Hyperuricemia is strongly associated with pulmonary hypertension in chronic lung disease

Hyperuricemia is strongly associated with pulmonary hypertension in chronic lung disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Hyperuricemia is strongly associated with pulmonary hypertension in chronic lung disease Shimon Izhakian, Alon Gorenshtein, Haya Engelstein, Lev Freidkin, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4298792/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Hyperuricemia has been identified as a powerful predictor of World Health Organization (WHO) group 1 pulmonary hypertension (PH) (pulmonary arterial hypertension). However, its relationship with PH secondary to chronic lung diseases (WHO group 3) remains unclear. Demographic, clinical, laboratory, lung function, and right heart catheterization data were retrospectively collected for 323 patients with various severe chronic pulmonary diseases undergoing evaluation for lung transplantation at a tertiary university medical center from June 2017 to February 2023. The data were analyzed to identify associations between hyperuricemia (serum uric acid level >6 mg/dL) and PH [mean pulmonary arterial pressure (MPAP) >20 mmHg]. Compared to the normouricemia group (n=211), patients with hyperuricemia (n=112) exhibited a higher likelihood of being younger ( P =0.02), male ( P 35 mmHg; P <0.001). They had elevated values of body mass index ( P =0.004), plasma N-terminal pro-B-type natriuretic peptide ( P <0.001), serum creatinine ( P <0.001) and C-reactive protein ( P =0.03). The following variables were significantly associated with PH: higher values of body mass index ( P =0.005), uric acid ( P <0.001), total lung capacity ( P =0.02), residual volume ( P =0.01), and pulmonary capillary wedge pressure ( P <0.001); shorter 6-minute walk test distance ( P =0.005); and lower forced expiratory volume in one second ( P =0.006) and diffusing lung capacity for carbon monoxide ( P <0.001). On multivariate analysis, elevated uric acid level remained one of the variables most significantly associated with PH (OR 1.29, 95% CI 1.05-1.58, P =0.01). In conclusion, in patients with severe chronic lung diseases, hyperuricemia is strongly associated with the presence of PH. Hyperuricemia uric acid pulmonary hypertension lung disease WHO group 3 Introduction Chronic respiratory diseases are a major cause of morbidity and rank as the third leading cause of death worldwide [1]. Pulmonary hypertension (PH) is prevalent among patients with various forms of chronic lung disease and serves as an indicator of poor prognosis [2—4]. Right heart catheterization (RHC) is acknowledged as the gold standard for diagnosing and classifying PH [4], but it is a costly and invasive procedure, not routinely performed in patients with advanced chronic lung diseases [2—4]. A variety of biomarkers, including serum uric acid, are recommended for the assessment of established PH [4]. Elevated serum levels of uric acid are commonly observed in patients with World Health Organization (WHO) group 1 PH (pulmonary arterial hypertension) and strongly correlate with disease severity [5—10]. However, information regarding the relationship of serum uric acid with PH associated with chronic lung diseases (WHO Group 3) is scarce. In the single available study comprising 212 patients with interstitial lung disease, the presence of hyperuricemia increased the probability of diagnosing PH [11]. We hypothesized that in a patient population with a broad spectrum of advanced chronic lung diseases, evaluation of serum uric acid levels could help clinicians predict or exclude PH when considering the need for RHC. The aim of this study was to assess the potential association of serum uric acid with PH among patients with severe chronic lung disease awaiting lung transplantation. Materials and methods Study population and design The target study population comprised consecutive adult patients with various severe chronic lung diseases who were evaluated for eligibility for lung transplantation from June 2017 to February 2023 at Rabin Medical Center, the national center for lung transplantation in Israel. The transplant candidates were selected and examined according to the International Society for Heart and Lung Transplantation guidelines [12]. The evaluation included a detailed medical interview, physical and laboratory examination, six-minute walk test (6MWT), lung function tests (LFTs), computed tomography of the chest, and echocardiography. Only patients who had undergone RHC and had available serum uric acid measurements were included. For analysis of the association of hyperuricemia with PH and other relevant parameters, the patients were stratified into two groups based on serum levels of uric acid: normal (≤6 mg/dL) or elevated (>6 mg/dL). The study was carried out in accordance with the Declaration of Helsinki and was approved by the institutional Ethics Committee. Data collection Baseline characteristics were collected retrospectively from the electronic medical records. The following demographic and clinical data were recorded: age, sex, lung disease diagnosis, body-mass index (BMI), and 6MWT distance. Laboratory data were obtained as follows: levels of serum creatinine, uric acid, C-reactive protein (CRP), and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP). The lung function test (LFT) parameters recorded included forced expiratory volume in one second (FEV1), forced vital capacity (FVC), total lung capacity (TLC), residual volume (RV), and diffusing lung capacity for carbon monoxide (DLCO). RHC data included cardiac output (CO), cardiac index (CI), pulmonary capillary wedge pressure (PCWP), mean pulmonary arterial pressure (MPAP), and pulmonary vascular resistance (PVR). Definitions Hyperuricemia was defined as a serum uric acid level above the reference value (>6 mg/dL) in our laboratory. In line with current guidelines, the diagnoses of PH and severe PH were based on MPAP values of >20 mmHg and >35 mmHg, respectively, on RHC [4]. Statistical analysis The results were summarized as mean and standard deviation for quantitative data and as number (percentage) of cases for qualitative data. Chi-square test was used to compare categorical variables, and Student t test, to compare continuous variables. Statistical comparisons of the collected data were conducted between groups of patients with normouricemia and hyperuricemia. Pearson’s correlation coefficient (r) was calculated to evaluate correlations of uric acid with BMI, creatinine, and LFT and RHC parameters. P values ≤0.05 were considered significant. Univariate analysis was conducted to identify variables significantly associated with PH. Relevant variables found to be significant on univariate analysis were entered into a stepwise logistic regression model to identify those most significantly associated with PH. Receiver operating characteristic (ROC) plots were generated to determine the area under the curve (AUC) and assess the relationship between severe PH and serum uric acid level. The statistical analysis was carried out using SAS software, version 9.2 (SAS Institute Inc., Cary, NC, USA). Results Baseline patient characteristics Of 458 patients with severe chronic lung disease under evaluation for lung transplantation during the study period, 135 were excluded from the analysis: 111 were found unfit for lung transplantation and did not undergo RHC, 18 were missing serum uric acid measurements, and 6 had WHO group 1 PH. The remaining 323 patients formed the study cohort. Table 1 presents their baseline characteristics. Mean age was 62.2±7.7 years; 66.3% were male. The most common pulmonary disease diagnoses were interstitial lung disease (n=176) and chronic obstructive pulmonary disease (COPD) (n=121). Groups comparison Serum uric acid levels were within normal range in 211 patients and elevated in 112. Compared to patients with normouricemia, patients with hyperuricemia were more likely to be younger ( P =0.02) and male ( P <0.001). They also exhibited higher values of BMI ( P =0.004), plasma NT-proBNP ( P <0.001), serum creatinine ( P <0.001), and CRP ( P =0.03), as well as elevated PCWP ( P <0.001) and MPAP ( P <0.001). A higher percentage of patients in the hyperuricemia than the normouricemia group had PH (80.4% vs. 63.0%, P =0.001) and severe PH (29.5% vs. 8.5%, P <0.001). Correlation analysis Table 2 shows the correlations between serum uric acid levels and the relevant baseline variables. Uric acid positively correlated with BMI (r=0.31, P <0.001), serum creatinine (r=0.49, P <0.001), CO (r=0.19, P <0.001), PCWP (r=0.22, P <0.001), MPAP (r=0.29, P <0.001), and PVR (r=0.14, P =0.01). An inverse correlation of uric acid was observed with RV (r=-0.10, P =0.03). Univariate