Abstract
Background: Pulmonary arterial hypertension (PAH) is a common complication in hemodialysis (HD) patients and its pathogenesis is not explained clearly. Arterio-venous fistulas (AVFs) creation may contribute to the development of PAH because of increased pulmonary artery blood flow. However, it was not prospectively evaluated that effect of AVF on the development of PAH. Aim: We aimed to evaluate the effects of AVF on PAH and the relationship between blood flow rate of AVF and pulmonary artery pressure (PAP) in HD patients. Patients and Method: The prospective study included 50 patients with end-stage renal disease. Before an AVF was surgically created for hemodialysis, the patients were evaluated by echocardiography. Then, an AVF was surgically created in the patients. After mean 76.14 ± 11.37 days, the second evaluation was performed by echocardiography. Results: Before AVF creation, 17 (34%) out of 50 patients had PAH. The systolic PAP was significantly higher in the patients with PAH compared with patients without PAH (47.82 ± 9.82 mmHg vs. 30.15 ± 5.70 mmHg, respectively, p = 0.001). In the second evaluation, 19 (38%) out of 50 patients had PAH. The systolic PAP values were significantly higher in the patients with PAH compared with patients without PAH (47.63 ± 8.92 mmHg vs. 25.03 ± 7.69 mmHg, P = 0.001, respectively). There was no relationship between the blood flow rate of AVF and PAP. Conclusion: PAH is a common problem in HD patients. AVF has no significant effect on the development of PAH within a short period. Similarly, blood flow rate of AVF also did not affect remarkably the systolic PAP.
INTRODUCTION
Pulmonary arterial hypertension (PAH) is characterized by elevated systolic pulmonary artery pressure (PAP) due to heart, lung, or systemic diseases.Citation1 Regardless of the cause, it is associated with increased mortality and morbidity.Citation2 Although specific mechanisms of PAH development are not fully known, several mechanisms have been suggested. The main vascular findings in PAH are vasoconstriction, proliferation of smooth muscle cells and endothelial cells, and thrombosis.Citation3 In literature there were a few studies, in which the prevalence and pathogenesis of the disease were investigated in hemodialysis (HD) patients. In these studies, the prevalence of PAH was detected to be approximately 25– 45% in HD patients.Citation4–7
Arterio-venous fistulas (AVFs) induce problems such as high-output cardiac failure and coronary ischemia in HD patients.Citation8,9 In addition, increase in cardiac output due to AVF creation contributes to the development of PAH because of increased pulmonary artery blood flow.Citation5
The aim of this study was to evaluate the effect of AVF, which was created surgically for vascular access, on the development of PAH and relationship between blood flow rate of AVF and PAP in the patients with end-stage renal disease (ESRD).
PATIENTS AND METHOD
The study was performed between March 2007 and January 2008 at the Department of Nephrology, Erciyes University Hospital, Kayseri, Turkey. The study protocol was approved by the local ethics committee. The study procedures were approved by all patients and healthy volunteers.
Patients
Sixty-one patients with ESRD, who were planned for an AVF creation for vascular access to HD, were enrolled to the study. Two patients died before the second echocardiographic evaluation. Primary failure developed after an AVF creation in five patients. Although two patients were included in this study, they underwent peritoneal dialysis (PD) without an AVF creation. One patient refused renal replacement treatment (RRT). Indication of RRT disappeared in one patient because renal function improved partially. Finally, 50 patients (26 males and 24 females) with ESRD, who underwent HD via an AVF which was surgically created, were enrolled to the study. Twenty PD patients (10 males and 10 females) and 15 healthy volunteers (8 males and 7 females) were included to the study as control groups.
The patients who were under the age of 18 and who had chronic obstructive pulmonary disease (COPD), connective tissue disease, left ventricular ejection fraction <50%, severe mitral or aortic valve disease, chest wall or parenchymal lung disease, and a history of pulmonary thromboembolism were excluded.
The patient’s demographic data such as age and gender, comorbid diseases such as diabetes mellitus, clinical data including use of antihypertensive drug and erythropoietin (EPO), smoking, height, weight, and cause of ESRD were recorded.
