Pulmonary Hypertension among Patients on Dialysis and Kidney Transplant Recipients

Abstract

Pulmonary arterial hypertension (PAH) is a serious cardiac complication among patients with end-stage renal disease (ESRD). We investigated pulmonary hypertension and its associated factors among patients who were on chronic dialysis and kidney transplant recipients. One hundred-eighty patients in three groups of hemodialysis (HD), peritoneal dialysis (PD), and kidney transplant were studied. Demographic and clinical characteristics and echocardiographic findings were evaluated. A multivariable linear regression model was used to find factors associated with pulmonary artery pressure. The mean age of participants was 50.3 ± 15.5 years and 63.9% were male. We found pulmonary hypertension (mean pulmonary artery pressure >25 mmHg) in 31.6%, 8.3%, and 5% of the patients on HD, PD, and transplant recipients, respectively (p < 0.001). In multivariate analyses, being on HD (B = 5.276, confidence interval [CI] 95%: 1.211–9.341), age (B = –0.319, CI 95%: –0.501 to –0.138), smoking (B = 11.631, CI 95%: 1.847–21.416), systolic cardiac dysfunction (B = 6.313, CI 95%: 3.073–9.554), and diastolic cardiac dysfunction (B = 5.227, CI 95%: 1.176–9.277) were associated with systolic pulmonary artery pressure. These results showed that pulmonary hypertension is a frequent cardiac complication among patients with ESRD, and the type of renal replacement therapy (HD), systolic and diastolic cardiac dysfunction, and smoking are associated with increased pulmonary artery pressure. Further studies with larger sample sizes and also prospective studies are recommended in this regard.

• pulmonary arterial hypertension
• end-stage renal disease
• dialysis
• renal transplantation
• cardiac function

INTRODUCTION

Cardiovascular disease is still a major cause of morbidity and mortality among patients with end-stage renal disease (ESRD). These patients frequently suffer from hypertension and left ventricular hypertrophy, systolic and diastolic cardiac dysfunction, and atherosclerosis and coronary artery disease.¹ Pulmonary arterial hypertension (PAH) is another severe and progressive cardiac complication that has been recently under attention and frequently seen among ESRD patients. Studies showed a frequency of about 19% to 70% in patients on chronic hemodialysis (HD)^2–9 and 6% to 19% in patients on continuous peritoneal dialysis (PD).^2,5,8,10 Several studies showed that PAH is associated with increased mortality and poor outcomes in patients on dialysis and also after renal transplantation.^6,11–13

The mechanisms underlying development of PAH in ESRD patients are still under investigation. The main mechanisms are proposed as (a) the pulmonary vascular stiffness and vasoconstriction in ESRD patients that is unable to accommodate to (b) the increased cardiac output caused by anemia, hypervolemia, and placement of an arteriovenous fistula (AVF).^3,10,14 However, results of previous studies were not consistent and studies were mostly retrospective. Also, little information is available from patients on PD and kidney transplant recipients in this regard. Considering the lack of information regarding PAH in patients on different types of renal replacement therapies (RRTs), we investigated this complication and associated factors among patients on chronic dialysis and kidney transplant recipients.

SUBJECT AND METHODS

Participants and Settings

This cross-sectional study was conducted on ESRD patients on chronic dialysis referring to two university hospitals and transplant recipients referring to two outpatient clinics in Isfahan city (central Iran) from November 2011 to April 2012. At the time of the study, about 500 ESRD patients on chronic dialysis and 210 transplant recipients have been registered at the mentioned centers. According to the following criteria, we selected our sample from these centers consecutively as they were referring for dialysis sessions or for routine visits. We included patients who have been on chronic HD or PD, or having a new kidney by renal transplantation for at least 6 months. We included those patients who have had good compliance with their care based on the comments from dialysis center staff and attending physicians. Those with history of congenital cardiac anomalies, chronic obstructive pulmonary diseases (COPDs), or pulmonary emboli and those for whom echocardiographic view was poor were excluded from the study. Considering type I error (alpha) = 0.05 and study power = 80%, and also expecting about 30% of difference in the frequency of PAH among patients on different RRTs, 60 patients were considered for each group. Sampling was done until reaching 60 cases in each group. The study was approved by the ethics committee of the Isfahan University of Medical Sciences and informed consent was obtained from patients.

