(Chest. 2003;124:2093-2097.)
© 2003
American College of Chest Physicians
Pulmonary Hypertension in Patients With Chronic Renal Failure*
Role of Parathyroid Hormone and Pulmonary Artery Calcifications
Mona Amin, MD;
Ashraf Fawzy, MD;
Magdy Abdel Hamid, MD and
Abdou Elhendy, MD, PhD
* From the Departments of Internal Medicine (Dr. Amin), Nuclear Medicine (Dr. Fawzy), and Cardiology (Dr. Hamid), Cairo University Hospital, Cairo, Egypt; and Department of Internal Medicine, Section of Cardiology, University of Nebraska Medical Center (Dr. Elhendy), Omaha, NE.
Correspondence to: Abdou Elhendy MD, PhD, 982055 Nebraska Medical Center, Omaha, NE 68198-2265; e-mail: Aelhendy{at}unmc.edu
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Abstract
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Rationale: The aim of this work was to study the association of pulmonary hypertension (PH) with pulmonary artery calcifications (PACs) and hyperparathyroidism in patients with chronic renal failure (CRF) receiving regular hemodialysis.
Background: Scarce data are available regarding the prevalence and the predictors of PH in patients with CRF. Abnormal 99mTc diphosphonate lung uptake was reported in these patients, suggesting a role of PACs.
Methods: We studied 51 patients (28 men and 23 women) with end-stage renal disease, who were receiving regular hemodialysis. Patients underwent two-dimensional, Doppler echocardiographic imaging. Laboratory investigations included BUN, serum creatinine, calcium, phosphorus, alkaline phosphatase, and intact molecule parathormone. PH was defined as pulmonary artery systolic pressure > 35 mm Hg as determined by Doppler echocardiographic evaluation.
Results: PH was detected in 15 patients (29%). Women had a higher prevalence of PH (48% vs 14%, p = 0.01). There was no significant differences between patients with PH and those without PH with regards to age, duration of dialysis, serum calcium (9.6 ± 2 mg/dL vs 10 ± 2 mg/dL), phosphorus (6 ± 1.4 mg/L vs 6.2 ± 1.9 mg/L), alkaline phosphatase (609 ± 768 U/L vs 473 ± 574 U/L), parathyroid hormone (PTH) [420 ± 512 pg/mL vs 354 ± 519 pg/mL] or the prevalence of an abnormal 99mTc diphosphate lung scan result (60% vs 73%, respectively [± SD]).
Conclusions: This study demonstrated that 29% of patients with CRF receiving regular hemodialysis have PH. The presence of PH was not related to the level of PTH or the severity of other metabolic abnormalities. There was no relation between PH and the presence or the severity of PAC. PH is detected more frequently in women. This study does not support a role of secondary hyperparathyroidism and subsequent PAC as the etiology of PH in patients with CRF.
Key Words: chronic renal failure • parathyroid hormone • pulmonary calcifications • pulmonary hypertension
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Introduction
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Cardiovascular complications are major causes of mortality in patients with chronic renal failure (CRF) receiving regular hemodialysis.1
2
Metastatic pulmonary artery calcifications (PACs) are detected at autopsy in 60 to 80% of patients receiving regular hemodialysis.3
4
However, calcifications are infrequently identified on conventional chest radiographs in these patients.5
6
7
An abnormal lung uptake of 99mTc diphosphate was reported in up to 60% of patients with CRF receiving regular hemodialysis in the presence of normal chest radiograph findings indicating the presence of PAC.5
Parathyroid hormone (PTH) is known to enhance the entry of calcium into many cells. Chronic exposure to excess blood levels of PTH is associated with increased calcium content of many tissues.8
Therefore, it is possible that the state of secondary hyperparathyroidism in patients with CRF is also responsible for the development of PAC.9
It was suggested that the abnormalities in right ventricular function in patients with CRF are in largely due to pulmonary hypertension (PH), which develops secondary to PAC.9
The prevention of PAC by parathyroidectomy in dogs with CRF was associated with normalization of the mean pulmonary artery pressure and reduction of right ventricular hypertrophy.9
Data regarding the incidence and the mechanisms of PH in patients with CRF receiving regular hemodialysis are scarce. The aim of this work was to find whether PH can be predicted by the severity of hormonal and metabolic abnormalities in patients with CRF receiving regular hemodialysis and to study the association of PH with PAC.