The Echocardiographic Evaluation
It has been reported that there was excellent correlation between the measurements of PAP by invasive method and by Doppler echocardiography.Citation10 Therefore, we used an echocardiographic method for evaluation of PAP. All echocardiographic evaluations were performed by the same cardiologist (MD) using the Vivid 7 Dimension (GE Medical Systems, Horten, Norway) echocardiography machine. Two-dimensional and M-mode Doppler echocardiographic images were obtained from apical or parasternal windows in the left lateral recumbent position in each patient and control. In the presence of tricuspid valve regurgitation, systolic right ventricular (or systolic pulmonary artery) pressure was calculated by using the modified Bernoulli equation: PAP = 4 × (tricuspid systolic jet)2 + 10 mmHg.Citation11 PAH is defined as an elevation of the mean PAP above 25 mmHg at rest in the setting of normal or reduced cardiac output and normal pulmonary capillary pressure. If echocardiographic criteria are used, it is defined as systolic PAP > 35 mmHg at rest.Citation12 Therefore, PAH was defined as systolic PAP > 35 mmHg at rest in the present study. End-diastolic left ventricular septal and posterior wall thickness and internal dimensions were used to calculate left ventricular mass by using the following equation: left ventricular mass = 1.04 × 0.8 [(left ventricular wall thickness + internal dimension) – (internal dimension)]+ 0.6 g. Left ventricular hypertrophy (LVH) was defined as left ventricular mass index (LVMI), which was calculated with left ventricular mass in grams divided by body surface area in square meters, higher than 116.0 g/mCitation2 for men and 104.0 g/mCitation2 for women.Citation13 Body surface area was calculated by using Mosteller’s formula.Citation14
Blood flow of AVF was automatically obtained by using Doppler echocardiography. The echocardiographic evaluation was performed once in PD patients and control subjects and twice in HD patients. In HD patients, it was performed before an AVF creation. Then an AVF was created surgically. After HD was started via an AVF after AVF maturation, the second echocardiographic evaluation, which was performed within 24 h after HD session to avoid volume loading, was performed. At the second evaluation, the blood flow rate of AVF was also measured.
Blood Samples
Blood samples were obtained from all patients and healthy volunteers for biochemical examinations, including whole blood count, blood urea nitrogen (BUN), serum creatinine, serum albumin, serum calcium, serum phosphorus, serum alkaline phosphatase, intact parathyroid hormone (iPTH), high-sensitive C-reactive protein (hsCRP), and total lipid profile at the same day in which were performed echocardiographic evaluation. The iPTH was measured by radioimmunoassay (Immunotect, Marseille, France). Serum hsCRP was measured by CardioPhase hsCRP (Dade Behring) on a Dade Behring.
Statistical Analysis
SPSS 11.0 statistic software was used for the statistical analysis. The Kolmogorov–Smirnov test was used to determine the normality of distributions of variables. Continuous variables with normal distribution were presented as mean ± standard deviation. Median value was used in variables without normal distribution. Statistical analysis for the parametric variables was performed by one-way ANOVA with Scheffe’s post-hoc test between three groups. The Kruskal–Wallis test was used to compare the nonparametric variables. Then, the Mann–Whitney U-test with Bonferroni correction was used to assess differences among the groups. The qualitative variables were given as percent and the correlation between categorical variables was investigated by the χCitation2 test. To compare variables before an AVF creation and after an AVF creation in HD group, paired t-test (for the parametric variables), Wilcoxon test (for the nonparametric variables), and McNemar test (for categorized variables) were performed. The correlation analysis was evaluated by the Pearson’s correlation test. p-Value <0.05 was considered to be significant.
RESULTS
ESRD is mostly caused by diabetes mellitus and hypertension (16 and 10 of 50 HD patients vs. 6 and 10 of 20 PD patients, respectively). There was significantly no difference between the HD and PD groups with regard to the presence of diabetes mellitus and hypertension.
