Plasma branched-chain amino acids in chronic kidney disease: Associations with atherogenic lipids and mortality

Plasma branched-chain amino acids in chronic kidney disease: Associations with atherogenic lipids and mortality | 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 Plasma branched-chain amino acids in chronic kidney disease: Associations with atherogenic lipids and mortality Mohamed E Suliman, Abdul Rashid Qureshi, Dario Troise, Qianying Zhang, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7849136/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Mar, 2026 Read the published version in Amino Acids → Version 1 posted 9 You are reading this latest preprint version Abstract Background Branched-chain amino acids (BCAAs) are essential nutrients that promote muscle protein anabolism but also associate with cardiometabolic diseases; however, their role in chronic kidney disease (CKD) remains unclear. We investigated plasma BCAA levels and their associations with metabolic parameters and survival in CKD patients. Methods Plasma BCAA levels, along with clinical and laboratory parameters, were measured in 328 patients with CKD stage 5 (median age 54 years, 60% males). BCAA concentrations in 83 healthy individuals (median age 51 years, 66% males) served as comparators. Multivariate linear regression analysis was employed to identify predictors of BCAA levels. Competing risk regression analysis was conducted to assess 5-year risk of all-cause and cardiovascular mortality in relation to total and individual BCAAs (valine, isoleucine, and leucine). Results Plasma BCAA levels were lower compared to healthy individuals (P < 0.0001) and positively associated with triglycerides and the atherogenic index of plasma, while inversely associated with high density lipoprotein-cholesterol (HDL-C), Apo-A, and Lp (a). After adjustments for confounders, low vs. high tertile of total BCAAs associated with increased risk of cardiovascular mortality (sub-hazard ratio [sHR] 2.37, 95% confidence interval [CI], 1.08–5.21) and low tertile of valine associated with higher risk of both all-cause mortality (sHR 2.05, 95% CI 1.10–3.79) and cardiovascular mortality (sHR 2.46, 95% CI 1.15–5.26). Conclusion In CKD, higher levels of BCAAs associated with an atherogenic lipid profile while lower BCAAs levels associated with increased cardiovascular mortality risk, and low valine was associated with higher both all-cause and cardiovascular mortality risk. Monitoring and potentially modulating BCAA levels could have prognostic or therapeutic implications in advanced CKD. Branched-chain amino acids lipid profile inflammation chronic kidney disease mortality Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Branched-chain amino acids (BCAAs), which include leucine (Leu), isoleucine (Ile), and valine (Val), are essential amino acids that play a crucial role in muscle protein synthesis and energy production. Beyond serving as substrates for protein synthesis, BCAAs act as signaling molecules, stimulating protein synthesis and regulating glucose and lipid metabolism, neurotransmitter and hormone synthesis, and mitochondrial biogenesis, and they have key roles for intestinal health and immunity 1 , 2 . On the other hand, high plasma BCAAs concentrations are closely associated with presence and severity of cardiometabolic alterations such as insulin resistance, metabolic syndrome, diabetes mellitus (DM), and obesity, as well as cardiovascular disease (CVD) 3 . Adipose tissue, a dynamic organ essential for glucose and lipid metabolism, also influences BCAA balance through nutrient storage and lipolysis 4 . Moreover, associations between BCAAs and metabolic dyslipidemia have been reported and several studies have explored the connections between BCAAs and the lipid profile 5 – 10 . Indeed, recent studies in the general population show that high levels of BCAAs are associated with elevated triglycerides (TG) and reduced high density lipoprotein-cholesterol (HDL-C) levels 5 – 8 . Whereas the connection between BCAAs and the lipid profile is not completely clear, it has been suggested that it is partially mediated by insulin resistance, a common feature in individuals with elevated BCAAs levels, which associates with increased lipolysis and reduced clearance of circulating lipids, contributing to dyslipidemia 11 . The finding of a significant association between BCAAs and insulin resistance suggests that BCAAs may play a major role in the modulation of insulin action 12 . Circulating levels of the BCAAs are significantly higher in obese individuals compared to lean ones 13 and BCAAs have been established as some of the most robust biomarkers for a range of cardiometabolic conditions, including obesity, insulin resistance, type 2 DM, and CVD 14 . Furthermore, genetic variants linked to dyslipidemia and insulin resistance have been associated with increased concentrations of circulating BCAAs, suggesting that obesity and insulin resistance may drive the obesity-related rise in BCAAs 15 . Chronic kidney disease (CKD) patients often exhibit insulin resistance and dyslipidemia, along with disturbances in amino acid metabolism, particularly involving BCAAs 16 . Patients with advanced CKD show decreased levels of plasma and intracellular BCAAs 16 – 21 , likely due to impaired kidney amino acid metabolism and metabolic changes such as acidosis, and malnutrition 16 , 22 and often present with elevated levels of TG and low-density lipoprotein cholesterol (LDL-C), decreased HDL-C levels, and altered lipoprotein composition. Whereas links between BCAAs and lipoproteins have been reported in the general population, the existence of such a linkage in CKD patients has to the best of our knowledge not yet been explored. Therefore, in the present study, we evaluated associations between plasma BCAA concentrations and serum cholesterol, TG, HDL-C, and LDL-C, and estimated the risk of atherogenic dyslipidemia in relation to plasma BCAA levels, in patients with advanced CKD. We used the atherogenic index of plasma (AIP), reflecting the TG to HDL-C ratio, as a biomarker for atherogenic dyslipidemia 23 . By considering two atherogenic lipid parameters, AIP provides insights into an individual's risk of atherosclerosis. While high plasma concentrations of BCAAs may be linked to cardiometabolic diseases, low circulating levels of essential nutrients such as BCAAs could potentially have a negative effect on survival. However, the association between BCAAs and mortality risk in CKD remains unclear and has not been conclusively determined. Therefore, we investigated these associations to gain a better understanding of possible links between plasma BCAA concentrations, atherogenic lipids, and clinical outcomes in CKD patients. Material and Methods Study populations This is a post hoc analysis of a cross-sectional study with follow-up data of mortality in a cohort of patients with CKD stage 5 24 ( Figure S1) . The study conformed to and was conducted in accordance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines 25 . The patients, who were recruited between December 1994 and April 2014, were investigated close to the start of dialysis treatment and were followed for up to five years. Exclusion criteria included age younger than 18 or older than 70 years, signs of overt infection, acute vasculitis, unwillingness to participate, and, for this study, missing BCAA measurement. Of 560 patients included in the cohort, 328 patients (198 (60%) males, median age 54 years, and median estimated glomerular filtration rate (eGFR) 6.3 ml/min per 1.73 m 2 ) met the study criteria and were included in the current analyses, see Table 1 . The causes of CKD were diabetic nephropathy (26%), hypertension and kidney vascular disease (21%), chronic glomerulonephritis (25%), and other causes (28%). Most patients (85%) were on antihypertensive medications, 59 (18%) patients were prescribed statins and other commonly used drugs in kidney failure such as erythropoietin, phosphate binders and potassium binders, and 61 (19%) patients received an oral amino acid supplementation. Data on BCAAs of 83 healthy subjects (66% males, median age 51 (range 21-80) years) served as comparator for BCAAs in the patient cohort (Supplementary material, Table S1 ). Informed written consent was obtained from each patient and control subject. The protocol of this study was approved by the Ethics Committee of the Karolinska Institute (EPN) at the Karolinska University Hospital Huddinge, Stockholm, Sweden. The study was conducted in adherence to the Declaration of Helsinki. Methods After an overnight fast, venous blood samples were taken for analysis. Plasma and serum were separated and kept frozen at −70 ◦ C if not analyzed immediately. Plasma amino acids including BCAAs (Leu, Ile and Val) were measured by reversed-phase high-performance liquid chromatography (HPLC) with fluorometric detection as previously described 26 . Serum cholesterol, HDL-C and TG were analyzed by standard enzymatic procedures (Boehringer Mannheim, Mannheim, Germany). High-sensitivity C-reactive protein (hsCRP) was measured by the nephelometry method. Interleukin-6 (IL-6) was measured with ELISA commercial kits (Roche Diagnostics GmbH, Penzberg, Germany). The remaining biochemical analyses were done using routine methods at Karolinska University Hospital at Huddinge. Glomerular filtration rate (GFR) was assessed in the CKD patients as an estimated GFR (eGFR) from serum creatinine levels. Atherogenic index of plasma (AIP) was calculated as the logarithmically transformed ratio of the serum TG to high-density lipoprotein cholesterol (HDL-C) as described in 27 : . Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was calculated based on the following equation: Fasting insulin in μU/mL)×fasting glucose in mmol/L) / 22.5. Body mass index (BMI) was calculated as the subject’s body weight in kilograms divided by the square of the subject’s height in meters (kg/m 2 ). Outcome ascertainment Survival among the 328 CKD stage 5 patients was measured from the day of examination until death or censoring for kidney transplantation or when they completed the 5-year follow-up period. No patients were lost to follow-up. The median follow-up period was 29.4 (range 0.9–60) months. Within the 5-year follow-up period, 82 patients (25%) died, of which 52 (63%) were cardiovascular deaths, and 166 patients (51%) underwent transplantation. Cardiovascular deaths were attributed to ischemic heart disease, heart failure, ischemic stroke, peripheral vascular disease, or hemorrhagic stroke. Statistical analysis Data are expressed as number (percentage) or median (interquartile range, IQR). Statistical significance was set at the level of P < 0.05. Comparisons between two groups were assessed with the non-parametric Wilcoxon test for continuous variables and Chi-square test ( χ 2 ) for nominal variables. When comparing more than two groups we applied the non-parametric Kruskal-Walli’s test for continuous variables and χ 2 test for nominal variables. Non-parametric Spearman rank correlation analysis was used to determine associations between variables. Multivariate linear regression analysis with stepwise backward selection of variables was used to determine the predictors of total and individual BCAAs. Restricted cubic spline curve analysis was performed to assess the associations between total BCAA and valine concentrations (as continuous variables) and the risk of all-cause mortality and cardiovascular mortality. Fine-Gray competing-risk regression analysis models with kidney transplantation as a competing risk were used to estimate the sub-distribution hazard ratio (sHR) with 95% confidence interval (95% CI) to quantify the association of total and individual BCAAs, expressed as tertiles, with mortality risk. Statistical analyses were performed using statistical software Stata Now 18.5 (Stata Corporation, College Station, TX, USA) and Statistical Analysis Systems (SAS) SAS 9.4 level 1 M8 (SAS Campus Drive, Cary, NC, USA). Results Characteristics of the CKD patients A total of 328 CKD patients (198 males and 130 females) with a median (IQR) age of 54 (43 – 63) years were included in the study ( Table 1) . Their median eGFR was 6.3 (4.9 – 7.9) ml/min/1.73 m 2 , 104 (32%) had DM and 111 (34%) had CVD. Moreover, Table 1 shows glucose-related parameters, plasma lipid profile including AIP, and total and individual BCAAs, for all patients and when patients are divided into tertiles of total BCAAs. BCAAs in patients and controls Plasma concentrations of total (T-BCAA) and individual BCAAs were significantly lower in CKD patients compared to healthy controls ( Fig. 1 and Table S1 ), except for Ile, for which the difference did not reach statistical significance. BCAAs in different CKD patient groups The plasma concentrations of T-BCAA ( Fig. S2 ) and the three individual BCAAs ( Table S2 ) were higher (all p<0.0001) in male patients compared to female patients. Similarly, plasma concentrations of total BCAAs (T-BCAA) and the three individual BCAAs were significantly higher in healthy males compared to healthy females ( Fig. S3 ). However, the plasma BCAA concentrations did not differ significantly between CKD patients with and without DM, CVD, and statin treatment, respectively ( Fig. S2 ). Moreover, the concentrations of BCAAs did not differ significantly between 61 patients (19%) who received amino acid supplementation and those who did not ( Table S3 ). Associations of BCAAs with lipid profile The individual BCAAs were strongly correlated with each other and with lipid components ( Table 2) . TG was positively and significantly correlated with T-BCAA and Val. Moreover, HDL-C was negatively and significantly correlated with T-BCAA, Val, Ile, and Leu. Similarly, AIP, Lp(a), and Apo-A were negatively and significantly correlated with T-BCAA, Val, and Ile, but not with Leu. Serum cholesterol, LDL-C, and Apo-B did not show significant associations with T-BCAA or individual BCAAs. To further explore links between AIP and BCAAs, we divided the patients into AIP tertiles and compared the concentration of T-BCAA and individual BCAAs between the AIP tertiles. The high AIP tertile had significantly higher levels of T-BCAA, Val and Ile, but not Leu, compared to the low tertile ( Fig. 2 ). The association between BCAAs and atherogenic lipids was further investigated by multivariate linear regression analysis to determine variables independently associated with BCAAs ( Table 3 ). In a model including age, sex, DM, CVD, BMI, AIP and plasma insulin, higher AIP, higher plasma insulin and male sex emerged as independent predictors of plasma T-BCAA concentration, whereas age, DM and BMI were not significantly associated with T-BCAA. Associations of BCAA with glucose-related factors and inflammatory biomarkers As shown in Table 4 , blood glucose, plasma insulin and HOMA-IR were positively and significantly correlated with T-BCAA and Val, and HbA1c was inversely and significantly correlated with Leu. TNF-α correlated inversely with T-BCAA, Val, and Leu (Table 4). Other inflammatory markers such as WBC, hsCRP, IL-6, IL-10, IL-18, ICAM-1, VCAM-1, and 8-OHdG were not significantly correlated with the concentrations of BCAAs. BCAAs and mortality The associations of low and middle tertiles vs. high tertile of T-BCAA and individual BCAAs with cardiovascular and all-cause mortality were investigated using competing-risk regression analysis models, adjusted for age, sex, DM, CVD, eGFR, BMI, AIP, serum albumin and plasma insulin ( Fig 3 and Table S4) . The low T-BCAA tertile was associated with increased risk of cardiovascular mortality (sub-hazard ratio [sHR] 2.37, 95% confidence interval [CI], 1.08 - 5.21) and the low tertile of valine was associated with higher risk of both all-cause mortality (sHR 2.05, 95% CI 1.10–3.79) and cardiovascular mortality (sHR 2.46, 95% CI 1.15–5.26). Restricted cubic spline curve analysis showed that lower plasma concentrations of T-BCAA and Val, as continuous variables, were associated with increased 5-year all-cause and cardiovascular mortality risk ( Fig. 4 ). Discussion Our study provides several important insights into the complex relationship between BCAAs, atherogenic lipids and mortality risk in patients with advanced CKD. Their plasma concentrations of BCAAs, which were lower than in healthy individuals, were inversely associated with increased cardiovascular mortality, and lower Val concentration was associated with increased both all-cause and cardiovascular mortality risk. Finally, higher plasma BCAA levels were positively associated with TG and AIP, and inversely associated with HDL-C, Apo-A, and Lp(a). BCAAs in different CKD groups During CKD, abnormalities in BCAA metabolism occur due to the reduced kidney contribution to amino acid metabolism, compounded by declining kidney function and the accumulation of uremic toxins, which disrupt whole body nitrogen metabolism. Previous studies have demonstrated that patients with advanced CKD, including those undergoing hemodialysis (HD) or peritoneal dialysis, exhibit reduced levels of essential amino acids, including BCAAs 18 , 19 , 21 , 28 . In our