Assessments

All patients were interviewed by a cardiologist who also reviewed patient’s hospital files for demographic and disease information. The gathered information included age, gender, body weight, height, body mass index (BMI), tobacco smoking, causes of ESRD, concurrent diseases (e.g., diabetes mellitus, hypertension, ischemic heart disease, etc.), RRT characteristics (type, duration, dialysis adequacy), having AVF or graft, and recent laboratory data including hemoglobin, lipid profile, albumin, calcium, phosphate, blood urea nitrogen, and creatinine.

Echocardiography

Complete transthoracic echocardiography including two-dimensional, M-Mode, and Doppler studies were performed by a single cardiologist for all patients. For patients on HD or PD, echocardiography was performed just early after the completion of dialysis, to avoid overestimation of systolic pulmonary artery pressure (sPAP) due to volume overload between the dialysis sessions. Cardiac dimensions and systolic (mild to severe) and diastolic (grades I to III) cardiac dysfunctions were assessed according to the guidelines of the American Society of Echocardiography.¹⁵ Systolic pulmonary artery pressure was calculated as = [4 × (peak tricuspid regurgitant jet velocity)² + right atrial pressure]. Continuous-wave Doppler echocardiography was used to estimate the sPAP when there was a tricuspid regurgitation. Mean PAP (mPAP) was estimated from sPAP by the formula; mPAP = (0.61 × sPAP) + 2,¹⁶ and according to the American College of Cardiology Foundation/American Heart Association 2009 expert consensus, PAH was defined as mPAP >25 mmHg at rest.¹⁷

Statistical Analysis

Data were analyzed using the SPSS software for windows version 16.0 (SPSS Inc., Chicago IL., USA). Appropriate univariate and multivariate analyses were performed to compare the three groups and to investigate factors associated with sPAP. A p value of less than 0.05 was considered significant in all analyses.

RESULTS

Demographic Data and Disease Characteristics

During the study period, we evaluated 90 patients on HD, 73 patients on PD, and 83 transplant recipients. Exclusions were as follows: among patients on HD, 14 had COPD, 2 had history of rheumatic fever, 1 had cirrhosis, and 13 were not willing to participate; among patients on PD, 3 had COPD, 7 were not willing to participate, and 3 had poor echocardiography view due to obesity; and among transplant recipients, 18 were not willing to participate (or could not due to distance from the our center), and 4 patients had poor echocardiography view due to obesity. Also, one transplant patient was found to have kidney rejection at the time of echocardiography and was excluded from the study. Thus, a total of 180 patients (mean age = 50.3 ± 15.5 years, 63.9% male) were entered into three groups. Patients among the three groups were different with regard to age, ESRD etiology and duration, concurrent diseases, and having AVF. Also, they were different regarding various laboratory data (Table 1).

Table 1.  Demographic and clinical characteristics of the patients.

