| Abstract|| |
Pulmonary hypertension (PHTN) is a recently recognized complication in dialysis and it is associated with a poor outcome. We estimated the prevalence of PHTN and its association with vascular calcification in chronic kidney disease (CKD) and hemodialysis (HD) patients. One hundred and thirteen adult CKD patients were included in this study, of which 56 (49.6%) were on conservative treatment (nondialysis group) and 57 (50.4%) were on maintenance HD (dialysis group). Demographic, clinical, and biochemical parameters were collected and compared between the groups. Thirty-nine (69.6%) and 33 (57.8%) males were included in nondialysis and dialysis group, respectively. Mean age was 47.5 ± 13.7 in nondialysis group and 52.8 ± 13.9 in the dialysis group. PHTN was estimated using Doppler echocardiography and peripheral vascular calcification by lateral lumbar X-ray with aortic calcification scoring. Patients with and without PHTN and vascular calcification in dialysis and nondialysis group were compared. PHTN was found in 55 patients (48.7%) and it was high in patients on dialysis compared to nondialysis(59.6% vs. 37.5%, P <0.019). Abdominal aortic calcification was present in 35 patients (30.9%), dialysis versus nondialysis group was 22.8% and 39.3%. Increased left atrial diameter was significantly associated with PHTN (P <0.003), whereas peripheral artery calcification was not related to PHT (P = 0.248). The prevalence of PHTN in CKD was 48.7% which was higher in dialysis group than non dialysis group. Increased left atrial (LA) diameter was associated with PHTN but not peripheral arterial calcification.
|How to cite this article:|
Nithiya N, Indhumathi E, Jagadeswaran D, Jayaprakash V, Jayakumar M. Pulmonary hypertension – prevalence, risk factors, and its association with vascular calcification in chronic kidney disease and hemodialysis patients. Saudi J Kidney Dis Transpl 2020;31:380-7
|How to cite this URL:|
Nithiya N, Indhumathi E, Jagadeswaran D, Jayaprakash V, Jayakumar M. Pulmonary hypertension – prevalence, risk factors, and its association with vascular calcification in chronic kidney disease and hemodialysis patients. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Jun 4];31:380-7. Available from: http://www.sjkdt.org/text.asp?2020/31/2/380/284012
| Introduction|| |
Pulmonary hypertension (PHTN) is defined as mean pulmonary arterial pressure (PAP) ≥25 mm Hg as measured by right heart catheterization. Recent studies have shown that the presence of PHTN in dialysis patients increases mortality rate. According to the WHO, PHTN has been classified into five groups. Group 1 PHTN includes idiopathic, hereditary and other connective tissue disorders. Group 2 is due to left side heart disease. Group 3 results from chronic obstructive pulmonary disease and other lung disorders. Group 4 occurs due to chronic thromboembolism. Group 5 PHTN is due to unclear mechanism and with varied systemic diseases such as multiple myeloma and chronic kidney disease (CKD)., Overlap can occur between the groups in CKD patients. Excess fluid volume contributes to the development of PHTN in majority of patients on hemodialysis (HD). Endothelial injury by uremic toxins, arterial calcification, recurrent minor thrombo-emboli, and left ventricular (LV) dysfunction with cardiac failure also increase pulmonary artery systolic pressure. The prevalence of PHTN varies from 18% to 68% in patients on HD, wherein up to 42% occurs in peritoneal dialysis (PD). Thus, there is a slight increase in prevalence rate in HD secondary to excess volume status. Once established, PHTN is often progressive and associated with high morbidity and mortality. PHTN is an independent predictor of mortality in HD patients. Anemia, arteriovenous fistula (AVF), LV dysfunction with cardiac failure, and increased LA diameter secondary to hyper- volemia contribute to increased prevalence of PHTN in dialysis patients. Kim et al observed that patients with PHTN in CKD were found to have peripheral vessel calcification.
Very limited studies are available relating to PHTN in dialysis and nondialysis CKD patients. In this study, we analyzed the prevalence of PHTN, risk factors, and its association with vascular calcification.
| Material and Methods|| |
All adult CKD patients older than 18 years including patients undergoing HD for ≥3 months were included in this study. Pediatric patients and those undergoing PD were excluded from the study. A total of 113 patients were included with 57 on HD (dialysis group) and 56 CKD patients not on dialysis (nondialysis group). Baseline characteristics including gender, age, body mass index (BMI), native kidney disease, duration of dialysis, associated diabetes, HTN, coronary artery disease, and laboratory parameters such as hemoglobin, lipid profile, serum calcium, phosphorous, and intact parathyroid hormone (iPTH) were collected.