study, BCAA levels were significantly lower in the CKD patients compared to a group of healthy individuals. The precise cause of lower BCAA levels in CKD remains unclear. It is plausible that the combination of impaired kidney amino acid metabolism, effects of uremic toxins, nutritional deficits, muscle wasting, metabolic stress, inflammation, and the process of adapting to kidney failure all contribute to the lower plasma amino acid concentrations. Our findings also revealed strong intercorrelations among plasma concentrations of BCAAs in CKD patients, consistent with findings by Ikeda et al. 28 in both HD patients and healthy older individuals and by Luo et al. 29 in patients with hypertension-attributed CKD. These observations support previous explanations that attributed the strong correlation among BCAAs to shared metabolic enzymes 30 . Furthermore, in CKD patients and in healthy controls, BCAA concentrations were significantly higher in males compared to females, consistent with previous findings in HD patients and healthy individuals 28 . The higher levels of BCAAs in males may be attributed to differences in muscle mass, hormone status, and body fat distribution, all of which affect amino acid metabolism differently between sexes. Many studies have reported a close association between elevated BCAA levels and the development of insulin resistance, DM, and hypertension 31 – 33 . However, the concentrations of BCAAs in CKD patients with DM or hypertension in our study did not significantly differ from those without these conditions. We did observe, however, significant associations between BCAA levels and both blood glucose and plasma insulin concentrations, suggesting a link between BCAAs and glucose regulation.. Although there was a trend towards a positive association with HbA1c, it did not reach statistical significance, except for leucine, which showed a significant association with HbA1c. This suggests that BCAAs may play a role in metabolic processes related to glucose and insulin regulation, although the precise nature of these relationships requires further investigation. Associations BCAAs with lipid profile A novel and intriguing finding in our study is the specific correlation between BCAA levels and lipid profiles. To our knowledge, this is the first study to examine the association between plasma BCAA concentrations and the circulating lipid profile in CKD patients. Although BCAA levels in our cohort were lower than those typically observed in healthy individuals, they were still positively associated with atherogenic lipids, as indicated by the Atherogenic Index of Plasma (AIP), a composite biomarker derived from the ratio of TG to HDL-C. Consistent with previous studies in non-kidney disease populations 5 – 8 , we found that BCAA concentrations were significantly positively correlated with TG and AIP, and negatively correlated with HDL-C, Apo-A, and Lp (a). Interestingly, no significant correlation was observed between BCAA levels and total cholesterol or LDL-C concentrations. BCAAs are crucial in protein synthesis and energy metabolism and have been shown to regulate both glucose and lipid metabolism 1 . The interaction between BCAAs and lipids involves complex metabolic pathways, where BCAAs influence enzymes and signalling pathways critical for lipid synthesis and breakdown 1 , 34 . Although BCAAs are primarily metabolized in skeletal muscle, their catabolism is linked to the production of acyl-CoA intermediates that can enter lipid synthesis pathways 35 , potentially leading to increased production of specific lipids. Low BCAA levels, as in CKD, may impair the regulation of these pathways, resulting in lipid accumulation in the bloodstream. Additionally, BCAAs may influence lipid transport by affecting lipoprotein levels, including those responsible for carrying cholesterol and triglycerides 36 . This interaction may contribute to dyslipidemia, further highlighting the complex role of BCAAs in lipid metabolism and cardiovascular risk. In CKD patients, the combination of dysregulated lipid metabolism and low BCAA levels may create a perfect storm for increased cardiovascular risk. This occurs through mechanisms including the promotion of atherogenesis, enhanced insulin resistance, chronic inflammation, oxidative stress, muscle wasting, and endothelial dysfunction 37 . Associations of BCAAs with glucose-related factors Many studies have reported a close association between elevated BCAA levels and the development of insulin resistance, DM, and hypertension 31 – 33 . However, in our study, BCAA concentrations in CKD patients with DM or hypertension did not significantly differ from those without these conditions. Insulin resistance is a common and early feature of kidney failure, regardless of diabetes status. In this study, we observed significant associations between BCAA levels and both blood glucose and plasma insulin concentrations, suggesting a potential link between BCAAs and glucose regulation. Moreover, the HOMA-IR was positively and significantly correlated with T-BCAA and valine concentrations. These findings imply that BCAAs may play a role in metabolic processes related to glucose and insulin regulation, although the precise nature of these relationships warrants further investigation. It is important to consider that the nature and direction of these associations may differ in individuals with CKD compared to those without. Notably, metabolomics work by Newgard et al. 11, 13, 14 reported strong associations between elevated circulating BCAA levels and the development of insulin resistance, type 2 diabetes mellitus, and related metabolic disorders. Their study demonstrated that a metabolic signature characterized by increased BCAAs and related metabolites was closely linked to insulin resistance and impaired glucose metabolism, suggesting a contributory role of BCAAs in the pathogenesis of metabolic disease. Further research is needed to elucidate the mechanisms through which BCAAs influence glucose homeostasis in CKD and to determine how these pathways may differ from those established in non-CKD populations. Associations of BCAAs with inflammatory markers Our study did not find significant associations between total or individual BCAAs and inflammatory markers such as CRP or IL-6. However, there was a significant negative association between TNF-α and total BCAAs, Val, and Ile, but not Leu. Inflammatory cytokines like TNF-α and IL-6 modulate BCAA metabolism and are key mediators of muscle protein breakdown, altering circulating amino acid levels, including BCAAs. TNF-α, in particular, promotes muscle protein catabolism via the ubiquitin-proteasome pathway, contributing to elevated BCAA levels and systemic metabolic disturbances 38 . TNF-α, IL-1β, and IL-6 are central pro-inflammatory cytokines that drive myofibrillar protein degradation, inhibit protein synthesis, and lead to muscle atrophy. TNF-α also stimulates reactive oxygen species (ROS) production via the mitochondrial electron transport chain, activating NF-κB, which further enhances the ubiquitin-proteasome system, accelerating muscle protein breakdown and atrophy 39 . TNF-α is produced by various cells, including macrophages, lymphocytes, and skeletal muscle cells, and contributes to local and systemic inflammation upon binding to its receptors 40 . In CKD patients and those on hemodialysis, persistent activation of innate and adaptive immunity results in "inflammaging," a state of chronic low-grade inflammation 41 , 42 . Simultaneously, BCAAs may exacerbate inflammation by directly activating NF-κB in inflammatory cells, leading to increased production of IL-6 and TNF-α 43 . Thus, TNF-α contributes to muscle wasting and altered amino acid levels, while BCAAs may further promote inflammation by enhancing cytokine production. BCAAs and mortality In our study, we observed that individuals in the low tertile of Val levels, compared to those in the high tertile, had an increased risk of cardiovascular and all-cause mortality. Additionally, lower levels of total BCAAs were linked to higher cardiovascular mortality risk but not to all-cause mortality risk. While in our study, no significant associations were found between Ile or Leu and neither cardiovascular nor all-cause mortality, a recent study by Luo et al. 29 reported that in hypertensive individuals with advanced non-diabetic CKD, higher levels of Val, Leu, and Ile were associated with reduced cardiovascular mortality, with higher levels of Leu and Ile, but not Val, also being linked to lower all-cause mortality. Previous studies in