	HD n = 60	PD n = 60	Transplant n = 60	p
Age (years)	52.1 ± 13.7	58.2 ± 13.8	40.8 ± 13.8	<0.001
Male/Female	37/23	40/20	38/22	0.845
BMI (kg/m^2)	23.4 ± 4.6	25.3 ± 4.1	24.2 ± 4.9	0.087
ESRD cause
Hypertension	13 (21.6)	15 (25)	10 (16.6)
Diabetes	14 (23.3)	14 (23.3)	9 (15)
Hypertension + diabetes	13 (21.6)	18 (30)	6 (10)
Glomerulonephritis	9 (15)	4 (6.6)	13 (21.6)	0.011
Others or unknown	11 (18.3)	9 (15)	22 (36.6)
ESRD duration (months)	50.2 ± 42.0	20.2 ± 12.9	46.6 ± 37.9	<0.001
RRT duration (months)	44.4 ± 38.1	18.9 ± 12.4	26.3 ± 24.6	<0.001
Kt/V	1.23 ± 0.36	1.74 ± 0.54	–	<0.001
Concurrent diseases
Hypertension	42 (70)	47 (78.3)	33 (55)	0.021
Diabetes	29 (48.3)	33 (55)	18 (30)	0.021
Ischemic heart disease	20 (33.3)	22 (36.6)	3 (5)	<0.001
Dyslipidemia	21 (35)	26 (43.3)	18 (30)	0.307
Smoking	4 (6.6)	5 (8.3)	0	0.086
AVF or Graft	50 (83.3)	19 (31.6)	34 (56.6)	<0.001
Hemoglobin (mg/dL)	10.38 ± 2.04	11.38 ± 2.00	13.56 ± 2.69	<0.001
Albumin (g/dL)	3.99 ± 0.50	3.69 ± 0.64	4.44 ± 0.53	<0.001
Calcium (mg/dL)	8.16 ± 0.80	8.84 ± 0.62	9.35 ± 0.73	<0.001
Phosphate (mg/dL)	4.57 ± 1.06	4.30 ± 0.88	3.75 ± 0.69	<0.001
Calcium × Phosphate (mg^2/dL^2)	37.1 ± 9.0	38.0 ± 7.7	35.1 ± 7.0	0.189
BUN (mg/dL)	53.6 ± 19.6	50.4 ± 22.5	26.3 ± 15.3	<0.001
Creatinine (mg/dL)	6.5 ± 2.0	5.0 ± 2.3	1.5 ± 1.1	<0.001

Notes: Data are presented as mean ± SD or number (%). BMI, body mass index; ESRD, end-stage renal disease; RRT, renal replacement therapy; AVF, arteriovenous fistula; BUN, blood urea nitrogen.

Echocardiographic Findings

Systolic and diastolic cardiac dysfunction was more frequent among patients on HD (p = 0.005 and 0.011). The sPAP was significantly higher in the HD compared with the PD and transplant recipients (p < 0.001), but patients on PD and transplant recipients were similar in this regard (p = 0.765). Based on the aforementioned formula in the method, PAH was observed in 31.6%, 8.3%, and 5% of the patients on HD, PD, and transplant recipients, respectively (p < 0.001), Table 2.

Table 2.  Comparison of patients with regard to the echocardiographic findings.

	HD n = 60	PD n = 60	Transplant n = 60	p
LVEF (%)	52.97 ± 10.83	53.22 ± 10.56	59.57 ± 6.01	<0.001
Systolic dysfunction
No	34 (56.6)	37 (61.6)	53 (88.3)
Mild	11 (18.3)	11 (18.3)	6 (10)	0.005
Moderate	14 (23.3)	11 (18.3)	1 (1.6)
Severe	1 (1.6)	1 (1.6)	0
Diastolic dysfunction
No	27 (45)	25 (41.6)	39 (65)
Grade I	20 (33.3)	27 (45)	18 (30)	0.011
Grade II	13 (21.6)	8 (13.3)	3 (5)
Grade III, IV	0	0	0
PE	6 (10)	9 (15)	1 (1.6)	0.035
Valve calcification	21 (35)	19 (31.6)	3 (5)	0.017
sPAP (mmHg)	29.43 ± 19.19	18.17 ±10.98	16.40 ± 9.28	<0.001
mPAP ≥ 25 mmHg	19 (31.6)	5 (8.3)	3 (5)	<0.001

Notes: Data are presented as mean ± SD or number (%). LVEF, left ventricle ejection fraction; PE, pleural effusion; sPAP, Systolic pulmonary artery pressure; mPAP, mean pulmonary artery pressure.