The comparison of clinical, biochemical, and echocardiographic parameters among the three groups are shown in . LVH and PAH were the most frequently observed in PD group and HD group, respectively. There was significantly no difference among the three groups in terms of gender, smoking, white blood cell (WBC), concentrations of serum glucose, triglyceride, and high-density lipoprotein (HDL).
Table 1. Comparison of clinical, biochemical, and echocardiographic parameters among the three groups.
In HD patients, when the parameters which were evaluated before an AVF was surgically created, were compared to those which were evaluated after an AVF was surgically created, there was meaningfully no difference in terms of body mass index (BMI), systolic and diastolic blood pressures, use of angiotensin-converting enzyme inhibitor, angiotensin 2 receptor blocker, and beta-blocker, WBC, level of serum glucose, total cholesterol and HDL, serum creatinine concentration, level of iPTH and hsCRP, systolic PAP value, and presence of PAH (p > 0.05). The levels of hemoglobin, triglyceride, alkaline phosphatase, and serum albumin, LVMI value and the presence of LVH were significantly higher in period after an AVF creation than in period before an AVF creation. On the other hand, the levels of low-density lipoprotein (LDL) and BUN, calcium-phosphorus product (Ca × P product), uric acid, use of antihypertensive drug and calcium canal blocker, and ejection fraction were significantly lower in period after an AVF creation than in period before an AVF creation (see ).
Table 2. Comparison of biochemical, clinical, and echocardiographic parameters in HD patients.
Systolic PAP value did not correlate with blood flow of AVF. Although there was no significant correlation between systolic PAP value and the duration after an AVF creation, the p-value was 0.052.
shows the comparison of clinical and echocardiographic parameters between HD patients with PAH and those without PAH at period before an AVF creation. Systolic blood pressure, systolic PAP, and the presence of hypertension and LVH were significantly higher in patients with PAH compared with those without PAH. On the other hand, ejection fraction value was significantly lower in patients with PAH compared with patients without PAH. However, there were no significant differences between patients with and without PAH in terms of age, gender, smoking, WBC, hemoglobin, serum glucose, total cholesterol, triglyceride, HDL, LDL, BUN, serum creatinine, Ca × P product, alkaline phosphatase, uric acid, serum albumin, iPTH, hsCRP, presence of diabetes mellitus, BMI, diastolic blood pressure, and LVMI (p > 0.05).
Table 3. Comparison of clinical and echocardiographic parameters between hemodialysis patients with PAH and those without PAH at period before an AVF creation.
Table 4. Comparison of clinical, biochemical, and echocardiographic parameters between hemodialysis patients with PAH and those without PAH at period before an AVF creation.
shows the comparison of clinical, biochemical, and echocardiographic parameters between HD patients with PAH and those without PAH at a period after an AVF creation. The duration of fistula, hsCRP level, and systolic PAP value were significantly higher in patients with PAH compared with patients without PAH. On the other hand, the levels of hemoglobin, HDL, and serum albumin were significantly lower in patients with PAH compared with those without PAH. However, there were no significant differences between patients with and without PAH in terms of age, gender, smoking, presence of diabetes mellitus and hypertension, EPO use, BMI, diastolic and systolic blood pressures, WBC, serum glucose, total cholesterol, triglyceride, LDL, BUN, serum creatinine, Ca × P product, alkaline phosphatase, uric acid, iPTH, ejection fraction, LVMI, presence of LVH, and blood flow of AVF (p > 0.05).
DISCUSSION
PAH is a disorder that is characterized by an increase of artery pressure and vessel resistance in the pulmonary vessels.Citation15 There are two mechanisms, namely high vessel resistance and increased pulmonary blood flow for the development of PAH.Citation5 Increment in pulmonary artery resistance is associated with three factors. The first and the most important factor is the pulmonary vascular remodeling, which is characterized by the presence of smooth muscle cells within small arterioles of respiratory acinus. The other factors are vasoconstriction and thrombosis.Citation16
The possible cause of vasoconstriction in pathogenesis of PAH in HD patients is increased endothelin 1 (ET-1) and decreased nitric oxide (NO). Nahhoul et al. reported that ET-1 levels were significantly higher in both HD patients with PAH and those without PAH compared with control subjects, and NO levels were significantly lower in HD patients with PAH compared with HD patients without PAH and controls.Citation17 Similarly, increased ET-1 expression and decreased NO synthesis within the pulmonary arteries of patients with PAH who had normal renal function has been demonstrated.Citation18,19
PAH is a frequent complication in HD patients. Its prevalence was found to be approximately 25–57% in different studies.Citation4–7,20 Similarly, in the present study we found that the prevalence of PAH was 34% and 38% at the period before an AVF creation and after an AVF creation, respectively.
