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(Chest. 2003;123:1577-1582.)
© 2003 American College of Chest Physicians

Pulmonary Hypertension in Patients With End-Stage Renal Disease*

Mordechai Yigla, MD; Farid Nakhoul, MD; Anat Sabag, MD; Naveh Tov, MD; Bella Gorevich, MD; Ziad Abassi, PhD and Shimon A. Reisner, MD

* From the Departments of Nephrology (Drs. Nakhoul and Gorevich) and Cardiology (Dr. Reisner), Division of Pulmonary Medicine (Drs. Yigla, Sabag and Tov), Rambam Medical Center and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa; and Nephrology Research Laboratory (Dr. Abassi), Technion-Israel Institute of Technology, Haifa, Israel.

Correspondence to: Mordechai Yigla, MD, Division of Pulmonary Medicine, Rambam Medical Center, PO Box 9602, Haifa 31096, Israel; e-mail: m_yigla{at}rambam.health.gov.il


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: The aims of this study were to evaluate the incidence of unexplained pulmonary hypertension (PH) among patients with end-stage renal disease (ESRD) and to suggest possible etiologic factors.

Methods: The incidence of PH was prospectively estimated by Doppler echocardiography in 58 patients with ESRD receiving long-term hemodialysis via arteriovenous access, and in control groups of 5 patients receiving peritoneal dialysis (PD) and 12 predialysis patients without a known other cause to suggest the presence of PH. Clinical variables were compared between patients with and without PH receiving hemodialysis. Changes in pulmonary artery pressure (PAP) values before and after onset of hemodialysis via arteriovenous access, arteriovenous access compression, and successful kidney transplantation were recorded.

Results: PH > 35 mm Hg was found in 39.7% of patients receiving hemodialysis (mean ± SD, 44 ± 7 mm Hg; range, 37 to 65 mm Hg), in none of the patients receiving PD, and in 1 of 12 predialysis patients. Patients with PH receiving hemodialysis had a significantly higher cardiac output (6.9 L/min vs 5.5 L/min, p = 0.017). PH developed in four of six patients with normal PAP after onset of hemodialysis therapy via arteriovenous access. One-minute arteriovenous access compression in four patients decreased the mean systolic PAP from 52 ± 7 to 41 ± 4 mm Hg (p = 0.024). PH normalized in four of five patients receiving hemodialysis following kidney transplantation. Kaplan-Meier survival analysis according to PAP values revealed significant survival differences (p < 0.024).

Conclusions: This study demonstrates a surprisingly high incidence of PH among patients with ESRD receiving long-term hemodialysis with surgical arteriovenous access. Both ESRD and long-term hemodialysis via arteriovenous access may be involved in the pathogenesis of PH by affecting pulmonary vascular resistance and cardiac output.

Key Words: arteriovenous access • end-stage renal disease • hemodialysis • pulmonary hypertension


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
In a previous study that examined the background diseases of patients with a Doppler echocardiographic diagnosis of pulmonary hypertension (PH), we reported elevated pulmonary artery pressure (PAP) in some patients with end-stage renal disease (ESRD) maintained on long-term hemodialysis via surgically created arteriovenous access. As these patients had no cardiac or pulmonary diseases, we assumed that PH was related to the ESRD and/or to long-term hemodialysis therapy via arteriovenous access.1

There are several potential explanations for the development of PH in patients with ESRD. Hormonal and metabolic derangement associated with ESRD might lead to pulmonary arterial vasoconstriction and an increase of the pulmonary vascular resistance.2 3 4 5 PAP may be further increased by high cardiac output resulting from the arteriovenous access itself, worsened by commonly occurring anemia and fluid overload.6

Despite almost 4 decades of long-term hemodialysis availability, the long-term effect on the pulmonary circulation of long-term hemodialysis performed via a surgically created, often large, arteriovenous access has not been studied. The aims of this study were to evaluate the incidence of PH in patients with ESRD who are maintained on long-term hemodialysis therapy via surgically created arteriovenous access, and to examine some possible etiologic factors for its occurrence.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
Our institutional clinical research ethics review board approved the research protocol, and all participants signed an informed consent before entering the study.

