Relationship Between Parathyroid Hormone and Pulmonary Artery Hypertension Among Patients Undergoing Hemodialysis

AUTHORS

Zahra Havoshki 1 , Zahiroddin Khajeh Karimoddini 2 , Maryam Miri 1 , *

1 Department of Internal Diseases, Mashhad University of Medical Sciences, Mashahd, Iran

2 Department of Urology, Mashhad University of Medical Sciences, Mashahd, Iran

How to Cite: Havoshki Z, Khajeh Karimoddini Z, Miri M. Relationship Between Parathyroid Hormone and Pulmonary Artery Hypertension Among Patients Undergoing Hemodialysis, Nephro-Urol Mon. Online ahead of Print ; 12(3):e104448. doi: 10.5812/numonthly.104448.

ARTICLE INFORMATION

Nephro-Urology Monthly: 12 (3); e104448
Published Online: August 15, 2020
Article Type: Research Article
Received: May 16, 2020
Accepted: June 27, 2020
Crossmark
Crossmark
CHECKING
READ FULL TEXT

Abstract

Background: Pulmonary artery hypertension (PAH) is linked with morbidity and mortality in hemodialysis (HD) patients. The relationship between serum parathyroid hormone (PTH) and PAH is still a subject of debate.

Objectives: The goal of the present study was to assess the association between PTH and PAH among HD patients.

Methods: This was a cross-sectional study that assessed HD patients in a tertiary hospital in Mashhad, Iran. Echocardiography was performed for all patients to measure pulmonary artery pressure (PAP) and ejection fraction. Laboratory data, including serum calcium, phosphorus, vitamin D, serum albumin, and alkaline phosphatase, were extracted from patient documents. The statistical tests included independent t-test, Mann-Whitney, chi-squared test, and logistic regression.

Results: A total of 78 patients (43 males and 35 females) participated in this study. The mean age was 37.25 ± 11.98 years old. There was a significant difference in the PAH distribution pattern between hyperparathyroidism and normal PTH groups (P = 0.003). PAH was significantly related to hyperparathyroidism (P = 0.004, OR = 4.557), age (P = 0.033, OR = 0.944), and calcium level (P = 0.005, OR = 0.336). After adjusting for other variables, the odds ratio for the relationship between PAH and hyperparathyroidism increased to 7.593.

Conclusions: The findings of this study supported the possible link between hyperparathyroidism, serum calcium level, and PAH in HD patients.

1. Background

Chronic kidney disease (CKD) occurs in 10% to 16% of the global population (1, 2). The prevalence of chronic kidney disease is increasing in developed and developing countries (1). This increase is much more eminent in low- and middle-income countries, where the annual increase in mortality due to CKD is estimated to be more than 5% (3). The economic burden of CKD is hard to calculate as CKD is associated with a variety of indirect treatment costs and harms that may not be easily taken into the calculation (4). Renal replacement therapy is the only life-saving treatment for end-stage renal disease (5). Renal replacement therapy includes hemodialysis (HD), continuous ambulatory peritoneal dialysis (CAPD), and renal transplantation (5).

Increased pulmonary artery blood pressure is defined as pulmonary artery hypertension (PAH) (6). PAH is defined as pulmonary artery pressure (PAP) above 25 mmHg based on angiography and 35 mmHg based on echocardiography measurements (7). PAH is a chronic progressive disease that may result in right ventricular heart failure and sudden death (6, 8). The underlying causes of PAH include heart and lung conditions, thromboembolic diseases, and systemic diseases, including rheumatoid arthritis as well as conditions involving the liver (6). PAH is also frequent among patients with chronic kidney disease (9% - 39% in chronic kidney disease classes) and hemodialysis (18.8% - 68.8%), and CAPD (0% - 42%) (9-11).