AVF induces high-output cardiac failure.Citation8,9 The possibility of heart failure is higher in HD patients who had AVF with high blood flow. In the most such patients, the blood flow rate of AVF is higher than 1.5 L/min.Citation21 Therefore, the risk of development of high-output cardiac failure is higher in upper arm fistulas, which have high blood flow rate.Citation22
As mentioned above, an increase in pulmonary blood flow rate is one of the two main mechanisms in the development of PAH. An AVF creation increases further pulmonary blood flow rate. Although it has been reported that 1500 mL/min of a fistula blood flow rate is a threshold for the development of high-output cardiac failure, there is no information about AVF blood rate required for the development of PAH in the literature. It is logical that the higher fistula blood flow, the higher pulmonary artery blood flow.
There were two studies which investigated the relationship between blood flow rate of AVF and PAP. Havlucu et al. detected the relationship between blood flow rate of AVF and systolic PAP value.Citation20 On the other hand, Acarturk et al. did not observe significant association between systolic PAP and fistula blood flow rate.Citation5 In these studies, HD patients had already an AVF for vascular access. To the best of our knowledge, in literature, there was no study which investigated the relationship between PAP and fistula blood flow in HD patients in whom evaluations before and after an AVF creation were performed. This study is the first such study. In the present study, we did not detect the relationship between and systolic PAP value and fistula blood flow rate.
In the literature also there was no information about the duration after an AVF creation for the development of PAH. It is logical that the longer the duration of AVF, the higher the risk of the PAH development. Acarturk et al.Citation5 in his study reported that the mean duration of AVF creation was 32.7 ± 34.1 months. This duration was 45.2 ± 40.0 months and 24.6 ± 28.0 months in PAH group and non-PAH group, respectively, and there was no significant difference between the two groups with regard to this duration. On the other hand, Havlucu et al.Citation20 reported that the duration of AVF creation was 16.2 ± 12.4 months and 6.7 ± 5.3 months in PAH group and non-PAH group, respectively, and there was significant difference between the two groups with regard to this duration. Also, the duration positively correlated with systolic PAP value. In a study performed Nakhoul et al.,Citation17 although this duration was higher in PAH group compared with non-PAH group (34.9 ± 25.2 months vs. 50 ± 30.1 months, respectively), there was no significant difference between the two groups. In our study, the duration of fistula was significantly higher in patients with PAH compared with patients without PAH. In addition, although the systolic PAP value did not correlate with the duration of AVF, the p-value was 0.052.
The interpretation of the above information is that it is logical that the duration of fistula and the blood flow rate of fistula may be a risk factor of the development of PAH in HD patients. However, data in literature and our study did not support precisely the opinion. The important point is that there are multiple mechanisms, including uremia, endothelial dysfunction, anemia, and hyperparathyroidism as well as increase in pulmonary blood flow for the development PAH in HD patients.