Patient Selection:
The original study population included 124 patients with ESRD who were maintained on long-term hemodialysis therapy via surgically created native arteriovenous access in our dialysis unit from January 1997 through December 1999. Fifty-five patients were excluded due to comorbid conditions with a high probability of secondary PH (cardiac disease [n = 42], pulmonary disease [n = 10], collagen vascular disease [n = 3]), 6 patients were excluded due to poor general condition, and 5 patients refused to participate. The final study group consisted of 58 eligible patients without a known cause of PH. The control group consisted of 5 patients with ESRD receiving long-term peritoneal dialysis (PD) and 12 patients with advanced renal failure followed up in the predialysis clinic, all without known cause for PH.

Patient Evaluation:
Systolic PAP was estimated in the 58 patients receiving hemodialysis and in the 17 control subjects by Doppler echocardiography. To avoid overestimation of PAP due to volume overload, the echocardiology studies in patients receiving hemodialysis were performed within 1 h after completion of dialysis, while the patients were at optimal dry weight according to clinical volume status assessment, including BP and weight.

An experienced operator (S.A.R.) performed all the echocardiographic studies, using Sequoia, Aspen, or 128 XP (Acuson; Mountain View, CA) ultrasound machines. A complete two-dimensional, M-mode, Doppler echocardiographic study was obtained on each patient. A tricuspid regurgitation systolic jet was recorded from the parasternal or apical window with the continuous-wave Doppler echocardiographic probe. Systolic right ventricular (or pulmonary artery) pressure was calculated using the modified Bernoulli equation: PAP = 4 x (tricuspid systolic jet)2 + 10 mm Hg (estimated right atrial pressure).7 The accuracy of systolic PAP estimation by Doppler echocardiography in our laboratory was previously published.8 PH was defined as a systolic PAP >= 35 mm Hg. Cardiac output was estimated from the left ventricular outflow tract velocity time integral x diameter.9

The patient’s general data (age, sex, comorbidities, medications used) and data regarding the kidney disease (etiology of renal failure, age at onset, duration of hemodialysis therapy, and access location [brachial or radial]) were recorded directly from the patients or from their hospital files. Blood tests for hemoglobin, hematocrit, calcium, phosphorus, and parathyroid hormone level were sampled at the end of the hemodialysis therapy within 1 week of the echocardiography study. The mean of the six monthly values preceding the echocardiography study of hemoglobin, hematocrit, calcium, and phosphorus were utilized.

Patients with PH > 35 mm Hg were evaluated further by an experienced pulmonologist (M.Y.) in order to uncover other potential causes of PH. This assessment included history, physical examination, chest radiograph, chest CT, complete pulmonary function tests, measurement of arterial blood gases and oxygen saturation, and ventilation-perfusion lung scan as previously described.1

We studied subgroups of patients with ESRD receiving hemodialysis at the following times: before and after entering the hemodialysis program (n = 5), after arteriovenous access compression with a sphygmomanometer (n = 4), and after successful kidney transplantation (n = 5). The respective PAP and cardiac output values were compared. Another nine patients with PH secondary to cardiac conditions (excluded from the study due to the cardiac comorbidity) were studied separately before and after entering the hemodialysis program.

Data Analysis
The prevalence of PH > 35 mm Hg was compared among subgroups of patients with ESRD receiving hemodialysis, patients receiving PD, and patients with advanced renal failure (predialysis) using the Fisher exact test. Clinical variables were compared between patients with and without PH receiving hemodialysis using analysis of variance. The correlation between categorical variables, such as PH and survival from onset of hemodialysis therapy, was evaluated using the {chi}2 statistic. Values are expressed as mean ± 1 SD. All p values < 0.05 were considered significant.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
PAP values are presented in Table 1 . PH was observed in 23 patients receiving hemodialysis (39.7%), with a mean systolic PAP of 44 mm Hg. Notably, all patients receiving PD and all but one patient (PAP of 38 mm Hg) in the predialytic state had PAP <= 35 mm Hg. Patient characteristics for the 58 patients receiving hemodialysis are presented in Table 2 . Mean duration of hemodialysis therapy prior to the echocardiography study was 45 ± 56 months. The common etiologies of renal failure were diabetes mellitus, arterial hypertension, and glomerulopathy.