analysis Table 3 demonstrates results of the univariate analysis. The following variables were found to be significantly associated with PH: higher values of BMI ( P =0.005), serum uric acid ( P <0.001), TLC ( P =0.02), RV ( P =0.01), and PCWP ( P <0.001), shorter 6MWT distance ( P =0.005), and lower FEV1 ( P =0.006) and DLCO ( P <0.001). Multivariate analysis In the stepwise logistic regression analysis, considering covariates of age, sex, BMI, serum creatinine, uric acid, plasma NT-proBNP, 6MWT distance, and DLCO, the variables most significantly associated with PH were elevated uric acid (OR 1.29, 95% CI 1.05-1.58, P =0.01), higher BMI (OR 1.08, 95% CI 1.02-1.12, P =0.007), and lower DLCO (OR 1.04, 95% CI 1.01-1.06, P =0.007). ROC curve analysis Figure 1 demonstrates the ROC curve for the relationship of severe PH (MPAP >35 mmHg) with serum uric acid level. The optimal cut-off for uric acid was identified as 5.7 mg/dL, yielding an AUC of 0.720, with sensitivity 72.5%, specificity 63.6%, positive predictive value 27.2%, and negative predictive value 92.5%. Discussion We evaluated the ability of serum uric acid level to serve as a predictor of PH in 323 patients with severe chronic pulmonary disease, all candidates for lung transplantation. A significant and novel aspect of our investigation is the demonstration that elevated levels of uric acid were strongly associated with the presence of WHO group 3 PH. Our findings align with the study of Andersen et al. [11] wherein an association was found between hyperuricemia and the presence of PH in 212 patients with interstitial lung disease. However, there are notable differences between the present and earlier study in design, population characteristics, and results. Firstly, our investigation comprised a larger sample and included patients with a broad spectrum of severe chronic pulmonary diseases, reflecting a real-world population of lung transplant candidates. Secondly, in our study, every patient underwent RHC, ensuring a comprehensive evaluation, whereas in the previous report, RHC was conducted in only 17 patients, potentially leading to misclassification of PH. Thirdly, we confirmed the robust association of increased uric acid levels with PH by multivariate analysis, accounting for crucial confounders such as age, sex, BMI, serum creatinine level, plasma NT-proBNP level, 6MWT distance, and DLCO. We specifically assessed the association of serum uric acid with severe PH (MPAP >35 mmHg) and determined an optimal cut-off of 5.7 mg/dL, with an AUC of 0.72. Seyyedi et al. [7] reported an identical optimal cut-off for serum uric acid levels in predicting severe PH in a cohort of 110 patients with established PH of various etiologies. RHC is not routinely performed in patients with severe chronic lung diseases, but rather selectively undertaken for those with high clinical and echocardiographic suspicion of severe PH. Our findings suggest that in this patient population, measuring serum uric acid can be a useful tool for ruling out severe PH. Furthermore, we propose that assessing uric acid levels in lung transplant candidates may aid physicians in decision-making regarding the need for RHC for diagnosing severe PH, given the known therapeutic benefits of bilateral lung transplantation for severe PH. The pathophysiological mechanisms underlying the relationship between hyperuricemia and PH associated with chronic lung diseases (WHO group 3) are not fully understood. The main proposed cause of elevated serum uric acid in patients with severe chronic pulmonary disease is tissue hypoxia [5,10]. Specifically, uric acid is the final product of xanthine-oxidase-generated purine metabolism, and tissue hypoxia increases this process by inducing a decrease in adenosine triphosphate synthesis [5, 10]. An additional contributing factor of hyperuricemia in patients with chronic lung disease may be concomitant metabolic syndrome and renal dysfunction [5, 13]. In our patients, hyperuricemia was indeed associated with higher values of BMI and serum creatinine. Hyperuricemia may itself play a role in the development of PH in chronic lung diseases. Firstly, hyperuricemia induces endothelial dysfunction by decreasing the production of nitric oxide [5, 10, 14]. As a result, the release of various vasoactive substances and cytokines from endothelial cells is increased, leading to pulmonary vasoconstriction and the development of PH [5, 10, 15]. Secondly, hyperuricemia promotes smooth muscle cell proliferation and inflammation by increasing the production of uric acid in pulmonary artery smooth muscle cells. This increase is a result of enhanced activity of xanthine oxidase and decreased expression of the voltage-driven urate transporter 1 [5, 10, 16, 17]. Third, elevated concentrations of serum uric acid are associated with activation of the renin-angiotensin-aldosterone system, which may contribute to impaired vascular remodeling and aggravated pulmonary vasoconstriction, resulting in increased pressure in the pulmonary artery [5, 10, 18]. Finally, the development of PH in patients with chronic lung diseases could aggravate tissue hypoxia and oxidative stress, leading to hyperuricemia which may, in turn, may further worsen PH [3, 10, 19]. An additional interesting observation in our study is the association of hyperuricemia with male sex, as well as higher values of serum CRP and plasma NT-proBNP. Our findings for male sex are in line with data from two studies on patients with COPD [20, 21]. The association of hyperuricemia with higher CRP concentrations likely reflects its proinflammatory effect [5, 17] and has been reported in a large cohort of community-dwelling patients [22]. To our knowledge, among patients with chronic lung diseases, the association of hyperuricemia with increased NT-proBNP levels has not been reported. However, a positive correlation between concentrations of uric acid and NT-proBNP has been observed in patients with left heart failure [23, 24]. The pathophysiological mechanism responsible for the association of hyperuricemia with NT-proBNP elevation in chronic lung disease is unclear. We suggest that in patients with severe pulmonary disorders, hyperuricemia promotes the development of WHO group 3 PH, while PH and right ventricular dysfunction cause an increase in NT-proBNP. The present study has limitations. Since the investigation was conducted at a single medical center, its generalizability to other medical centers is unknown. Furthermore, data collection was limited to a single timepoint during evaluation for lung transplantation so that misclassification could arise due to time-dependent changes in the variables obtained. Conclusion Among patients with a broad spectrum of severe chronic pulmonary diseases who are candidates for lung transplantation, elevated levels of serum uric acid are strongly associated with the presence and the severity of PH. Assessment of serum uric acid levels in this population could assist physicians in the decision-making process regarding the need for performing RHC. Declarations Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Competing Interests The authors have no relevant financial or non-financial interests to disclose. Author Contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by [Shimon Izhakian], [Alon Gorenshtein] and [Haya Engelstein] and [Lev Freidkin]. The first draft of the manuscript was written by [Shimon Izhakian] and [Dror Rosengarten] and [Mordechai R Kramer] all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Ethics approval This study was performed in accordance with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Rabin Medical Center (2305/2023/0375-23-RMC). Consent to participates The need for informed patient consent was waived the Ethics Committee because of the retrospective design of the study. References GBD Chronic Respiratory Disease Collaborators. 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Hellenic J Cardiol. 