The most important cause of mortality in patients with ESRD is cardiovascular diseases, which resulted mainly from atherosclerosis. Inflammation plays a central role in the pathogenesis of atherosclerosis.Citation23 C-reactive protein (CRP), an acute-phase reactant, is the most important inflammatory marker for the risk of the development of cardiovascular disease.Citation24 There are a few studies that investigated the effects of inflammation in pathogenesis of PAH, which is a vascular disease.Citation25–27 Joppa et al.25Citation reported that in patients with COPD, the levels of serum CRP and tumor necrosis factor alpha (TNF-α) were significantly higher in patients with PAH compared to those without PAH. They also detected that PAP value significantly correlated with CRP. Elstein et al.Citation26 found that high CRP levels were important risk factor for the development of PAH in patients with Gaucher disease. High levels of inflammatory cytokines and acute-phase reactants are a frequent condition in patients with ESRD.Citation28 Several causes of this condition include underlying progressive kidney disease, infections, and interactions between blood and dialysis membrane.Citation28,29 There was only one study in which the relationship between inflammation and PAH was evaluated in patients with ESRD.Citation27 In this study, we reported that there was no correlation between inflammation markers such as hsCRP and WBC and PAP value and there was no significant difference between patients with PAH and those without PAH in terms of hsCRP and WBC.Citation27 In the present study, we found that hsCRP levels were significantly higher in HD and PD patients compared with controls. However, at period before an AVF creation, there was no significant difference between patients with PAH and those without PAH with regard to hsCRP. On the other hand, at period after an AVF creation, the hsCRP levels were significantly higher in patients with PAH compared to those without PAH. With findings of our study, it is difficult to say that inflammation is an important factor for the development of PAH in HD patients.
Vascular calcifications, a common finding, are the risk factors for cardiovascular mortality in patients with ESRD. Impairment in calcium–phosphorus balance and secondary hyperparathyroidism play an important role in the pathogenesis of the calcifications.Citation30 They develop in the interstitial space of the alveolar septum and in the walls of pulmonary vessels in lungs and negatively affect the functions of both the lung and right ventriculi.Citation31,32 It was reported that high PTH levels induce pulmonary calcification and pulmonary hypertension in animals with chronic renal failure.Citation32 Kumbar et al.Citation33 found that there was a significant relation between PAP values and PTH levels in PD patients. Similarly, Havlucu et al.Citation20 detected that PTH levels were meaningfully higher in HD patients with PAH compared with patients without PAH. On the other hand, in a study performed in 39 HD patients, Yigla et al.Citation34 investigated the role of extra-osseous pulmonary calcifications, which were detected by 99mTc-MDP scintigraphy, in the development of PAH. They find that there is no significant difference between patients with pulmonary calcifications and those without the calcifications in terms of systolic PAP value, PTH level, and Ca × P product. Similarly, Amin et al.Citation6 find that there is no relationship between PAH and frequency and severity of pulmonary artery calcifications in 51 HD patients. In the present study, we observed no significant difference between patients with PAH and those without PAH with regard to PTH levels and Ca × P product at periods before and after an AVF creation.
Anemia, a common complication of chronic kidney disease, can contribute to the development of PAH through increase in cardiac output.Citation35 However, in most studies that investigated PAH in HD patients, it was found that there was no significant difference between patients with PAH and those without PAH in terms of hemoglobin levels.Citation5,7,17,20 In the present study, it was it was found that there was significant difference between period before AVF creation and period after AVF creation with regard to hemoglobin levels, which were meaningfully higher at period after AVF creation. The cause of this condition was possibly the use of EPO for the treatment of anemia at period after an AVF creation, in which the hemoglobin level was significantly lower in patients with PAH compared with those without PAH. On the other hand, at period before an AVF creation there was no difference between the two groups in terms of hemoglobin levels. However, the patients did not receive EPO for the treatment of anemia and had severe anemia. This condition appears to cause no difference between patients with PAH and those without PAH with regard to hemoglobin levels at period before an AVF creation. All findings about hemoglobin levels in this study support the opinion that anemia is an important factor in the development of PAH in HD patients.
LVH is a predictor for cardiovascular mortality and morbidity. In literature, there are a few prospective studies, in which short-duration effects of a newly created AVF on left ventriculi has been investigated.Citation36,37 Iwashima et al.Citation36 reported that in 16 HD patients with a newly created AVF, 15% increase in cardiac output and a significant increase in left ventricular end-diastolic diameter had occurred at the second week after an AVF creation. Similarly, Ori et al.Citation37 reported that a significant increase in stroke volume, ejection fraction, cardiac output, cardiac index, and left ventricular end-diastolic diameter had occurred at 10th day after an AVF creation in 10 patients on HD. However, in these studies, LVMI and LVH were not evaluated. On the other hand, unfortunately, there was no prospective study, in which long-term effects of a newly created AVF on left ventriculi had been investigated. In a few studies that was performed in patients with renal transplantation, it was shown regression of LVF after AVF closure.Citation38,39 The finding indirectly indicates that AVF creation is a contributing factor for the development of LVH.