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  		Table 1. Systolic PAP in the Three Subgroups of Patients With ESRD

 

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  		Table 2. Data on 58 Patients With ESRD Receiving Hemodialysis via Surgical Arteriovenous Access

 
Data on the 23 patients with PH receiving hemodialysis were compared with the 35 patients without PH receiving hemodialysis (Table 3 ). The cardiac output was significantly higher among the PH subgroup (6.9 ± 1.8 L/min vs 5.5 ± 0.7 L/min, p < 0.017). The hemoglobin and hematocrit levels were significantly lower in the PH subgroup (9.7 ± 1 g/dL vs 10.9 ± 1.1 g/dL and 30.4 ± 2.1% vs 34.6 ± 2.5%, p = 0.012 and 0.007, respectively). The elevated cardiac output in both subgroups was not explained by the hemoglobin level as a covariant (analysis of variance). There was no significant difference in the recorded use of antihypertensive medications (PH, 87%; no PH, 82.3%), nor was the distribution of ß-blocker and vasodilator agents significantly different between the two subgroups.


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  		Table 3. Clinical and Laboratory Data Between Patients With and Without PH*

 
The mean duration of hemodialysis therapy was not significantly shorter in the PH subgroup (36 ± 30 months vs 53 ± 69 months). Other variables, such as anatomic location of the dialysis vascular access, parathyroid hormone activity, and calcium-phosphate product, did not differ significantly.

Nine patients (15.5%) died during follow-up: six patients with PH and three patients without PH, corresponding to mortality rates of 30.4% and 8.5%, respectively. Kaplan-Meier survival analysis (Fig 1 ) according to PAP values revealed significantly survival differences (p < 0.024). Nonsurviving patients were significantly older than surviving patients: 70.8 ± 10.5 years vs 56.6 ± 15.5 years (p = 0.012). Other clinical variables did not differ significantly.



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  		Figure 1. Kaplan-Meier survival analysis according to PH group (PHT) revealed significant survival differences (p < 0.024). Cum = cumulative.

 
Six hemodialysis patients underwent Doppler echocardiography before entering hemodialysis therapy, showing normal PAP values (Table 4 ). Repeated echocardiography after 3 to 52 months of hemodialysis showed significant elevation of mean PAP values to 37 to 45 mm Hg in four of six patients, while mean PAP values of the other two patients remained normal.


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  		Table 4. Prehemodialysis and Posthemodialysis Systolic PAP Values in Six Patients*

 
Five patients with PH receiving hemodialysis underwent successful kidney transplantation during the study period. The pretransplantation mean systolic PAP of 47 ± 11 mm Hg (range, 42 to 65 mm Hg) decreased to 32 ± 8 mm Hg (range, 22 to 37 mm Hg) [p < 0.05]. In four of five patients, the posttransplant systolic PAP was < 35 mm Hg (Table 5 ).


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  		Table 5. Pretransplantation and Posttransplantation PAP Values*

 
PAP was estimated before and 1 min after arteriovenous access compression in four patients with significant PH receiving hemodialysis. During this maneuver, the mean cardiac output decreased from 7 ± 1.9 to 6 ± 2 L/min, while the mean systolic PAP decreased from 52 ± 7 to 41 ± 4 mm Hg, p = 0.024.

