhEPO was also administered intravenously from one to three times per week after dialysis to keep the hematocrit at about 30%.
These parameters were measured once using blood samples drawn from the shunt line before dialysis in this study. Blood samples for measuring ANP and BNP were collected into tubes containing EDTA · 2Na. After collection, blood samples were centrifuged immediately and stored at -80°C until assay within a 2-wk period. The serum EPO concentration was measured by RIA kit (Nippon DPC Corp., Tokyo, Japan), using 125I-labeled rhEPO as the tracer, a rabbit antiserum against rhEPO as the primary antibody, a goat anti-rabbit IgG antiserum as the secondary antibody, and rhEPO standards at 0, 5, 10, 25, 50, 100, and 200 mU/ml, as described previously (8). The serum ANP level was measured by immunoradiometric assay kit (Shionogi & Co., Osaka, Japan), using two different monoclonal antibodies that recognize the C-terminal region and the intramolecular ring structure of ANP (9). The BNP level was also measured by immunoradiometric assay (9). The reproducibility of these assays was good. The interassay and intra-assay coefficients of variation for the EPO, ANP, and BNP assays were <4.3%, <7.9%, and <6.4%, respectively. We also measured PaO2 levels in some patients using blood from the shunt line before dialysis, because it was difficult to obtain agreement in the collection of arterial blood in all patients.
Statistical Analyses
Results are shown as mean ± SD. Data were analyzed by the
Mann-Whitney U test, with P < 0.05 indicating a
significant difference. The Spearman rank correlation test was used for
analysis of correlations between two variables.
Results
The mean EPO level was 256.3 ± 481.8 mU/ml in the heart failure group, and was significantly higher than in the control group (17.0 ± 10.0 mU/ml, P < 0.01) (Figure 1). Eight of the 15 (53.3%) patients from the heart failure group maintained a hematocrit of 30% or more without rhEPO therapy, whereas 29 of the 45 control patients (64.4%) required rhEPO. The EPO level was significantly correlated with the levels of ANP and BNP in the heart failure group (both P < 0.01) (Figures 2 and 3). Five patients with a markedly increased EPO level died of heart failure within 3 mo after the completion of this study.
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PaO2 levels showed no significant differences among five patients with heart failure (88.9 ± 16.0 mmHg), and five with normal cardiac function (87.6 ± 10.3 mmHg).
Discussion
In the present study, EPO levels in dialysis patients with severe chronic heart failure were found to be significantly increased compared with those of the control group who were on dialysis without heart failure. Usually, EPO production is not increased in patients with ESRD, but our heart failure group had abnormally high EPO levels.
The EPO level is generally increased in patients with acquired cystic kidney disease and renal cancer (2, 3, 4). This is currently attributed to either production of EPO in the cyst or tumor tissue or to the hypoxic enhancement of EPO production secondary to vascular compression by a renal mass (10). However, it seemed unlikely that such factors were responsible for the elevated EPO level in our heart failure group, because no cysts or renal tumors were detected by abdominal computed tomography.
It has been reported that atrial distension secondary to overhydration and/or an increased systemic BP and afterload represents the primary cause of an elevated plasma ANP level in dialysis patients (11,12), and that the highest predialysis ANP levels are found in patients with heart failure who are in need of ultrafiltration (13). The BNP level is reported to be correlated with the severity of heart failure, particularly the left ventricular end diastolic pressure (5), and with the prognosis of heart failure patients. There are also reports that the BNP level is correlated with cardiomegaly (6), and that BNP is a predictor of cardiovascular events (14). Therefore, markedly elevated values of ANP and BNP suggest cardiac overload or severe heart failure. We found a significant correlation between ANP and EPO levels in the heart failure group. In addition, BNP levels showed a significant correlation with EPO in this group. Thus, we suggest that heart failure may provide a stimulus for EPO production in ESRD, despite the fact that ESRD usually interferes with EPO production. However, it is still unclear whether ANP and BNP directly stimulate EPO production. Our findings suggest that EPO production is stimulated by hypoxia, even in hemodialysis patients. In the present study, however, there were no significant differences in PaO2 levels between patients with and without heart failure. It seems possible that renal hypoxia related to local circulatory insufficiency can stimulate EPO production. To confirm this, however, it will be necessary in the future to measure the EPO level and the oxygen content of renal arterial blood.
It is also suggested that sites of EPO production include the residual kidney (peritubular interstitial cells) (10) and the liver in rats (15,16), as well as the posterior fossa (17) and the liver (18) in humans. In conclusion, even in long-term dialysis patients with complete loss of renal function, we found that EPO levels increased in association with the aggravation of heart failure.
Footnotes
American Society of Nephrology
References
This article has been cited by other articles:
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  Y. Tanaka, N. Joki, and H. Hase History of acute coronary events during the predialysis phase of chronic kidney disease is a strong risk factor for major adverse cardiac events in patients initiating haemodialysis Nephrol. Dial. Transplant., October 1, 2007; 22(10): 2917 - 2923. [Abstract] [Full Text] [PDF]
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 D. M. Mancini, S. D. Katz, C. C. Lang, J. LaManca, A. Hudaihed, and A.-S. Androne Effect of Erythropoietin on Exercise Capacity in Patients With Moderate to Severe Chronic Heart Failure Circulation, January 21, 2003; 107(2): 294 - 299. [Abstract] [Full Text] [PDF]
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