Relationship Between Parathyroid Hormone Levels and Abdominal Aortic Calcification in Incident Hemodialysis Patients Not Treated with Calcium or Vitamin D

Relationship Between Parathyroid Hormone Levels and Abdominal Aortic Calcification in Incident Hemodialysis Patients Not Treated with Calcium or Vitamin D | 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 Relationship Between Parathyroid Hormone Levels and Abdominal Aortic Calcification in Incident Hemodialysis Patients Not Treated with Calcium or Vitamin D Jin He, Shubei Chen, Kewen Mao, Xiaoyan Sun, Rongjian Nie This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-962363/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 Vascular calcification (VC) and secondary hyperparathyroidism (SHPT) are important causes of high incidence of cardiovascular events in chronic kidney disease (CKD) patients. The relationship between parathyroid hormone (PTH) and VC is very complex. Different studies have inconsistent reports on the effect of PTH on VC. The present study investigated the correlation between PTH levels and abdominal aortic calcification (AAC) in incident hemodialysis patients who did not receive calcium, calcium-containing phosphorus binders, calcitriol or vitamin D analogs. Our data confirm that serum PTH levels is significantly negatively correlated with AAC within a certain concentration range in incident hemodialysis patients who not treated with calcium or vitamin D. Urology & Nephrology Chronic kidney disease (CKD) Vascular calcification (VC) abdominal aortic calcification (AAC) parathyroid hormone (PTH) Introduction The incidence and mortality of cardiovascular disease (CVD) significantly increased in chronic kidney disease (CKD) patients. Even after stratification by age, gender, race, and presence of diabetes, CVD mortality in end-stage renal disease (ESRD) patients treated by hemodialysis or peritoneal dialysis is 10 to 20 times higher than in the general population 1 . Vascular calcification (VC), defined as the inappropriate and pathological deposition of mineral in the form of calcium phosphate salts into the vascular tissues, is a very common complication in CKD patients and associated with significantly increased all-cause and cardiovascular mortality 2 – 5 . Secondary hyperparathyroidism (SHPT) is another common complication of CKD and has also been associated with increased cardiovascular mortality and CKD progression, especially in CKD stage 3–5 patients 6 – 8 . The relationship between VC and parathyroid hormone (PTH) is very complex. A study of 1095 hemodialysis patients (aged 65-88) showed that abdominal aortic calcification (AAC) was more severe in male patients with serum PTH levels within the upper normal range than patients with serum PTH levels within the lower normal range 9 . Another study revealed that in non-dialysis CKD stage 2-5 patients with AAC score > 6 or pelvic arterial calcifcation (PAC) score > 1 had higher serum PTH 10 . In addition, among patients receiving hemodialysis, serum PTH levels were significantly associated with AAC progression 11 . However, in clinical practice, it is very common that PTH levels do not match the severity of AAC. The present study examined the relationship between PTH levels and AAC in incident hemodialysis patients who did not receive calcium, calcium-containing phosphorus binders, calcitriol or vitamin D analogs in order to determine whether PTH levels are associated with the severity of AAC. Results Clinical characteristics and biochemistry of all patients are shown in Table 1 . There were 22 males (73.3%) and 8 females (26.7%). The mean age was 55.7 ± 14.47 years (23-75 years). The cause of ESRD in our patients was diabetes mellitus in 15, glomerulonephritis in 8, systemic hypertension in 6 and autosomal dominant poly-cystic kidney disease in 1. Shapiro-Wilk test showed that iPTH, AAC, diastolic blood pressure (DBP), C-reactive protein (CRP), albumin, triglycerides are skewed distribution, and age, serum calcium, serum phosphorus, systolic pressure (SBP), hemoglobin (Hb), serum total protein (TP),alkaline phosphatase (ALP), serum total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) are normal distribution. Because AAC is a skewd distribution which Pearson’s correlation or multiple linear regression analysis is not suitable, so Spearman's rank correlation analysis was employed to analyze the relationship between AAC and other variables. Table 1 Clinical characteristics and biochemistry of whole cohort (N=30) Age (23-75 years) 55.7±14.47 male 73.3% Causes of ESRD diabetes mellitus 15 (30) glomerulonephritis 8 (30) systemic hypertension 6 (30) autosomal dominant poly-cystic kidney disease 1 (30) SBP (116-196 mmHg) 155.17±21.15 DBP (61-108 mmHg) 84.63±14.50 ACC (0-14) 3.27±4.29 iPTH (31.3-594.5 pg/mL) 242.95±145.51 serum calcium (0.88-2.27 mmol/L) 1.75±0.34 serum phosphorus (0.86-4.15 mmol/L) 2.12±0.69 Hb (39-105 g/L) 77.2±16.41 CRP (1-172 mg/L) 20.63±35.38 serum total protein (13.9-80.8 g/L) 62.57±9.22 Albumin (21.9-48.9 g/L) 36.47±7.23 ALP (49-154 U/L) 95.2±33.93 Triglycerides (0.79-3.89 mmol/L) 1.82±0.88 total cholesterol (2.33-6.63mmol/L) 4.10±1.04 HDL (0.59-1.89 mmol/L) 1.11±0.35 2.35±0.75 ESRD,end-stage renal disease; SBP, systolic pressure; DBP, diastolic blood pressure; ACC,abdominal aortic calcification; CRP, C-reactive protein; Hb, hemoglobin; ALP, alkaline phosphatase;HDL, high-density lipoprotein; LDL, low-density lipoprotein; iPTH, intact parathyroid hormone. Our results suggested that there was a strong negative correlations between serum PTH and AAC (Spearman's rho -0.618, P <0.001). There was a strong positive correlations between age and AAC (Spearman's rho 0.605, P <0.001). We also found that there was a moderate negative correlation between Pi and AAC (Spearman's rho -0.435 P=0.016) (Table 2 ). Table 2 Spearman's rank correlation analysis for relationship between abdominal aortic calcifcation scores and baseline characteristics. Spearman's rho AAC P-value Age 0.605 0.000** iPTH -0.618 0.000** serum phosphorus -0.435 0.016* serum calcium 0.159 0.401 SBP -0.136 0.475 DBP -0.268 0.153 Hb 0.283 0.130 CRP -0.081 0.669 serum total protein -0.062 0.746 albumin 0.067 0.725 ALP 0.086 0.653 triglycerides 0.050 0.794 total cholesterol 0.300 0.108 HDL 0.245 0.192 LDL 0.210 0.265 SBP, systolic pressure; DBP, diastolic blood pressure; ACC,abdominal aortic calcification; CRP, C-reactive protein; Hb, hemoglobin; ALP, alkaline phosphatase;HDL, high-density lipoprotein; LDL, low-density lipoprotein; iPTH, intact parathyroid hormone. *: correlation is significant at the 0.05 level; **: correlation is significant at the 0.01 level. To further analyze why there is a negative correlation between serum phosphorus and AAC, the