2022;65:35—41. https://doi.org/10.1016/j.hjc.2022.03.009 Tables Table 1 Baseline characteristics of 323 lung transplant candidates with severe chronic lung disease, whole cohort and by serum uric acid level Characteristic Entire group (n=323) Normouricemia (n=211) Hyperuricemia (n=112) P value* Age (yrs) 62.2±7.7 62.9±7.4 60.8±8.0 0.02 Male sex 214 (66.3%) 124 (58.8%) 90 (80.4%) <0.001 BMI (kg/m 2 ) 26.4±5.4 25.8±5.6 27.6±4.8 0.004 Chronic lung disease Chronic interstitial lung disease 176 (54.5%) 113 (53.6%) 63 (56.3%) 0.64 COPD 121 (37.5%) 84 (39.8%) 37 (33.0%) 0.23 Other 26 (8.0%) 14 (6.6%) 12 (10.7%) 0.20 Laboratory data Serum creatinine (normal 0.5-0.9 mg/dL) 1.32±0.2 1.26±0.2 1.44±0.2 <0.001 Serum uric acid (normal 2.4-6.0 mg/dL) 5.5±1.9 4.4±1.0 7.5±1.4 <0.001 Serum CRP (normal 0-0.5 mg/dL 0.84±0.3 0.77±0.2 0.96±0.5 0.03 Plasma NT-proBNP (pg/mL) 358.1±1155.7 158.2±278.4 737.7±1873.2 <0.001 6MWT distance (meters) 271.8±130.4 270.4±126.7 274.4±137.8 0.86 Data of lung function test FEV1 (% of predicted value) 42.3±19.7 42.1±20.2 42.6±18.7 0.68 FVC (% of predicted value) 51.7±16.9 51.8±16.7 51.4±17.3 0.51 TLC (% of predicted value) 81.9±37.0 83.6±38.4 78.7±34.4 0.27 RV (% of predicted value) 138.6±96.9 142.9±98.7 130.9±93.4 0.45 DLCO (% of predicted value) 32.9±13.4 33.2±13.4 32.4±13.3 28 Data of right heart catheterization CO (1/min) 4.4±1.3 4.2±1.2 4.5±1.4 0.11 CI (1/min/m 2 ) 2.38±0.6 2.4±0.6 2.35±0.6 0.61 PCWP (mmHg) 9.9±6.3 8.9±5.8 11.7±6.7 <0.001 MPAP (mmHg) 24.8±10.2 22.7±8.7 28.9±11.5 20 mmHg), n(%) 223 (69.0%) 133 (63.0%) 90 (80.4%) 35 mmHg), n(%) 55 (15.8%) 18 (8.5%) 33 (29.5%) <0.001 Data are presented as means ± standard deviations or numbers (percentages) of presented cases. *Difference between normouricemic and hyperuricemic groups. CRP: C-reactive protein; NT-proBNP: Bold entries in the table indicate a P -value of ≤0.05. 6MWT, 6-minute walk test; BMI, body mass index; CI, cardiac index; CO, cardiac output; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; DLCO, diffusing lung capacity for carbon monoxide; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; MPAP, mean pulmonary artery pressure; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PCWP, pulmonary capillary wedge pressure; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RV, residual volume; TLC, total lung capacity; WU, Wood units Table 2 Correlations between serum levels of uric acid and other baseline parameters in lung transplant candidates with chronic lung disease Parameter Pearson's correlation coefficient (r) P -value BMI (kg/m 2 ) 0.31 <0.001 Serum creatinine (mg/dL) 0.49 <0.001 6MWT distance (meters) -0.01 0.82 FEV1 (% of predicted value) 0.07 0.17 FVC (% of predicted value) 0.08 0.11 TLC (% of predicted value) -0.09 0.08 RV (% of predicted value) -0.10 0.03 DLCO (% of predicted value) 0.01 0.86 CO (L/min) 0.19 <0.001 CI (L/min/m 2 ) -0.02 0.67 PCWP (mmHg) 0.22 <0.001 MPAP (mmHg) 0.29 <0.001 PVR (WU) 0.14 0.01 *Bold entries in the table indicate a P -value of ≤0.05. 6MWT, 6-minute walk test; BMI, body mass index; CI, cardiac index; CO, cardiac output; DLCO, diffusing lung capacity for carbon monoxide; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; MPAP, mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RV, residual volume; TLC, total lung capacity; WU, Wood units. Table 3 Variables evaluated for association with PH (MPAP >20 mmHg) in lung transplant candidates with severe chronic pulmonary disease (univariate analysis) Variable OR 95% CI P -value Age (yrs) 0.97 0.94-1.01 0.13 Male sex 2.36 0.51-1.36 0.48 BMI (kg/m 2 ) 1.06 1.02-1.11 0.005 Serum creatinine (mg/dL) 1.07 0.52-2.19 0.84 Serum uric acid (mg/dL) 1.29 1.11-1.49 <0.001 Serum CRP (mg/dL) 1.05 0.92-1.20 0.43 Plasma NT-proBNP (pg/mL) 1.00 1.00-1.00 0.15 6MWT distance (meters) 0.99 0.99-1.00 0.005 FEV1 (% of predicted value) 0.98 0.97-0.99 0.006 FVC (% of predicted value) 1.00 0.99=1.01 0.97 TLC (% of predicted value) 1.01 1.00-1.01 0.02 RV (% of predicted value) 1.00 1.00-1.01 0.01 DLCO (% of predicted value) 0.96 0.95-0.98 <0.001 CO (L/min) 1.09 0.90-1.33 0.36 CI (L/min/m 2 ) 0.91 0.60-1.39 0.67 PCWP (mmHg) 1.36 1.27-1.47 <0.001 PVR (WU) 1.47 0.99-1.01 0.36 *Bold entries in the table indicate a P -value of ≤0.05. 6MWT, 6-minute walk test; BMI, body mass index; CI, cardiac index; CO, cardiac output; DLCO, diffusing lung capacity for carbon monoxide; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; MPAP, mean pulmonary artery pressure; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PCWP, pulmonary capillary wedge pressure; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RV, residual volume; TLC, total lung capacity; WU, Wood units Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4298792","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":294961352,"identity":"fc64a213-c54e-4caa-93a8-47ad4a700c0c","order_by":0,"name":"Shimon Izhakian","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzklEQVRIiWNgGAWjYDACCcYGhgQgzQ/iJBSQokWyAaTFgCgtUNrgAJgkQof87ObWDQ/bDtsbn1+d+OGBAYM8v9gB/FoM7hxsu5Fw5jCz2Y23myWADjOcOTuBgBaJRKCWisNsZjfObgBpSTC4TUCL/AyQFoPDPMYzzm7+QZQWhhsQWyQM+Hu3EWeLAVjLmXQDiRu82ywSDCQI+0V+Rvqzmz/brO35+89uvvmjwkaeX5qQwyCgGRhBYJUSBBQiQB0wxRwgWvUoGAWjYBSMMAAA2rZJFG1cm9sAAAAASUVORK5CYII=","orcid":"","institution":"Rabin Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Shimon","middleName":"","lastName":"Izhakian","suffix":""},{"id":294961353,"identity":"0355ff65-e5cd-4bdd-9fdd-06c71082cc55","order_by":1,"name":"Alon Gorenshtein","email":"","orcid":"","institution":"Rabin Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Alon","middleName":"","lastName":"Gorenshtein","suffix":""},{"id":294961354,"identity":"fe2e0af4-c608-427e-ac76-fd2f8bdbd72e","order_by":2,"name":"Haya Engelstein","email":"","orcid":"","institution":"Rabin Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Haya","middleName":"","lastName":"Engelstein","suffix":""},{"id":294961355,"identity":"72f0b037-3dbd-4cb8-b527-7370e04c3517","order_by":3,"name":"Lev Freidkin","email":"","orcid":"","institution":"Rabin Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Lev","middleName":"","lastName":"Freidkin","suffix":""},{"id":294961356,"identity":"ccf4ba27-63da-4f5b-8684-f27567d32ff4","order_by":4,"name":"Dror Rosengarten","email":"","orcid":"","institution":"Rabin Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Dror","middleName":"","lastName":"Rosengarten","suffix":""},{"id":294961357,"identity":"895a3249-5ba8-4ece-89c0-0ca27f1f31dc","order_by":5,"name":"Mordechai R Kramer","email":"","orcid":"","institution":"Rabin Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Mordechai","middleName":"R","lastName":"Kramer","suffix":""}],"badges":[],"createdAt":"2024-04-20 21:24:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4298792/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4298792/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":59400063,"identity":"82d096c1-be77-41b7-bf6e-5712ba9d0591","added_by":"auto","created_at":"2024-07-01 10:02:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":521200,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4298792/v1/ef4d3875-997d-4918-9d3d-396559fffb48.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Hyperuricemia is strongly associated with pulmonary hypertension in chronic lung disease","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChronic respiratory diseases are a major cause of morbidity and rank as the third leading cause of death worldwide [1]. Pulmonary hypertension (PH) is prevalent among patients with various forms of chronic lung disease and serves as an indicator of poor prognosis [2\u0026mdash;4]. Right heart catheterization (RHC) is acknowledged as the gold standard for diagnosing and classifying PH [4], but it is a costly and invasive procedure, not routinely performed in patients with advanced chronic lung diseases [2\u0026mdash;4].\u003c/p\u003e\n\u003cp\u003eA variety of biomarkers, including serum uric acid, are recommended for the assessment of established PH [4]. Elevated serum levels of uric acid are commonly observed in patients with World Health Organization (WHO) group 1 PH (pulmonary arterial hypertension) and strongly correlate with disease severity [5\u0026mdash;10]. However, information regarding the relationship of serum uric acid with PH associated with chronic lung diseases (WHO Group 3) is scarce. In the single available study comprising 212 patients with interstitial lung disease, the presence of hyperuricemia increased the probability of diagnosing PH [11].\u003c/p\u003e\n\u003cp\u003eWe hypothesized that in a patient population with a broad spectrum of advanced chronic lung diseases, evaluation of serum uric acid levels could help clinicians predict or exclude PH when considering the need for RHC. The aim of this study was to assess the potential association of serum uric acid with PH among patients with severe chronic lung disease awaiting lung transplantation.