Furthermore, PAH is associated with an increased risk for cardiovascular complications in HD patients (12). The risk factors for PAH in HD patients include systolic and diastolic dysfunction, age, smoking, urea reduction rate, and vitamin D receptor activator use (10, 13). It is also hypothesized that secondary hyperparathyroidism might result in PAH in HD patients due to vascular calcification, but the results of previous studies regarding the effect of parathyroid hormone (PTH) on PAH are controversial (13-16).

2. Objectives

This study was aimed to assess the association between PAH and PTH among patients undergoing regular HD.

3. Methods

This was a cross-sectional study conducted among HD patients who visited a tertiary hospital in Mashhad, Iran. This study was approved by the Ethics Committee of Mashhad University of Medical Sciences (reg. no.: IR.MUMS.MEDICAL REC1397.156). All the patients signed a written informed consent before beginning the study.

The inclusion criteria were age above 18 years old, being on regular dialysis for at least 6 months, and willingness to participate in the study. Patients with other diseases or conditions that affected PAP were excluded from the study.

All the patients underwent echocardiography by a trained echocardiography subspecialist. All the echocardiographic assessments were performed by a single subspecialist. Patients were categorized into PAH and non-PAH based on the measured PAP and the previously defined cut off for PAH (PAP > 35 mmHg) (7). Ejection fraction (EF) was also measured and recorded for each patient.

Laboratory measurements were extracted from the latest laboratory assessments in patient documents and included serum calcium, phosphorus, PTH, vitamin D, albumin (Alb), alkaline phosphatase (Alp), and hemoglobin (Hb).

3.1. Statistical Analysis

SPSS version 21.0 (IBM Inc, Chicago, Il, USA) was used for data analysis. Normality distribution was assessed by performing the Shapiro-Wilk test. A comparison of variables between the groups was performed using independent t-test and Mann Whitney U-test for normally distributed and non-normally distributed variables, respectively. Categorical variables were described using the chi-squared test. The relationship between pulmonary hypertension and hyperparathyroidism was assessed using logistic regression analysis before and after adjustment for other study variables. Logistic regression results were presented using P value, odds ratio (OR), and 95% confidence interval (CI) for OR. The statistical significance level was considered as P < 0.05.

4. Results

Seventy-eight patients (43 males and 35 females) were enrolled in this study. The mean age was 37.25 ± 11.98 years. The demographic characteristics of the study patients are presented in Table 1. PAH was present in 29 (37.2%) patients, while hyperparathyroidism was present in 42 (53.8%) patients. The most common causes of renal failure among the patients were unknown (50.0%), hypertension (12.8%), proteinuria (12.8%), and diabetes mellitus (10.3%).

Table 1. Demographic Characteristics of the Studied Patientsa
Values
Sex
Male43 (55.1)
Female35 (44.9)
Causes of Renal failure
Unknown39 (50.0)
HTN10 (12.8)
Proteinuria10 (12.8)
DM8 (10.3)
Neurogenic bladder4 (5.1)
ADPKD3 (3.8)
SLE2 (2.6)
MPGN1 (1.3)
MM1 (1.3)
Fistula position
Right3 (3.8)
Left75 (96.2)
Pulmonary hypertension29 (37.2)
Hyperparathyroidism42 (53.8)

Abbreviations: ADPKD, adult polycystic kidney disease; DM, diabetes mellitus; HTN, hypertension; MPGN, membranoproliferative glomerulonephritis; MM, multiple myeloma; SLE, systemic lupus erythematosus.

aValues are expressed as No. (%).

The distribution pattern of PAH among the hyperparathyroidism group was compared using the Chi-squared test. There was a significant difference in the distribution pattern of PAH between hyperparathyroidism and normal PTH groups (P = 0.003).

No significant difference was observed in the study parameters between patients with PAH and patients with normal pulmonary artery pressure (P > 0.05; Table 2).