non-kidney disease populations have yielded inconsistent results. For instance, a meta-analysis by Teymoori et al. 44 , which included nine cohort studies and one case–control study, found no association between total or individual BCAAs and the risk of all-cause mortality. On the other hand, Fung et al. 45 demonstrated a U-shaped relationship between BCAA levels and mortality in older individuals with hypertension and/or diabetes mellitus, with both high and low BCAA levels being associated with increased mortality. In contrast, among individuals without these conditions 45 , higher BCAA levels were associated with improved survival. Moreover, the LURIC study 46 found that elevated BCAA levels in a Caucasian population were associated with a reduced long-term risk of both all-cause and cardiovascular mortality, with this relationship persisting regardless of obesity and/or diabetes status. The study by Deelen et al. 47 further supported these findings, showing that higher levels of Val and Ile were associated with decreased mortality. Moreover, in a recent study Li et al 48 reported that lower total BCAA levels were associated with increased all-cause mortality in patients with liver cirrhosis. Our study is so far the most comprehensive exploration of the relationship between BCAAs, lipid profiles, and mortality risk among individuals with advanced CKD, with a relatively large sample size, detailed phenotyping and inclusion of age- and sex-matched controls for comparative analysis of BCAA concentrations. Additionally, no patients were lost to follow-up. However, some limitations should be considered when interpreting our findings. First, as this is an observational study, causality cannot be established. Second, BCAAs were measured only at the study's outset. Third, unmeasured confounders may have influenced the results, despite our efforts to account for potential confounders such as age, sex, BMI, DM, CVD, eGFR, plasma insulin, atherogenic lipids, and inflammation. Finally, the lack of detailed dietary information for CKD patients that potentially may influence circulating BCAA levels limits our ability to fully account for dietary contributions. However, previous studies suggest that metabolic alterations in CKD often outweigh the effects of diet, indicating that the observed changes in BCAA levels are likely driven primarily by the disease itself. Summary and conclusion In patients with CKD stage 5, plasma concentrations of total and individual BCAAs were lower than in age- and sex matched healthy controls, lower in females than in males, and inversely correlated with TNF-α. Whereas higher levels of BCAAs were associated with an atherogenic lipid profile including higher AIP and glucose-related factors including HOMA-IR, competing risk regression analysis showed that lower levels of total BCAAs and valine were associated with increased cardiovascular mortality risk and lower plasma valine concentration was associated also with higher all-cause mortality risk. These results provide insights into the intricate relationships between BCAA levels, lipid profiles, glucose-related compounds, inflammatory markers, and mortality in CKD patients and underscore the role of BCAAs in modulating cardiovascular risk and mortality in the context of CKD. While our study highlights significant associations, it also raises questions about the causality and clinical implications of these findings, and the underlying mechanisms remain complex and warrant further investigation. Further research, particularly longitudinal studies and interventional trials is needed to clarify the role of BCAAs in CKD in relation to metabolic alterations, progression of underlying disease and patient outcomes. Understanding these relationships could potentially contribute to new therapeutic strategies aimed at improving the prognosis for CKD patients. Declarations Acknowledgements We thank all patients and healthy subjects who participated in present study, and those who carried out the extensive clinical and laboratory work at the clinical investigational unit and the Renal Laboratory at Department of Renal Medicine, Karolinska University Hospital Huddinge. Baxter Novum is the result of a grant from Baxter Healthcare to Karolinska Institutet. The study also benefited from support from Martin Rind Foundation, Heart and Lung Foundation, Njurfonden, and Westmans Foundation. Conflict of interest Bengt Lindholm has been affiliated with Baxter Healthcare Corporation. Peter Stenvinkel is or has been on scientific advisory boards of REATA, Baxter, GSK, Astra Zeneca, Invizius, Behring, and Vifor and educational advisory boards for Astellas and FMC. Other authors do not declare any conflict of interest. Credit Authorship Contribution Statement Mohamed E Suliman: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Visualization, and Writing – original draft, Writing - review & editing Abdul Rashid Qureshi: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Visualization, and Writing – original draft. Dario Troise: Formal analysis and Writing – original draft and review & editing Qianying Zhang: Formal analysis and Writing – original draft and review & editing Peter Barany: Patient recruitment, Investigation, Methodology, Writing - review & editing Olof Heimbürger: Patient recruitment, Investigation, Methodology, Writing - review & editing Peter Stenvinkel: Investigation, Methodology, Funding acquisition, Project administration, Resources, Writing - review & editing Bengt Lindholm: Conceptualization, Funding acquisition, Project administration, Resources, Supervision, and Writing – review & editing. All authors have read and approved the final manuscript. Data Availability : Data described in the manuscript, code book, and analytic code will be made available upon request pending application to the corresponding author. Supplementary Data: Supplementary data to this article can be found online at References Nie C, He T, Zhang W, Zhang G, Ma X. Branched Chain Amino Acids: Beyond Nutrition Metabolism. Int J Mol Sci 2018; 19 (4). e-pub ahead of print 20180323; doi: 10.3390/ijms19040954 Holecek M. Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements. Nutr Metab (Lond) 2018; 15: 33. e-pub ahead of print 20180503; doi: 10.1186/s12986-018-0271-1 Batch BC, Hyland K, Svetkey LP. Branch chain amino acids: biomarkers of health and disease. Curr Opin Clin Nutr Metab Care 2014; 17 (1) : 86-89. doi: 10.1097/MCO.0000000000000010 Gannon NP, Schnuck JK, Vaughan RA. BCAA metabolism and insulin sensitivity–dysregulated by metabolic status? Molecular nutrition & food research 2018; 62 (6) : 1700756. Yang P, Hu W, Fu Z, Sun L, Zhou Y, Gong Y et al. The positive association of branched-chain amino acids and metabolic dyslipidemia in Chinese Han population. Lipids Health Dis 2016; 15: 120. e-pub ahead of print 20160725; doi: 10.1186/s12944-016-0291-7 Hamaya R, Mora S, Lawler PR, Cook NR, Ridker PM, Buring JE et al. Association of Plasma Branched-Chain Amino Acid With Biomarkers of Inflammation and Lipid Metabolism in Women. Circ Genom Precis Med 2021; 14 (4) : e003330. e-pub ahead of print 20210715; doi: 10.1161/CIRCGEN.121.003330 Fukushima K, Harada S, Takeuchi A, Kurihara A, Iida M, Fukai K et al. Association between dyslipidemia and plasma levels of branched-chain amino acids in the Japanese population without diabetes mellitus. J Clin Lipidol 2019; 13 (6) : 932-939 e932. e-pub ahead of print 20190911; doi: 10.1016/j.jacl.2019.09.002 Wang FH, Liu J, Deng QJ, Qi Y, Wang M, Wang Y et al. Association between plasma essential amino acids and atherogenic lipid profile in a Chinese population: A cross-sectional study. Atherosclerosis 2019; 286: 7-13. e-pub ahead of print 20190425; doi: 10.1016/j.atherosclerosis.2019.04.225 Yamaguchi N, Mahbub MH, Takahashi H, Hase R, Ishimaru Y, Sunagawa H et al. Plasma free amino acid profiles evaluate risk of metabolic syndrome, diabetes, dyslipidemia, and hypertension in a large Asian population. Environ Health Prev Med 2017; 22 (1) : 35. e-pub ahead of print 20170407; doi: 10.1186/s12199-017-0642-7 Yamakado M, Nagao K, Imaizumi A, Tani M, Toda A, Tanaka T et al. Plasma Free Amino Acid Profiles Predict Four-Year Risk of Developing Diabetes, Metabolic Syndrome, Dyslipidemia, and Hypertension in Japanese Population. Sci Rep 2015; 5: 11918. e-pub ahead of print 20150709; doi: 10.1038/srep11918 Newgard CB. Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab 2012; 15 (5) : 606-614. doi: 10.1016/j.cmet.2012.01.024 Lu J, Xie G, Jia W, Jia W. Insulin resistance and the metabolism of branched-chain amino acids. Front Med 2013; 7 (1) : 53-59. e-pub ahead of print 20130206; doi: 10.1007/s11684-013-0255-5 Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 2009; 9 (4) : 311-326. doi: 10.1016/j.cmet.2009.02.002 White PJ, McGarrah RW, Herman MA, Bain JR, Shah SH, Newgard CB. Insulin action, type 2 diabetes, and branched-chain amino acids: a two-way street. Molecular metabolism 2021; 52: 101261. Wang Q, Holmes MV, Davey Smith G, Ala-Korpela M. Genetic Support for a Causal Role of Insulin Resistance on Circulating Branched-Chain Amino Acids and Inflammation. Diabetes Care 2017; 40 (12) : 1779-1786. e-pub ahead of print 20171018; doi: 10.2337/dc17-1642 Cano NJ, Fouque D, Leverve XM. Application of branched-chain amino acids in human pathological states: renal failure. J Nutr 2006; 136 (1 Suppl) : 299S-307S. doi: 10.1093/jn/136.1.299S Alvestrand A, Fürst P, Bergström J. Intracellular amino acids in uremia. Kidney international. Supplement 1983; 16: S9-16. Bergström J, Alvestrand A, Fürst P. Plasma and muscle free amino acids in maintenance hemodialysis patients without protein malnutrition. Kidney international 1990; 38 (1) : 108-114. Lindholm B, Alvestrand A, Fürst P, Bergström J. Plasma and muscle free amino acids during continuous ambulatory peritoneal dialysis. Kidney international 1989; 35 (5) : 1219-1226. Jones MR, Kopple JD. Valine metabolism in normal and chronically uremic man. Am J Clin Nutr 1978; 31 (9) : 1660-1664. doi: 10.1093/ajcn/31.9.1660 Qureshi AR, Alvestrand A, Danielsson A, Divino-Filho JC, Gutierrez A, Lindholm B et al. Factors predicting malnutrition in hemodialysis patients: a cross-sectional study. Kidney Int 1998; 53 (3) : 773-782. doi: 10.1046/j.1523-1755.1998.00812.x Kopple JD, Kalantar-Zadeh K, Mehrotra R. Risks of chronic metabolic acidosis in patients with chronic kidney disease. Kidney Int Suppl 2005; (95) : S21-27. doi: 10.1111/j.1523-1755.2005.09503.x Niroumand S, Khajedaluee M, Khadem-Rezaiyan M, Abrishami M, Juya M, Khodaee G et al. Atherogenic Index of Plasma (AIP): A marker of cardiovascular disease. Med J Islam Repub Iran 2015; 29: 240. e-pub ahead of print 20150725; Stenvinkel P, Heimburger O, Paultre F, Diczfalusy U, Wang T, Berglund L et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int 1999; 55 (5) : 1899-1911. doi: 10.1046/j.1523-1755.1999.00422.x Von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies. International journal of surgery 2014; 12 (12) : 1495-1499. Suliman ME, Anderstam B, Bergstrom J. Evidence of taurine depletion and accumulation of cysteinesulfinic acid in chronic dialysis patients. Kidney Int 1996; 50 (5) : 1713-1717. doi: 10.1038/ki.1996.490 Dobiasova M, Frohlich J. [The new atherogenic plasma index reflects the triglyceride and HDL-cholesterol ratio, the lipoprotein particle size and the cholesterol esterification rate: changes during lipanor therapy]. Vnitr Lek 2000; 46 (3) : 152-156. Ikeda H. Cross-correlation of plasma concentrations of branched-chain amino acids: A comparison between healthy participants and patients with chronic kidney disease. Clin Nutr ESPEN 2020; 38: 201-210. e-pub ahead of print 20200521; doi: 10.1016/j.clnesp.2020.04.014 Luo S, Surapaneni A, Rebholz CM, Appel LJ, Coresh J, Grams ME. Circulating Branched-Chain Amino Acids, Incident Cardiovascular Disease, and Mortality in the African American Study of Kidney Disease and Hypertension. Circ Genom Precis Med 2023; 16 (1) : e003729. e-pub ahead of print 20230130; doi: 10.1161/CIRCGEN.122.003729 Brosnan JT, Brosnan ME. Branched-chain amino acids: enzyme and substrate regulation. J Nutr 2006; 136 (1 Suppl) : 207S-211S. doi: 10.1093/jn/136.1.207S Cuomo P, Capparelli R, Iannelli A, Iannelli D. Role of Branched-Chain Amino Acid Metabolism in Type 2 Diabetes, Obesity, Cardiovascular Disease and Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2022; 23 (8). e-pub ahead of print 20220413; doi: 10.3390/ijms23084325 Alqudah A, Qnais E, Wedyan M, Awali A, Bseiso Y, Gammoh O. Amino acid profiles: exploring their diagnostic and pathophysiological significance in hypertension. Mol Biol Rep 2024; 51 (1) : 200. e-pub ahead of print 20240125; doi: 10.1007/s11033-023-09107-8 Bloomgarden Z. Diabetes and branched-chain amino acids: What is the link? J Diabetes 2018; 10 (5) : 350-352. e-pub ahead of print 20180213; doi: 10.1111/1753-0407.12645 Choi BH, Hyun S, Koo S-H. The role of BCAA metabolism in metabolic health and disease. Experimental & Molecular Medicine 2024 : 1-8. Zhang S, Zeng X, Ren M, Mao X, Qiao S. Novel metabolic and physiological functions of branched chain amino acids: a review. Journal of animal science and biotechnology 2017; 8: 1-12. Galli A, Arunagiri A, Dule N, Castagna M, Marciani P, Perego C. Cholesterol redistribution in pancreatic β-cells: a flexible path to regulate insulin secretion. Biomolecules 2023; 13 (2) : 224. Gai Z, Wang T, Visentin M, Kullak-Ublick GA, Fu X, Wang Z. Lipid Accumulation and Chronic Kidney Disease. Nutrients 2019; 11 (4). e-pub ahead of print 20190328; doi: 10.3390/nu11040722 Sandri M. Signaling in muscle atrophy and hypertrophy. Physiology 2008; 23 (3) : 160-170. Wang DT, Yin Y, Yang YJ, Lv PJ, Shi Y, Lu L et al. Resveratrol prevents TNF-alpha-induced muscle atrophy via regulation of Akt/mTOR/FoxO1 signaling in C2C12 myotubes. Int Immunopharmacol 2014; 19 (2) : 206-213. e-pub ahead of print 20140215; doi: 10.1016/j.intimp.2014.02.002 Zhou J, Liu B, Liang C, Li Y, Song YH. Cytokine Signaling in Skeletal Muscle Wasting. Trends Endocrinol Metab 2016; 27 (5) : 335-347. e-pub ahead of print 20160326; doi: 10.1016/j.tem.2016.03.002 Jofre R, Rodriguez-Benitez P, Lopez-Gomez JM, Perez-Garcia R. Inflammatory syndrome in patients on hemodialysis. J Am Soc Nephrol 2006; 17 (12 Suppl 3) : S274-280. doi: 10.1681/ASN.2006080926 Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of Cellular Senescence. Trends Cell Biol 2018; 28 (6) : 436-453. e-pub ahead of print 20180221; doi: 10.1016/j.tcb.2018.02.001 Zhenyukh O, Civantos E, Ruiz-Ortega M, Sanchez MS, Vazquez C, Peiro C et al. High concentration of branched-chain amino acids promotes oxidative stress, inflammation and migration of human peripheral blood mononuclear cells via mTORC1 activation. Free Radic Biol Med 2017; 104: 165-177. e-pub ahead of print 20170113; doi: 10.1016/j.freeradbiomed.2017.01.009 Teymoori F, Ahmadirad H, Jahromi MK, Mokhtari E, Farhadnejad H, Mohammadzadeh M et al. Serum branched amino acids and the risk of all-cause mortality: a meta-analysis and systematic review. Amino Acids 2023; 55 (11) : 1475-1486. e-pub ahead of print 20230919; doi: 10.1007/s00726-023-03329-7 Fung E, Ng KH, Kwok T, Lui L-T, Palaniswamy S, Chan Q et al. Divergent Survival Outcomes Associated with Elevated Branched-Chain Amino Acid Levels among Older Adults with or without Hypertension and Diabetes: A Validated, Prospective, Longitudinal Follow-Up Study. Biomolecules 2023; 13 (8) : 1252. Moissl AP, Lorkowski S, Meinitzer A, Pilz S, Scharnagl H, Delgado GE et al. Association of branched-chain amino acids with mortality-the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. iScience 2023; 26 (4) : 106459. e-pub ahead of print 20230321; doi: 10.1016/j.isci.2023.106459 Deelen J, Kettunen J, Fischer K, van der Spek A, Trompet S, Kastenmuller G et al. A metabolic profile of all-cause mortality risk identified in an observational study of 44,168 individuals. Nat Commun 2019; 10 (1) : 3346. e-pub ahead of print 20190820; doi: 10.1038/s41467-019-11311-9 Li Y, Chvatal-Medina M, Trillos-Almanza MC, Connelly MA, Moshage H, Bakker SJL et al. Branched-chain amino acids and all-cause mortality in patients with liver cirrhosis, and the onset of diabetes in liver transplant recipients. Eur J Clin Invest 2025 : e70096. e-pub ahead of print 20250710; doi: 10.1111/eci.70096 Tables Table 1 . Baseline characteristics of all CKD stage 5 patients and when divided into tertiles based on plasma concentration of total branched-chain amino acids (BCAAs). Patient characteristics Total BCAAs First tertile BCAAs Middle tertile BCAAs Third tertile P-value Number 328 108 109 111 Age, years 54 (43 – 63) 56 (47-63) 53 (44-63.) 