\u003c/p\u003e"},{"header":"Materials and methods ","content":"\u003cp\u003e\u003cstrong\u003eStudy population and design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe target study population comprised consecutive adult patients with various severe chronic lung diseases who were evaluated for eligibility for lung transplantation from June 2017 to February 2023 at Rabin Medical Center, the national center for lung transplantation in Israel. The transplant candidates were selected and examined according to the International Society for Heart and Lung Transplantation guidelines [12]. The evaluation included a detailed medical interview, physical and laboratory examination, six-minute walk test (6MWT), lung function tests (LFTs), computed tomography of the chest, and echocardiography. Only patients who had undergone RHC and had available serum uric acid measurements were included. \u0026nbsp;For analysis of the association of hyperuricemia with PH and other relevant parameters, the patients were stratified into two groups based on serum levels of uric acid: normal (\u0026le;6 mg/dL) or elevated (\u0026gt;6 mg/dL). The study was carried out in accordance with the Declaration of Helsinki and was approved by the institutional Ethics Committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBaseline characteristics were collected retrospectively from the electronic medical records. The following demographic and clinical data were recorded: age, sex, lung disease diagnosis, body-mass index (BMI), and 6MWT distance. Laboratory data were obtained as follows: levels of serum creatinine, uric acid, C-reactive protein (CRP), and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP). The lung function test (LFT) parameters recorded included forced expiratory volume in one second (FEV1), forced vital capacity (FVC), total lung capacity (TLC), residual volume (RV), and diffusing lung capacity for carbon monoxide (DLCO). RHC data included cardiac output (CO), cardiac index (CI), pulmonary capillary wedge pressure (PCWP), mean pulmonary arterial pressure (MPAP), and pulmonary vascular resistance (PVR).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDefinitions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHyperuricemia was defined as a serum uric acid level above the reference value (\u0026gt;6 mg/dL) in our laboratory. In line with current guidelines, the diagnoses of PH and severe PH were based on MPAP values of \u0026gt;20 mmHg and \u0026gt;35 mmHg, respectively, on RHC [4].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results were summarized as mean and standard deviation for quantitative data and as number (percentage) of cases for qualitative data. Chi-square test was used to compare categorical variables, and Student t test, to compare continuous variables. Statistical comparisons of the collected data were conducted between groups of patients with normouricemia and hyperuricemia. Pearson\u0026rsquo;s correlation coefficient (r) was calculated to evaluate correlations of uric acid with BMI, creatinine, and LFT and RHC parameters. \u003cem\u003eP\u003c/em\u003e values \u0026le;0.05 were considered significant.\u003c/p\u003e\n\u003cp\u003eUnivariate analysis was conducted to identify variables significantly associated with PH. Relevant variables found to be significant on univariate analysis were entered into a stepwise logistic regression model to identify those most significantly associated with PH. Receiver operating characteristic (ROC) plots were generated to determine the area under the curve (AUC) and assess the relationship between severe PH and serum uric acid level. The statistical analysis was carried out using SAS software, version 9.2 (SAS Institute Inc., Cary, NC, USA).\u003c/p\u003e"},{"header":"Results ","content":"\u003cp\u003e\u003cstrong\u003eBaseline patient characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf 458 patients with severe chronic lung disease under evaluation for lung transplantation during the study period, 135 were excluded from the analysis: 111 were found unfit for lung transplantation and did not undergo RHC, 18 were missing serum uric acid measurements, and 6 had WHO group 1 PH. The remaining 323 patients formed the study cohort. Table 1 presents their baseline characteristics. Mean age was 62.2±7.7 years; 66.3% were male. The most common pulmonary disease diagnoses were interstitial lung disease (n=176) and chronic obstructive pulmonary disease (COPD) (n=121).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGroups comparison\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSerum uric acid levels were within normal range in 211 patients and elevated in 112. \u0026nbsp;Compared to patients with normouricemia, patients with hyperuricemia were more likely to be younger (\u003cem\u003eP\u003c/em\u003e=0.02) and male (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001). They also exhibited higher values of BMI (\u003cem\u003eP\u003c/em\u003e=0.004), plasma NT-proBNP (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001), serum creatinine (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001), and CRP (\u003cem\u003eP\u003c/em\u003e=0.03), as well as elevated PCWP (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001) and MPAP (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001). A higher percentage of patients in the hyperuricemia than the normouricemia group had PH (80.4% vs. 63.0%, \u003cem\u003eP\u003c/em\u003e=0.001) and severe PH (29.5% vs. 8.5%, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrelation analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 2 shows the correlations between serum uric acid levels and the relevant baseline variables. Uric acid positively correlated with BMI (r=0.31, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001), serum creatinine (r=0.49, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001), CO (r=0.19, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001), PCWP (r=0.22, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001), MPAP (r=0.29, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001), and PVR (r=0.14, \u003cem\u003eP\u003c/em\u003e=0.01). An inverse correlation of uric acid was observed with RV (r=-0.10, \u003cem\u003eP\u003c/em\u003e=0.03).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUnivariate analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 3 demonstrates results of the univariate analysis. \u0026nbsp;The following variables were found to be significantly associated with PH: higher values of BMI (\u003cem\u003eP\u003c/em\u003e=0.005), serum uric acid (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001), TLC (\u003cem\u003eP\u003c/em\u003e=0.02), RV (\u003cem\u003eP\u003c/em\u003e=0.01), and PCWP (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001), shorter 6MWT distance (\u003cem\u003eP\u003c/em\u003e=0.005), and lower FEV1 (\u003cem\u003eP\u003c/em\u003e=0.006) and DLCO (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMultivariate analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the stepwise logistic regression analysis, considering covariates of age, sex, BMI, serum creatinine, uric acid, plasma NT-proBNP, 6MWT distance, and DLCO, the variables most significantly associated with PH were elevated uric acid (OR 1.29, 95% CI 1.05-1.58, \u003cem\u003eP\u003c/em\u003e=0.01), higher BMI (OR 1.08, 95% CI 1.02-1.12, \u003cem\u003eP\u003c/em\u003e=0.007), and lower DLCO (OR 1.04, 95% CI 1.01-1.06, \u003cem\u003eP\u003c/em\u003e=0.007).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eROC curve analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 1 demonstrates the ROC curve for the relationship of severe PH (MPAP \u0026gt;35 mmHg) with serum uric acid level. The optimal cut-off for uric acid was identified as 5.7 mg/dL, yielding an AUC of 0.720, with sensitivity 72.5%, specificity 63.6%, positive predictive value 27.2%, and negative predictive value 92.5%.\u003c/p\u003e"},{"header":"Discussion ","content":"\u003cp\u003eWe evaluated the ability of serum uric acid level to serve as a predictor of PH in 323 patients with severe chronic pulmonary disease, all candidates for lung transplantation. A significant and novel aspect of our investigation is the demonstration that elevated levels of uric acid were strongly associated with the presence of WHO group 3 PH.\u003c/p\u003e\n\u003cp\u003eOur findings align with the study of Andersen et al. [11] wherein an association was found between hyperuricemia and the presence of PH in 212 patients with interstitial lung disease. However, there are notable differences between the present and earlier study in design, population characteristics, and results. Firstly, our investigation comprised a larger sample and included patients with a broad spectrum of severe chronic pulmonary diseases, reflecting a real-world population of lung transplant candidates. Secondly, in our study, every patient underwent RHC, ensuring a comprehensive evaluation, whereas in the previous report, RHC was conducted in only 17 patients, potentially leading to misclassification of PH. Thirdly, we confirmed the robust association of increased uric acid levels with PH by multivariate analysis, accounting for crucial confounders such as age, sex, BMI, serum creatinine level, plasma NT-proBNP level, 6MWT distance, and DLCO.