patients were divided into two groups based on the cut-off point of 50 years old. The AAC and serum PTH of the two groups were skewed distribution, the calcium and phosphorus was normal distribution, so we used Mann-Whitney U test and T-test to compare between groups respectively. Our results showed that the serum phosphorus and serum PTH of patients under 50 years old (10/30) was significantly higher (2.62 mmol/L vs 1.88 mmol/L, T -test, P =0.004; 348.47 pg/ml vs 190.19 pg/ml, Mann-Whitney U test, P= 0.002) than that of patients over 50 years old (20/30), and the AAC score was significantly lower than that in patients over 50 years old (0.100 vs 4.85, Mann-Whitney U test, P ༜0.001). There was no significant difference in serum calcium between the two groups (1.63 mmol/L vs 1.80 mmol/L༌ T -test, P =0.315) (Table 3 ). Table 3. Groups analysis between different age groups (<50 years old or ≥50 years old). Group 1 (<50 ) N=10 Group 2 (≥50) N=20 P-value Age 39 ±8.72 64.05±7.96 AAC 0.10 4.85 ＜0.001* iPTH 348.47 ±157.19 190.19 ±108.74 0.002* serum phosphorus 2.62±0.68 1.88±0.58 0.004* serum calcium 1.63±0.49 1.80±0.22 0.315 ACC,abdominal aortic calcification; iPTH, intact parathyroid hormone. *: significant P-value <0.01. Discussion The present study investigated the correlation between PTH levels and AAC in incident hemodialysis patients who did not receive calcium, calcium-containing phosphorus binders, calcitriol or vitamin D analogs. Our results suggested that lower serum PTH levels were associated with higher AAC scores in this population. Although the prevalence of VC in CKD patients is higher, the incidence of arterial calcification in different sites is not consistent, and the risk factors of arterial calcification in different locations and their influence on cardiovascular events are also different 12 – 14 . AAC is an independent risk factor for all-cause mortality or CVD events in the non-CKD patients, peritoneal dialysis patients and hemodialysis patients 15 – 17 . The Kidney Disease Improving Global Outcomes (KDIGO) guidelines also suggest that a lateral abdominal radiograph can be used to detect the presence or absence of vascular calcification in patients with CKD stage 3-5 to guide the management of chronic kidney disease-mineral and bone disorder (CKD-MBD) 18 . The researches have demonstrated that PTH receptors exist in myocardial cells, vascular smooth muscle cells and endothelial cells, indicating that inappropriate (excessive or insufficient) secretion of PTH may have adverse effects on the cardiovascular system 19 , 20 . It has been found that PTH perfusion can lead to intense aortic medial calcification in rats with parathyroidectomy and this effect has nothing to do with uremia or serum phosphorus levels 21 . Another study also found that cinacalcet could inhibit the calcification of aorta and heart in 5/6 nephrectomized rats by by decreasing serum PTH levels 22 . These results suggest that PTH has a direct pro-calcification effect, at least in the animal model of CKD. As for the exact effects that PTH has on AAC in CKD patients, this is still a matter of debate. Studies have shown that serum PTH level is related to the severity of AAC 9 , 10 , 11 . However, some studies have also found that there is no association between the two or even negative correlation 12 – 14 , 23 , 24 . One possible explanation for these contradictory conclusions is that the widespread use of calcium, calcium-containing phosphorus binder, calcitriol or vitamin D analogs affects the natural process of AAC. Currently, calcium, calcium-containing phosphorus binder, calcitriol or vitamin D analogs are widely used to treat mineral metabolism abnormalities. The DOPPS study found that up to 52% of participants received vitamin D supplementation; 72.9% of participants used calcium-containing phosphorus binder for the control of hyperphosphatemia 8 . However, if the above drugs are used improperly, it may lead to adverse clinical consequences. For example, prolonged and disproportionate consumption of vitamin D supplements may lead to excessive inhibition of PTH and aggravation of vascular calcification 25 , 26 ; the use of high-dose calcium salts (oral calcium or calcium-based phosphate binders) can easily lead to hypercalcemia, resulting in low serum PTH levels and vascular calcification 27 , 28 . Therefore, it is difficult to draw reliable conclusions when discussing the association between PTH and AAC in the CKD population using calcium and vitamin D. In view of this, in this study, we purposely selected incident hemodialysis patients who have not used calcium, calcium-containing phosphorus binders, calcitriol or vitamin D analogs as the research objects. Interestingly, even after eliminating the interference factors such as calcium and vitamin D, PTH and AAC are still significantly negatively correlated. For the negative correlation, one explanation is that lower serum PTH levels may lead to adynamic bone disease, and adynamic bone disease will impair the ability of patients handling and buffering of calcium loads and pose a higher risk of extraosseous calcifications 29 , 30 . It should be emphasized that although lower serum PTH levels do contribute to the risk of adynamic bone disease, there is currently no evidence that low PTH alone can represent adynamic bone disease. Another possible explanation for the negative correlation between AAC and PTH is that low serum PTH levels may only be a manifestation of malnutrition, inflammation or cachexia syndrome (MICs) and malnutrition-inflammation is associated with vascular calcification in uremic patients 31 . However, in another study that included 97 hemodialysis patients who were followed up for one year, patients with malnutrition and chronic inflammation (defined as serum albumin <40 g/L and hs-CRP≥28.57 nmol/L) had significantly higher PTH levels than the control group (241.5 pg/ml vs 161.8 pg/ml) 11 . Therefore, neither adynamic bone disease nor malnutrition can fully explain why low PTH levels can aggravate AAC. Further studies are needed to elucidate the mechanism of AAC deterioration caused by low PTH levels. Another surprising finding of the present study is that there is also a significant negative correlation between AAC and serum phosphorus. Serum phosphorus plays a very important role in the occurrence and development of vascular calcification 32 . Subgroup analysis of the MESA study indicated that each 1-mg/dl increment in serum phosphate concentration was associated with a 21%, 33%, 25% and 62% greater prevalence of coronary artery, thoracic, aortic valve, and mitral valve calcification, respectively 33 . However, some researchers found that there was no significant difference in serum phosphorus levels between the