Estimation of pulmonary hypertension
Using Standard 2D M-mode Doppler echocardiography, Modified Bernoulli’s equation was done in all patients to assess the presence of PHTN. Pulmonary artery systolic pressure of ≥37 mm Hg was considered as PHTN. LV mass, LA diameter and LV fractional shortening were also calculated.
Detection and grading of vascular calcification
In CKD patients, calcification of the vessels can be assessed using plain X-ray, ultrasound, and computed tomography, of which, plain X- ray was recommended by several guidelines for screening. It is also cost-effective.
Lateral lumbar X-ray was taken in the standing position using standard radiographic equipment for all the patients. Part of the aorta anterior to the lumbar vertebra was given points 1 to 3 as per the length of calcification. The severity of the calcification was detected using composite score and affected segment score.
| Statistical Analysis|| |
Statistical analysis was performed with IBM SPSS Statistics version 20.0 (IBM Corp., Armonk, NY, USA). CKD patients were evaluated after dividing into those undergoing HD, and not undergoing dialysis, with and without PHTN as well with the presence or absence of abdominal aortic calcification. The data collected were expressed as mean ± standard deviation and percentage. Mean values between various groups were analyzed using Student t-test. Continuous and categorical variables were assessed with Mann-Whitney U test and Chi-square test, respectively. ANOVA was used to measure whether the mean values of several groups are equal or not.
| Results|| |
The study was conducted prospectively among two groups, CKD patients undergoing maintenance HD (dialysis group) and CKD patients not on dialysis (nondialysis). A total of 113 patients were enrolled and of which, 56 were not on dialysis (49.6%) and 57 patients were on dialysis (50.4%). Baseline characteristics, clinical data, laboratory investigations, echocardio- graphic findings, and lateral lumbar X-ray findings of both the groups are summarized in [Table 1].
|Table 1: Demographics of patients on hemodialysis and non-dialysis chronic kidney disease (n=113).|
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The mean age of nondialysis patients was 52.8 ± 13.9 and the mean age of dialysis patients was 47.5 ± 13.7. Within the dialysis group, 39 were male (68.4%) and in the nondialysis group, 33 were male (58.9%). Diabetes and HTN were the common etiologies for CKD.
Laboratory investigations such as hemoglobin, lipid profile, alkaline phosphatase, calcium, phosphorus, serum albumin, and iPTH levels were done for all patients, and no difference was noted between groups.
Echocardiographic findings In our study, 55 patients (48.7%) had PHTN and it was high in patients on dialysis compared to nondialysis (59.6% vs. 37.5%, P <0.019). Increased LA diameter was seen more in dialysis patients (38.6% vs. 14.3%, P <0.01). Patients with PHT in dialysis and non-dialysis groups are compared in [Table 2]. LV fractional shortening abnormality was common in dialysis patients and was related to the development of PHTN (P =0.001).
|Table 2: Clinical profile and demographics of patients with pulmonary hypertension in patients on hemodialysis and nondialysis CKD (n=55).|
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Abdominal aortic calcification was present in 35 patients (30.9%).
Risk factors for pulmonary hypertension
We analyzed risk factors such as calcium, phosphorus, iPTH, alkaline phosphatase, LV mass, LA diameter, LV fractional shortening, abdominal aortic calcification, and its association with PHTN. We found that LA diameter P = 0.01) was significantly associated with PHTN. No significant association between abdominal aortic calcification and PHTN in our study P = 0.673). Patients with and without PHTN were compared as given in [Table 3].