\u003c/p\u003e\n\u003cp\u003eWe specifically assessed the association of serum uric acid with severe PH (MPAP \u0026gt;35 mmHg) and determined an optimal cut-off of 5.7 mg/dL, with an AUC of 0.72. Seyyedi et al. [7] reported an identical optimal cut-off for serum uric acid levels in predicting severe PH in a cohort of 110 patients with established PH of various etiologies. RHC is not routinely performed in patients with severe chronic lung diseases, but rather selectively undertaken for those with high clinical and echocardiographic suspicion of severe PH. Our findings suggest that in this patient population, measuring serum uric acid can be a useful tool for ruling out severe PH. Furthermore, we propose that assessing uric acid levels in lung transplant candidates may aid physicians in decision-making regarding the need for RHC for diagnosing severe PH, given the known therapeutic benefits of bilateral lung transplantation for severe PH.\u003c/p\u003e\n\u003cp\u003eThe pathophysiological mechanisms underlying the relationship between hyperuricemia and PH associated with chronic lung diseases (WHO group 3) are not fully understood. The main proposed cause of elevated serum uric acid in patients with severe chronic pulmonary disease is tissue hypoxia [5,10]. Specifically, uric acid is the final product of xanthine-oxidase-generated purine metabolism, and tissue hypoxia increases this process by inducing a decrease in adenosine triphosphate synthesis [5, 10]. An additional contributing factor of hyperuricemia in patients with chronic lung disease may be concomitant metabolic syndrome and renal dysfunction [5, 13]. In our patients, hyperuricemia was indeed associated with higher values of BMI and serum creatinine.\u003c/p\u003e\n\u003cp\u003eHyperuricemia may itself play a role in the development of PH in chronic lung diseases. Firstly, hyperuricemia induces endothelial dysfunction by decreasing the production of nitric oxide [5, 10, 14]. As a result, the release of various vasoactive substances and cytokines from endothelial cells is increased, leading to pulmonary vasoconstriction and the development of PH [5, 10, 15]. Secondly, hyperuricemia promotes smooth muscle cell proliferation and inflammation by increasing the production of uric acid in pulmonary artery smooth muscle cells. This increase is a result of enhanced activity of xanthine oxidase and decreased expression of the voltage-driven urate transporter 1 [5, 10, 16, 17]. Third, elevated concentrations of serum uric acid are associated with activation of the renin-angiotensin-aldosterone system, which may contribute to impaired vascular remodeling and aggravated pulmonary vasoconstriction, resulting in increased pressure in the pulmonary artery [5, 10, 18]. Finally, the development of PH in patients with chronic lung diseases could aggravate tissue hypoxia and oxidative stress, leading to hyperuricemia which may, in turn, may further worsen PH [3, 10, 19].\u003c/p\u003e\n\u003cp\u003eAn additional interesting observation in our study is the association of hyperuricemia with male sex, as well as higher values of serum CRP and plasma NT-proBNP. Our findings for male sex are in line with data from two studies on patients with COPD [20, 21]. The association of hyperuricemia with higher CRP concentrations likely reflects its proinflammatory effect [5, 17] and has been reported in a large cohort of community-dwelling patients [22]. \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo our knowledge, among patients with chronic lung diseases, the association of hyperuricemia with increased NT-proBNP levels has not been reported. However, a positive correlation between concentrations of uric acid and NT-proBNP has been observed in patients with left heart failure [23, 24]. The pathophysiological mechanism responsible for the association of hyperuricemia with NT-proBNP elevation in chronic lung disease is unclear. We suggest that in patients with severe pulmonary disorders, hyperuricemia promotes the development of WHO group 3 PH, while PH and right ventricular dysfunction cause an increase in NT-proBNP.\u003c/p\u003e\n\u003cp\u003eThe present study has limitations. Since the investigation was conducted at a single medical center, its generalizability to other medical centers is unknown. Furthermore, data collection was limited to a single timepoint during evaluation for lung transplantation so that misclassification could arise due to time-dependent changes in the variables obtained.\u003c/p\u003e"},{"header":"Conclusion ","content":"\u003cp\u003eAmong patients with a broad spectrum of severe chronic pulmonary diseases who are candidates for lung transplantation, elevated levels of serum uric acid are strongly associated with the presence and the severity of PH. Assessment of serum uric acid levels in this population could assist physicians in the decision-making process regarding the need for performing RHC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by [Shimon Izhakian], [Alon Gorenshtein] and [Haya Engelstein] and [Lev Freidkin]. The first draft of the manuscript was written by [Shimon Izhakian] and [Dror Rosengarten] and [Mordechai R Kramer] all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in accordance with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Rabin Medical Center (2305/2023/0375-23-RMC).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participates\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe need for informed patient consent was waived the Ethics Committee because of the retrospective design of the study.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGBD Chronic Respiratory Disease Collaborators. Prevalence and attributable health burden of chronic respiratory diseases, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet Respir Med. 2020;8(6):585\u0026mdash;96. https://doi.org/10.1016/S2213-2600(20)30105-3\u003c/li\u003e\n\u003cli\u003eSeeger W, Adir Y, Barber\u0026agrave; JA, et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol. 2013;62(25 Suppl):D109\u0026mdash;16. https://doi.org/10.1016/j.jacc.2013.10.036\u003c/li\u003e\n\u003cli\u003eNathan SD, Barbera JA, Gaine SP, et al. Pulmonary hypertension in chronic lung disease and hypoxia. Eur Respir J. 2019;53(1):1801914. https://doi.org/10.1183/13993003.01914-2018\u003c/li\u003e\n\u003cli\u003eHumbert M, Kovacs G, Hoeper MM, et al; ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(38):3618\u0026mdash;731. https://doi.org/10.1093/eurheartj/ehac237\u003c/li\u003e\n\u003cli\u003eZharikov SI, Swenson ER, Lanaspa M, Block ER, Patel JM, Johnson RJ. Could uric acid be a modifiable risk factor in subjects with pulmonary hypertension. Med Hypotheses. 2010;74(6):1069\u0026mdash;74. https://doi.org/10.1016/j.mehy.2009.12.023\u003c/li\u003e\n\u003cli\u003eZhang CY, Ma LL, Wang LX. Relationship between serum uric acid levels and ventricular function in patients with idiopathic pulmonary hypertension. Exp Clin Cardiol. 2013;18(1):e37\u0026mdash;9. \u003c/li\u003e\n\u003cli\u003eSeyyedi SR, Malekmohammad M, Chitsazan M, et al. Relationship between serum uric acid levels and the severity of pulmonary hypertension. Tanaffos. 2017;16(4):283\u0026mdash;8. \u003c/li\u003e\n\u003cli\u003eCerik IB, Dindas F, Koyun E, et al. New prognostic markers in pulmonary arterial hypertension: CRP to albumin ratio and uric acid. Clin Biochem. 2022;100:22\u0026mdash;8. https://doi.org/10.1016/j.clinbiochem.2021.11.004 \u003c/li\u003e\n\u003cli\u003eLuo J, Li Y, Chen J, et al. Evaluating the role of serum uric acid in the risk stratification and therapeutic response of patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD). Front Pharmacol. 2023;14:1238581. https://doi.org/10.3389/fphar.2023.1238581 \u003c/li\u003e\n\u003cli\u003eZhou Y, Chen M, Zheng J, et al. Insights into the relationship between serum uric acid and pulmonary hypertension. Mol Med Rep. 2024;29(1):10. https://doi.org/10.3892/mmr.2023.13133\u003c/li\u003e\n\u003cli\u003eAndersen CU, Mellemkj\u0026aelig;r S, Nielsen-Kudsk JE, Bendstrup E, Simonsen U, Hilberg O. Diagnostic and prognostic role of biomarkers for pulmonary hypertension in interstitial lung disease. Respir Med. 2012;106(12):1749\u0026mdash;55. https://doi.org/10.1016/j.rmed.2012.09.003 \u003c/li\u003e\n\u003cli\u003eWeill D, Benden C, Corris PA, et al. A consensus document for the selection of lung transplant candidates: 2014--an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2015;34(1):1\u0026mdash;15. https://doi.org/10.1016/j.healun.2014.06.014\u003c/li\u003e\n\u003cli\u003eKim GH, Jun JB. Altered serum uric acid levels in kidney disorders. Life (Basel).2022;12(11):1891. https://doi.org/10.3390/life12111891\u003c/li\u003e\n\u003cli\u003eZharikov S, Krotova K, Hu H, et al. Uric acid decreases NO production and increases arginase activity in cultured pulmonary artery endothelial cells. Am J Physiol Cell Physiol. 