Univariate Analyses of Factors Associated with PAH

Regarding differences among the three RRT groups in demographic and clinical data and the frequency of PAH, we evaluated factors associated with PAH in separate analyses of each group and also conducted a multivariate analysis. Among patients on HD, levels of hemoglobin (r = –0.328, p = 0.010) and albumin (r = –0.386, p = 0.003) were associated with sPAP. Among patients on PD, age (r = 0.242, p = 0.031) and BMI (r = 0.315, p = 0.014) were associated with sPAP. And, among transplant recipients, sPAP was associated with creatinine level (r = 0.271, p = 0.050), duration of being on dialysis (r = 0.491, p < 0.001), and non-significantly with calcium × phosphate product (r = 0.252, p = 0.081). Higher sPAP was associated with history of ischemic heart disease only among PD patients (21.0 ± 14.4 vs. 15.7 ± 7.5 mmHg, p = 0.022). It was also associated with smoking only among HD patients (49.5 ± 21.0 vs. 28.0 ± 18.4 mmHg, p = 0.029), and with hypertension only among transplant recipients (49.5 ± 21.0 vs. 28.0 ± 18.4 mmHg, p = 0.029). There was no difference between those with and without AVF or between those with and without diabetes regarding the sPAP in any group (p > 0.05). In patients on dialysis, the association between Kt/V and sPAP was low and not significant (r = –0.112, p = 0.113).

Multivariate Analyses of Factors Associated with sPAP

With linear regression analysis, being on HD (B = 5.276, confidence interval [CI] 95%: 1.211 to 9.341), age (B = –0.319, CI 95%: –0.501 to –0.138), smoking (B = 11.631, CI 95%: 1.847 to 21.416), systolic cardiac dysfunction (B = 6.313, CI 95%: 3.073–9.554), and diastolic cardiac dysfunction (B = 5.227, CI 95%: 1.176 to 9.277) were independently associated with sPAP. The association between hypertension (B = 3.715, CI 95%: –0.887 to 8.318) and having AVF (B = 3.326, CI 95%: –0.939 to 7.592) with sPAP was not significant.

DISCUSSION

We investigated the frequency of and associated factors to PAH among patients on chronic dialysis and kidney transplant recipients. Our study showed a high prevalence of PAH among HD patients and less frequent in PD and transplant recipients. Previous studies, though reported various frequency of PAH, have indicated a significantly higher frequency of PAH in HD than in PD patients^2–9 and improvement of PAH in ESRD patients after kidney transplantation.¹⁸ These results indicate that patients on PD and transplant recipients are at a significantly lower risk for PAH compared with patients on HD.

Underlying Mechanisms for PAH

Elevated pulmonary blood flow and an increased pulmonary vascular resistance are the two main mechanisms described for the development of PAH.¹¹ With regard to pulmonary blood flow, several studies focused on the role of AVF and its consequent increased cardiac output. Although not confirmed by our results and some other studies,^6,19 current evidence is in favor of a role of AVF presence, duration, and blood flow in the pathogenesis of PAH in patients on dialysis.^3,11,20,21 Another factor that can contribute to the development of PAH by increasing cardiac output is anemia,^5,7,10,18 which was confirmed by our univariate but not multivariate analyses probably due to the small sample size. The relationship between hypo-albuminemia and sPAP, which is reported by some studies and found in our study as well,^7,10 is another factor that is probably a consequence of hypervolemia.

Regarding vascular resistance theory, dysregulation of calcium/phosphate metabolism in ESRD patients can lead to vascular calcification and increased pulmonary vascular resistance and thus might be a risk factor for PAH. Some studies showed an association of calcium × phosphate product with sPAP,^20,22 and we found such association in transplant recipients; however, there are other reports against this result.^3,8,10,21,23 Other risk factors introduced by some of the previous studies are age^3,6,21 and smoking^3,22 for which the exact mechanisms are not yet clear. In our study, multivariate analyses showed an inverse association of age with sPAP, which might be related to lower age in transplant recipients in whom the frequency of PAH was very low. Indeed, age was positively associated with sPAP among PD patients. Regarding smoking, our study results suggest an association between smoking and PAH. Intravascular thrombosis in pulmonary arteries occurs with increasing age, and the role of cigarette smoke in PAH may be mediated by endothelial dysfunction.³ Another factor that may increase the risk of PAH, particularly in ESRD patients, is diabetes, and the proposed underlying mechanism is diabetes-induced endothelial dysfunction.^24,25 Although we found more severe cardiac dysfunction in patients with, than without, diabetes (data not presented), similar to other studies^2,3,26 we found no association between diabetes and PAH. These results highlight that the underlying pathophysiology of PAH in ESRD patients is multifactorial, and some factors might have large while others have only minimal effects on PAH. Thus, larger studies are required to investigate the independent effect of each possible risk factor, and evaluation of endothelial function would be informative in this regard.