|Table 3: Clinical and laboratory data, echo and vascular findings of patients with and without pulmonary hypertension.|
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| Discussion|| |
In this prospective comparative study, patients with CKD and on dialysis were selected to ascertain the prevalence and risk factors of PHTN. We also analyzed the association of abdominal aortic calcification with the develop-ment of PHTN. Mean arterial pressure ≥25 using right heart catheterization being invasive,
Doppler echo with modified Bernoulli equation was done by which PHTN was considered with PAP ≥ 35 mm Hg.,,,,, Increased cardiac output by arteriovenous (AV) fistula, anemia, and hypervolemia in patients undergoing dialysis may also increase PAP. Increased left atrial diameter was strongly related to the occurrence of PHTN indicating hypervolemic status in dialysis patients. Pulmonary artery calcification with high pulmonary vascular resistance also attri-butes to the development of PHTN. Study by Abdelwhab and Elshinnawy observed increased AVF blood flow, proBNP, throm- boxane A2 and left ventricular diastolic dysfunction in patients with high PAP which was not found in our study. Age is an important factor for the occurrence of PHTN in dialysis patients with higher incidence in older age group. In our study, the mean value of patients age with PHTN was 48.87 compared to 51.56 in patients without PHTN. The prevalence of PHTN varied from 27% to 58% in dialysis patients.,,,,, Severe PHTN with PAP ≥45-50 mm Hg was seen up to 29% in patients on dialysis. We observed that 48.5% of the study population had PHTN which was high in patients on HD than in nondialysis (59.6% vs. 37.5%, P <0.019). This finding was in concurrence with another study that showed higher prevalence of PHTN in dialysis than on conservative treatment. Prevalence of PHTN in a study of 84 HD patients was higher than in PD patients (51.2% vs. 22.7%). In this study, increased LV filling pressure secondary to volume overload was an important factor contributing to PHTN.
This is in contrast to other studies, on HD patients where lower rate of prevalence was observed. This may be due to varying definitions for PHTN in different studies.
We also determined risk factors for the development of PHTN. Development of PHTN was found to be directly related to the duration of dialysis., In our study, LA diameter was found to be significantly associated with the development of PHTN. Data on the prevalence of PHTN in pre dialysis CKD were scarce. Yigla et al reported slightly lower prevalence of PHTN (13.7%) in nondialysis CKD patients.
Another study on nondialysis CKD patients also showed similar results with the prevalence of 21.1% and found that old age, anemia, and LV dysfunction were related to increased PAP. In our study, 37.5% of nondialysis CKD patients had PHTN with LA diameter strongly associated with PHTN. Rajiv Agarwal et al in their study found that LA diameter and URR were related to PHTN.
Vascular calcification occurring in CKD is associated with arterial stiffness and cardiovascular mortality. Diagnosis of vascular calcification can be done with electron beam computed tomography or ultrasonographic measurement of pulse wave velocity though confirmation is by arterial biopsy., KDOQI guidelines 2009 suggested lateral abdominal X- ray for the assessment of vascular calcification.[Figure 1]
Akmal et al in their study on dogs had demonstrated that when exposed to high levels of PTHN developed pulmonary artery calcification and hence the development of PHTN.
However, in humans, only a small number of studies showed the association of excess PTH with PHTN,,, whereas others did not find such an association.,,,,, Our study also showed the lack of relationship between iPTH and PHTN as well as with vascular calcification. Further studies are required to confirm the association.
In our study, we used X-ray lateral lumbar spine for the detection of vascular calcification and aortic calcification scoring was done to assess the severity. Vascular calcification was seen in 35 patients (30.9%), dialysis and non- dialysis group was 22.8% and 39.3%, respectively. Kim et al in their study had shown that peripheral vessel calcification, mitral valve disease, and increased LA diameter were related to PHTN in dialysis patients.
The exact cause for increased mortality in patients with PHTN is not known; increased vascular calcification may be a possibility for the development of PHTN. In one study, patients on HD with PHTN showed a mortality of 30.4% compared to 8.5% in those without PHTN.
Therefore, in addition to the efforts taken to maintain euvolemic status to reduce left atrial size, Doppler echocardiography for all patients with CKD, and before initiation of dialysis may be advisable. Furthermore, early initiation of CKD-MBD management to reduce vascular calcification would be useful.
| Limitations of the Study|| |
- This is a single-center observational study with smaller sample size.
- PHTN was detected by echocardiography rather than by direct measurement.
To conclude, PHTN in CKD is not an uncommon disorder and the prevalence in our prospective cross-sectional study was 48.7%. It was high in patients on dialysis compared to non-dialysis. Increased LA diameter was strongly related to PHTN. In our study, patients with CKD and on HD with peripheral arterial calcification were not found to have PHTN.
| Acknowledgment|| |
The authors would like to thank the patients who consented for the study and staff for helping to collect the data.