Table 2. Comparison of the Studied Parameters Between Hyperparathyroidism and Non-Hyperparathyroidism Patientsa
PAHNumberValuesP
Age, yNo4936.90 ± 11.480.743
Yes2937.83 ± 12.97
Ca, mg/dLNo498.92 ± 0.890.505
Yes298.78 ± 0.96
P, mg/dLNo495.39 ± 1.590.768b
Yes295.49 ± 1.37
Alb, g/dLNo494.17 ± 0.480.184
Yes294.02 ± 0.46
PTH, pg/mLNo49348.45 ± 311.870.103b
Yes29464.89 ± 331.61
Vitamin D, ng/mLNo4930.66 ± 7.850.660b
Yes2930.38 ± 9.22
Alp, IU/LNo49329.96 ± 304.840. 079b
Yes29388.86 ± 238.23
Hb, g/dLNo4911.70 ± 1.640.169
Yes2911.19 ± 1.43
EF, %No4952.80 ± 4.120.427b
Yes2952.07 ± 5.26

Abbreviations: ALB, albumin; ALP, alkaline phosphatase; Ca, calcium; EF, ejection fraction; Hb, hemoglobin; P, phosphorus; PAH, pulmonary artery hypertension; PAP, pulmonary artery pressure; PTH, parathyroid hormone.

aValues are expressed as mean ± SD.

bThe Mann-Whitney test was used for the comparison due to non-normal distribution of the data.

There was a significant association between hyperparathyroidism and pulmonary hypertension based on the chi-squared test (Table 3). Logistic regression revealed that PAH was significantly related to hyperparathyroidism (P = 0.004, OR = 4.557, 95% CI for OR = 1.637, 12.684). There was a significant relationship between hyperparathyroidism and age (P = 0.033, OR = 0.944, 95% CI for OR = 0.895, 0.995) and serum calcium level (P = 0.005, OR = 0.336, 95% CI for OR = 0.156, 0.720) . After adjusting for other variables including calcium and age, the odds ratio for the relationship between pulmonary hypertension and hyperparathyroidism increased from 4.557 to 7.593, indicating that after adjusting for confounders, the odds of having hyperparathyroidism in the presence of pulmonary hypertension increases by 7.593 times compared to normal pulmonary artery pressure (Table 4).

Table 3. Comparison of the Distribution of Secondary Hyperparathyroidism Among Pulmonary Hypertension Groupsa
Pulmonary Hypertensionχ2P
NoYes
Hyperparathyroidism8.9470.003b
No30 (81.1)7 (18.9)
Yes21 (48.8)22 (51.2)

aValues are expressed as No. (%).

bSignificant at α = 0.001.

Table 4. Relationship Between the Studied Parameters and Hyperparathyroidism State
VariablePOR95% CI for OR
LowerUpper
Pulmonary hypertensionb
Unadjusted0.004c4.5571.63712.684
Adjusted0.003c7.5932.03328.362
Ca0.005c0.3360.1560.720
P0.4080.8480.5731.254
Alb0.5111.5610.4145.884
Alp0.7281.0000.9981.003
Hb0.2611.2510.8471.850
EF0.4630.9490.8271.091
Vitamin D0.4760.9740.9061.047
Age0.033c0.9440.8950.995

Abbreviations: ALB, albumin; ALP, alkaline phosphatase; Ca, calcium; CI, confidence interval; EF, ejection fraction; P, phosphorus; PTH, parathyroid hormone; PAP, pulmonary artery pressure; Hb, hemoglobin; OR, odds ratio.

bRelationship between pulmonary hypertension and hyperparathyroidism was assessed as univariable (unadjusted) and multivariable (adjusted for other variables) models.

cSignificant at α = 0.001.

5. Discussion

The findings of this study revealed that PAH was present in 37.2% of the HD patients. This finding was in line with the results of previous studies in different regions (12-16). One possible reason for the discrepancy in observations might be the difference in the cut off value for PAP to detect PAH. In a study in Iran among 62 HD patients, the prevalence of PAH was reported 62.3% based on a similar PAP cut off used in our study (17). However, the reported prevalence of PAH was higher than the observed prevalence of PAH in our study. One reason for this difference might be the difference in the age of the subjects as our patients were younger than the mentioned study.