The Effects of Dialysis Type

Our study, similar to other ones,^5,8,27 showed an increased risk of PAH in patients on HD compared with patients on PD. Multivariate analyses in our study showed that this higher risk is independent of anemia, presence of AVF, level of creatinine, and degree of systolic and diastolic cardiac dysfunction. Thus, it seems that other factors among patients on HD make them more prone to the development of PAH. We did not assess AVF blood flow which might be higher in HD than in PD patients who had AVF and has been shown to have significant effects on sPAP.^3,20,21 Dialysis adequacy was also not associated with sPAP in our study. A recent study found a non-significantly higher frequency of PAH among patients on PD compared with those on HD and attributed it to higher prevalence of left ventricular hypertrophy associated with hypervolemia.²⁵ Unfortunately, we did not assess volume status of our patients, which can have effects on the development of PAH. It is also possible that factors associated with the formation of PAH in patients on HD and PD does not have a complete overlap. For example, the formation of microbubble pulmonary emboli (originating from the tubing or the dialyzer), which in turn results in lung injury is seen in HD and not in PD patients. Even, membrane composition in patients on HD seems to have effects.⁹ Anyway, further studies are required to find the possible factors associated with HD, which may increase the risk of PAH in these patients compared with PD patients.

Role of Cardiac Dysfunction

Our study showed significant effect of pre-existing or acquired cardiac dysfunction on PAH in ESRD patients, which has been shown by previous reports.^3,7,10,21,22 We found that left ventricular systolic and diastolic dysfunctions are important independent factors associated with PAH. Diastolic dysfunction in dialysis patients can be due to multiple factors. Left ventricle hypertrophy, mainly as a result of chronic hypertension, is common and strongly associated with impaired left ventricular diastolic function in patients on dialysis. Furthermore, a large number of dialysis patients have diabetes which, by itself, is associated with increased myocardial stiffness and diastolic dysfunction.^27,28

Implications of the Findings

Since PAH is associated with significant morbidity and mortality in ESRD patients, its prevention and early diagnosis and treatment is of great importance. In patients who are at known risk for development of PAH, such as those with pre-existing moderate to severe systolic/diastolic cardiac dysfunction, changing the dialysis type from HD to PD or preparing the patients for transplantation may be a reasonable option to prevent PAH. Strategies for treatment of fluid overload and high cardiac output should be enhanced to prevent the development of PAH in dialysis patients. Surgical reduction and standardization of AVF may be considered in patients with PAH and extremely high cardiac output. In this regard, demonstration of reduction of both cardiac output and PAP following temporary closure of arteriovenous access may be a guide in finding appropriate candidate cases. Future studies should also investigate the role of drugs that can decrease pulmonary vascular resistance in the treatment of PAH in ESRD patients.

Our study has some limitations. Although we included a relatively large sample of patients in each group, because of several possible covariates, it was better to include a larger sample size for better multivariate analysis. We have conducted a cross-sectional study and conducted echocardiography based on no specific indication, and thus we prevented a selection bias; however, our sampling was consecutive and a bias in selecting patients with better health condition is possible.

CONCLUSION

The results of this study showed that PAH is a frequent complication seen in ESRD patients with significantly more frequency in patients on HD than PD and transplant recipients. Analyses showed important factors associated with increased pulmonary artery pressure as type of RRT, systolic and diastolic cardiac dysfunction, and smoking. Our results also suggest that risk factors might have different load among different types of RRT. Anemia, hypoalbuminemia, hypertension, and history of ischemic heart disease are other possible risk factors for PAH, which should be evaluated in studies with larger sample sizes and also in prospective studies.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

The authors’ work is supported by the Isfahan University of Medical Sciences. The funders had no role in the preparation, review, or approval of this manuscript.

The authors declare that they have no relevant financial interests.