2008;295(5):C1183\u0026mdash;90. https://doi.org/10.1152/ajpcell.00075.2008 \u003c/li\u003e\n\u003cli\u003eEvans CE, Cober ND, Dai Z, Stewart DJ, Zhao YY. Endothelial cells in the pathogenesis of pulmonary arterial hypertension. Eur Respir J. 2021;58(3):2003957. https://doi.org/10.1183/13993003.03957-2020\u003c/li\u003e\n\u003cli\u003eSavale L, Akagi S, Tu L, et al. Serum and pulmonary uric acid in pulmonary arterial hypertension. Eur Respir J. 2021;58(2):2000332. doi: 10.1183/13993003.00332-2020\u003c/li\u003e\n\u003cli\u003eKanellis J, Kang DH. Uric acid as a mediator of endothelial dysfunction, inflammation, and vascular disease. Semin Nephrol. 2005;25(1):39\u0026mdash;42. https://doi.org/10.1016/j.semnephrol.2004.09.007\u003c/li\u003e\n\u003cli\u003ePerlstein TS, Gumieniak O, Hopkins PN, et al. Uric acid and the state of the intrarenal renin-angiotensin system in humans. Kidney Int. 2004;66(4):1465\u0026mdash;70. https://doi.org/10.1111/j.1523-1755.2004.00909.x\u003c/li\u003e\n\u003cli\u003eWatanabe T, Ishikawa M, Abe K, et al. Increased lung uric acid deteriorates pulmonary arterial hypertension. J Am Heart Assoc. 2021;10(23):e022712. https://doi.org/10.1161/JAHA.121.022712\u003c/li\u003e\n\u003cli\u003eKahnert K, Alter P, Welte T, et al. Uric acid, lung function, physical capacity and exacerbation frequency in patients with COPD: a multi-dimensional approach. Respir Res. 2018;19(1):110. https://doi.org/10.1186/s12931-018-0815-y\u003c/li\u003e\n\u003cli\u003eTrudzinski FC, J\u0026ouml;rres RA, Alter P, et al. Sex-specific associations of comorbidome and pulmorbidome with mortality in chronic obstructive pulmonary disease: results from COSYCONET. Sci Rep. 2022;12(1):8790. https://doi.org/10.1038/s41598-022-12828-8\u003c/li\u003e\n\u003cli\u003eKaspar CDW, Lu J. Hyperuricemia, elevated body mass index, female sex, and albuminuria increase the probability of elevated high-sensitivity C-reactive protein: results from the National Health and Nutrition Examination Survey 2015-2018. Front Public Health. 2021:9:689219. https://doi.org/10.3389/fpubh.2021.689219\u003c/li\u003e\n\u003cli\u003eSabaka P, Dukat A, Gajdosik J, Caprnda M, Bendzala M, Simko F. Uric acid level is positively associated with NT-proBNP concentration in Slovak heart failure patients. Physiol Res. 2019;68(5):767\u0026mdash;74. https://doi.org/10.33549/physiolres.934186\u003c/li\u003e\n\u003cli\u003eYılmaz \u0026Ouml;ztekin GM, Gen\u0026ccedil; A, \u0026Ccedil;ağırcı G, Arslan Ş. Prognostic value of the combination of uric acid and NT-proBNP in patients with chronic heart failure. Hellenic J Cardiol. 2022;65:35\u0026mdash;41. https://doi.org/10.1016/j.hjc.2022.03.009 \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e\u0026nbsp; \u0026nbsp;Baseline characteristics of 323 lung transplant candidates with severe chronic lung disease, whole cohort and by serum uric acid level\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"718\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003eEntire group\u003c/p\u003e\n \u003cp\u003e(n=323)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003eNormouricemia\u003c/p\u003e\n \u003cp\u003e(n=211)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003eHyperuricemia\u003c/p\u003e\n \u003cp\u003e(n=112)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e\u003cem\u003eP\u0026nbsp;\u003c/em\u003evalue*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003eAge (yrs)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e62.2\u0026plusmn;7.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e62.9\u0026plusmn;7.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e60.8\u0026plusmn;8.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003eMale sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e214 (66.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e124 (58.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e90 (80.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e26.4\u0026plusmn;5.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e25.8\u0026plusmn;5.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e27.6\u0026plusmn;4.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003eChronic lung disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Chronic interstitial lung disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e176 (54.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e113 (53.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e63 (56.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e0.64\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;COPD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e121 (37.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e84 (39.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e37 (33.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e26 (8.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e14 (6.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e12 (10.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003eLaboratory data\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Serum creatinine (normal 0.5-0.9 mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e1.32\u0026plusmn;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e1.26\u0026plusmn;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e1.44\u0026plusmn;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Serum uric acid (normal 2.4-6.0 mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e5.5\u0026plusmn;1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e4.4\u0026plusmn;1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e7.5\u0026plusmn;1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Serum CRP (normal 0-0.5 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e0.84\u0026plusmn;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e0.77\u0026plusmn;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e0.96\u0026plusmn;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.03\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Plasma NT-proBNP (pg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e358.1\u0026plusmn;1155.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e158.2\u0026plusmn;278.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e737.7\u0026plusmn;1873.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003e6MWT distance (meters)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e271.8\u0026plusmn;130.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e270.4\u0026plusmn;126.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e274.4\u0026plusmn;137.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003eData of lung function test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;FEV1 (% of predicted value)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e42.3\u0026plusmn;19.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e42.1\u0026plusmn;20.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e42.6\u0026plusmn;18.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;FVC (% of predicted value)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e51.7\u0026plusmn;16.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e51.8\u0026plusmn;16.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e51.4\u0026plusmn;17.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;TLC (% of predicted value)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e81.9\u0026plusmn;37.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e83.6\u0026plusmn;38.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e78.7\u0026plusmn;34.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e0.27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;RV (% of predicted value)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e138.6\u0026plusmn;96.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e142.9\u0026plusmn;98.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e130.9\u0026plusmn;93.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;DLCO (% of predicted value)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e32.9\u0026plusmn;13.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e33.2\u0026plusmn;13.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e32.4\u0026plusmn;13.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"53.899721448467965%\" colspan=\"2\"\u003e\n \u003cp\u003eData of right heart catheterization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;CO (1/min)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e4.4\u0026plusmn;1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e4.2\u0026plusmn;1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e4.5\u0026plusmn;1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;CI (1/min/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e2.38\u0026plusmn;0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e2.4\u0026plusmn;0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e2.35\u0026plusmn;0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e0.61\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;PCWP (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e9.9\u0026plusmn;6.