Prehemodialysis and posthemodialysis Doppler echocardiographic studies were available from nine patients with cardiac diseases, who had initially elevated PAP values of 35 to 61 mm Hg. The PAP of four patients increased further by 14 to 16 mm Hg, decreased by 10 to 13 mm Hg in three patients, and did not change in the remaining two patients.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
During the last 4 decades, patients with ESRD maintain life with the aid of hemodialysis via surgical arteriovenous access. The impact of this often large arteriovenous shunt on the pulmonary circulation has not been studied. In this study, we looked for the first time at the PAP of an entire population of patients with ESRD followed up in a large general hospital. After exclusion of patients with possible secondary PH, we had a small but clear-cut group of dialytic (hemodialysis and PD) and predialytic patients.

Almost 40% of patients undergoing long-term hemodialysis via an arteriovenous access had unexplained PH. Eight patients (13.8%) had systolic PAP >= 45 mm Hg, which is considered clinically significant.1 The PAP of five patients receiving PD and all but one predialysis patient were within the normal range. Since PAP increased significantly following initiation of hemodialysis therapy via arteriovenous access and decreased significantly after successful kidney transplantation, as well as after short arteriovenous access compression, we could hypothesize that both ESRD and arteriovenous access contribute to the pathogenesis of PH.

We compared clinical, hemodynamic, and metabolic variables among patients with and without PH receiving hemodialysis. Patients with PH had significantly higher cardiac output, lower hemoglobin and hematocrit levels, and experienced a short duration of hemodialysis therapy, which is attributed to shorter survival or to referral of patients with PH to kidney transplantation or to arteriovenous access reduction.

Although anemia is associated with a compensatory increased cardiac output, the more pronounced anemia in the patients with PH does not explain all the differences in the cardiac output. It appears that other factors, such as the size (or the amount of blood shunted) of arteriovenous access, are involved in the mechanism that increases cardiac output. The effects of calcium-phosphate product, parathyroid hormone activity, and shunt location was not statistically significant. The mortality rate of the elevated PAP group was higher than the normal PAP group (30.8% vs 3.5%), and these values reach statistical significance in Kaplan-Meier survival analysis (p < 0.024). In a multivariant analysis, mortality was found to be correlated only to age.

Pathophysiology of PH in Patients With ESRD
From a physiologic point of view, due to the enormous capacity of the pulmonary microcirculation, increased cardiac output by itself cannot cause PH. We may assume that the pulmonary circulation of many patients with ESRD cannot maintain arteriovenous access-mediated elevated cardiac output. This may result from increased pulmonary vascular resistance or diminished vasodilatory response to the increased cardiac output.

Diminished pulmonary vasodilatory response could result from anatomic or functional changes. A study in dogs with experimental ESRD showed pulmonary calcification, increased pulmonary vascular resistance, and right ventricular hypertrophy only in dogs with intact parathyroid glands.10 The authors concluded that pulmonary involvement was secondary to increased parathyroid hormone activity. The present study indicates reversible changes without a confirmed role for parathyroid hormone.

Endothelin 1, a potent pulmonary vasoconstrictor that has been shown to be involved in primary and secondary PH,11 12 is increased in patients with chronic renal failure.13 We have observed significantly increased endothelin 1 activity in patients with PH receiving hemodialysis (M. Yigla, MD; unpublished observations; May 2002).

The vascular access formed for hemodialysis therapy is artificial, often causing a large left-to-right shunt whose capacity often increases with time. Currently, there are no standard criteria regarding optimal arteriovenous access size. Available methods for quantitative evaluation of the amount of blood shunted through the vascular access such as Doppler echocardiography and thermodilution have not become commonplace yet.

Study Limitations
The exclusion criteria used in our protocol resulted in a small study group, since the majority of patients with ESRD had concomitant cardiac or pulmonary disease. Since the number of eligible patients in any center is limited, further studies, including a multicenter approach, are required.

The exclusion of patients with ESRD with cardiac or pulmonary disease from analysis was a methodologic necessity. In clinical practice, a further increase in existing PAP as a result of hemodialysis with a large arteriovenous access may be even more detrimental; however, we found that the PAP of some patients receiving hemodialysis with coexisting cardiac diseases decreased significantly following hemodialysis therapy, presumably due to improved congestive heart failure management and control.