Several studies reported that there was no significant difference in LVH between ESRD patients with and without PAH. However, in study that was performed in PD patients, we found that PAP significantly correlated with LVMI and LVMI was the most important parameter, which affects PAP value in multivariate analysis.Citation27 In the present study, we observed that LVMI value and the presence of LVH were significantly higher at period after an AVF creation compared to at period before an AVF creation, and so severe negative effects of AVF creation on the development of LVH.
Hypoalbuminemia is one of the most important risk factors for mortality in patients with ESRD.Citation40 In only two studies evaluated PAH in patients with ESRD, there was information about serum albumin concentration. Kumbar et al.Citation33 found that serum albumin level was higher in PD patients with PAH compared with patients without PAH, although the difference between the two groups was not statistically significant. We found that there was negatively significant correlation between PAP and serum albumin level, and albumin level was an independent risk factor for PAP value in multivariate analysis in PD patients.Citation27 Similarly, in the present study, serum albumin level was significantly lower in patients with PAH compared with those without PAH at period after an AVF creation. The findings can indicate that one of causes of the condition, that hypoalbuminemia is a risk factor for mortality in patients with ESRD, is that hypoalbuminemia is more frequent in patients with PAH.
There is controversial information about the effects of EPO on pulmonary vessels. In some studies, it was found that EPO decreased the PAP values.Citation41,42 On the other hand, in the other studies, it was detected that EPO induces the development of PAH.Citation43,44 However, in the present study, we observed that there was no significant relationship between EPO use and PAH. Similar finding was observed in our study performed in PD patients.Citation27
Perhaps, increase in pulmonary blood flow induced by AVF and detrimental effects of inflammation on pulmonary circulation might be balanced by several factors, was induced by HD, including better clearance of uremic toxins with HD, correction of anemia with EPO treatment, a better calcium–phosphorus balance with HD and use of phosphorus binding agents, correction nutrition and hence increase of serum albumin level with correction of appetite. Also, there may be effects of the other factors, which were not evaluated in the present study, on the development of PAH in patients with HD.
In conclusion, PAH was a common complication in HD patients. There was no significant short-term effect of an AVF created surgically on the development of PAH. Similarly, there was considerable no relationship between fistula blood flow rate and systolic PAP measurement.
STUDY LIMITATIONS
| 1. | The invasive procedure (right heart catheterization) is the best method to estimate PAP. However, in literature, to the best of our knowledge, in all studies, in which pulmonary hypertension was investigated in patients with ESRD, PAP was estimated by echocardiographic method. Also, Marangoni et al.Citation10 reported that there was excellent correlation between the measurements of PAP by Doppler echocardiography and by invasive method. In addition, invasive method in estimating PAP is difficult and traumatic procedure for the patients. Also, it was so difficult that approval of the patients, which were included to the study, for invasive procedure because of the above–mentioned reasons. Therefore, we chose echocardiographic method to estimate systolic PAP because of the above–mentioned reasons. | ||||
| 2. | The patients with double–lumen tunneled cuffed catheters could be included in the study as control group. However, we never prefer the catheters as the first choice for vascular access. The patients, who were enrolled to the study, had newly diagnosed ESRD and started HD for renal replacement therapy. During the study, only one patient, who had cervix cancer, was dialyzed using double–lumen tunneled cuffed catheters as the first choice for vascular access. Therefore, patients with tunneled cuffed catheters were not include in the present study because of above–mentioned reasons. | ||||
| 3. | The number of patients in this study was relatively low. In literature, however, the number of patients was low, in which PAH was investigated in patients with ESRD. In the future, the matter will be evaluated in multicenter studies. | ||||
| 4. | In the present study, our observation that the AVF creation had no significant effect on PAP may be due to the evaluation of PAP too shortly after the AVF creation. A longer follow–up could have provided different results. | ||||
Declaration of interest: The authors report no conflicts of interest.