52 (42-64) 0.67 Males, n (%) 198 (60%) 49 (45%) 69 (63%) 80 (72%) <0.001 DM, n (%) 104 (32%) 32 (30%) 37 (34%) 35 (32%) 0.79 CVD, n (%) 111 (34%) 38 (35%) 36 (33%) 37 (33%) 0.94 BMI, kg/m 2 24 (22- 27) 24 (22-27) 24 (22-28) 24 (22-28) 0.74 eGFR, ml/min/1.73m 2 6.4 (5.0-8.2) 6.3 (5.0-8.2) 6.6 (5.1-7.9) 6.5 (5.0-8.7) 0.60 CRP, mg/L 5.0 (2.0-15.0) 4.0 (1.6-15.0) 4.8 (2.0-15.0) 5.7 (2.6-14.0) 0.71 Glucose-related parameters HbA1c, % 5.1 (4.5 – 6.1) 5.0 (4.4-5.8) 5.1 (4.4-6.4) 5.1 (4.6-6.2) 0.83 Blood glucose, mmol/L 5.4 (4.8-6.6) 5.3 (4.7-5.9) 5.3 (4.8-7.4) 5.5 (5.0-7.3) 0.08 Plasma insulin, mU/L 16 (11 – 29) 14 (11-22) 16 (10-27) 18 (11-29) 0.20 HOMA-IR 3.9 (2.5-7.1) 3.3 (2.4-5.4) 4.7 (2.4-7.9) 4.4 (2.9-9.1) 0.02 Plasma lipid profile Triglycerides, mmol/L 1.9 (1.3-2.5) 1.8 (1.2-2.3) 1.9 (1.4-2.5) 2.0 (1.4-2.9) 0.23 Total cholesterol, mmol/L 5.2 (4.4-6.3) 5.5 (4.5-6.5) 5.3 (4.4-6.4) 4.9 (4.1-6.2) 0.21 HDL-C, mmol/L 1.2 (0.9-1.5) 1.4 (1.0-1.9) 1.1 (0.9-1.4) 1.1 (0.8-1.4) <0.001 LDL-C, mmol/L 3.1 (2.2-4.0) 3.0 (2.2-4.0) 3.2 (2.3-4.2) 2.9 (2.0-4.0) 0.31 AIP, ratio 0.4 (0.0-1.0) 0.2 (-0.2-0.7) 0.5 (0.0-1.0) 0.5 (0.1-1.2) 0.003 Lipoprotein(a), nmol/L 213 (91-499) 212 (85-596) 271 (113-562) 180 (64-381) 0.02 Apolipoprotein-A, g/L 1.3 (1.1-1.5) 1.4 (1.2-1.6) 1.2 (1.1-1.4) 1.2 (1.0-1.4) <0.001 Apolipoprotein-B, g/L 1.0 (0.8-1.3) 1.1 (0.8-1.2) 1.1 (0.8-1.3) 1.0 (0.8-1.3) 0.60 Plasma BCAAs Total BCAAs , mmol/L 281 (232-329) 219 (191-232) 281 (263-291) 356 (328-397) <0.001 Valine , mmol/L 152 (126 – 179) 112 (96-129) 152 (140-163) 195 (174-231) <0.001 Isoleucine , mmol/L 56 (43-68) 41 (35-50) 57 (49-65) 69 (58-85) <0.001 Leucine , mmol/L 67 (54-84) 54 (46-62) 72 (58-81) 88 (68-108) <0.001 Data presented as median (IQR, interquartile range). Abbreviations: DM, diabetes mellitus; CVD, cardiovascular disease; BMI, body mass index; eGFR, estimated glomerular filtration rate; CRP, C-reactive protein; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; AIP, atherogenic index of plasma; BCAAs, branched-chain amino acids. Table 2 . Spearman rank correlation matrix of branched chain amino acids and lipid profile in 328 CKD stage 5 patients. BCAAs Val Ile Leu TG HDL AIP Chol LDL Lp(a) Apo-A Val 0.93 d Ile 0.73 d 0.59 d Leu 0.63 d 0.40 d 0.29 d TG 0.13 a 0.15 b 0.08 0.02 HDL -0.26 d -0.24 d -0.24 d -0.15 b -0.45 d AIP 0.22 c 0.22 c 0.17 b 0.10 0.89 d -0.79 d Chol -0.08 -0.05 -0.05 -0.10 0.41 d 0.11 0.22 c LDL -0.02 -0.01 0.02 -0.05 0.29 d -0.09 0.23 c 0.91 d Lp(a) -0.12 a -0.13 a -0.10 -0.05 -0.08 0.15 b -0.13 a 0.12 a 0.11 Apo-A -0.23 c -0.24 d -0.21 c -0.07 -0.25 d 0.75 d -0.53 d 0.26 d 0.09 0.12 a Apo-B 0.02 0.01 0.04 -0.02 0.46 d -0.18 b 0.39 d 0.84 d 0.87 d 0.12 a 0.08 Significance levels: a<0.05, b<0.01, c<0.001 and d<0.0001. Abbreviations: BCAAs, branched-chain amino acids; Val, valine; Ile, isoleucine; Leu, leucine; TG, triglycerides; HDL, high-density lipoprotein-cholesterol; AIP, atherogenic index of plasma; Chol, cholesterol; LDL, low-density lipoprotein-cholesterol; Lp(a), lipoprotein (a); Apo-A, Apolipoprotein A; Apo-B, Apolipoprotein B. Table 3. Predictors of 1-standard deviation (SD) increase of plasma concentrations of total (T-BCAAs) and individual branched-chain amino acids in 328 CKD 5 patients. T-BCAAs Valine Isoleucine Leucine Beta P-value Beta P-value Beta P-value Beta P-value 1-SD of age, years -0.012 ns -0.007 ns -0.019 ns -0.008 ns Sex, F vs. M -0.258 0.0001 -0.215 0.0001 -0.253 0.0001 0.163 0.004 Presence of DM 0.021 ns -0.020 ns 0.010 ns 0.090 ns Presence of CVD -0.067 ns -0.075 ns -0.102 ns 0.189 ns 1-SD of BMI 0.050 ns 0.041 ns 0.003 ns 0.070 ns 1-SD of AIP 0.153 0.006 0.177 0.002 0.120 0.03 0.031 ns 1-SD of plasma insulin 0.127 0.02 0.099 0.07 0.097 0.07 0.113 0.04 Multivariate linear regression analysis with stepwise backward selection of variables. The model including sex, age, diabetes mellitus (DM), cardiovascular disease (CVD), body mass index (BMI), plasma insulin and atherogenic index of plasma (AIP). AIP is a ratio of the log of TG to HDL-C. ns= non-significant. Table 4. Correlation between plasma concentrations of total (T-BCAA) and individual BCAAs with glucose-related parameters, estimated glomerular filtration rate (eGFR) and tumor necrosis factor-α (TNF-α) in 328 CKD 5 patients. T-BCAA Val Ile Leu HbA1c 0.10 0.06 0.03 0.17 *** Glucose 0.12 * 0.12 * 0.06 0.06 Insulin 0.12 * 0.14 ** 0.06 0.02 HOMA-IR 0.17 ** 0.20 *** 0.10 0.05 eGFR 0.15 ** 0.18 *** 0.08 0.02 TNF-α -0.15 ** -0.14 ** -0.18 *** 0.01 Additional Declarations Competing interest reported. Bengt Lindholm has been affiliated with Baxter Healthcare Corporation. Peter Stenvinkel is or has been on scientific advisory boards of REATA, Baxter, GSK, Astra Zeneca, Invizius, Behring, and Vifor and educational advisory boards for Astellas and FMC. Other authors do not declare any conflict of interest. Supplementary Files Supplementarymaterial.docx Cite Share Download PDF Status: Published Journal Publication published 08 Mar, 2026 Read the published version in Amino Acids → Version 1 posted Editorial decision: Revision requested 04 Dec, 2025 Reviews received at journal 03 Dec, 2025 Reviews received at journal 01 Dec, 2025 Reviewers agreed at journal 17 Nov, 2025 Reviewers agreed at journal 08 Nov, 2025 Reviewers invited by journal 05 Nov, 2025 Editor assigned by journal 14 Oct, 2025 Submission checks completed at journal 14 Oct, 2025 First submitted to journal 13 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7849136","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":545783415,"identity":"5a9de608-dcc7-4c4b-8d04-38b36901d02e","order_by":0,"name":"Mohamed E Suliman","email":"","orcid":"","institution":"Karolinska University Hospital Huddinge, Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Mohamed","middleName":"E","lastName":"Suliman","suffix":""},{"id":545783416,"identity":"4a8d056f-805a-4627-a39a-6c9f9c02db8f","order_by":1,"name":"Abdul Rashid Qureshi","email":"","orcid":"","institution":"Karolinska University Hospital Huddinge, Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Abdul","middleName":"Rashid","lastName":"Qureshi","suffix":""},{"id":545783417,"identity":"53694f83-e72e-4800-b6c4-1d15f9288dd8","order_by":2,"name":"Dario Troise","email":"","orcid":"","institution":"Karolinska University Hospital Huddinge, Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Dario","middleName":"","lastName":"Troise","suffix":""},{"id":545783418,"identity":"eb0dacf2-2774-43d7-b650-9b1acf12a1f2","order_by":3,"name":"Qianying Zhang","email":"","orcid":"","institution":"Karolinska University Hospital Huddinge, Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Qianying","middleName":"","lastName":"Zhang","suffix":""},{"id":545783419,"identity":"2e5ee5ff-4218-42d6-adbe-06a7e9d22a04","order_by":4,"name":"Peter Bárány","email":"","orcid":"","institution":"Karolinska University Hospital Huddinge, Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"","lastName":"Bárány","suffix":""},{"id":545783420,"identity":"9e3b5edb-23f5-4405-9fc9-9df1c4036be9","order_by":5,"name":"Olof Heimbürger","email":"","orcid":"","institution":"Karolinska University Hospital Huddinge, Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Olof","middleName":"","lastName":"Heimbürger","suffix":""},{"id":545783421,"identity":"5880980e-89ce-4f9f-b81f-20ccbd0fb0e2","order_by":6,"name":"Peter Stenvinkel","email":"","orcid":"","institution":"Karolinska University Hospital Huddinge, Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"","lastName":"Stenvinkel","suffix":""},{"id":545783422,"identity":"02f0b75b-0712-4ec4-a222-787ffb8b8760","order_by":7,"name":"Bengt Lindholm","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2UlEQVRIie2QMQrCMBiFHwjJUpw7eIiUQKpQ9CpKoVPce4Mu9QzeonOlg0vRVXAwnRwUqZujKXWwS9pRMN+SDP+X/70AFssPwtpj6gASUAgYGaTkcFtliWi4go9SsN5gPt0UtxruxKfrnVrJIx+DVsqkzNJDNG2CzdJHyFbZWRA43LiKnaRgjdJcXK0EWiGuUbncO8pBK/T6Mm9xuPpSch0MwmToLlKgZFop71x3CTkZOdwYzKclr+M4WLC99NQzm3vbJKlq4xpAl+380Khnvhnpe9NisVj+nTem/EPHvj6q9AAAAABJRU5ErkJggg==","orcid":"","institution":"Karolinska University Hospital Huddinge, Karolinska Institutet","correspondingAuthor":true,"prefix":"","firstName":"Bengt","middleName":"","lastName":"Lindholm","suffix":""}],"badges":[],"createdAt":"2025-10-13 12:38:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7849136/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7849136/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00726-026-03511-7","type":"published","date":"2026-03-08T15:59:22+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":96156896,"identity":"b52eebd8-3413-46ff-8ca0-65ee110e8fc9","added_by":"auto","created_at":"2025-11-18 08:31:23","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1007026,"visible":true,"origin":"","legend":"","description":"","filename":"BCAAsmanuscript251013.docx","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/c0019be273d858c08fc9247b.docx"},{"id":96156898,"identity":"dbe3a4f4-a856-46e0-942d-60f068b6e98a","added_by":"auto","created_at":"2025-11-18 