This study also found that the most prevalent cause of CKD was unknown, followed by hypertension, proteinuria, and diabetes mellitus. This finding was in contrast to the findings of a previous study in the same province that reported hypertension and diabetes as the most common etiologies of CKD in 2404 HD patients (18). Similarly, in a study of 633 HD patients in Shiraz, hypertension, and diabetes were reported as the most common causes of CKD (19). The reason for this difference might be due to the larger sample size in the mentioned study. As our study was not designed to determine the prevalence of CKD etiologies, the shortcoming of our study in determining the prevalence of the etiology of CKD was not a limitation. On the other hand, this finding might affect the generalizability of the findings of this study to the whole HD population.

The findings of this study revealed that the prevalence of PAH was higher among hyperparathyroidism patients than those with normal parathyroid function. This study also showed a significant relationship between PAH and PTH levels. In a study of HD patients, PTH was significantly lower in patients with PAH and vascular calcification (16). Our study results were in contrast with the findings of recent studies (11, 15, 20). In a study among 77 HD patients in Turkey, no significant relationship was observed between serum PTH level and PAH (15). In another study of 119 HD patients in Brazil, no significant relationship was observed between PTH and PAH (20). In our previous study among 30 HD patients, no statistically significant relationship was observed between PTH and PAH (11). In another study of 69 HD patients, no significant relationship was found between PAH and PTH (17). Although these findings were in contrast to the present findings, in two studies that assessed arterial calcification, a significantly higher calcification was observed in patients with PAH regardless of the lack of a relationship between PAH and PTH levels (17, 21).

One of the limitations of this study was relying on serum markers for PAH. Future studies should focus on other possible indicators of PAH, including vascular calcification or stiffness. Studies with larger sample sizes and using a unified cut off for the detection of PAH are needed to better identify the relationship between PAH and PTH. Another limitation of this study was the inclusion of young HD patients in the study. As patient age might affect PAP and regarding the fact that chronicity of dialysis might also affect PTH, further studies with stratified sampling are required to assess the relationship between PAH and PTH in different age groups. The strength of this study was its sample size, which was larger than most published papers.

Footnotes

References

  • 1.

    Atkins RC. The epidemiology of chronic kidney disease. Kidney Int Suppl. 2005;(94):S14-8. doi: 10.1111/j.1523-1755.2005.09403.x. [PubMed: 15752232].

  • 2.

    Levey AS, Coresh J. Chronic kidney disease. Lancet. 2012;379(9811):165-80. doi: 10.1016/s0140-6736(11)60178-5.

  • 3.

    Stanifer JW, Muiru A, Jafar TH, Patel UD. Chronic kidney disease in low- and middle-income countries. Nephrol Dial Transplant. 2016;31(6):868-74. doi: 10.1093/ndt/gfv466. [PubMed: 27217391]. [PubMed Central: PMC4876969].

  • 4.

    Wang V, Vilme H, Maciejewski ML, Boulware LE. The economic burden of chronic kidney disease and end-stage renal disease. Semin Nephrol. 2016;36(4):319-30. doi: 10.1016/j.semnephrol.2016.05.008. [PubMed: 27475662].

  • 5.

    Liyanage T, Ninomiya T, Jha V, Neal B, Patrice HM, Okpechi I, et al. Worldwide access to treatment for end-stage kidney disease: A systematic review. Lancet. 2015;385(9981):1975-82. doi: 10.1016/S0140-6736(14)61601-9. [PubMed: 25777665].

  • 6.

    Hoeper MM. Definition, classification, and epidemiology of pulmonary arterial hypertension. Semin Respir Crit Care Med. 2009;30(4):369-75. doi: 10.1055/s-0029-1233306. [PubMed: 19634076].

  • 7.

    Sise ME, Courtwright AM, Channick RN. Pulmonary hypertension in patients with chronic and end-stage kidney disease. Kidney Int. 2013;84(4):682-92. doi: 10.1038/ki.2013.186. [PubMed: 23739239].

  • 8.