AAC score >6 group and AAC score≤6 group in hemodialysis patients 10 ; Study on chinese hemodialysis population (CDCS study) also found that serum phosphorus is a risk factor for coronary artery calcification, but not a risk factor for AAC 13 . It should be pointed out that there are deficiencies in the above studies, that is, all participants received hemodialysis or peritoneal dialysis which can effectively remove serum phosphorus and a large proportion of the participants took phosphate binders (64.6% in CDCS study). Therefore, it can not concluded that there is no correlation between serum phosphorus and AAC. In the present study, serum phosphorus was not affected by dialysis, and the patient did not use any form of phosphorus bonding agent, but there is still a significant negative correlation between AAC and serum phosphorus. This finding is consistent with that of Harin Rhee et al 31 , who also found that the prevalence of baseline AAC and its progression in low serum phosphorus group was significantly higher than that in high serum phosphorus group. Further analysis of the patients’ characteristics showed that the serum phosphate of patients under 50 years old was significantly higher than that of patients over 50 years old, but the AAC score was significantly lower than that in patients over 50 years old. We speculate that age may have a greater impact on AAC than serum phosphorus in CKD patients. Indeed, a study of young patients with ESRD who were undergoing dialysis also confirmed that there was no significant difference in serum phosphorus between patients with or without coronary artery calcification 28 . Another study involving 174 Chinese patients also found that age may be the most important factor affecting coronary artery calcification in maintenance hemodialysis patients 34 . In our study, most of the patients were relatively young with an average age of 55.7 years, so the effect of phosphorus on AAC may not be obvious. Therefore, serum phosphorus may be statistically negatively correlated with AAC, but it does not mean that serum phosphorus has no effect on AAC from a pathophysiological perspective. Our results once again show that the mechanism of VC is very complex, and even serum phosphorus, a recognized pro-calcification factor, has different effects on specific arteries in specific CKD populations. There are several limitations to our study. First, the sample size for our study was small. More CKD stage 5D patients who did not receive calcium, calcium-containing phosphorus binder, calcitriol or vitamin D analogs would be necessary to attain adequate power in determining the correlation between serum PTH levels and AAC. Unfortunately, this was beyond our capacity. Second, We only evaluated the degree of AAC by abdominal radiographs, which is less sensitive and accurate than electron beam computed tomography (EBCT), multislice CT (MSCT). However, due to the relatively high cost and the risk of exposure to higher radiation doses, these tests cannot be performed routinely. Third, the serum PTH levels of our observation population was in the range of 31.3-594.5pg/ml. The correlation between PTH and AAC is not clear in CKD patients with serum PTH levels exceeding 600 pg/ml or higher. In conclusion, the present study, which is the only study focused on the association between PTH levels and AAC in incident hemodialysis patients who did not receive calcium, calcium-containing phosphorus binder, calcitriol or vitamin D analogs, demonstrates that PTH levels is significantly negatively correlated with AAC within a certain concentration range. Inappropriate inhibition of PTH may lead to deterioration of AAC in CKD stage 5D patients. Methods Patients This study was approved by the Ethical Committee of the Chonggang general hospital. Written informed consent was obtained from each person at recruitment. We confirm that all experiments of the study were performed in accordance with relevant guidelines and regulations. Incident hemodialysis patients who have not used calcium, calcium-containing phosphorus binders, calcitriol or vitamin D analogsage between January 2020 and june 2021 were initially screened for enrollment in the cross-sectional study. Of the total 47 incident hemodialysis patients, patients with malignancy, decompensated liver Cirrhosi, lupus nephritis, crescentic glomerulonephritis and acute kidney injury (AKI), as well as the elderly over 75 years old were excluded. Finally, 30 patients were enrolled. Biochemical data and vascular calcifcation Pre-dialysis blood samples and plain radiographs were obtained at the time of enrollment. Serum intact parathormone hormone (iPTH) levels were determined by Chongqing DIAN medical laboratory ( reference range 15–65 pg/ml). AAC was determined by a lateral lumbar spine radiograph, and quantitative analysis of AAC was performed using the method previously described by kauppila et al. (total score 0-24) 35 . All X-rays were reviewed by two physicians who had the expertise to score the X-rays. Statistical analysis Data are presented as mean ± standard deviation (SD). The normality of the distribution was determined using the Shapiro-Wilk test. The correlation between two continuous variables was analyzed by the Pearson’s correlation (normal distribution) or Spearman's correction (Skew distribution). Two continuous variables were compared using the Student’s t test (normal distribution) or non-parametric test (Skew distribution). P value <0.05 is considered statistically signifcant. All computations were performed using the SPSS 20.0 software (Chicago, IL, USA). Declarations Acknowledgements. Not applicable. Authors' contributions jin he conceived and wrote the manuscript. jin he, Shubei Chen ,Kewen Mao, Xiaoyan Sun collected clinical date. jin he and Rongjian Nie reviewed lateral lumbar spine radiograph and performed semi-quantitative scoring. jin he, Shubei Chen, Kewen Mao, Xiaoyan Sun and Rongjian Nie confirm the authenticity of all the raw data. All authors have read and approved the final manuscript. Additional Information Conflict of interest. The authors declare that they have no competing interests. References Foley, R. N., Parfrey, P. S. & Sarnak, M. J. Clinical epidemiology of cardiovascular disease in chronic renal disease.Am J Kidney Dis. 1998Nov;32(5 Suppl 3):S112-9. Neil, J., Paloian, Cecilia, M. & Giachelli A current understanding of vascular calcification in CKD.Am J Physiol Renal Physiol. 2014 Oct15; 307(8):F891–F900. Masahide Mizobuchi, D., Towler, E. & Slatopolsky Vascular calcification: the killer of patients with chronic kidney disease. 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N Engl J Med , 18 (20), 1478–1483 (2000 May). Kurz, P. et al. Evidence for abnormal calcium homeostasis in patients with adynamic bone disease. Kidney Int , 46 (3), 855–861 https://doi.org/10.1038/ki.1994.342 (1994 Sep). Cannata, J. B. Andí. Adynamic bone and chronic renal failure: an overview. Am J Med Sci , 320 (2), 81–84 (2000 Aug). Harin Rhee, S. H. et al. Persistently low intact parathyroid hormone levels predict a progression of aortic arch calcification in incident hemodialysis patients. Clin Exp Nephrol , 16 (3), 433–441 (2012 Jun). Navid Shobeiri, M. A., Adams, Rachel, M. & Holden Phosphate: an old bone molecule but new cardiovascular risk factor. Br J Clin Pharmacol , 77 (1), 39–54 (2014 Jan). Kathryn, L., Adeney, D. S., Siscovick, Joachim, H. & Ix Association of serum phosphate with vascular and valvular calcification in moderate CKD. J Am Soc Nephrol , 20 (2), 381–387 (2009 Feb). Wen, Y. et al. Safety of Low-calcium Dialysate and its Effects on Coronary Artery Calcification in Patients Undergoing Maintenance Hemodialysis.Sci Rep2018 04 13;8(1). Kauppila, L. I. et al. New indices to classify location, severity and progression of calcific lesions in the abdominal aorta: a 25-year follow-up study. Atherosclerosis , 25 (2), 245–250 (1997 Jul). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-962363","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":58860480,"identity":"d7389d14-e84c-4622-826e-17f1505b446e","order_by":0,"name":"Jin He","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIie2PMQrCMBRAfwmYJdVZEL1CwEHEgoMXiQi6ODg6SKkUnATXFsRjdE4J6FJw7abiBVJcHUzVSTDtKJg3hfAf/30Ag+EHoQCMA3WaFWR5XM6BlFRm43YVo2UcJOUUhRTDXQ37wl6VCOtg7yJmVLTzsDjcuY0O5pbMpt+V7pozEdDJ65YsEqS7ZqgeRpqwlDFBaO+9JeKEclZBtk45nXMFDVdKEfbWJfR4LlBSyJXBW/EQUXsLlOQZNn6FBXv1Ti++/pZDMrqRu9NsbQ5XKRdunx5Hscw0CgBhnz+Wp5tXYF4wYDAYDH/PA8KcV+jnwkeWAAAAAElFTkSuQmCC","orcid":"","institution":"The Chonggang general hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jin","middleName":"","lastName":"He","suffix":""},{"id":58860481,"identity":"4c46ad3b-09f1-42c9-b8ea-efa215b1bf4b","order_by":1,"name":"Shubei Chen","email":"","orcid":"","institution":"The Chonggang general hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shubei","middleName":"","lastName":"Chen","suffix":""},{"id":58860482,"identity":"1f6bea1b-220b-4c56-92ce-19c202db2369","order_by":2,"name":"Kewen Mao","email":"","orcid":"","institution":"The Chonggang general hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kewen","middleName":"","lastName":"Mao","suffix":""},{"id":58860483,"identity":"d8d93e08-9e1b-4e93-8a0f-df801936ac7d","order_by":3,"name":"Xiaoyan Sun","email":"","orcid":"","institution":"The Chonggang general hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaoyan","middleName":"","lastName":"Sun","suffix":""},{"id":58860484,"identity":"3154d0df-5b10-4d50-baee-6b3c9004ba33","order_by":4,"name":"Rongjian Nie","email":"","orcid":"","institution":"The Chonggang general hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rongjian","middleName":"","lastName":"Nie","suffix":""}],"badges":[],"createdAt":"2021-10-10 05:14:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-962363/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-962363/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":18183889,"identity":"ed429f21-1c1d-43c0-84bf-a8ce7ec9cfaa","added_by":"auto","created_at":"2022-02-14 04:59:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":244832,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-962363/v1/546b32ca-f9bb-406b-9df3-1a632519aa88.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eRelationship Between Parathyroid Hormone Levels and Abdominal Aortic Calcification in Incident Hemodialysis Patients Not Treated with Calcium or Vitamin D\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe incidence and mortality of cardiovascular disease (CVD) significantly increased in chronic kidney disease (CKD) patients. Even after stratification by age, gender, race, and presence of diabetes, CVD mortality in end-stage renal disease (ESRD) patients treated by hemodialysis or peritoneal dialysis is 10 to 20 times higher than in the general population\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eVascular calcification (VC), defined as the inappropriate and pathological deposition of mineral in the form of calcium phosphate salts into the vascular tissues, is a very common complication in CKD patients and associated with significantly increased all-cause and cardiovascular mortality\u003csup\u003e\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Secondary hyperparathyroidism (SHPT) is another common complication of CKD and has also been associated with increased cardiovascular mortality and CKD progression, especially in CKD stage 3\u0026ndash;5 patients\u003csup\u003e\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe relationship between VC and parathyroid hormone (PTH) is very complex. A study of 1095 hemodialysis patients (aged 65-88) showed that abdominal aortic calcification (AAC) was more severe in male patients with serum PTH levels within the upper normal range than patients with serum PTH levels within the lower normal range\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Another study revealed that in non-dialysis CKD stage 2-5 patients with AAC score \u0026gt; 6 or pelvic arterial calcifcation (PAC) score \u0026gt; 1 had higher serum PTH\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. In addition, among patients receiving hemodialysis, serum PTH levels were significantly associated with AAC progression\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. However, in clinical practice, it is very common that PTH levels do not match the severity of AAC. The present study examined the relationship between PTH levels and AAC in incident hemodialysis patients who did not receive calcium, calcium-containing phosphorus binders, calcitriol or vitamin D analogs in order to determine whether PTH levels are associated with the severity of AAC.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eClinical characteristics and biochemistry of all patients are shown in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. There were 22 males (73.3%) and 8 females (26.7%). The mean age was 55.7 \u0026plusmn; 14.47 years (23-75 years). The cause of ESRD in our patients was diabetes mellitus in 15, glomerulonephritis in 8, systemic hypertension in 6 and autosomal dominant poly-cystic kidney disease in 1. Shapiro-Wilk test showed that iPTH, AAC, diastolic blood pressure (DBP), C-reactive protein (CRP), albumin, triglycerides are skewed distribution, and age, serum calcium, serum phosphorus, systolic pressure (SBP), hemoglobin (Hb), serum total protein (TP),alkaline phosphatase (ALP), serum total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) are normal distribution. Because AAC is a skewd distribution which Pearson\u0026rsquo;s correlation or multiple linear regression analysis is not suitable, so Spearman's rank correlation analysis was employed to analyze the relationship between AAC and other variables.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eClinical characteristics and biochemistry of whole cohort (N=30)\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAge (23-75 years)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e55.7\u0026plusmn;14.47\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e73.3%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCauses of ESRD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ediabetes mellitus\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (30)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eglomerulonephritis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (30)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003esystemic hypertension\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (30)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eautosomal dominant poly-cystic\u003c/p\u003e\n\u003cp\u003ekidney disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (30)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSBP (116-196 mmHg)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e155.17\u0026plusmn;21.15\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDBP (61-108 mmHg)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e84.63\u0026plusmn;14.50\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eACC (0-14)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.27\u0026plusmn;4.29\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eiPTH (31.3-594.5 pg/mL)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e242.95\u0026plusmn;145.51\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eserum calcium (0.88-2.27 mmol/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.75\u0026plusmn;0.34\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eserum phosphorus (0.86-4.15 mmol/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.12\u0026plusmn;0.69\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHb (39-105 g/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e77.2\u0026plusmn;16.41\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCRP (1-172 mg/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20.63\u0026plusmn;35.38\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eserum total protein (13.9-80.8 g/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e62.57\u0026plusmn;9.22\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlbumin (21.9-48.9 g/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e36.47\u0026plusmn;7.23\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eALP (49-154 U/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e95.2\u0026plusmn;33.93\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTriglycerides (0.79-3.89 mmol/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.82\u0026plusmn;0.88\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003etotal cholesterol (2.33-6.63mmol/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.10\u0026plusmn;1.04\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHDL (0.59-1.89 mmol/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.11\u0026plusmn;0.35\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.35\u0026plusmn;0.75\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\"\u003eESRD,end-stage renal disease; SBP, systolic pressure; DBP, diastolic blood pressure; ACC,abdominal aortic calcification; CRP, C-reactive protein; Hb, hemoglobin; ALP, alkaline phosphatase;HDL, high-density lipoprotein; LDL, low-density lipoprotein; iPTH, intact parathyroid hormone.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eOur results suggested that there was a strong negative correlations between serum PTH and AAC (Spearman's rho -0.618, \u003cem\u003eP\u003c/em\u003e \u0026lt;0.001). There was a strong positive correlations between age and AAC (Spearman's rho 0.605, \u003cem\u003eP\u003c/em\u003e \u0026lt;0.001). We also found that there was a moderate negative correlation between Pi and AAC (Spearman's rho -0.435 P=0.016) (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eSpearman's rank correlation analysis for relationship between abdominal aortic calcifcation scores and baseline characteristics.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSpearman's rho\u003c/p\u003e\n\u003cp\u003eAAC\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003eP-value\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.605\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.000**\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eiPTH\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e-0.618\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.000**\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eserum phosphorus\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e-0.435\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.016*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eserum calcium\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.159\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.401\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSBP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e-0.136\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.475\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDBP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e-0.268\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.153\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHb\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.283\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.130\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCRP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e-0.081\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.669\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eserum total protein\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e-0.062\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.746\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ealbumin\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.067\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.725\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eALP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.086\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.653\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003etriglycerides\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.050\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.794\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003etotal cholesterol\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.300\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.108\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHDL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.245\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.192\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLDL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.210\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.265\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSBP, systolic pressure; DBP, diastolic blood pressure; ACC,abdominal aortic calcification; CRP, C-reactive protein; Hb, hemoglobin; ALP, alkaline phosphatase;HDL, high-density lipoprotein; LDL, low-density lipoprotein; iPTH, intact parathyroid hormone.\u003c/p\u003e\n\u003cp\u003e*: correlation is significant at the 0.05 level; **: correlation is significant at the 0.01 level.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cp\u003eTo further analyze why there is a negative correlation between serum phosphorus and AAC, the patients were divided into two groups based on the cut-off point of 50 years old. The AAC and serum PTH of the two groups were skewed distribution, the calcium and phosphorus was normal distribution, so we used Mann-Whitney U test and T-test to compare between groups respectively.\u003c/p\u003e\n\u003cp\u003eOur results showed that the serum phosphorus and serum PTH of patients under 50 years old (10/30) was significantly higher (2.62 mmol/L vs 1.88 mmol/L, \u003cem\u003eT\u003c/em\u003e-test, \u003cem\u003eP\u003c/em\u003e =0.004; 348.47 pg/ml vs 190.19 pg/ml, Mann-Whitney \u003cem\u003eU\u003c/em\u003e test, \u003cem\u003eP=\u003c/em\u003e0.002) than that of patients over 50 years old (20/30), and the AAC score was significantly lower than that in patients over 50 years old (0.100 vs 4.85, Mann-Whitney \u003cem\u003eU\u003c/em\u003e test, \u003cem\u003eP\u003c/em\u003e༜0.001). There was no significant difference in serum calcium between the two groups (1.63 mmol/L vs 1.80 mmol/L༌ \u003cem\u003eT\u003c/em\u003e-test, \u003cem\u003eP\u003c/em\u003e =0.315) (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eTable 3. Groups analysis between different age groups (\u0026lt;50 years old or \u0026ge;50 years old).\u003c/p\u003e\n\u003ctable style=\"width: 591px;\" border=\"1\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 129px;\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 129px;\"\u003e\u003cbr /\u003e\n\u003cp\u003eGroup 1 (\u0026lt;50 )\u003c/p\u003e\n\u003cp\u003eN=10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 130px;\"\u003e\n\u003cp\u003eGroup 2 (\u0026ge;50)\u003c/p\u003e\n\u003cp\u003eN=20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 175px;\"\u003e\n\u003cp\u003eP-value\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 129px;\"\u003e\n\u003cp\u003eAge\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 129px;\"\u003e\n\u003cp\u003e39 \u0026plusmn;8.72\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 130px;\"\u003e\n\u003cp\u003e64.05\u0026plusmn;7.96\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 175px;\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 129px;\"\u003e\n\u003cp\u003eAAC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 129px;\"\u003e\n\u003cp\u003e0.10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 130px;\"\u003e\n\u003cp\u003e4.85\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 175px;\"\u003e\n\u003cp\u003e＜0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 129px;\"\u003e\n\u003cp\u003eiPTH\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 129px;\"\u003e\n\u003cp\u003e348.47 \u0026plusmn;157.19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 130px;\"\u003e\n\u003cp\u003e190.19 \u0026plusmn;108.74\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 175px;\"\u003e\n\u003cp\u003e0.002*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 129px;\"\u003e\n\u003cp\u003eserum phosphorus\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 129px;\"\u003e\n\u003cp\u003e2.62\u0026plusmn;0.68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 130px;\"\u003e\n\u003cp\u003e1.88\u0026plusmn;0.58\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 175px;\"\u003e\n\u003cp\u003e0.004*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 129px;\"\u003e\n\u003cp\u003eserum calcium\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 129px;\"\u003e\n\u003cp\u003e1.63\u0026plusmn;0.49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 130px;\"\u003e\n\u003cp\u003e1.80\u0026plusmn;0.22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 175px;\"\u003e\n\u003cp\u003e0.315\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eACC,abdominal aortic calcification; iPTH, intact parathyroid hormone.\u003c/p\u003e\n\u003cp\u003e*: significant P-value \u0026lt;0.01.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present study investigated the correlation between PTH levels and AAC in incident hemodialysis patients who did not receive calcium, calcium-containing phosphorus binders, calcitriol or vitamin D analogs. Our results suggested that lower serum PTH levels were associated with higher AAC scores in this population.\u003c/p\u003e \u003cp\u003eAlthough the prevalence of VC in CKD patients is higher, the incidence of arterial calcification in different sites is not consistent, and the risk factors of arterial calcification in different locations and their influence on cardiovascular events are also different\u003csup\u003e\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAAC is an independent risk factor for all-cause mortality or CVD events in the non-CKD patients, peritoneal dialysis patients and hemodialysis patients\u003csup\u003e\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. The Kidney Disease Improving Global Outcomes (KDIGO) guidelines also suggest that a lateral abdominal radiograph can be used to detect the presence or absence of vascular calcification in patients with CKD stage 3-5 to guide the management of chronic kidney disease-mineral and bone disorder (CKD-MBD)\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe researches have demonstrated that PTH receptors exist in myocardial cells, vascular smooth muscle cells and endothelial cells, indicating that inappropriate (excessive or insufficient) secretion of PTH may have adverse effects on the cardiovascular system \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. It has been found that PTH perfusion can lead to intense aortic medial calcification in rats with parathyroidectomy and this effect has nothing to do with uremia or serum phosphorus levels\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Another study also found that cinacalcet could inhibit the calcification of aorta and heart in 5/6 nephrectomized rats by by decreasing serum PTH levels\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. These results suggest that PTH has a direct pro-calcification effect, at least in the animal model of CKD.\u003c/p\u003e \u003cp\u003eAs for the exact effects that PTH has on AAC in CKD patients, this is still a matter of debate. Studies have shown that serum PTH level is related to the severity of AAC \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. However, some studies have also found that there is no association between the two or even negative correlation \u003csup\u003e\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. One possible explanation for these contradictory conclusions is that the widespread use of calcium, calcium-containing phosphorus binder, calcitriol or vitamin D analogs affects the natural process of AAC.\u003c/p\u003e \u003cp\u003eCurrently, calcium, calcium-containing phosphorus binder, calcitriol or vitamin D analogs are widely used to treat mineral metabolism abnormalities. The DOPPS study found that up to 52% of participants received vitamin D supplementation; 72.9% of participants used calcium-containing phosphorus binder for the control of hyperphosphatemia \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. However, if the above drugs are used improperly, it may lead to adverse clinical consequences. For example, prolonged and disproportionate consumption of vitamin D supplements may lead to excessive inhibition of PTH and aggravation of vascular calcification \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e; the use of high-dose calcium salts (oral calcium or calcium-based phosphate binders) can easily lead to hypercalcemia, resulting in low serum PTH levels and vascular calcification \u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Therefore, it is difficult to draw reliable conclusions when discussing the association between PTH and AAC in the CKD population using calcium and vitamin D.\u003c/p\u003e \u003cp\u003eIn view of this, in this study, we purposely selected incident hemodialysis patients who have not used calcium, calcium-containing phosphorus binders, calcitriol or vitamin D analogs as the research objects. Interestingly, even after eliminating the interference factors such as calcium and vitamin D, PTH and AAC are still significantly negatively correlated. For the negative correlation, one explanation is that lower serum PTH levels may lead to adynamic bone disease, and adynamic bone disease will impair the ability of patients handling and buffering of calcium loads and pose a higher risk of extraosseous calcifications \u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. It should be emphasized that although lower serum PTH levels do contribute to the risk of adynamic bone disease, there is currently no evidence that low PTH alone can represent adynamic bone disease. Another possible explanation for the negative correlation between AAC and PTH is that low serum PTH levels may only be a manifestation of malnutrition, inflammation or cachexia syndrome (MICs) and malnutrition-inflammation is associated with vascular calcification in uremic patients \u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. However, in another study that included 97 hemodialysis patients who were followed up for one year, patients with malnutrition and chronic inflammation (defined as serum albumin \u0026lt;40 g/L and hs-CRP\u0026ge;28.57 nmol/L) had significantly higher PTH levels than the control group (241.5 pg/ml vs 161.8 pg/ml) \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Therefore, neither adynamic bone disease nor malnutrition can fully explain why low PTH levels can aggravate AAC. Further studies are needed to elucidate the mechanism of AAC deterioration caused by low PTH levels.\u003c/p\u003e \u003cp\u003eAnother surprising finding of the present study is that there is also a significant negative correlation between AAC and serum phosphorus. Serum phosphorus plays a very important role in the occurrence and development of vascular calcification \u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Subgroup analysis of the MESA study indicated that each 1-mg/dl increment in serum phosphate concentration was associated with a 21%, 33%, 25% and 62% greater prevalence of coronary artery, thoracic, aortic valve, and mitral valve calcification, respectively \u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. However, some researchers found that there was no significant difference in serum phosphorus levels between the AAC score \u0026gt;6 group and AAC score\u0026le;6 group in hemodialysis patients \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e; Study on chinese hemodialysis population (CDCS study) also found that serum phosphorus is a risk factor for coronary artery calcification, but not a risk factor for AAC \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. It should be pointed out that there are deficiencies in the above studies, that is, all participants received hemodialysis or peritoneal dialysis which can effectively remove serum phosphorus and a large proportion of the participants took phosphate binders (64.6% in CDCS study). Therefore, it can not concluded that there is no correlation between serum phosphorus and AAC. In the present study, serum phosphorus was not affected by dialysis, and the patient did not use any form of phosphorus bonding agent, but there is still a significant negative correlation between AAC and serum phosphorus. This finding is consistent with that of Harin Rhee et al \u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e, who also found that the prevalence of baseline AAC and its progression in low serum phosphorus group was significantly higher than that in high serum phosphorus group.\u003c/p\u003e \u003cp\u003eFurther analysis of the patients\u0026rsquo; characteristics showed that the serum phosphate of patients under 50 years old was significantly higher than that of patients over 50 years old, but the AAC score was significantly lower than that in patients over 50 years old. We speculate that age may have a greater impact on AAC than serum phosphorus in CKD patients. Indeed, a study of young patients with ESRD who were undergoing dialysis also confirmed that there was no significant difference in serum phosphorus between patients with or without coronary artery calcification \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Another study involving 174 Chinese patients also found that age may be the most important factor affecting coronary artery calcification in maintenance hemodialysis patients \u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn our study, most of the patients were relatively young with an\u003c/p\u003e \u003cp\u003eaverage age of 55.7 years, so the effect of phosphorus on AAC may not be obvious. Therefore, serum phosphorus may be statistically negatively correlated with AAC, but it does not mean that serum phosphorus has no effect on AAC from a pathophysiological perspective. Our results once again show that the mechanism of VC is very complex, and even serum phosphorus, a recognized pro-calcification factor, has different effects on specific arteries in specific CKD populations.\u003c/p\u003e \u003cp\u003eThere are several limitations to our study. First, the sample size for our study was small. More CKD stage 5D patients who did not receive calcium, calcium-containing phosphorus binder, calcitriol or vitamin D analogs would be necessary to attain adequate power in determining the correlation between serum PTH levels and AAC. Unfortunately, this was beyond our capacity. Second, We only evaluated the degree of AAC by abdominal radiographs, which is less sensitive and accurate than electron beam computed tomography (EBCT), multislice CT (MSCT). However, due to the relatively high cost and the risk of exposure to higher radiation doses, these tests cannot be performed routinely. Third, the serum PTH levels of our observation population was in the range of 31.3-594.5pg/ml. The correlation between PTH and AAC is not clear in CKD patients with serum PTH levels exceeding 600 pg/ml or higher.\u003c/p\u003e \u003cp\u003eIn conclusion, the present study, which is the only study focused on the association between PTH levels and AAC in incident hemodialysis patients who did not receive calcium, calcium-containing phosphorus binder, calcitriol or vitamin D analogs, demonstrates that PTH levels is significantly negatively correlated with AAC within a certain concentration range. Inappropriate inhibition of PTH may lead to deterioration of AAC in CKD stage 5D patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003e This study was approved by the Ethical Committee of the Chonggang general hospital. Written informed consent was obtained from each person at recruitment. We confirm that all experiments of the study were performed in accordance with relevant guidelines and regulations. Incident hemodialysis patients who have not used calcium, calcium-containing phosphorus binders, calcitriol or vitamin D analogsage between January 2020 and june 2021 were initially screened for enrollment in the cross-sectional study. Of the total 47 incident hemodialysis patients, patients with malignancy, decompensated liver Cirrhosi, lupus nephritis, crescentic glomerulonephritis and acute kidney injury (AKI), as well as the elderly over 75 years old were excluded. Finally, 30 patients were enrolled.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eBiochemical data and vascular calcifcation\u003c/h2\u003e \u003cp\u003ePre-dialysis blood samples and plain radiographs were obtained at the time of enrollment. Serum intact parathormone hormone (iPTH) levels were determined by Chongqing DIAN medical laboratory ( reference range 15\u0026ndash;65 pg/ml). AAC was determined by a lateral lumbar spine radiograph, and quantitative analysis of AAC was performed using the method previously described by kauppila et al. (total score 0-24)\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. All X-rays were reviewed by two physicians who had the expertise to score the X-rays.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eData are presented as mean \u0026plusmn; standard deviation (SD). The normality of the distribution was determined using the Shapiro-Wilk test. The correlation between two continuous variables was analyzed by the Pearson\u0026rsquo;s correlation (normal distribution) or Spearman's correction (Skew distribution). Two continuous variables were compared using the Student\u0026rsquo;s t test (normal distribution) or non-parametric test (Skew distribution). P value \u0026lt;0.05 is considered statistically signifcant. All computations were performed using the SPSS 20.0 software (Chicago, IL, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ejin he conceived and wrote the manuscript. jin he, Shubei Chen ,Kewen Mao, Xiaoyan Sun collected clinical date. jin he and Rongjian Nie reviewed lateral lumbar spine radiograph and performed semi-quantitative scoring. jin he, Shubei Chen, Kewen Mao, Xiaoyan Sun and Rongjian Nie confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFoley, R. N., Parfrey, P. S. \u0026amp; Sarnak, M. J. 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I. \u003cem\u003eet al.\u003c/em\u003e New indices to classify location, severity and progression of calcific lesions in the abdominal aorta: a 25-year follow-up study. \u003cem\u003eAtherosclerosis\u003c/em\u003e, \u003cb\u003e25\u003c/b\u003e (2), 245\u0026ndash;250 (1997 Jul).\u003c/span\u003e\u003c/li\u003e\u003c/ol\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":"Chronic kidney disease (CKD), Vascular calcification (VC), abdominal aortic calcification (AAC), parathyroid hormone (PTH)","lastPublishedDoi":"10.21203/rs.3.rs-962363/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-962363/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eVascular calcification (VC) and secondary hyperparathyroidism (SHPT) are important causes of high incidence of cardiovascular events in chronic kidney disease (CKD) patients. The relationship between parathyroid hormone (PTH) and VC is very complex. Different studies have inconsistent reports on the effect of PTH on VC. The present study investigated the correlation between PTH levels and abdominal aortic calcification (AAC) in incident hemodialysis patients who did not receive calcium, calcium-containing phosphorus binders, calcitriol or vitamin D analogs. Our data confirm that serum PTH levels is significantly negatively correlated with AAC within a certain concentration range in incident hemodialysis patients who not treated with calcium or vitamin D.\u003c/p\u003e","manuscriptTitle":"Relationship Between Parathyroid Hormone Levels and Abdominal Aortic Calcification in Incident Hemodialysis Patients Not Treated with Calcium or Vitamin D","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-10-27 15:18:49","doi":"10.21203/rs.3.rs-962363/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":"ef477764-eb54-4148-a478-226d7e3a2b7d","owner":[],"postedDate":"October 27th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":8136698,"name":"Urology \u0026 Nephrology"}],"tags":[],"updatedAt":"2022-02-14T04:59:12+00:00","versionOfRecord":[],"versionCreatedAt":"2021-10-27 15:18:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-962363","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-962363","identity":"rs-962363","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}