Conclusions and Clinical Implications
Based on our observations, we can conclude that a substantial number of patients with ESRD have functional abnormality of pulmonary circulation. Pathologic elevation of PAP occurs in those patients whose pulmonary circulation cannot compensate for the arteriovenous access-related high cardiac output. This unrecognized complication of hemodialysis therapy is not uncommon and, perhaps most importantly, is associated with reduced survival.

Long-standing significant PH of any etiology is associated with anatomic changes in the pulmonary capillaries and the right ventricle, with increased morbidity and mortality.14 15 Estimation and follow-up of PAP using Doppler echocardiography may be indicated in all patients with ESRD undergoing hemodialysis via an arteriovenous access. Increased unexplained, frequently symptomatic PAP is a call for further investigation, which may include assessment under careful temporary compression of the arteriovenous access. On the basis of our findings, several patients have been referred for successful surgical reduction of their arteriovenous access. Standardization of arteriovenous access size and a reliable method for shunt estimation will be of great assistance in the future. Amelioration of PH following kidney transplantation raises the question of adding significant, progressive PH in patients with ESRD as another criterion for expeditious kidney transplantation.


   Acknowledgements
 
The authors thank Dr. Karl Skorecki, and Mrs. Myrna Perlmutter for help in the preparation of this article.


   Footnotes
 
Abbreviations: ESRD = end-stage renal disease; PAP = pulmonary artery pressure; PD = peritoneal dialysis; PH = pulmonary hypertension

Received for publication April 11, 2002. Accepted for publication October 10, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Yigla, M, Azzam, Z, Rubin, AHE, et al (2000) Background diseases in 714 patients with moderate to severe pulmonary hypertension. Isr Med Assoc J 2,501-506[ISI][Medline]
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  3. Ifudu, O Care of patients undergoing hemodialysis. N Engl J Med 1998;339,1054-1062[Free Full Text]
  4. Kooman, JP, Leunissen, KM Cardiovascular aspects in renal disease. Curr Opin Nephrol Hypertens 1993;2,791-797[Medline]
  5. Michel, RP, Hakim, TS, Hanson, RE, et al Distribution of lung resistance after chronic systemic-to-pulmonary shunts. Am J Physiol 1985;249,106-113
  6. Okura, H, Takatsu, Y High output failure as cause of pulmonary hypertension. Intern Med 1994;33,363-365[ISI][Medline]
  7. Berger, M, Haimowitz, A, Van Tosh, P, et al Quantitative assessment of pulmonary hypertension in patients with tricuspid regurgitation using continuous wave Doppler ultrasound. J Am Coll Cardiol 1985;6,359-365[Abstract]
  8. Reisner, SA, Azzam, Z, Halmann, M, et al Septal to free wall curvature ratio: a non-invasive index of pulmonary arterial pressure. J Am Soc Echocardiogr 1994;7,27-35[Medline]
  9. Ihlen, H, Endresen, K, Golf, S, et al Cardiac stroke volume during exercise measured by Doppler echocardiography: comparison with the thermodilution technique and evaluation of reproducibility. Br Heart J 1987;58,455-459[Abstract/Free Full Text]
  10. Akmal, M, Barnatt, RR, Ansari, AN, et al Excess PTH in CRF induces pulmonary calcification, pulmonary hypertension and right ventricular hypertrophy. Kidney Int 1995;47,158-163[ISI][Medline]
  11. Stewart, DJ, Levy, RD, Cernacek, P, et al Increased plasma endothelin 1 in pulmonary hypertension: marker or mediator of disease. Ann Intern Med 1991;144,464-469
  12. Giaid, A, Yanagisawa, M, Langleben, D, et al Expression of endothelin-1 in the lungs of patients with primary pulmonary hypertension. N Engl J Med 1993;328,1732-1739[Abstract/Free Full Text]
  13. Brooks, DP Role of endothelin in renal function and dysfunction. Clin Exp Pharmacol Physiol 1996;23,345-348[ISI][Medline]
  14. Reeves, JT, Rich, S, Vreim, CE, et al Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991;115,343-349[ISI][Medline]
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