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Materials and Methods
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The study population consisted of 51 patients (28 men and 23 women), with end-stage renal disease, who were treated by regular hemodialysis through arteriovenous fistula three times per week in 4-h sessions. Patients were consecutively enrolled at the dialysis unit of our institute if they agreed to participate in the study, had adequate echocardiographic window, and had no exclusion criteria. All patients gave an informed consent to participate in the study. The hospital ethics committee approved the protocol of the study. Exclusion criteria were chronic obstructive lung disease, chest wall or parenchymal lung disease, primary PH, previous pulmonary embolism, collagen vascular disease, left ventricular ejection fraction 
50%, left-to-right shunt, and significant mitral or aortic valve disease. Patients were subjected to the following:
Clinical and Laboratory Investigations
All patients underwent full clinical evaluation with special emphasis to detect any clinical condition that predispose to PH, chest radiography, and a standard 12-leads ECG. Laboratory investigations included BUN, creatinine, serum calcium, phosphorus, alkaline phosphatase, hemoglobin and complete lipid profile. Intact molecule parathormone (PTH) was measured by radioimmunoassay using commercially available kits (Biosource Europe S.A; Nivelles, Belgium).10
Doppler Echocardiography
Two-dimensional and M-mode echocardiography was performed in all patients within 4 h following dialysis. Imaging was performed with Hewlett-Packard (Bathell, WA) Sonos 1000 equipped with 2.5 MHz and 3.2 MHz phased pulsed array transducers. Cardiac dimensions were measured according to the guidelines of the American Society of Echocardiography.11
In the presence of tricuspid regurgitation, continuous-wave Doppler echocardiography was used to estimate the pulmonary artery systolic pressure. Transtricuspid systolic pressure gradient was estimated according to the modified Bernoulli equation.12
To calculate pulmonary artery systolic pressure, 10 mm Hg (estimated systolic right atrial pressure) was added. PH was defined as calculated pulmonary artery systolic pressure > 35 mm Hg.
99mTc Diphosphate Scintigraphy
99mTc diphosphate was prepared from a freeze-dried kit by reconstitution with 6 mL of sterile Na pertechnetate solution containing 740 to 930 megabecquerel (20 to 25 mCi). Bone single-photon emission CT was performed over the chest 2 h after injection of the radiopharmaceutical into the antecubital vein. Images were acquired using a dual-headed gamma camera equipped with a low-energy, all-purpose collimator interfaced to a Pegasys (Cleveland, OH) computer. Patients were studied in the supine position with both arms next to them, and a head strap was used for fixation. A total of 32 projections were acquired over 180° rotation. Acquisition time was 30 s per frame. The radius of rotation was 15 cm. Images projections were smoothed and reconstructed in a 64x matrix using a Butterworth filtered back projection. No attenuation or scatter projection was performed. Transverse, sagittal, and coronal cuts were computed. In addition, whole-body scan was performed. Interpretation of images was performed by an observer unaware of clinical and Doppler echocardiographic findings. Images were classified according to tracer uptake as normal (no uptake) and abnormal (mild, moderate, and severe abnormalities according to the amount of tracer uptake).
Statistical Analysis
Unless specified, data are presented as mean ± SD. The 
2 test was used to compare differences between proportions. The Student t test was used for analysis of continuous data; p < 0.05 was considered statistically significant.