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e8.9\u0026plusmn;5.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e11.7\u0026plusmn;6.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;MPAP (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e24.8\u0026plusmn;10.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e22.7\u0026plusmn;8.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e28.9\u0026plusmn;11.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;PVR (WU)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e3.7\u0026plusmn;2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e3.4\u0026plusmn;1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e4.2\u0026plusmn;3.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;PH (MPAP\u0026gt;20 mmHg), n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e223 (69.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e133 (63.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e90 (80.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.16155988857939%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Severe PH (MPAP\u0026gt;35 mmHg), n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e55 (15.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.13091922005571%\"\u003e\n \u003cp\u003e18 (8.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.73816155988858%\"\u003e\n \u003cp\u003e33 (29.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.231197771587743%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eData are presented as means\u003cstrong\u003e\u003cspan dir=\"RTL\"\u003e\u0026plusmn;\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e standard deviations or numbers (percentages) of presented cases. *Difference between normouricemic and hyperuricemic groups. CRP: C-reactive protein; NT-proBNP: Bold entries in the table indicate a \u003cem\u003eP\u003c/em\u003e-value of \u0026le;0.05.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e6MWT, 6-minute walk test; BMI, body mass index; CI, cardiac index; CO, cardiac output; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; DLCO, diffusing lung capacity for carbon monoxide; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; MPAP, mean pulmonary artery pressure; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PCWP, pulmonary capillary wedge pressure; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RV, residual volume; TLC, total lung capacity; WU, Wood units\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"557\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2\u0026nbsp;\u003c/strong\u003eCorrelations between serum levels of uric acid and other baseline parameters\u003cem\u003e\u0026nbsp;\u003c/em\u003ein lung transplant candidates with chronic lung disease\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.69892473118279%\"\u003e\n \u003cp\u003eParameter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.85304659498208%\"\u003e\n \u003cp\u003ePearson\u0026apos;s correlation coefficient (r)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.448028673835125%\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.69892473118279%\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.85304659498208%\"\u003e\n \u003cp\u003e0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.448028673835125%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.69892473118279%\"\u003e\n \u003cp\u003eSerum creatinine (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.85304659498208%\"\u003e\n \u003cp\u003e0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.448028673835125%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.69892473118279%\"\u003e\n \u003cp\u003e6MWT distance (meters)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.85304659498208%\"\u003e\n \u003cp\u003e-0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.448028673835125%\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.69892473118279%\"\u003e\n \u003cp\u003eFEV1 (% of predicted value)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.85304659498208%\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.448028673835125%\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.69892473118279%\"\u003e\n \u003cp\u003eFVC (% of predicted value)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.85304659498208%\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.448028673835125%\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.69892473118279%\"\u003e\n \u003cp\u003eTLC (% of predicted value)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.85304659498208%\"\u003e\n \u003cp\u003e-0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.448028673835125%\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.69892473118279%\"\u003e\n \u003cp\u003eRV (% of predicted value)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.85304659498208%\"\u003e\n \u003cp\u003e-0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.448028673835125%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.03\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.69892473118279%\"\u003e\n \u003cp\u003eDLCO (% of predicted value)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.85304659498208%\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.448028673835125%\"\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.69892473118279%\"\u003e\n \u003cp\u003eCO (L/min)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.85304659498208%\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.448028673835125%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.69892473118279%\"\u003e\n \u003cp\u003eCI (L/min/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.85304659498208%\"\u003e\n \u003cp\u003e-0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.448028673835125%\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.69892473118279%\"\u003e\n \u003cp\u003ePCWP (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.85304659498208%\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.448028673835125%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.69892473118279%\"\u003e\n \u003cp\u003eMPAP (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.85304659498208%\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.448028673835125%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.69892473118279%\"\u003e\n \u003cp\u003ePVR (WU)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.85304659498208%\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.448028673835125%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*Bold entries in the table indicate a \u003cem\u003eP\u003c/em\u003e-value of \u0026le;0.05.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e6MWT, 6-minute walk test; BMI, body mass index; CI, cardiac index; CO, cardiac output; DLCO, diffusing lung capacity for carbon monoxide; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; MPAP, mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure;\u0026nbsp;PH, pulmonary hypertension; PVR, pulmonary vascular resistance;\u0026nbsp;RV, residual volume; TLC, total lung capacity;\u0026nbsp;WU, Wood units.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e Variables evaluated for association with PH (MPAP \u0026gt;20 mmHg) in lung transplant candidates with severe chronic pulmonary disease (univariate analysis)\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"529\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.04545454545455%\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.696969696969695%\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.803030303030305%\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.04545454545455%\"\u003e\n \u003cp\u003eAge (yrs)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.696969696969695%\"\u003e\n \u003cp\u003e0.94-1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.803030303030305%\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.04545454545455%\"\u003e\n \u003cp\u003eMale sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003e2.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.696969696969695%\"\u003e\n \u003cp\u003e0.51-1.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.803030303030305%\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.04545454545455%\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003e1.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.696969696969695%\"\u003e\n \u003cp\u003e1.02-1.