Conflict of interest: None declared.
| References|| |
Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013;62:D34-41
Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54:S43-54
Sharma J, Mongia A, Schoenaman M, Chang S, D’Angelo A, Rao M. Nephrogenic fibrosing dermatopathy, cardiac calcification and pulmonary hypertension in an adolescent on chronic hemodialysis. Indian J Nephrol 2008;18:70-3
Sise ME, Courtwright AM, Channick RN. Pulmonary hypertension in patients with chronic and end-stage kidney disease. Kidney Int 2013; 84:682-92
Bolignano D, Rastelli S, Agarwal R, et al. Pulmonary hyper-tension in CKD. Am J Kidney Dis 2013;61:612-22
Adragao T, Pires A, Lucas C, et al. A simple vascular calcification score predicts cardiovascular risk in haemodialysis patients. Nephrol Dial Transplant 2004;19:1480-8
Yigla M, Fruchter O, Aharonson D, et al. Pulmonary hypertension is an independent predictor of mortality in hemodialysis patients. Kidney Int 2009;75:969-75
Kim SC, Chang HJ, Kim MG, Jo SK, Cho WY, Kim HK. Relationship between pulmonary hypertension, peripheral vascular calcification, and major cardiovascular events in dialysis patients. Kidney Res Clin Pract 2015;34:28-34
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: 2093-7
Havlucu Y, Kursat S, Ekmekci C, et al. Pulmonary hypertension in patients with chronic renal failure. Respiration 2007;74:503-10
Kumbar L, Fein PA, Rafiq MA, Borawski C, Chattopadhyay J, Avram MM. Pulmonary hypertension in peritoneal dialysis patients. Adv Perit Dial 2007;23:127-31
Nakhoul F, Yigla M, Gilman R, Reisner SA, Abassi Z. The pathogenesis of pulmonary hypertension in haemodialysis patients via arterio- venous access. Nephrol Dial Transplant 2005;20: 1686-92
Abdelwhab S, Elshinnawy S. Pulmonary hypertension in chronic renal failure patients. Am J Nephrol 2008;28:990-7
Harp RJ, Stavropoulos SW, Wasserstein AG, Clark TW. Pulmonary hypertension among end- stage renal failure patients following hemodialysis access thrombectomy. Cardiovasc Intervent Radiol 2005;28:17-22
Etemadi J, Zolfaghari H, Firoozi R, et al. Unexplained pulmonary hypertension in peritoneal dialysis and hemodialysis patients. Rev Port Pneumol 2012;18:10-4
Yigla M, Nakhoul F, Sabag A, et al. Pulmonary hypertension in patients with end-stage renal disease. Chest 2003;123:1577-82
Acarturk G, Albayrak R, Melek M, et al. The relationship between arteriovenous fistula blood flow rate and pulmonary artery pressure in hemodialysis patients. Int Urol Nephrol 2008;40: 509-13
Tarrass F, Benjelloun M, Medkouri G, Hachim K, Benghanem MG, Ramdani B. Doppler echo- cardiograph evaluation of pulmonary hypertension in patients undergoing hemo-dialysis. Hemodial Int 2006;10:356-9
Mahdavi-Mazdeh M, Alijavad-Mousavi S, Yahyazadeh H, Azadi M, Yoosefnejad H, Ataiipoor Y. Pulmonary hypertension in hemo- dialysis patients. Saudi J Kidney Dis Transpl 2008;19:189-93
Fabbian F, Cantelli S, Molino C, Pala M, Longhini C, Portaluppi F. Pulmonary hypertension in dialysis patients: A cross-sectional Italian study. Int J Nephrol 2010;2011:283475
Issa N, Krowka MJ, Griffin MD, Hickson LJ, Stegall MD, Cosio FG. Pulmonary hypertension is associated with reduced patient survival after kidney transplantation. Transplantation 2008;86: 1384-8
Bozbas SS, Akcay S, Altin C, et al. Pulmonary hypertension in patients with end-stage renal disease undergoing renal transplantation. Transplant Proc 2009;41:2753-6
Navaneethan SD, Wehbe E, Heresi GA, et al. Presence and outcomes of kidney disease in patients with pulmonary hypertension. Clin J Am Soc Nephrol 2014;9:855-63
Agarwal R. Prevalence, determinants and prognosis of pulmonary hypertension among hemo- dialysis patients. Nephrol Dial Transplant 2012; 27:3908-14
Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM. Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 2001;38:938-42
Safar ME, Blacher J, Pannier B, et al. Central pulse pressure and mortality in end-stage renal disease. Hypertension 2002;39:735-8
Bellasi A, Ferramosca E, Muntner P, et al. Correlation of simple imaging tests and coro-nary artery calcium measured by computed tomography in hemodialysis patients. Kidney Int 2006;70: 1623-8
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl 2009;113:S1-130
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;47:158-63.
Department of Nephrology, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Porur, Chennai - 600 116, Tamil Nadu
[Table 1], [Table 2], [Table 3]