REFERENCES
- Yigla M, Abassi Z, Reisner SA, Nakhoul F. Pulmonary hypertension in hemodialysis patients: an unrecognized threat. Semin Dial. 2006;19:353–357.
- Rubin LJ. Pulmonary arterial hypertension. Proc Am Thorac Soc. 2006;3:111–115.
- Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004;351:1655–1665.
- Yigla M, Nakhoul F, Sabag A, Pulmonary hypertension in patients with end-stage renal disease. Chest. 2003;123:1577–1582.
- Acarturk G, Albayrak R, Melek M, The relationship between arteriovenous fistula blood flow rate and pulmonary artery pressure in hemodialysis patients. Int Urol Nephrol. 2008;40:509–513.
- Amin M, Fawzy A, Hamid MA, Elhendy A. Pulmonary hypertension in patients with chronic renal failure: role of parathyroid hormone and pulmonary artery calcifications. Chest. 2003;124:2093–2097.
- Tarrass F, Benjelloun M, Medkouri G, Hachim K, Benghanem MG, Ramdani B. Doppler echocardiograph evaluation of pulmonary hypertension in patients undergoing hemodialysis. Hemodial Int. 2006;10:356–359.
- Engelberts I, Tordoir JH, Boon ES, Schreij G. High-output cardiac failure due to excessive shunting in a hemodialysis access fistula: an easily overlooked diagnosis. Am J Nephrol. 1995;15:323–326.
- MacRae JM, Levin A, Belenkie I. The cardiovascular effects of arteriovenous fistulas in chronic kidney disease: a cause for concern? Semin Dial. 2006;19:349–352.
- Marangoni S, Quadri A, Dotti A, Noninvasive assessment of pulmonary hypertension: a simultaneous echo-Doppler hemodynamic study. Cardiology. 1988;75:401–408.
- Dabestani A, Mahan G, Gardin JM, Evaluation of pulmonary artery pressure and resistance by pulsed Doppler echocardiography. Am J Cardiol. 1987;59:662–668.
- Barst RJ, McGoon M, Torbicki A, Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12 Suppl. S):40S–47S.
- Devereux RB, Wachtell K, Gerdts E, Prognostic significance of left ventricular mass change during treatment of hypertension. J Am Med Assoc. 2004;292:2350–2356.
- Mosteller RD. Simplified calculation of body surface area. N Engl J Med. 1987;317:1098.
- Rosenkranz S. Pulmonary hypertension: current diagnosis and treatment. Clin Res Cardiol. 2007;96:527–541.
- Minai OA, Budev MM. Diagnostic strategies for suspected pulmonary arterial hypertension: a primer for the internist. Cleve Clin J Med. 2007;74:737–747.
- Nakhoul F, Yigla M, Gilman R, Reisner SA, Abassi Z. The pathogenesis of pulmonary hypertension in hemodialysis patients via arterio-venous access. Nephrol Dial Transplant. 2005;20:1686–1692.
- Giaid A, Yanagisawa M, Langleben D, Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328:1732–1799.
- Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995;333:214–221.
- Havlucu Y, Kursat S, Ekmekci C, Pulmonary hypertension in patients with chronic renal failure. Respiration. 2007;74: 503–510.
- MacRae JM. Vascular access and cardiac disease: is there a relationship? Curr Opin Nephrol Hypertens. 2006;15:577–582.
- Begin V, Ethier J, Dumont M, Leblanc M. Prospective evaluation of the intra-access flow of recently created native arteriovenous fistulae. Am J Kidney Dis. 2002;40: 1277–1282.
- Li JJ, Fang CH. C-reactive protein is not only an inflammatory marker but also a direct cause of cardiovascular diseases. Med Hypotheses. 2004;62:499–506.
- Rifai N, Ridker PM. High-sensitivity C-reactive protein: a novel and promising marker of coronary heart disease. Clin Chem. 2001;47:403–411.