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.803030303030305%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.005\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.04545454545455%\"\u003e\n \u003cp\u003eSerum creatinine (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003e1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.696969696969695%\"\u003e\n \u003cp\u003e0.52-2.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.803030303030305%\"\u003e\n \u003cp\u003e0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.04545454545455%\"\u003e\n \u003cp\u003eSerum uric acid (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003e1.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.696969696969695%\"\u003e\n \u003cp\u003e1.11-1.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.803030303030305%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.04545454545455%\"\u003e\n \u003cp\u003eSerum CRP (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003e1.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.696969696969695%\"\u003e\n \u003cp\u003e0.92-1.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.803030303030305%\"\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.04545454545455%\"\u003e\n \u003cp\u003ePlasma NT-proBNP (pg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.696969696969695%\"\u003e\n \u003cp\u003e1.00-1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.803030303030305%\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.04545454545455%\"\u003e\n \u003cp\u003e6MWT distance (meters)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.696969696969695%\"\u003e\n \u003cp\u003e0.99-1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.803030303030305%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.005\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.04545454545455%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;FEV1 (% of predicted value)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003e0.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.696969696969695%\"\u003e\n \u003cp\u003e0.97-0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.803030303030305%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.006\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.04545454545455%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;FVC (% of predicted value)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.696969696969695%\"\u003e\n \u003cp\u003e0.99=1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.803030303030305%\"\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.04545454545455%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;TLC (% of predicted value)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003e1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.696969696969695%\"\u003e\n \u003cp\u003e1.00-1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.803030303030305%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.04545454545455%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;RV (% of predicted value)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.696969696969695%\"\u003e\n \u003cp\u003e1.00-1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.803030303030305%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.04545454545455%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;DLCO (% of predicted value)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.696969696969695%\"\u003e\n \u003cp\u003e0.95-0.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.803030303030305%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.04545454545455%\"\u003e\n \u003cp\u003eCO (L/min)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003e1.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.696969696969695%\"\u003e\n \u003cp\u003e0.90-1.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.803030303030305%\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.04545454545455%\"\u003e\n \u003cp\u003eCI (L/min/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.696969696969695%\"\u003e\n \u003cp\u003e0.60-1.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.803030303030305%\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.04545454545455%\"\u003e\n \u003cp\u003ePCWP (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003e1.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.696969696969695%\"\u003e\n \u003cp\u003e1.27-1.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.803030303030305%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.04545454545455%\"\u003e\n \u003cp\u003ePVR (WU)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003e1.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.696969696969695%\"\u003e\n \u003cp\u003e0.99-1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.803030303030305%\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*Bold entries in the table indicate a \u003cem\u003eP\u003c/em\u003e-value of \u0026le;0.05.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e6MWT, 6-minute walk test; BMI, body mass index; CI, cardiac index; CO, cardiac output; DLCO, diffusing lung capacity for carbon monoxide; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; MPAP, mean pulmonary artery pressure; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PCWP, pulmonary capillary wedge pressure; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RV, residual volume; TLC, total lung capacity; WU, Wood units\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hyperuricemia, uric acid, pulmonary hypertension, lung disease, WHO group 3","lastPublishedDoi":"10.21203/rs.3.rs-4298792/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4298792/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHyperuricemia has been identified as a powerful predictor of World Health Organization (WHO) group 1 pulmonary hypertension (PH) (pulmonary arterial hypertension). However, its relationship with PH secondary to chronic lung diseases (WHO group 3) remains unclear. Demographic, clinical, laboratory, lung function, and right heart catheterization data were retrospectively collected for 323 patients with various severe chronic pulmonary diseases undergoing evaluation for lung transplantation at a tertiary university medical center from June 2017 to February 2023. The data were analyzed to identify associations between hyperuricemia (serum uric acid level \u0026gt;6 mg/dL) and PH [mean pulmonary arterial pressure (MPAP) \u0026gt;20 mmHg]. Compared to the normouricemia group (n=211), patients with hyperuricemia (n=112) exhibited a higher likelihood of being younger (\u003cem\u003eP\u003c/em\u003e=0.02), male (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001), presenting with PH (\u003cem\u003eP\u003c/em\u003e=0.001) and severe PH (MPAP \u0026gt;35 mmHg; \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001). They had elevated values of body mass index (\u003cem\u003eP\u003c/em\u003e=0.004), plasma N-terminal pro-B-type natriuretic peptide (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001), serum creatinine (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001) and C-reactive protein (\u003cem\u003eP\u003c/em\u003e=0.03). The following variables were significantly associated with PH: higher values of body mass index (\u003cem\u003eP\u003c/em\u003e=0.005), uric acid (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001), total lung capacity (\u003cem\u003eP\u003c/em\u003e=0.02), residual volume (\u003cem\u003eP\u003c/em\u003e=0.01), and pulmonary capillary wedge pressure (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001); shorter 6-minute walk test distance (\u003cem\u003eP\u003c/em\u003e=0.005); and lower forced expiratory volume in one second (\u003cem\u003eP\u003c/em\u003e=0.006) and diffusing lung capacity for carbon monoxide (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001). On multivariate analysis, elevated uric acid level remained one of the variables most significantly associated with PH (OR 1.29, 95% CI 1.05-1.58, \u003cem\u003eP\u003c/em\u003e=0.01). In conclusion, in patients with severe chronic lung diseases, hyperuricemia is strongly associated with the presence of PH.\u003c/p\u003e","manuscriptTitle":"Hyperuricemia is strongly associated with pulmonary hypertension in chronic lung disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-30 19:50:21","doi":"10.21203/rs.3.rs-4298792/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9906f447-fdf6-420f-b695-f2afa1712ad5","owner":[],"postedDate":"April 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-01T09:53:57+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-30 19:50:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4298792","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4298792","identity":"rs-4298792","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}