08:31:23","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10801,"visible":true,"origin":"","legend":"","description":"","filename":"76ed75329eb0407fbb94b67cffc9cb38.json","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/03515b67bba0571292b0f40a.json"},{"id":96156901,"identity":"bf452801-183c-4122-be4f-1fe55af3db87","added_by":"auto","created_at":"2025-11-18 08:31:23","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":190347,"visible":true,"origin":"","legend":"","description":"","filename":"76ed75329eb0407fbb94b67cffc9cb381enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/ddc5ea6fe1781cde77a28481.xml"},{"id":96251693,"identity":"013ab2bb-a065-47ed-84eb-95befa77d230","added_by":"auto","created_at":"2025-11-19 07:39:55","extension":"eps","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":190312,"visible":true,"origin":"","legend":"","description":"","filename":"drawingimage4.eps","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/df29ea6cce36e8e466c8cd43.eps"},{"id":96251647,"identity":"8947702a-ea86-4bc0-bc31-0d4d152f76e8","added_by":"auto","created_at":"2025-11-19 07:39:52","extension":"emf","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":16600,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.emf","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/dc9c918c9f575bd5b577bd62.emf"},{"id":96156905,"identity":"0b3d8ae0-3903-435b-bffa-ae5634abb503","added_by":"auto","created_at":"2025-11-18 08:31:23","extension":"jpeg","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":167784,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage10.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/616c47c3a495f43f477e2975.jpeg"},{"id":96156906,"identity":"84fb26f1-2105-4121-b34b-ac863c3021c3","added_by":"auto","created_at":"2025-11-18 08:31:23","extension":"jpeg","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":34845,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage11.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/f9dc2c58a0d9bb40fc894ff5.jpeg"},{"id":96249324,"identity":"8e5a80f1-235e-42d7-bfd9-3ea90c19c1fb","added_by":"auto","created_at":"2025-11-19 07:32:59","extension":"jpeg","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":30321,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage12.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/87b77e8c22cb73efce93e6e3.jpeg"},{"id":96249918,"identity":"4abb5dfd-068f-4766-9d70-3ad2127c15e1","added_by":"auto","created_at":"2025-11-19 07:36:46","extension":"jpeg","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2286,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage13.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/afa013b9b3df1e862348d4d5.jpeg"},{"id":96251881,"identity":"76c4686f-6884-44e9-9f6f-3a189eff6c3f","added_by":"auto","created_at":"2025-11-19 07:40:09","extension":"jpeg","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1074,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage14.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/df67d660b3da9f0e77b6e358.jpeg"},{"id":96249559,"identity":"83703795-873b-4838-8a5b-5d7913834ae1","added_by":"auto","created_at":"2025-11-19 07:34:16","extension":"wmf","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":97250,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.wmf","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/c5e5f6bbd6c6f2cfba418fc1.wmf"},{"id":96250781,"identity":"db96748a-53bf-4a50-93f5-03262e6a05c3","added_by":"auto","created_at":"2025-11-19 07:38:59","extension":"wmf","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":335762,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.wmf","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/8636f6fd0ed134bbc59f5585.wmf"},{"id":96156907,"identity":"912c7542-20b0-4298-9e1e-67cfd41837dd","added_by":"auto","created_at":"2025-11-18 08:31:23","extension":"jpeg","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1074,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage14.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/88a58b6cae1c46d0dd73ed13.jpeg"},{"id":96156910,"identity":"eb790131-dd55-40d2-bedc-7199da5ec2ec","added_by":"auto","created_at":"2025-11-18 08:31:23","extension":"jpeg","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":199885,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/7907a0e95740c90d19fa3316.jpeg"},{"id":96156916,"identity":"cd12e3de-a778-4a86-a42d-cb60cc8386b6","added_by":"auto","created_at":"2025-11-18 08:31:23","extension":"jpeg","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":146306,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage6.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/0334d4bce76d4c1e54c04d52.jpeg"},{"id":96251935,"identity":"3222e8cc-0872-42d8-b024-ccf302a1fe64","added_by":"auto","created_at":"2025-11-19 07:40:11","extension":"jpeg","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":257917,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage7.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/04b9613b55fa275cdf0b97bc.jpeg"},{"id":96156918,"identity":"a7c13f6e-09d7-4194-838c-d9debe12cb38","added_by":"auto","created_at":"2025-11-18 08:31:23","extension":"jpeg","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":262999,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage8.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/05f3b17166a797a45bfd7018.jpeg"},{"id":96156914,"identity":"bbafadd9-0dcf-4da7-92bf-2d77893d88ae","added_by":"auto","created_at":"2025-11-18 08:31:23","extension":"jpeg","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":35459,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage9.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/2357c97e0483038cfba5ce65.jpeg"},{"id":96156912,"identity":"72b21b97-6cc5-4455-8a77-0597d20ad036","added_by":"auto","created_at":"2025-11-18 08:31:23","extension":"jpeg","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":59956,"visible":true,"origin":"","legend":"","description":"","filename":"groupimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/a9abadd56d7439755062ab51.jpeg"},{"id":96249340,"identity":"ef238aad-8f8d-4568-a031-7d02873394f0","added_by":"auto","created_at":"2025-11-19 07:33:05","extension":"jpeg","order_by":22,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":43632,"visible":true,"origin":"","legend":"","description":"","filename":"groupimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/874ca7c633372d04fee8f936.jpeg"},{"id":96249554,"identity":"14a9e03b-041e-4a29-aaf8-65d90397a646","added_by":"auto","created_at":"2025-11-19 07:33:57","extension":"jpeg","order_by":23,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":39753,"visible":true,"origin":"","legend":"","description":"","filename":"groupimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/5c8c3e0899c1bbe1644b3bf6.jpeg"},{"id":96249569,"identity":"6e03fee4-ca08-4f9d-bcc1-9da0cc240dd6","added_by":"auto","created_at":"2025-11-19 07:34:24","extension":"wmf","order_by":24,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":97250,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.wmf","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/644b9fc11a41b4c4bf4a4c60.wmf"},{"id":96156922,"identity":"89924411-e746-4940-bce8-01e6ffa5d3ec","added_by":"auto","created_at":"2025-11-18 08:31:24","extension":"wmf","order_by":25,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":335762,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.wmf","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/d862cb53d07ecf0f4e4cd9e5.wmf"},{"id":96156924,"identity":"c566fb49-6200-4532-9c6c-2bcd175b6920","added_by":"auto","created_at":"2025-11-18 08:31:24","extension":"png","order_by":26,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":36800,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/fbe21527f170d38c565ca9ae.png"},{"id":96156919,"identity":"cbc28ced-a8e0-4edd-8460-c7aa90c37e19","added_by":"auto","created_at":"2025-11-18 08:31:23","extension":"png","order_by":27,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":34731,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage10.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/69f5dc283200bdf1362a470b.png"},{"id":96251998,"identity":"6da60b09-bc2d-4ee2-a760-c4b5ff1f7403","added_by":"auto","created_at":"2025-11-19 07:40:18","extension":"png","order_by":28,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6650,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage11.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/64703e95121ba5fc831c4d30.png"},{"id":96251719,"identity":"8722f560-2797-4936-98dc-34ff5637cfd0","added_by":"auto","created_at":"2025-11-19 07:39:58","extension":"png","order_by":29,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6644,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage12.