- Joppa P, Petrasova D, Stancak B, Tkacova R. Systemic inflammation in patients with COPD and pulmonary hypertension. Chest. 2006;130:326–333.
- Elstein D, Nir A, Klutstein M, Rudensky B, Zimran A. C-reactive protein and NT-proBNP as surrogate markers for pulmonary hypertension in Gaucher disease. Blood Cells Mol Dis. 2005;34:201–215.
- Unal A, Sipahioglu MH, Oguz F, Pulmonary hypertension in peritoneal dialysis patients: the prevalence and risk factors. Perit Dial Int. 2009;29:191–198.
- Ikizler TA. Nutrition, inflammation and chronic kidney disease. Curr Opin Nephrol Hypertens. 2008;17:162–167.
- Caglar K, Peng Y, Pupim LB, Inflammatory signals associated with hemodialysis. Kidney Int. 2002;62:1408–1416.
- Davies MR, Hruska KA. Pathophysiological mechanisms of vascular calcification in end-stage renal disease. Kidney Int. 2001;60:472–479.
- Bendayan D, Barziv Y, Kramer MR. Pulmonary calcifications: a review. Respir Med. 2000;94:190–193.
- Akmal M, Barndt RR, Ansari AN, Mohler JG, Massry SG. Excess PTH in CRF induces pulmonary calcification, pulmonary hypertension and right ventricular hypertrophy. Kidney Int. 1995;47:158–163.
- Kumbar L, Fein PA, Rafiq MA, Borawski C, Chattopadhyay J, Avram MM. Pulmonary hypertension in peritoneal dialysis patients. Adv Perit Dial. 2007;23:127–131.
- Yigla M, Keidar Z, Safadi I, Tov N, Reisner SA, Nakhoul F. Pulmonary calcification in hemodialysis patients: correlation with pulmonary artery pressure values. Kidney Int. 2004;66:806–810.
- Abassi Z, Nakhoul F, Khankin E, Reisner SA, Yigla M. Pulmonary hypertension in chronic dialysis patients with arteriovenous fistula: pathogenesis and therapeutic prospective. Curr Opin Nephrol Hypertens. 2006;15:353–360.
- Iwashima Y, Horio T, Takami Y, Effects of the creation of arteriovenous fistula for hemodialysis on cardiac function and natriuretic peptide levels in CRF. Am J Kidney Dis. 2002;40:974–982.
- Ori Y, Korzets A, Katz M, Perek Y, Zahavi I, Gafter U. Hemodialysis arteriovenous access—a prospective hemodynamic evaluation. Nephrol Dial Transplant. 1996;11:94–97.
- Unger P, Velez-Roa S, Wissing KM, Hoang AD, van de Borne P. Regression of left ventricular hypertrophy after arteriovenous fistula closure in renal transplant recipients: a long-term follow-up. Am J Transplant. 2004;4:2038–2044.
- Unger P, Wissing KM, de Pauw L, Neubauer J, van de Borne P. Reduction of left ventricular diameter and mass after surgical arteriovenous fistula closure in renal transplant recipients. Transplantation. 2002;74:73–79.
- Lowrie EG, Lew NL. Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis. 1990;15:458–482.
- Satoh K, Kagaya Y, Nakano M, Important role of endogenous erythropoietin system in recruitment of endothelial progenitor cells in hypoxia-induced pulmonary hypertension in mice. Circulation. 2006;113:1442–1450.
- Weissmann N, Manz D, Buchspies D, Congenital erythropoietin over-expression causes “anti-pulmonary hypertensive” structural and functional changes in mice, both in normoxia and hypoxia. Thromb Hemost. 2005;94:630–638.
- Hasegawa J, Wagner KF, Karp D, Altered pulmonary vascular reactivity in mice with excessive erythrocytosis. Am J Respir Crit Care Med. 2004;169:829–835.
- Briest W, Homagk L, Baba HA, Cardiac remodeling in erythropoietin-transgenic mice. Cell Physiol Biochem. 2004;14:277–284.