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Results
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PH by Doppler echocardiographic criteria was detected in 15 patients (29%). The etiology of CRF was hypertension in 5 patients (33%), chronic pyelonephritis in 2 patients (13%), glomerulonephritis in 2 patients (13%), diabetes mellitus in 1 patient (7%), polycystic kidney in 1 patient (7%), eclampsia in 1 patient (7%), and unknown in 3 patients (20%). In the 36 patients without PH, the etiology of CRF was hypertension in 5 patients (14%), chronic pyelonephritis in 6 patients (17%), diabetes mellitus in 4 patients (11%), polycystic kidney in 1 patient (3%), obstructive uropathy in 5 patients (14%), analgesic nephropathy in 2 patients (6%), glomerulonephritis in 4 patients (11%), and unknown in 9 patients (25%). Clinical and laboratory data of patients with and without PH are shown in Table 1
. There was no significant difference between both groups with regards to age, duration of dialysis, BUN, cholesterol, triglycerides, hemoglobin, calcium, phosphorous, alkaline phosphatase, and parathyroid hormone levels. PH was more prevalent in women. There was no recognizable evidence of calcification on the chest radiograph in any patient.
There were two patients with left atrial diameter > 40 mm in the group with PH. There was no significant correlation between left atrial diameter and pulmonary artery systolic pressure (r = 0.1, p = not significant).
99mTc Diphosphate Scintigraphy
The study was performed in the 15 patients with PH and in 15 randomly selected patients without PH. Table 2
demonstrates the distribution of 99mTc diphosphate scintigraphy results in patients with and without PH. No significant difference was detected between both groups regarding the prevalence or the severity of scintigraphic abnormalities. Clinical and laboratory parameters in patients with normal and those with abnormal 99mTc diphosphate scintigraphy results are presented in Table 3
. There was no significant difference between the two groups regarding age, duration of dialysis, BUN, creatinine, cholesterol, triglyceride, hemoglobin, calcium, phosphorous, alkaline phosphatase, PTH, and pulmonary artery systolic pressure. Figure 1
provides examples of normal scan, and moderate and severe abnormalities.
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Discussion
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Metastatic PAC is a complication of chronic renal failure, which may be a significant etiology of pulmonary dysfunction.4
5
Radionuclide imaging may detect PAC in the setting of normal chest radiographs, and confirm the diagnosis when there are nonspecific radiographic findings without macroscopic calcification.5
Alekseevskikh and Kolybin13
studied the development of PH in patients with end-stage renal disease who were maintained on regular hemodialysis. Successful kidney transplantation resulted in late postoperative reduction of PH. This finding suggested the possibility of a reversible cause of PH in these patients. Akmal et al9
examined the role of chronic excess of PTH in the genesis of PAC in dogs with experimental CRF, and evaluated the pathophysiologic consequences of PAC on the function of the lungs and right side of the heart. CRF was associated with reduced pulmonary diffusing capacity, which was attributed to marked PAC. Both the calcium content and the diffusing capacity of the lungs were restored to normal by the correction of secondary hyperparathyroidism. It was therefore, proposed that PH develops secondary to PAC. The prevention of PAC by parathyroidectomy in dogs with CRF was associated with normalization of the mean pulmonary artery pressure and reduction of right ventricular hypertrophy. Other suggested mechanisms of PH are sleep apnea and increased cardiac output and, subsequently, pulmonary flow due to anemia and the presence of arteriovenous fistula.14
15
In this study, we assessed the prevalence of PH in 51 patients with CRF receiving regular hemodialysis. Patients with significant left ventricular systolic dysfunction, valvular heart disease, pulmonary parenchymal or vascular disease, or intracardiac shunts were not included in the study because of the independent association between these conditions and PH. The prevalence of PH as defined by Doppler echocardiographic assessment of tricuspid valve was 29%. Age, duration of dialysis, urea, and creatinine were not different in patients with and without PH. Women had a higher incidence of PH. The significance of this finding is unclear. It is known that women have a higher incidence of primary PH.16
17
Whether this observation also applies for PH complicating CRF is to be determined by further studies.