    Wolfe JD, Hickey GW, Althouse AD, Sharbaugh MS, Kliner DE, Mathier MA, et al. Pulmonary vascular resistance determines mortality in end-stage renal disease patients with pulmonary hypertension. Clin Transplant. 2018;32(6). e13270. doi: 10.1111/ctr.13270. [PubMed: 29697854].

  • 9.

    Nasir EF. Aspects of Oral Health Care Services in the context of HIV and AIDS in the Sudan. The University of Bergen; 2018. Available from: https://bora.uib.no/handle/1956/15222.

  • 10.

    Abedini M, Sadeghi M, Naini AE, Atapour A, Golshahi J. Pulmonary hypertension among patients on dialysis and kidney transplant recipients. Ren Fail. 2013;35(4):560-5. doi: 10.3109/0886022X.2013.766567. [PubMed: 23438072].

  • 11.

    Miri M, Hejazi S, Maghsoudlou F, Ahmadi M. Prevalence of pulmonary hypertension in end-stage renal disease patients undergoing hemodialysis and Peritoneal Dialysis at a Referral Center in Mashhad, Iran, From 2015 to 2016. Iran J Kidney Dis. 2018;12(6):364-8. [PubMed: 30595566].

  • 12.

    Afzal A, Bhatti MA, Manzoor S. Pulmonary hypertension: An emerging problem in patients undergoing regular hemodialysis. J Coll Physicians Surg Pak. 2018;28(8):594-6. doi: 10.29271/jcpsp.2018.08.594. [PubMed: 30060786].

  • 13.

    Agarwal R. Prevalence, determinants and prognosis of pulmonary hypertension among hemodialysis patients. Nephrol Dial Transplant. 2012;27(10):3908-14. doi: 10.1093/ndt/gfr661. [PubMed: 22290987]. [PubMed Central: PMC3484729].

  • 14.

    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. doi: 10.4061/2011/283475. [PubMed: 21151534]. [PubMed Central: PMC2989699].

  • 15.

    Yilmaz S, Yildirim Y, Taylan M, Demir M, Yilmaz Z, Kara AV, et al. The relationship of fluid overload as assessed by bioelectrical impedance analysis with pulmonary arterial hypertension in hemodialysis patients. Med Sci Monit. 2016;22:488-94. doi: 10.12659/msm.896305. [PubMed: 26874785]. [PubMed Central: PMC4755666].

  • 16.

    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(1):28-34. doi: 10.1016/j.krcp.2015.01.003. [PubMed: 26484016]. [PubMed Central: PMC4570633].

  • 17.

    Hayati F, Beladi Mousavi SS, Mousavi Movahed SM, Mofrad Bushehri M. Pulmonary hypertension among patients undergoing hemodialysis. J Renal Inj Prev. 2017;6(2):122-6. doi: 10.15171/jrip.2017.24. [PubMed: 28497088]. [PubMed Central: PMC5423279].

  • 18.

    Morovatdar N, Tayebi Nasrabad G, Tsarouhas K, Rezaee R. Etiology of renal replacement therapy in Iran. Int J Nephrol. 2019;2019:5010293. doi: 10.1155/2019/5010293. [PubMed: 31885918]. [PubMed Central: PMC6899269].

  • 19.

    Malekmakan L, Haghpanah S, Pakfetrat M, Malekmakan A, Khajehdehi P. Causes of chronic renal failure among Iranian hemodialysis patients. Saudi J Kidney Dis Transpl. 2009;20(3):501-4. [PubMed: 19414964].

  • 20.

    Yoo HHB, Dos Reis R, Telini WM, Telini LR, Hueb JC, Bazan SGZ, et al. Association of pulmonary hypertension with inflammation and fluid overload in hemodialysis patients. Iran J Kidney Dis. 2017;11(4):303-8. [PubMed: 28794293].

  • 21.

    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(6):2093-7. doi: 10.1378/chest.124.6.2093. [PubMed: 14665485].

  • Copyright © 2020, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.
    COMMENTS

    LEAVE A COMMENT HERE: