The Effects of Roxadustat on Thyroid Hormone Levels in Chinese Patients Undergoing Maintenance Hemodialysis

The Effects of Roxadustat on Thyroid Hormone Levels in Chinese Patients Undergoing Maintenance Hemodialysis | 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 The Effects of Roxadustat on Thyroid Hormone Levels in Chinese Patients Undergoing Maintenance Hemodialysis Aiqun Chen, Huan Chen, Shasha Han, Lengnan Xu, Ying Sun, Jie Zhang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8294615/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 Background Recent studies have indicated that patients with chronic kidney disease (CKD) experience central hypothyroidism (CH) following treatment with roxadustat. Our objective is to assess the effect of roxadustat on the hypothalamic-pituitary-thyroid (HPT) axis in patients undergoing maintenance hemodialysis (MHD) and to explore whether it may cause potential tissue toxicity. Methods A total of 140 patients undergoing MHD were enrolled in this cross-sectional study. Thyroid hormones, including thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4), as well as parameters of lipid metabolism, cardiac function, and bone metabolism, were assessed. The patients were divided into two groups based on their roxadustat treatment status: the roxadustat group (n = 53) and the control group (n = 87), differences between groups were evaluated using the Student’s t-test or the Mann-Whitney U test. Unconditional logistic regression analysis was utilized to identify risk factors for hypothyroidism. Results The roxadustat group demonstrated lower serum levels of TSH, FT3, and FT4 compared to the control group. Additionally, four cases (7.5%) exhibited abnormalities in all three indicators, and seven cases had TSH levels below 0.4 mU/L. Notably, none of the patients exhibited clinical symptoms of hypothyroidism. Unconditional logistic regression analysis indicated that roxadustat was an independent risk factor for hypothyroidism, with an odds ratio (95% confidence interval) of 3.635 (1.593, 8.291). Furthermore, the roxadustat group had lower levels of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and N-terminal pro-B-type natriuretic peptide (NT-proBNP), and higher levels of serum total procollagen type I N-terminal propeptide (TPINP). Conclusions Roxadustat is an independent risk factor for hypothyroidism; however, no adverse off-target effects on organs were observed. maintenance hemodialysis organ toxicity roxadustat hypothyroidism Figures Figure 1 Figure 2 Figure 3 BACKGROUND Based on China's epidemiological survey data from 2018 to 2019, the incidence rate of Chronic Kidney Disease (CKD) is 8.2%, affecting approximately 115 million individuals[ 1 ]. Renal anemia, one of the most common complications among CKD patients, occurs in 51.5% of non-dialysis CKD patients and reaches as high as 91.6% to 98.2% in those undergoing dialysis[ 2 ]. Anemia not only impacts patients' quality of life but also accelerates the progression of kidney function decline, increases the risk of cardiovascular diseases, and raises all-cause mortality-thus establishing a vicious cycle of "renal anemia-heart-kidney" [ 3 , 4 ]. The fundamental pathological mechanism of renal anemia is impaired production of erythropoietin (EPO), which results from damage to the renal interstitial cells [ 5 ]. For decades, the treatment of renal anemia has primarily involved iron supplementation and the use of erythropoiesis-stimulating agents (ESAs) [ 6 ]. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), representing a novel class of oral medications for treating renal anemia, consist of an oxygen-sensitive α subunit and a constitutively expressed β subunit [ 7 ]. Its mechanisms of action include: (1) stabilizing HIF-α to promote EPO production and EPO receptor expression; (2) downregulating hepcidin levels to enhance intestinal iron absorption and mobilize stored iron; and (3) upregulating transferrin and transferrin receptor expression to improve functional iron deficiency [ 8 ]. Roxadustat stands as the world's first approved HIF-PHI. Both previous studies and real-world data have shown that roxadustat is equally effective as ESAs in treating renal anemia [ 9 – 11 ], with particularly superior outcomes observed in patients with comorbid inflammation. However, in 2021, Japanese researchers first reported roxadustat could induce central hypothyroidism (CH) [ 12 ]. Subsequent studies have also suggested that roxadustat may trigger CH [ 13 , 14 ], highlighting this potential risk as clinically significant and warranting attention. Currently, it remains unclear whether the hypothyroidism associated with roxadustat holds clinical significance and whether the medication should be discontinued. Given these reports, we aimed to determine whether roxadustat independently induces hypothyroidism, characterize the distribution pattern of roxadustat's off-target effects based on lipid, bone metabolism, and cardiac function parameters, and preliminarily assess potential risks of tissue toxicity. METHODS Participants A total of 150 participants undergoing maintenance hemodialysis (MHD) for ≥ 3 months at the Nephrology Department of Beijing Hospital were screened between February and March 2025. The inclusion criteria were: age ≥ 18 years, dialysis vintage ≥ 3 months. Exclusion criteria included: pregnant or breastfeeding women, patients with active malignant tumors, those with severe active infections (e.g., pulmonary infections, dialysis catheter-related infections) that significantly impact metabolic status, individuals previously diagnosed with thyroid dysfunction who are currently undergoing pharmacological intervention, and patients who have received massive transfusions of blood or blood products within the past three months, which may interfere with hormone levels. Among them, 140 eligible MHD patients were included in the study, participants were categorized into the roxadustat group (n = 53) and the control group (n = 87) based on whether they had stabilized and continued to use roxadustat for renal anemia in the three months preceding enrollment (Fig. 1 ). Roxadustat received marketing approval in China in 2018, and the groups utilizing roxadustat primarily consisted of: individuals who persisted with the treatment after completing the phase III clinical trial in 2018, patients with a suboptimal response to ESA therapy, and newly enrolled patients who opted to continue with roxadustat from the CKD-ND stage, drawn by the ease of oral administration. This study adhered to the principles of the Helsinki Declaration, and written informed consent was obtained from all patients. The protocol was approved by the Ethics Committee of Beijing Hospital (2025BJYYEC-KY107-01). General Information The baseline demographic data collected included gender, age, duration of dialysis, primary underlying diseases, and comorbidities such as diabetes mellitus, hypertension, coronary artery disease, and others. Hypertension encompassed both essential hypertension and renal hypertension. Concurrent medication usage was documented, with a particular focus on renin-angiotensin system inhibitors (RASI) and beta-blockers. Biochemical analyses All patients underwent fasting venous blood sampling. Serum levels of hemoglobin, albumin, creatinine, blood urea nitrogen (BUN), uric acid, calcium, phosphorus, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), parathyroid hormone (PTH), alkaline phosphatase (ALP), total procollagen type I N-terminal propeptide (TPINP), β-collagen specific sequences (β-CTX), N-terminal pro-brain natriuretic peptide (NT-proBNP), creatine kinase isoenzyme MB (CK-MB), troponin T (TnT), and thyroid function parameters including thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) were measured in our hospital’s clinical laboratory. Statistical analyses Statistical analyses were performed with SPSS v20.0 software (IBM, Armonk, NY, USA). Normality distribution of raw data was assessed by Kolmogorov-Smirnov test. Normally distributed continuous variables are expressed as mean ± standard deviation, while non-normally distributed variables are expressed as median with 25th and 75th percentiles. Differences between groups were evaluated using the Student’s t-test or the Mann-Whitney U test, depending on whether the data were normally distributed. Categorical data were reported as percentages and were assessed with the chi-squared test. Participants were divided into the roxadustat treatment group and control group based on whether they received roxadustat therapy. Patients were also divided into thyroid function normal and abnormal group based on their thyroid hormone status. Risk factors for hypothyroidism were evaluated by unconditional logistic regression. P < 0.05 was considered as statistically significant. RESULTS Baseline Patient characteristics and clinical features The clinical and demographic characteristics of the participants are detailed in Table 1 . A total of 140 subjects, comprising 83 males and 57 females with an age range of 26–95 years, were enrolled in this study. The median duration of dialysis was 76.5 months. Of these, 64 patients (45.7%) had diabetes mellitus, and 135 patients (96.4%) had hypertension. The causes of dialysis were diabetic nephropathy (n = 48, 34.3%), chronic glomerulonephritis (n = 46, 32.9%), hypertensive nephrosclerosis (n = 16, 11.4%), chronic interstitial nephropathy (n = 12, 8.6%), autosomal dominant polycystic kidney disease (n = 9, 6.4%), and other causes (n = 9, 6.4%). Table 1 The fundamental demographic and clinical characteristics of the cohorts participating in this study, as well as the comparisons between patients in the roxadustat group and those in the control group. Variables All patients n = 140 The control group n = 87 The roxadustat group n = 53 P Age, years 67 (56, 75) 68 (60, 76) 65 (53, 71) 0.028 Male, n (%) 83, (59.3%) 48, (55.2%) 35, (66.0%) 0.204 Vintage, months 76.5 (26.0, 134.8) 90.0 (49.0, 159) 28.0 (10.5, 82.5) < 0.001 Diabetes, n (%) 64, (45.7%) 34, (39.1%) 30, (56.6%) 0.044 Hypertension, n (%) 135, (96.4%) 84, (96.6%) 51, (96.2%) 0.920 Cardiovascular disease, n (%) 54, (38.6%) 34, (39.1%) 20, (37.7%) 0.874 Cerebrovascular Disease, n (%) 22, (15.7%) 14, (16.1%) 8, (15.1%) 0.875 Malignancy, n (%) 22, (15.7%) 17, (19.5%) 5, (9.4%) 0.111 Beta-blockers, n (%) 78, (55.7%) 47, (54.0%) 31, (58.5%) 0.606 RASI, n (%) 50, (35.7%) 27, (31.0%) 23, (43.4%) 0.139 Free triiodothyronine (pg/mL) 2.00 (1.74, 2.19) 2.06 (1.87, 2.23) 1.82 (1.61, 2.05) < 0.001 Free thyroxine (ng/mL) 1.11 (0.97, 1.27) 1.17 (1.09, 1.33) 0.95 (0.73, 1.05) < 0.001 TSH (uIU/mL) 1.54 (1.03, 2.78) 2.14 (1.29, 2.99) 1.08 (0.73, 1.77) < 0.001 Hemoglobin (g/L) 110 ± 14 114 ± 13 106 ± 15 0.001 Albumin (g/L) 37 (35, 38) 37 (35, 39) 36 (34, 38) 0.002 Creatinine (umol/L) 832 (644, 1000) 873 (707, 1003) 773 (604, 998) 0.028 Uric acid (umol/L) 434 ± 101 453 ± 93 402 ± 99 0.003 Hs-CRP (mg/L) 2.5 (1.0, 6.5) 2.8 (1.0, 6.5) 2.2 (1.0, 6.4) 0.677 Total cholesterol (mmol/L) 3.34 ± 1.02 3.64 ± 0.97 2.87 ± 0.91 < 0.001 LDL-C (mmol/L) 1.58 (1.20, 2.19) 1.88 (1.39, 2.42) 1.26 (1.02, 1.70) < 0.001 HDL-C (mmol/L) 0.97 ± 0.33 1.05 ± 0.33 0.84 ± 0.28 < 0.001 Creatine kinase (U/L) 71 (48, 111) 67 (45, 111) 74 (56, 115) 0.179 CK-MB (ug/L) 1.75 (1.36, 2.60) 1.71 (1.37, 2.67) 1.94 (1.33, 2.58) 0.966 Troponin T (pg/mL) 48 (34, 71) 48 (35, 73) 48 (33, 69) 0.566 NT-proBNP (pg/mL) 6480 (2284, 13866) 7590 (3517, 21245) 2968 (1315, 9605) 0.001 Alkaline phosphatase (U/L) 91 (72, 115) 96 (72, 119) 85 (69, 109) 0.151 Parathyroid hormone (pg/mL) 172 (110, 299) 202 (122, 328) 153 (86, 256) 0.030 β-CTX (ng/mL) 1.996 (1.229, 2.287) 2.269 (1.396, 2.812) 1.738(1.112, 2.727) 0.151 TPINP (ug/L) 329.8 ± 106.9 304.5 ± 97.7 371.5 ± 109.3 < 0.001 Abbreviation: β-CTX, β-collagen specific sequences; CK-MB, creatine kinase isoenzyme MB; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; Hs-CRP, high-sensitivity C-reactive protein; NT-proBNP, N-terminal pro-brain natriuretic peptide; RASI, renin-angiotensin system inhibitors; TPINP, total procollagen type I N-terminal propeptide; TSH, thyroid stimulating hormone. Comparisons between the roxadustat group and the control group Participants were divided into the roxadustat group (n = 53) and the control group (n = 87) based on whether they received roxadustat therapy. Compared with the control group, patients in the roxadustat group were younger (P = 0.028), had a shorter dialysis vintage (P < 0.001), and a higher proportion of diabetes mellitus (P = 0.044). Furthermore, the roxadustat group also exhibited lower serum levels of hemoglobin, albumin, creatinine, and uric acid (P < 0.05). There were significant differences in serum levels of FT4, FT3, and TSH (P < 0.001, Fig. 2 ), as well as in the proportion of thyroid dysfunction (P < 0.05) between the two groups. Notably, none of the patients treated with roxadustat presented clinical manifestations of hypothyroidism. The details were summarized in Table 1 . Comparisons between patients with and without thyroid dysfunction Thyroid dysfunction is defined as having one or more of the TSH, FT3, or FT4 below the normal range. The subjects were divided into two groups based on their thyroid hormone status: the normal group (n = 80) and the abnormal group (n = 60). Compared to the normal group, the abnormal group exhibited higher proportions of roxadustat and RASI administration, elevated TPINP levels, and lower levels of albumin and LDL-C (P 0.05) in hemoglobin, albumin, serum creatinine, lipid metabolism, bone metabolism, and cardiac function between the normal thyroid hormone group (n = 17) and the abnormal thyroid hormone group (n = 36). Table 2 Comparisons of general data and laboratory indicators between patients with normal and abnormal thyroid hormone. Variables The normal thyroid hormone group n = 80 The abnormal thyroid hormone group n = 60 P Age, years 65 (55, 75) 68 (61, 75) 0.283 Male, n (%) 47, (58.8%) 36, (60.0%) 0.882 Vintage, months 86.0 (29.8, 141.3) 57.0 (24.0, 123.5) 0.200 Diabetes, n (%) 33, (41.3%) 31, (51.7%) 0.221 Hypertension, n (%) 78, (97.5%) 57, (95.0%) 0.430 Cardiovascular disease, n (%) 27, (33.8%) 27, (45.0%) 0.176 Cerebrovascular Disease, n (%) 10, (12.5%) 12, (20.0%) 0.228 Malignancy, n (%) 11, (13.8%) 11, (18.3%) 0.461 Beta-blockers, n (%) 46, (57.5%) 32, (53.3%) 0.623 RASI, n (%) 23, (28.7%) 27, (45.0%) 0.047 Roxadustat, n (%) 17, (21.3%) 36, (60.0%) < 0.001 Hemoglobin (g/L) 112 ± 13 108 ± 15 0.083 Albumin (g/L) 37 (35, 39) 36 (34, 38) 0.042 Creatinine (umol/L) 871 (678, 1064) 787 (618, 936) 0.088 Uric acid (umol/L) 448 ± 105 415 ± 93 0.060 Hs-CRP (mg/L) 2.7 (1.0, 6.1) 2.4 (0.8, 7.1) 0.961 Total cholesterol (mmol/L) 3.51 ± 1.02 3.12 ± 0.97 0.023 LDL-C (mmol/L) 1.71 (1.27, 2.35) 1.45 (1.07, 1.89) 0.008 HDL-C (mmol/L) 0.97 ± 0.31 0.97 ± 0.35 0.983 Creatine kinase (U/L) 72 (50, 111) 67 (48, 111) 0.958 CK-MB (ug/L) 1.71 (1.36, 2.54) 1.89 (1.34, 2.74) 0.530 Troponin T (pg/mL) 46 (33, 63) 51 (37, 76) 0.237 NT-proBNP (pg/mL) 6355 (2284, 14699) 7093 (2130, 12326) 0.934 Alkaline phosphatase (U/L) 92 (69, 117) 90 (74, 114) 0.815 Parathyroid hormone (pg/mL) 188 (118, 309) 168 (105, 276) 0.363 β-CTX (ng/mL) 1.889 (1.200, 2.684) 2.095 (1.392, 3.055) 0.234 TPINP (ug/L) 305.8 ± 103.4 361.9 ± 103.8 0.002 Abbreviation: β-CTX, β-collagen specific sequences; CK-MB, creatine kinase isoenzyme MB; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; NT-proBNP, N-terminal pro-brain natriuretic peptide; RASI, renin-angiotensin system inhibitors; TPINP, total procollagen type I N-terminal propeptide. Factors related to thyroid dysfunction Unconditional logistic regression analysis was used to identify factors related to thyroid dysfunction. The administered of roxadustat and RASI, and the serum levels of TPINP, albumin and LDL-C (p < 0.05) were independent variables, and the presence of thyroid dysfunction was the dependent variable. The results showed that roxadustat was an independent factor for thyroid dysfunction, with an odds ratio (95% confidence interval) of 3.635 (1.593, 8.291). (Table 3 ). Effects of Roxadustat on Lipid Metabolism, Bone, and Cardiovascular. Regarding lipid metabolism, the roxadustat group demonstrated significantly lower levels of TC, LDL-C, and HDL-C compared to the control group (P < 0.001). In bone metabolism, the roxadustat group showed decreased PTH and elevated TPINP levels (P = 0.001). For cardiovascular disease, CK-MB and TnT levels were comparable between the groups; however, the roxadustat cohort had notably lower NT-proBNP levels (P = 0.001). These results are detailed in Table 1 and Fig. 3 . Table 3 Factors related to thyroid dysfunction Variable Coefficient(r) or β P OR (OR 95% CI) Albumin (1g/L) -0.060 .371 0.942 (0.826, 1.074) LDL-C (1 mmol/L) -0.260 .359 0.771 (0.442, 1.344) TPINP (1 ug/L) 0.003 .115 1.003 (0.999, 1.007) RASI (Y versus N) -0.546 .172 0.579 (0.265, 1.267) Roxadustat (Y versus N) 1.291 .002 3.635(1.593, 8.291) Abbreviation: LDL-C, low-density lipoprotein cholesterol; RASI, renin-angiotensin system inhibitors;TPINP, total procollagen type I N-terminal propeptide. DISCUSSION Our study revealed that roxadustat poses a risk factor for hypothyroidism in patients undergoing MHD. Of the participants treated with roxadustat, 67.9% displayed abnormalities in at least one of the following: FT3, FT4, or TSH levels. Additionally, 7 patients presented with TSH levels below 0.4 mU/L. Roxadustat, as the first globally approved HIF-PHI, has demonstrated efficacy in increasing hemoglobin levels comparable to ESAs. However, recent studies have found that patients treated with roxadustat exhibited significant reductions-either singly or in combination-in TSH, FT3, and FT4 levels after administration, suggesting potential suppression of the hypothalamic-pituitary-thyroid (HPT) axis [ 12 – 14 ]. Emiko et al. have evaluated TSH, FT3, and FT4 levels in 51 MHD patients prior to, during, and following roxadustat treatment. They observed a decrease in mean TSH and FT4 levels during therapy, with subsequent normalization after discontinuation (P < 0.001)[ 13 ]. These findings suggest roxadustat can induce reversible CH in MHD patients. Thyroid hormone receptors (THRs) are distributed across cellular membranes throughout the body. Among these, three isoforms-THR-α1, THR-β1, and THR-β2-can specifically bind to T3 and regulate downstream gene transcription, thereby modulating various physiological and metabolic processes[ 15 ]. It has been proposed that roxadustat induces CH by interfering with the HPT axis at multiple levels. First, due to its structural resemblance to T3 negative ligands, it binds to pituitary THR-β with an affinity that may surpass that of T3, consequently suppressing TSH release via a negative feedback mechanism[ 13 , 16 , 17 ]. Second, studies in mice have demonstrated that roxadustat partially crosses the blood-brain barrier to bind hypothalamic thyrotropin releasing hormone (TRH) receptors, inducing allosteric effects that inhibit TRH secretion and subsequently reduce circulating TSH, FT3, and FT4[ 18 ]. Studies have found that although roxadustat can induce CH, patients typically do not exhibit symptoms of hypothyroidism[ 13 ], which is consistent with our findings. It is speculated that, despite roxadustat's suppression of the HPT axis, its structural similarity to T3 may enable it to bind to THRs in other organs and exert effects. Additionally, hemodialysis patients often have multiple underlying comorbidities, which may mask the identification of hypothyroidism. Although patients currently exhibit no obvious clinical signs of hypothyroidism, it remains unclear whether thyroid function within tissues and organs is normal. Some studies suggest that while roxadustat suppresses the HPT axis, it may act as an agonist in other organs[ 19 ]. The liver is a crucial target organ for thyroid hormones, and processes such as lipid and carbohydrate metabolism rely on thyroid hormone signaling. Thyroid hormones bind to hepatic THR-β1 receptors to lower cholesterol levels, and various liver-related conditions, including hypercholesterolemia and non-alcoholic fatty liver disease, are associated with thyroid hormone status[ 15 ]. Previous studies have found roxadustat has no adversely affect on lipid levels[ 20 ], with some patients even showing reduced cholesterol levels [ 9 , 21 , 22 ]. We also observed that patients treated with roxadustat exhibited lower levels of TC, LDL-C, and HDL-C compared to the control group. Furthermore, among patients treated with roxadustat, no significant differences in lipid parameters were observed between those with normal and abnormal thyroid hormone levels. It is hypothesized that roxadustat may reduce blood lipid levels independently of thyroid hormone through several pathways: (1) Roxadustat may enhance the transcription rates of genes involved in lipogenesis and β-oxidation and induce hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase expression by binding to hepatic THR-β2[ 15 ]; (2) Binding to THR-β2 upregulates the expression of hepatic LDL-C receptors, thereby promoting the clearance of LDL-C[ 19 , 21 ]; (3) Activation of the downstream HIF pathway induces the degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, leading to reduced acetyl-CoA synthesis and ceramide levels, ultimately lowering TC and LDL-C [ 19 ]; (4) Regulation of LDL-C gene expression via thyroid hormone response elements (TREs), thereby enhancing LDL-C clearance[ 23 ]; and (5) Potentiation of the efficacy of statin drugs[ 24 ]. NT-proBNP functions as a biomarker secreted by ventricular cardiomyocytes in response to increased pressure overload or myocardial stretching. Research has indicated that serum NT-proBNP levels in individuals with hyperthyroidism are significantly higher than those in individuals with hypothyroidism and euthyroid controls[ 25 ]. In vitro studies have also demonstrated that T3 and T4 stimulate the release of BNP from cultured atrial and ventricular cardiomyocytes in a dose-dependent manner, with T3 specifically enhancing BNP gene transcription[ 26 ]. Our findings suggest that despite lower levels of nutritional markers, including hemoglobin, albumin, and uric acid, in the roxadustat group, the NT-proBNP level was still lower than that in the control group (P = 0.001). Subgroup analysis indicated that among patients treated with roxadustat, NT-proBNP levels were comparable between those with normal and abnormal thyroid function. We hypothesize that roxadustat may exert positive effects on cardiac function by binding to the cardiac THRα receptor, and this effect is independent of thyroid function levels. The mechanisms remain unclear, but several explanations for the proposed mechanisms have been suggested. Patients treated with roxadustat exhibited significantly lower blood lipid levels, which could reduce atherogenic burden and improve endothelial function, thereby alleviating myocardial stress. Additionally, cardiac function may be enhanced through downstream pathways of HIF. Roxadustat stabilizes HIF, activating downstream pathways that promote angiogenesis, mitochondrial biogenesis, and glycolytic adaptation. These processes enhance myocardial oxygen utilization efficiency and ATP production under conditions of relative hypoxia—common in dialysis patients with uremic cardiomyopathy. Thyroid hormones, acting through the THRα receptor in osteoblasts, influence the process of bone remodeling[ 27 ]. PINP, a type I collagen precursor synthesized by osteoblasts, represents new bone formation and serves as a biomarker reflecting the activity level of bone formation[ 28 , 29 ]. Studies have found that PINP concentrations increase during hyperthyroidism and decrease during hypothyroidism[ 30 , 31 ]. These reciprocal changes parallel the thyroid hormone's direct stimulatory effects on osteoblast activity-where excess T3 accelerates bone turnover by enhancing collagen synthesis. Our study revealed that TPINP levels were significantly higher in the roxadustat group (P = 0.001). However, subgroup analysis indicated no significant difference in TPINP levels between patients with normal and abnormal thyroid hormone levels among those treated with roxadustat. This suggests that the osteogenic effects of roxadustat may operate independently of systemic thyroid status, implicate a direct interaction with osteoblast THRα as a plausible mechanism for stimulating new bone matrix deposition. In summary, our current study has found that some MHD patients treated with roxadustat developed CH. Due to its structural similarity to the T3 ligand, roxadustat can precisely bind to THR-β in the hypothalamus and pituitary gland, thereby negatively feedback inhibiting the secretion of FT3, FT4, and TSH. Furthermore, by monitoring lipid metabolism, bone metabolism, and cardiac function, there was no evidence of pathological tissue toxicity associated with these off-target effects. Lastly, none of the patients exhibited clinical symptoms of hypothyroidism. This dissociation between biochemical abnormalities and symptomatology supports the hypothesis that roxadustat maintains tissue-level thyroid hormone signaling through interactions with peripheral THRs in target organs (liver, heart, bone), thereby compensating for central axis suppression. This study provides critical insights for anemia management in CKD patients. It reveals roxadustat’s dual mechanism of action—simultaneously suppressing the central axis while activating peripheral signaling pathways. Additionally, its off-target effect profile delivers essential safety data for clinical evaluation. This investigation is subject to several methodological limitations: First, its single-center design with a relatively small sample size inherently carries risks of selection bias and limits statistical power for detecting subtle effects. Second, the absence of crossover trials—such as switching patients with thyroid dysfunction on roxadustat to ESAs for comparative analysis—poses a limitation. Third, the lack of in vitro and animal model validation hinders a thorough characterization of off-target organ impacts at cellular and molecular levels. CONCLUSIONS The results of this study indicate that roxadustat induces CH in MHD patients because its structure, which resembles T3 ligands, enables binding to THR-β in the hypothalamus and pituitary gland. Roxadustat may act as an agonist in organs by binding to THR, maintaining normal physiological functions; therefore, none of the patients exhibited clinical symptoms of hypothyroidism. Declarations Conflict of interest statement The authors declare that they have no competing interests. Ethics approval and consent to participate The study protocol was approved by the Ethics Committee of our hospital, with the ethics number 2025BJYYEC-KY107-01, and written informed consent was obtained from all patients Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Funding This work was supported by the National Natural Science Foundation of China under Grant 82400820, and Beijing Hospital Clinical Research 121 Project under Grant BJ-2019-197. The funding body had no role in the study design, data collection, data interpretation, or manuscript writing. Author Contribution AQ. Chen designed the experiments, performed the experiments, collected the data, performed the formal analysis, and wrote the manuscript. H.Chen designed the experiments, performed the experiments, collected the data, and edited the manuscript. Y. Sun, LN. Xu, and SS. Han performed the experiments and collected the data. J. Zhang designed the experiments and reviewed the manuscript. X. Liu designed experiments and reviewed/edited the manuscript. Acknowledgments Not applicable. Data Availability The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. References Wang L, Xu X, Zhang M, Hu C, Zhang X, Li C, Nie S, Huang Z, Zhao Z, Hou FF, et al. Prevalence of Chronic Kidney Disease in China: Results From the Sixth China Chronic Disease and Risk Factor Surveillance. JAMA Intern Med. 2023;183(4):298–310. Li Y, Shi H, Wang WM, Peng A, Jiang GR, Zhang JY, Ni ZH, He LQ, Niu JY, Wang NS, et al. 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Roxadustat: First Global Approval. Drugs. 2019;79(5):563–72. Li ZL, Tu Y, Liu BC. Treatment of Renal Anemia with Roxadustat: Advantages and Achievement. Kidney Dis (Basel). 2020;6(2):65–73. Chen N, Hao C, Peng X, Lin H, Yin A, Hao L, Tao Y, Liang X, Liu Z, Xing C, et al. Roxadustat for Anemia in Patients with Kidney Disease Not Receiving Dialysis. N Engl J Med. 2019;381(11):1001–10. Akizawa T, Yamaguchi Y, Otsuka T, Reusch M. A Phase 3, Multicenter, Randomized, Two-Arm, Open-Label Study of Intermittent Oral Dosing of Roxadustat for the Treatment of Anemia in Japanese Erythropoiesis-Stimulating Agent-Naive Chronic Kidney Disease Patients Not on Dialysis. Nephron. 2020;144(8):372–82. Zheng L, Tian J, Liu D, Zhao Y, Fang X, Zhang Y, Liu Y. Efficacy and safety of roxadustat for anaemia in dialysis-dependent and non-dialysis-dependent chronic kidney disease patients: A systematic review and meta-analysis. Br J Clin Pharmacol. 2022;88(3):919–32. 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Low cholesterol levels are good markers for central hypothyroidism in case with dialysis using roxadustat. Clin Case Rep. 2024;12(9):e9400. Chen N, Hao C, Liu BC, Lin H, Wang C, Xing C, Liang X, Jiang G, Liu Z, Li X, et al. Roxadustat Treatment for Anemia in Patients Undergoing Long-Term Dialysis. N Engl J Med. 2019;381(11):1011–22. Hones GS, Rakov H, Logan J, Liao XH, Werbenko E, Pollard AS, Praestholm SM, Siersbaek MS, Rijntjes E, Gassen J, et al. Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo. Proc Natl Acad Sci U S A. 2017;114(52):E11323–32. Dong J, Prieto Garcia L, Huang Y, Tang W, Lundahl A, Elebring M, Ahlstrom C, Vildhede A, Sjogren E, Nagard M. Understanding Statin-Roxadustat Drug-Drug-Disease Interaction Using Physiologically-Based Pharmacokinetic Modeling. Clin Pharmacol Ther. 2023;114(4):825–35. Schultz M, Kistorp C, Langdahl B, Raymond I, Hildebrandt P, Faber J. N-terminal-pro-B-type natriuretic peptide in acute hyperthyroidism. Thyroid. 2007;17(3):237–41. Liang F, Webb P, Marimuthu A, Zhang S, Gardner DG. Triiodothyronine increases brain natriuretic peptide (BNP) gene transcription and amplifies endothelin-dependent BNP gene transcription and hypertrophy in neonatal rat ventricular myocytes. J Biol Chem. 2003;278(17):15073–83. Siddiqi A, Parsons MP, Lewis JL, Monson JP, Williams GR, Burrin JM. TR expression and function in human bone marrow stromal and osteoblast-like cells. J Clin Endocrinol Metab. 2002;87(2):906–14. Vasikaran S, Cooper C, Eastell R, Griesmacher A, Morris HA, Trenti T, Kanis JA. International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine position on bone marker standards in osteoporosis. Clin Chem Lab Med. 2011;49(8):1271–4. Vasikaran S, Eastell R, Bruyere O, Foldes AJ, Garnero P, Griesmacher A, McClung M, Morris HA, Silverman S, Trenti T, et al. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int. 2011;22(2):391–420. Kuzma M, Vanuga P, Binkley N, Sagova I, Pavai D, Blazicek P, Kuzmova Z, Jackuliak P, Vanuga A, Killinger Z, et al. High Serum Fractalkine is Associated with Lower Trabecular Bone Score in Premenopausal Women with Graves' Disease. Horm Metab Res. 2018;50(8):609–14. Mat Ali MH, Tuan Ismail TS, Wan Azman WN, Yaacob NM, Yahaya N, Draman N, Wan Mohamed WMI, Abdullah MS, Ibrahim HA, Wan Nik W et al. Comparison of Vitamin D Levels, Bone Metabolic Marker Levels, and Bone Mineral Density among Patients with Thyroid Disease: A Cross-Sectional Study. Diagnostics (Basel) 2020, 10(12). 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-8294615","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":576451194,"identity":"df5b38a5-484e-40f1-ae35-d0c0da71c3a3","order_by":0,"name":"Aiqun Chen","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Aiqun","middleName":"","lastName":"Chen","suffix":""},{"id":576451195,"identity":"507088a4-3913-472b-93d9-43e51f1b9d83","order_by":1,"name":"Huan Chen","email":"","orcid":"","institution":"Chinese Academy of Medical 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2","display":"","copyAsset":false,"role":"figure","size":379483,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of thyroid hormone levels, including free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH), between patients in the roxadustat group and the control group.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8294615/v1/86afbfb5326c060a47d89101.jpg"},{"id":100750249,"identity":"075914ca-7d11-4422-b344-b846b70f5718","added_by":"auto","created_at":"2026-01-21 04:30:38","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":396960,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of total cholesterol (TC), low-density lipoprotein cholesterol ((LDL-C), N-terminal pro-brain natriuretic peptide (NT-proBNP), and total procollagen type I N-terminal propeptide (TPINP) between patients in the roxadustat group and the control group.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8294615/v1/9fdd47b7099e1a4a5d24fbe2.jpg"},{"id":108639024,"identity":"d34fcacf-055e-49be-91b9-824acde61c8b","added_by":"auto","created_at":"2026-05-06 18:55:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1480145,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8294615/v1/e3de189c-c82d-49b1-a55c-5f2e68adef38.pdf"},{"id":100750246,"identity":"31f1fde1-6431-404c-a9bf-93602a3c0e71","added_by":"auto","created_at":"2026-01-21 04:30:36","extension":"jpg","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":546647,"visible":true,"origin":"","legend":"","description":"","filename":"Graphicalabstract.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8294615/v1/c9e7f1f72bd707a00be5dd6f.jpg"},{"id":100750332,"identity":"e78b79f5-19d8-4e67-be4a-13fead844701","added_by":"auto","created_at":"2026-01-21 04:31:12","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":31933,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8294615/v1/a7e5df46a2d2f513b99688ba.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Effects of Roxadustat on Thyroid Hormone Levels in Chinese Patients Undergoing Maintenance Hemodialysis","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eBased on China's epidemiological survey data from 2018 to 2019, the incidence rate of Chronic Kidney Disease (CKD) is 8.2%, affecting approximately 115\u0026nbsp;million individuals[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Renal anemia, one of the most common complications among CKD patients, occurs in 51.5% of non-dialysis CKD patients and reaches as high as 91.6% to 98.2% in those undergoing dialysis[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Anemia not only impacts patients' quality of life but also accelerates the progression of kidney function decline, increases the risk of cardiovascular diseases, and raises all-cause mortality-thus establishing a vicious cycle of \"renal anemia-heart-kidney\" [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe fundamental pathological mechanism of renal anemia is impaired production of erythropoietin (EPO), which results from damage to the renal interstitial cells [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. For decades, the treatment of renal anemia has primarily involved iron supplementation and the use of erythropoiesis-stimulating agents (ESAs) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), representing a novel class of oral medications for treating renal anemia, consist of an oxygen-sensitive α subunit and a constitutively expressed β subunit [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Its mechanisms of action include: (1) stabilizing HIF-α to promote EPO production and EPO receptor expression; (2) downregulating hepcidin levels to enhance intestinal iron absorption and mobilize stored iron; and (3) upregulating transferrin and transferrin receptor expression to improve functional iron deficiency [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRoxadustat stands as the world's first approved HIF-PHI. Both previous studies and real-world data have shown that roxadustat is equally effective as ESAs in treating renal anemia [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], with particularly superior outcomes observed in patients with comorbid inflammation. However, in 2021, Japanese researchers first reported roxadustat could induce central hypothyroidism (CH) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Subsequent studies have also suggested that roxadustat may trigger CH [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], highlighting this potential risk as clinically significant and warranting attention. Currently, it remains unclear whether the hypothyroidism associated with roxadustat holds clinical significance and whether the medication should be discontinued. Given these reports, we aimed to determine whether roxadustat independently induces hypothyroidism, characterize the distribution pattern of roxadustat's off-target effects based on lipid, bone metabolism, and cardiac function parameters, and preliminarily assess potential risks of tissue toxicity.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eA total of 150 participants undergoing maintenance hemodialysis (MHD) for \u0026ge;\u0026thinsp;3 months at the Nephrology Department of Beijing Hospital were screened between February and March 2025. The inclusion criteria were: age\u0026thinsp;\u0026ge;\u0026thinsp;18 years, dialysis vintage\u0026thinsp;\u0026ge;\u0026thinsp;3 months. Exclusion criteria included: pregnant or breastfeeding women, patients with active malignant tumors, those with severe active infections (e.g., pulmonary infections, dialysis catheter-related infections) that significantly impact metabolic status, individuals previously diagnosed with thyroid dysfunction who are currently undergoing pharmacological intervention, and patients who have received massive transfusions of blood or blood products within the past three months, which may interfere with hormone levels. Among them, 140 eligible MHD patients were included in the study, participants were categorized into the roxadustat group (n\u0026thinsp;=\u0026thinsp;53) and the control group (n\u0026thinsp;=\u0026thinsp;87) based on whether they had stabilized and continued to use roxadustat for renal anemia in the three months preceding enrollment (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e Roxadustat received marketing approval in China in 2018, and the groups utilizing roxadustat primarily consisted of: individuals who persisted with the treatment after completing the phase III clinical trial in 2018, patients with a suboptimal response to ESA therapy, and newly enrolled patients who opted to continue with roxadustat from the CKD-ND stage, drawn by the ease of oral administration. This study adhered to the principles of the Helsinki Declaration, and written informed consent was obtained from all patients. The protocol was approved by the Ethics Committee of Beijing Hospital (2025BJYYEC-KY107-01).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eGeneral Information\u003c/h3\u003e\n\u003cp\u003eThe baseline demographic data collected included gender, age, duration of dialysis, primary underlying diseases, and comorbidities such as diabetes mellitus, hypertension, coronary artery disease, and others. Hypertension encompassed both essential hypertension and renal hypertension. Concurrent medication usage was documented, with a particular focus on renin-angiotensin system inhibitors (RASI) and beta-blockers.\u003c/p\u003e\n\u003ch3\u003eBiochemical analyses\u003c/h3\u003e\n\u003cp\u003eAll patients underwent fasting venous blood sampling. Serum levels of hemoglobin, albumin, creatinine, blood urea nitrogen (BUN), uric acid, calcium, phosphorus, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), parathyroid hormone (PTH), alkaline phosphatase (ALP), total procollagen type I N-terminal propeptide (TPINP), β-collagen specific sequences (β-CTX), N-terminal pro-brain natriuretic peptide (NT-proBNP), creatine kinase isoenzyme MB (CK-MB), troponin T (TnT), and thyroid function parameters including thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) were measured in our hospital\u0026rsquo;s clinical laboratory.\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eStatistical analyses were performed with SPSS v20.0 software (IBM, Armonk, NY, USA). Normality distribution of raw data was assessed by Kolmogorov-Smirnov test. Normally distributed continuous variables are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, while non-normally distributed variables are expressed as median with 25th and 75th percentiles. Differences between groups were evaluated using the Student\u0026rsquo;s t-test or the Mann-Whitney U test, depending on whether the data were normally distributed. Categorical data were reported as percentages and were assessed with the chi-squared test. Participants were divided into the roxadustat treatment group and control group based on whether they received roxadustat therapy. Patients were also divided into thyroid function normal and abnormal group based on their thyroid hormone status. Risk factors for hypothyroidism were evaluated by unconditional logistic regression. P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered as statistically significant.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eBaseline Patient characteristics and clinical features\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe clinical and demographic characteristics of the participants are detailed in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. A total of 140 subjects, comprising 83 males and 57 females with an age range of 26\u0026ndash;95 years, were enrolled in this study. The median duration of dialysis was 76.5 months. Of these, 64 patients (45.7%) had diabetes mellitus, and 135 patients (96.4%) had hypertension. The causes of dialysis were diabetic nephropathy (n\u0026thinsp;=\u0026thinsp;48, 34.3%), chronic glomerulonephritis (n\u0026thinsp;=\u0026thinsp;46, 32.9%), hypertensive nephrosclerosis (n\u0026thinsp;=\u0026thinsp;16, 11.4%), chronic interstitial nephropathy (n\u0026thinsp;=\u0026thinsp;12, 8.6%), autosomal dominant polycystic kidney disease (n\u0026thinsp;=\u0026thinsp;9, 6.4%), and other causes (n\u0026thinsp;=\u0026thinsp;9, 6.4%).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eThe fundamental demographic and clinical characteristics of the cohorts participating in this study, as well as the comparisons between patients in the roxadustat group and those in the control group.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAll patients\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;140\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eThe control group\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;87\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eThe roxadustat group\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;53\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP\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\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67 (56, 75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68 (60, 76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65 (53, 71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.028\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83, (59.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48, (55.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35, (66.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.204\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVintage, months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e76.5 (26.0, 134.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90.0 (49.0, 159)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.0 (10.5, 82.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiabetes, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e64, (45.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34, (39.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30, (56.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.044\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHypertension, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e135, (96.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e84, (96.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51, (96.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.920\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCardiovascular disease, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54, (38.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34, (39.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20, (37.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.874\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCerebrovascular Disease, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22, (15.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14, (16.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8, (15.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.875\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMalignancy, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22, (15.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17, (19.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5, (9.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.111\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBeta-blockers, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e78, (55.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47, (54.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31, (58.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.606\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRASI, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50, (35.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27, (31.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23, (43.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.139\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFree triiodothyronine (pg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.00 (1.74, 2.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.06 (1.87, 2.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.82 (1.61, 2.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFree thyroxine (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.11 (0.97, 1.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.17 (1.09, 1.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.95 (0.73, 1.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTSH (uIU/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.54 (1.03, 2.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.14 (1.29, 2.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.08 (0.73, 1.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHemoglobin (g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e110\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e114\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e106\u0026thinsp;\u0026plusmn;\u0026thinsp;15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlbumin (g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37 (35, 38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37 (35, 39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36 (34, 38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCreatinine (umol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e832 (644, 1000)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e873 (707, 1003)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e773 (604, 998)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.028\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUric acid (umol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e434\u0026thinsp;\u0026plusmn;\u0026thinsp;101\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e453\u0026thinsp;\u0026plusmn;\u0026thinsp;93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e402\u0026thinsp;\u0026plusmn;\u0026thinsp;99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHs-CRP (mg/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.5 (1.0, 6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.8 (1.0, 6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.2 (1.0, 6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.677\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal cholesterol (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.34\u0026thinsp;\u0026plusmn;\u0026thinsp;1.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.87\u0026thinsp;\u0026plusmn;\u0026thinsp;0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLDL-C (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.58 (1.20, 2.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.88 (1.39, 2.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.26 (1.02, 1.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHDL-C (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.97\u0026thinsp;\u0026plusmn;\u0026thinsp;0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.84\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCreatine kinase (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e71 (48, 111)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67 (45, 111)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e74 (56, 115)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.179\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCK-MB (ug/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.75 (1.36, 2.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.71 (1.37, 2.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.94 (1.33, 2.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.966\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTroponin T (pg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48 (34, 71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48 (35, 73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48 (33, 69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.566\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNT-proBNP (pg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6480 (2284, 13866)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7590 (3517, 21245)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2968 (1315, 9605)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlkaline phosphatase (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e91 (72, 115)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96 (72, 119)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e85 (69, 109)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.151\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eParathyroid hormone (pg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e172 (110, 299)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e202 (122, 328)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e153 (86, 256)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.030\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026beta;-CTX (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.996 (1.229, 2.287)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.269 (1.396, 2.812)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.738(1.112, 2.727)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.151\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTPINP (ug/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e329.8\u0026thinsp;\u0026plusmn;\u0026thinsp;106.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e304.5\u0026thinsp;\u0026plusmn;\u0026thinsp;97.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e371.5\u0026thinsp;\u0026plusmn;\u0026thinsp;109.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eAbbreviation: \u0026beta;-CTX, \u0026beta;-collagen specific sequences; CK-MB, creatine kinase isoenzyme MB; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; Hs-CRP, high-sensitivity C-reactive protein; NT-proBNP, N-terminal pro-brain natriuretic peptide; RASI, renin-angiotensin system inhibitors; TPINP, total procollagen type I N-terminal propeptide; TSH, thyroid stimulating hormone.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eComparisons between the roxadustat group and the control group\u003c/h2\u003e\n \u003cp\u003eParticipants were divided into the roxadustat group (n\u0026thinsp;=\u0026thinsp;53) and the control group (n\u0026thinsp;=\u0026thinsp;87) based on whether they received roxadustat therapy. Compared with the control group, patients in the roxadustat group were younger (P\u0026thinsp;=\u0026thinsp;0.028), had a shorter dialysis vintage (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and a higher proportion of diabetes mellitus (P\u0026thinsp;=\u0026thinsp;0.044). Furthermore, the roxadustat group also exhibited lower serum levels of hemoglobin, albumin, creatinine, and uric acid (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). There were significant differences in serum levels of FT4, FT3, and TSH (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e), as well as in the proportion of thyroid dysfunction (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) between the two groups. Notably, none of the patients treated with roxadustat presented clinical manifestations of hypothyroidism. The details were summarized in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eComparisons between patients with and without thyroid dysfunction\u003c/strong\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eThyroid dysfunction is defined as having one or more of the TSH, FT3, or FT4 below the normal range. The subjects were divided into two groups based on their thyroid hormone status: the normal group (n\u0026thinsp;=\u0026thinsp;80) and the abnormal group (n\u0026thinsp;=\u0026thinsp;60). Compared to the normal group, the abnormal group exhibited higher proportions of roxadustat and RASI administration, elevated TPINP levels, and lower levels of albumin and LDL-C (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). (See Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.)\u003c/p\u003e\n\u003cp\u003eSubgroup analysis of the 53 patients treated with roxadustat revealed no significant differences (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) in hemoglobin, albumin, serum creatinine, lipid metabolism, bone metabolism, and cardiac function between the normal thyroid hormone group (n\u0026thinsp;=\u0026thinsp;17) and the abnormal thyroid hormone group (n\u0026thinsp;=\u0026thinsp;36).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"char\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eComparisons of general data and laboratory indicators between patients with normal and abnormal thyroid hormone.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eThe normal thyroid hormone group\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;80\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eThe abnormal thyroid hormone group\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;60\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP\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\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65 (55, 75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68 (61, 75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.283\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47, (58.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36, (60.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.882\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVintage, months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e86.0 (29.8, 141.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e57.0 (24.0, 123.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.200\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiabetes, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33, (41.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31, (51.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.221\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHypertension, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e78, (97.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e57, (95.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.430\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCardiovascular disease, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27, (33.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27, (45.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.176\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCerebrovascular Disease, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10, (12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12, (20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.228\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMalignancy, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11, (13.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11, (18.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.461\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBeta-blockers, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e46, (57.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32, (53.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.623\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRASI, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23, (28.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27, (45.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.047\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRoxadustat, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17, (21.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36, (60.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHemoglobin (g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e112\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e108\u0026thinsp;\u0026plusmn;\u0026thinsp;15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.083\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlbumin (g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37 (35, 39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36 (34, 38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.042\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCreatinine (umol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e871 (678, 1064)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e787 (618, 936)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.088\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUric acid (umol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e448\u0026thinsp;\u0026plusmn;\u0026thinsp;105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e415\u0026thinsp;\u0026plusmn;\u0026thinsp;93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.060\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHs-CRP (mg/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.7 (1.0, 6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.4 (0.8, 7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.961\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal cholesterol (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.51\u0026thinsp;\u0026plusmn;\u0026thinsp;1.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLDL-C (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.71 (1.27, 2.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.45 (1.07, 1.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHDL-C (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.97\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.97\u0026thinsp;\u0026plusmn;\u0026thinsp;0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.983\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCreatine kinase (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e72 (50, 111)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67 (48, 111)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.958\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCK-MB (ug/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.71 (1.36, 2.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.89 (1.34, 2.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.530\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTroponin T (pg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e46 (33, 63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51 (37, 76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.237\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNT-proBNP (pg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6355 (2284, 14699)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7093 (2130, 12326)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.934\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlkaline phosphatase (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e92 (69, 117)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90 (74, 114)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.815\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eParathyroid hormone (pg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e188 (118, 309)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e168 (105, 276)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.363\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026beta;-CTX (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.889 (1.200, 2.684)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.095 (1.392, 3.055)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.234\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTPINP (ug/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e305.8\u0026thinsp;\u0026plusmn;\u0026thinsp;103.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e361.9\u0026thinsp;\u0026plusmn;\u0026thinsp;103.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eAbbreviation: \u0026beta;-CTX, \u0026beta;-collagen specific sequences; CK-MB, creatine kinase isoenzyme MB; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; NT-proBNP, N-terminal pro-brain natriuretic peptide; RASI, renin-angiotensin system inhibitors; TPINP, total procollagen type I N-terminal propeptide.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ch3\u003eFactors related to thyroid dysfunction\u003c/h3\u003e\n\u003cp\u003eUnconditional logistic regression analysis was used to identify factors related to thyroid dysfunction. The administered of roxadustat and RASI, and the serum levels of TPINP, albumin and LDL-C (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) were independent variables, and the presence of thyroid dysfunction was the dependent variable. The results showed that roxadustat was an independent factor for thyroid dysfunction, with an odds ratio (95% confidence interval) of 3.635 (1.593, 8.291). (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEffects of Roxadustat on Lipid Metabolism, Bone, and Cardiovascular.\u003c/strong\u003e Regarding lipid metabolism, the roxadustat group demonstrated significantly lower levels of TC, LDL-C, and HDL-C compared to the control group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In bone metabolism, the roxadustat group showed decreased PTH and elevated TPINP levels (P\u0026thinsp;=\u0026thinsp;0.001). For cardiovascular disease, CK-MB and TnT levels were comparable between the groups; however, the roxadustat cohort had notably lower NT-proBNP levels (P\u0026thinsp;=\u0026thinsp;0.001). These results are detailed in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"char\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\" class=\"fr-table-selection-hover\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eFactors related to thyroid dysfunction\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCoefficient(r) or \u0026beta;\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOR (OR 95% CI)\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\u003eAlbumin (1g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.060\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.371\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.942 (0.826, 1.074)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLDL-C (1 mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.260\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.359\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.771 (0.442, 1.344)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTPINP (1 ug/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.115\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.003 (0.999, 1.007)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRASI (Y versus N)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.546\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.172\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.579 (0.265, 1.267)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRoxadustat (Y versus N)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.291\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.635(1.593, 8.291)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eAbbreviation: LDL-C, low-density lipoprotein cholesterol; RASI, renin-angiotensin system inhibitors;TPINP, total procollagen type I N-terminal propeptide.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eOur study revealed that roxadustat poses a risk factor for hypothyroidism in patients undergoing MHD. Of the participants treated with roxadustat, 67.9% displayed abnormalities in at least one of the following: FT3, FT4, or TSH levels. Additionally, 7 patients presented with TSH levels below 0.4 mU/L. Roxadustat, as the first globally approved HIF-PHI, has demonstrated efficacy in increasing hemoglobin levels comparable to ESAs. However, recent studies have found that patients treated with roxadustat exhibited significant reductions-either singly or in combination-in TSH, FT3, and FT4 levels after administration, suggesting potential suppression of the hypothalamic-pituitary-thyroid (HPT) axis [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Emiko et al. have evaluated TSH, FT3, and FT4 levels in 51 MHD patients prior to, during, and following roxadustat treatment. They observed a decrease in mean TSH and FT4 levels during therapy, with subsequent normalization after discontinuation (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001)[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. These findings suggest roxadustat can induce reversible CH in MHD patients.\u003c/p\u003e \u003cp\u003eThyroid hormone receptors (THRs) are distributed across cellular membranes throughout the body. Among these, three isoforms-THR-α1, THR-β1, and THR-β2-can specifically bind to T3 and regulate downstream gene transcription, thereby modulating various physiological and metabolic processes[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. It has been proposed that roxadustat induces CH by interfering with the HPT axis at multiple levels. First, due to its structural resemblance to T3 negative ligands, it binds to pituitary THR-β with an affinity that may surpass that of T3, consequently suppressing TSH release via a negative feedback mechanism[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Second, studies in mice have demonstrated that roxadustat partially crosses the blood-brain barrier to bind hypothalamic thyrotropin releasing hormone (TRH) receptors, inducing allosteric effects that inhibit TRH secretion and subsequently reduce circulating TSH, FT3, and FT4[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eStudies have found that although roxadustat can induce CH, patients typically do not exhibit symptoms of hypothyroidism[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], which is consistent with our findings. It is speculated that, despite roxadustat's suppression of the HPT axis, its structural similarity to T3 may enable it to bind to THRs in other organs and exert effects. Additionally, hemodialysis patients often have multiple underlying comorbidities, which may mask the identification of hypothyroidism. Although patients currently exhibit no obvious clinical signs of hypothyroidism, it remains unclear whether thyroid function within tissues and organs is normal. Some studies suggest that while roxadustat suppresses the HPT axis, it may act as an agonist in other organs[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe liver is a crucial target organ for thyroid hormones, and processes such as lipid and carbohydrate metabolism rely on thyroid hormone signaling. Thyroid hormones bind to hepatic THR-β1 receptors to lower cholesterol levels, and various liver-related conditions, including hypercholesterolemia and non-alcoholic fatty liver disease, are associated with thyroid hormone status[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Previous studies have found roxadustat has no adversely affect on lipid levels[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], with some patients even showing reduced cholesterol levels [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. We also observed that patients treated with roxadustat exhibited lower levels of TC, LDL-C, and HDL-C compared to the control group. Furthermore, among patients treated with roxadustat, no significant differences in lipid parameters were observed between those with normal and abnormal thyroid hormone levels. It is hypothesized that roxadustat may reduce blood lipid levels independently of thyroid hormone through several pathways: (1) Roxadustat may enhance the transcription rates of genes involved in lipogenesis and β-oxidation and induce hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase expression by binding to hepatic THR-β2[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]; (2) Binding to THR-β2 upregulates the expression of hepatic LDL-C receptors, thereby promoting the clearance of LDL-C[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]; (3) Activation of the downstream HIF pathway induces the degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, leading to reduced acetyl-CoA synthesis and ceramide levels, ultimately lowering TC and LDL-C [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]; (4) Regulation of LDL-C gene expression via thyroid hormone response elements (TREs), thereby enhancing LDL-C clearance[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]; and (5) Potentiation of the efficacy of statin drugs[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eNT-proBNP functions as a biomarker secreted by ventricular cardiomyocytes in response to increased pressure overload or myocardial stretching. Research has indicated that serum NT-proBNP levels in individuals with hyperthyroidism are significantly higher than those in individuals with hypothyroidism and euthyroid controls[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In vitro studies have also demonstrated that T3 and T4 stimulate the release of BNP from cultured atrial and ventricular cardiomyocytes in a dose-dependent manner, with T3 specifically enhancing BNP gene transcription[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Our findings suggest that despite lower levels of nutritional markers, including hemoglobin, albumin, and uric acid, in the roxadustat group, the NT-proBNP level was still lower than that in the control group (P\u0026thinsp;=\u0026thinsp;0.001). Subgroup analysis indicated that among patients treated with roxadustat, NT-proBNP levels were comparable between those with normal and abnormal thyroid function. We hypothesize that roxadustat may exert positive effects on cardiac function by binding to the cardiac THRα receptor, and this effect is independent of thyroid function levels. The mechanisms remain unclear, but several explanations for the proposed mechanisms have been suggested. Patients treated with roxadustat exhibited significantly lower blood lipid levels, which could reduce atherogenic burden and improve endothelial function, thereby alleviating myocardial stress. Additionally, cardiac function may be enhanced through downstream pathways of HIF. Roxadustat stabilizes HIF, activating downstream pathways that promote angiogenesis, mitochondrial biogenesis, and glycolytic adaptation. These processes enhance myocardial oxygen utilization efficiency and ATP production under conditions of relative hypoxia\u0026mdash;common in dialysis patients with uremic cardiomyopathy.\u003c/p\u003e \u003cp\u003eThyroid hormones, acting through the THRα receptor in osteoblasts, influence the process of bone remodeling[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. PINP, a type I collagen precursor synthesized by osteoblasts, represents new bone formation and serves as a biomarker reflecting the activity level of bone formation[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Studies have found that PINP concentrations increase during hyperthyroidism and decrease during hypothyroidism[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. These reciprocal changes parallel the thyroid hormone's direct stimulatory effects on osteoblast activity-where excess T3 accelerates bone turnover by enhancing collagen synthesis. Our study revealed that TPINP levels were significantly higher in the roxadustat group (P\u0026thinsp;=\u0026thinsp;0.001). However, subgroup analysis indicated no significant difference in TPINP levels between patients with normal and abnormal thyroid hormone levels among those treated with roxadustat. This suggests that the osteogenic effects of roxadustat may operate independently of systemic thyroid status, implicate a direct interaction with osteoblast THRα as a plausible mechanism for stimulating new bone matrix deposition.\u003c/p\u003e \u003cp\u003eIn summary, our current study has found that some MHD patients treated with roxadustat developed CH. Due to its structural similarity to the T3 ligand, roxadustat can precisely bind to THR-β in the hypothalamus and pituitary gland, thereby negatively feedback inhibiting the secretion of FT3, FT4, and TSH. Furthermore, by monitoring lipid metabolism, bone metabolism, and cardiac function, there was no evidence of pathological tissue toxicity associated with these off-target effects. Lastly, none of the patients exhibited clinical symptoms of hypothyroidism. This dissociation between biochemical abnormalities and symptomatology supports the hypothesis that roxadustat maintains tissue-level thyroid hormone signaling through interactions with peripheral THRs in target organs (liver, heart, bone), thereby compensating for central axis suppression. This study provides critical insights for anemia management in CKD patients. It reveals roxadustat\u0026rsquo;s dual mechanism of action\u0026mdash;simultaneously suppressing the central axis while activating peripheral signaling pathways. Additionally, its off-target effect profile delivers essential safety data for clinical evaluation.\u003c/p\u003e \u003cp\u003eThis investigation is subject to several methodological limitations: First, its single-center design with a relatively small sample size inherently carries risks of selection bias and limits statistical power for detecting subtle effects. Second, the absence of crossover trials\u0026mdash;such as switching patients with thyroid dysfunction on roxadustat to ESAs for comparative analysis\u0026mdash;poses a limitation. Third, the lack of in vitro and animal model validation hinders a thorough characterization of off-target organ impacts at cellular and molecular levels.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eThe results of this study indicate that roxadustat induces CH in MHD patients because its structure, which resembles T3 ligands, enables binding to THR-β in the hypothalamus and pituitary gland. Roxadustat may act as an agonist in organs by binding to THR, maintaining normal physiological functions; therefore, none of the patients exhibited clinical symptoms of hypothyroidism.\u003c/p\u003e"},{"header":"Declarations","content":" \u003ch2\u003eConflict of interest statement\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003e The study protocol was approved by the Ethics Committee of our hospital, with the ethics number 2025BJYYEC-KY107-01, and written informed consent was obtained from all patients\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e \u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work was supported by the National Natural Science Foundation of China under Grant 82400820, and Beijing Hospital Clinical Research 121 Project under Grant BJ-2019-197. The funding body had no role in the study design, data collection, data interpretation, or manuscript writing.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAQ. Chen designed the experiments, performed the experiments, collected the data, performed the formal analysis, and wrote the manuscript. H.Chen designed the experiments, performed the experiments, collected the data, and edited the manuscript. Y. Sun, LN. Xu, and SS. Han performed the experiments and collected the data. J. Zhang designed the experiments and reviewed the manuscript. X. Liu designed experiments and reviewed/edited the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWang L, Xu X, Zhang M, Hu C, Zhang X, Li C, Nie S, Huang Z, Zhao Z, Hou FF, et al. Prevalence of Chronic Kidney Disease in China: Results From the Sixth China Chronic Disease and Risk Factor Surveillance. JAMA Intern Med. 2023;183(4):298\u0026ndash;310.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi Y, Shi H, Wang WM, Peng A, Jiang GR, Zhang JY, Ni ZH, He LQ, Niu JY, Wang NS, et al. Prevalence, awareness, and treatment of anemia in Chinese patients with nondialysis chronic kidney disease: First multicenter, cross-sectional study. 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Int J Med Sci. 2024;21(10):1806\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHaraguchi T, Hamamoto Y, Kuwata H, Yamazaki Y, Nakatani S, Hyo T, Yamada Y, Yabe D, Seino Y. Effect of Roxadustat on Thyroid Function in Patients With Renal Anemia. J Clin Endocrinol Metab. 2023;109(1):e69\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKita S, Okuyama H, Kondo T, Hayashi M, Nakao S, Sawamura T, Fujimoto K, Nakagawa A, Yokoyama H, Furuichi K. Low cholesterol levels are good markers for central hypothyroidism in case with dialysis using roxadustat. Clin Case Rep. 2024;12(9):e9400.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen N, Hao C, Liu BC, Lin H, Wang C, Xing C, Liang X, Jiang G, Liu Z, Li X, et al. Roxadustat Treatment for Anemia in Patients Undergoing Long-Term Dialysis. N Engl J Med. 2019;381(11):1011\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHones GS, Rakov H, Logan J, Liao XH, Werbenko E, Pollard AS, Praestholm SM, Siersbaek MS, Rijntjes E, Gassen J, et al. Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo. Proc Natl Acad Sci U S A. 2017;114(52):E11323\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDong J, Prieto Garcia L, Huang Y, Tang W, Lundahl A, Elebring M, Ahlstrom C, Vildhede A, Sjogren E, Nagard M. Understanding Statin-Roxadustat Drug-Drug-Disease Interaction Using Physiologically-Based Pharmacokinetic Modeling. Clin Pharmacol Ther. 2023;114(4):825\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchultz M, Kistorp C, Langdahl B, Raymond I, Hildebrandt P, Faber J. N-terminal-pro-B-type natriuretic peptide in acute hyperthyroidism. Thyroid. 2007;17(3):237\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiang F, Webb P, Marimuthu A, Zhang S, Gardner DG. Triiodothyronine increases brain natriuretic peptide (BNP) gene transcription and amplifies endothelin-dependent BNP gene transcription and hypertrophy in neonatal rat ventricular myocytes. J Biol Chem. 2003;278(17):15073\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSiddiqi A, Parsons MP, Lewis JL, Monson JP, Williams GR, Burrin JM. TR expression and function in human bone marrow stromal and osteoblast-like cells. J Clin Endocrinol Metab. 2002;87(2):906\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVasikaran S, Cooper C, Eastell R, Griesmacher A, Morris HA, Trenti T, Kanis JA. International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine position on bone marker standards in osteoporosis. 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Comparison of Vitamin D Levels, Bone Metabolic Marker Levels, and Bone Mineral Density among Patients with Thyroid Disease: A Cross-Sectional Study. Diagnostics (Basel) 2020, 10(12).\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":"maintenance hemodialysis, organ toxicity, roxadustat, hypothyroidism","lastPublishedDoi":"10.21203/rs.3.rs-8294615/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8294615/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eRecent studies have indicated that patients with chronic kidney disease (CKD) experience central hypothyroidism (CH) following treatment with roxadustat. Our objective is to assess the effect of roxadustat on the hypothalamic-pituitary-thyroid (HPT) axis in patients undergoing maintenance hemodialysis (MHD) and to explore whether it may cause potential tissue toxicity.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA total of 140 patients undergoing MHD were enrolled in this cross-sectional study. Thyroid hormones, including thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4), as well as parameters of lipid metabolism, cardiac function, and bone metabolism, were assessed. The patients were divided into two groups based on their roxadustat treatment status: the roxadustat group (n\u0026thinsp;=\u0026thinsp;53) and the control group (n\u0026thinsp;=\u0026thinsp;87), differences between groups were evaluated using the Student\u0026rsquo;s t-test or the Mann-Whitney U test. Unconditional logistic regression analysis was utilized to identify risk factors for hypothyroidism.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe roxadustat group demonstrated lower serum levels of TSH, FT3, and FT4 compared to the control group. Additionally, four cases (7.5%) exhibited abnormalities in all three indicators, and seven cases had TSH levels below 0.4 mU/L. Notably, none of the patients exhibited clinical symptoms of hypothyroidism. Unconditional logistic regression analysis indicated that roxadustat was an independent risk factor for hypothyroidism, with an odds ratio (95% confidence interval) of 3.635 (1.593, 8.291). Furthermore, the roxadustat group had lower levels of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and N-terminal pro-B-type natriuretic peptide (NT-proBNP), and higher levels of serum total procollagen type I N-terminal propeptide (TPINP).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eRoxadustat is an independent risk factor for hypothyroidism; however, no adverse off-target effects on organs were observed.\u003c/p\u003e","manuscriptTitle":"The Effects of Roxadustat on Thyroid Hormone Levels in Chinese Patients Undergoing Maintenance Hemodialysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-21 04:27:37","doi":"10.21203/rs.3.rs-8294615/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":"02c1ccda-c7a9-4dd3-85a0-315c0151bc17","owner":[],"postedDate":"January 21st, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Rejected","date":"2026-05-06T18:42:53+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-06T18:54:42+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-21 04:27:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8294615","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8294615","identity":"rs-8294615","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}