Investigations of the parathyroid gland activity revealed no difference between patients with and without PH, with regards to values of PTH, calcium, phosphorous and alkaline phosphatase. These findings indicate that the PH is not related to the presence of hyperparathyroidism.
The prevalence and the severity of PAC as assessed by 99mTc diphosphate were not different in patients with and without PH. Similarly, pulmonary artery systolic pressure was not different between patients with and without PAC, defined as a positive 99mTc diphosphate study. There was no significant difference between patients with positive and those with negative 99mTc diphosphate lung uptake regarding clinical and metabolic parameters.
One possible explanation of PH in this study is the increased pulmonary arterial stiffness as previously demonstrated in patients with PH of different etiologies.18
19
20
21
Berger et al20
showed that pulmonary arterial wall distensibility was progressively decreased in patients with congenital heart disease and pulmonary vascular disease. The decreased distensibility was related to increased distending pressure as a result of PH but also, in part, to stiffening of the arterial wall during the disease process. Therefore, arterial wall distensibility may be of additional value in the evaluation of pulmonary vasculature and ventricular workload. Laskey et al21
showed that in addition to the expected abnormalities in steady measures of pulmonary artery hemodynamics at rest in patients with primary PH, rest and exercise measures of oscillatory behavior (characteristic impedance and pulse-wave reflection) were perturbed. Measures of steady and pulsatile behavior, particularly wave reflection, appeared to have an important role in the exercise response of these patients.
Arteriovenous shunts created for hemodialysis have been recently identified as causes of unexplained PH in patients with end-stage renal disease. Yigla et al22
studied 58 patients with CRF receiving long-term hemodialysis via arteriovenous access, and in control groups of 5 patients receiving peritoneal dialysis and 12 predialysis patients. PH > 35 mm Hg was found in 39.7% of patients receiving hemodialysis, in none of the patients receiving peritoneal dialysis, and in 1 of 12 predialysis patients. PH developed in four of six patients with normal pulmonary artery pressure after onset of hemodialysis therapy via arteriovenous access. PH normalized in four of five patients receiving hemodialysis following kidney transplantation. The authors concluded that long-term hemodialysis via arteriovenous access may be involved in the pathogenesis of PH by affecting pulmonary vascular resistance and cardiac output. All patients in our study had arteriovenous fistulae; therefore, the relation between these fistulae and PH could not be assessed.
Limitations of the Study
Pulmonary artery pressure was noninvasively measured by Doppler echocardiography without obtaining direct invasive measurements. However, measurements of pulmonary artery pressure by the applied Doppler echocardiographic method were reported to have an excellent correlation with measurements obtained by invasive methods.23
Pulmonary function tests were not performed; therefore, the relations among respiratory function, pulmonary hypertension, and calcification were not evaluated. Finally, the study did not assess the relation between arterial wall distensibility and PH. Further studies are required to assess this relation.
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Conclusions
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This study demonstrated that 29% of patients with CRF receiving regular hemodialysis have PH. The presence of PH was not related to the level of PTH or the severity of other metabolic abnormalities. PH was detected more frequently in women than in men. PAC are common finding in these patients of basis of 99mTc diphosphate single-photon emission CT imaging. However, there was no relation between PH and the presence or the severity of PAC assessed by this method. Therefore, the theory of secondary hyperparathyroidism and subsequent PAC as the etiology of PH in patients with CRF did not hold in this study. The mechanism of PH in patients with CRF receiving hemodialysis may in part be secondary to increased pulmonary blood flow from an arteriovenous fistula,22
but other factors such as pulmonary vascular resistance or impedance may also play a role.
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Footnotes
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Abbreviations: CRF = chronic renal failure; PAC = pulmonary artery calcification; PH = pulmonary hypertension; PTH = parathyroid hormone
Received for publication August 22, 2002.
Accepted for publication July 29, 2003.
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References
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Abstract
Introduction