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/592b1121f38289c95d582aa1.png"},{"id":96156935,"identity":"5acd12a9-11a7-4e06-864e-5d53985e91b5","added_by":"auto","created_at":"2025-11-18 08:31:24","extension":"png","order_by":30,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1021,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage13.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/35498fb966f82868560e63a0.png"},{"id":96250763,"identity":"8cb2320e-c8b7-44b7-9255-641b106b8385","added_by":"auto","created_at":"2025-11-19 07:38:57","extension":"png","order_by":31,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":935,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage14.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/e48bfc70770d3c82c11bd281.png"},{"id":96156939,"identity":"865dceda-4008-4db6-bb3a-3689d907c950","added_by":"auto","created_at":"2025-11-18 08:31:24","extension":"png","order_by":32,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":18718,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/a436d7ac3309443bfd21db07.png"},{"id":96156925,"identity":"713a88eb-9b81-4e5e-8e73-6d60663c15ad","added_by":"auto","created_at":"2025-11-18 08:31:24","extension":"png","order_by":33,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":22264,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/f508fc799a4ebd331d97364e.png"},{"id":96252002,"identity":"72ea9482-b4e9-4b93-a9a6-6c3eb5fa9977","added_by":"auto","created_at":"2025-11-19 07:40:18","extension":"png","order_by":34,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":935,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage14.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/6b20f2ecf631ce63d0f1b050.png"},{"id":96250882,"identity":"baf0ec71-41d8-444f-bf00-00d821fd9fd3","added_by":"auto","created_at":"2025-11-19 07:39:05","extension":"png","order_by":35,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":28322,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/76f5a5d056b612f545e6407e.png"},{"id":96156942,"identity":"94d76df1-0db6-4ceb-8d53-17aff4f3826e","added_by":"auto","created_at":"2025-11-18 08:31:24","extension":"png","order_by":36,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":27133,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/64a2f1f1ef02253d9e062392.png"},{"id":96250672,"identity":"a5188d1e-b2a9-4142-97f7-dbf8cf5996cc","added_by":"auto","created_at":"2025-11-19 07:38:50","extension":"png","order_by":37,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":54178,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/a94b4e0a571cd33dfc1b27fd.png"},{"id":96156937,"identity":"f8de02a4-0a69-49b8-a8f8-8d760d080745","added_by":"auto","created_at":"2025-11-18 08:31:24","extension":"png","order_by":38,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":49330,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/6c4808c657c75c3e058febfa.png"},{"id":96156933,"identity":"249e8763-abc8-423e-a6b8-d9aa39335b64","added_by":"auto","created_at":"2025-11-18 08:31:24","extension":"png","order_by":39,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":7133,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage9.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/4ca4e6c96e49fee0d7256b57.png"},{"id":96251025,"identity":"6280c922-735f-4518-bcde-f2ffe97e2f45","added_by":"auto","created_at":"2025-11-19 07:39:14","extension":"png","order_by":40,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":15387,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinegroupimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/c3d39762c7aa9d6a18967ba8.png"},{"id":96249236,"identity":"ff28ae7f-6875-48b9-a9fd-129b74ad26ce","added_by":"auto","created_at":"2025-11-19 07:30:56","extension":"png","order_by":41,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10522,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinegroupimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/e669da597f6f0554f9ea9dfe.png"},{"id":96249647,"identity":"9f7639ca-d699-4ee3-aad6-f4f6f4fa5f19","added_by":"auto","created_at":"2025-11-19 07:35:52","extension":"png","order_by":42,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":7545,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinegroupimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/4ee35716893848bb0206b6db.png"},{"id":96156941,"identity":"200778d9-aca7-4e30-879c-935ffa1a88f5","added_by":"auto","created_at":"2025-11-18 08:31:24","extension":"png","order_by":43,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":18718,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/4251cfb010192f5851a3c6f3.png"},{"id":96156928,"identity":"de1adc8e-f77b-4285-84d1-ce2a524947ce","added_by":"auto","created_at":"2025-11-18 08:31:24","extension":"png","order_by":44,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":22264,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/4bd936a3d9d92d9daef68e56.png"},{"id":96156943,"identity":"479c4b01-4cea-40b5-a396-e2a024ed4950","added_by":"auto","created_at":"2025-11-18 08:31:24","extension":"xml","order_by":45,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":187012,"visible":true,"origin":"","legend":"","description":"","filename":"76ed75329eb0407fbb94b67cffc9cb381structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/85c3d678d6aa13330a90982a.xml"},{"id":96156932,"identity":"b0a54ef1-d2d4-4de3-88d3-bc99bf29101a","added_by":"auto","created_at":"2025-11-18 08:31:24","extension":"html","order_by":46,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":202133,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/1f0e12603c23f389f29f267e.html"},{"id":96156894,"identity":"6c4533c6-c57b-46e8-8eaa-0f2c60ed3414","added_by":"auto","created_at":"2025-11-18 08:31:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":19408,"visible":true,"origin":"","legend":"\u003cp\u003eBox plots of plasma concentrations (mmol/L) of total branched-chain amino acids in 44 healthy subjects (HS) and 328 patients with CKD stage 5.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/8a286f219dac2a7d781f723b.png"},{"id":96156895,"identity":"36180713-ab7b-4b58-befc-4b86ac1cb6e6","added_by":"auto","created_at":"2025-11-18 08:31:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":33861,"visible":true,"origin":"","legend":"\u003cp\u003eBox plots of the concentrations (mmol/L) of individual (valine, Val; isoleucine, Ile; leucine, Leu) and total branched-chain amino acids (BCAA) for each tertile of atherogenic index of plasma (AIP) of 328 CKD stage 5 patients. The median (interquartile range) AIP ratio for the low, middle and high tertiles were -0.262 (-0.642-0.000), 0.379 (0.223-0.565) and 1.220 (0.963-1.584), respectively.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/9fba45e0875efe6247a90a6c.png"},{"id":96249910,"identity":"38ac984f-0e5c-4ea8-b0b8-6ae62960a829","added_by":"auto","created_at":"2025-11-19 07:36:44","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":58519,"visible":true,"origin":"","legend":"\u003cp\u003eCompeting-risk regression analysis models for cardiovascular and all-cause mortality risk based on tertiles of total BCAA, valine (Val), leucine (Leu) and isoleucine (Ile), respectively, among 328 CKD stage 5 patients during a follow-up period of up to five years. Values are estimated sub-hazard ratio (sHR) with 95% confidence interval. The high tertile served as the reference group. Each model was adjusted for age, sex, diabetes mellitus, cardiovascular diseases, estimated glomerular filtration rate, body mass index, serum albumin, atherogenic index of plasma (AIP) and plasma insulin.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/9c1c3f0fc22d5745f92111c5.png"},{"id":96156904,"identity":"dfd63a28-d0ae-4c2d-afb1-4b6f34720381","added_by":"auto","created_at":"2025-11-18 08:31:23","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":86612,"visible":true,"origin":"","legend":"\u003cp\u003eRestricted cubic spline curves showing the relationship between baseline plasma concentrations (mmol/L) of total branched chain amino acids (BCAA) (\u003cstrong\u003eA1\u003c/strong\u003eand \u003cstrong\u003eA2\u003c/strong\u003e) and valine (\u003cstrong\u003eB1\u003c/strong\u003e and \u003cstrong\u003eB2\u003c/strong\u003e), as continuous variables, and the subsequent 5-year all-cause and cardiovascular mortality risk, expressed as HRs and 95% CI, in 326 CKD stage 5 patients.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/78874729b4e2de2d8c7a054d.png"},{"id":104250924,"identity":"3abf9594-8fa0-4dc5-9b8c-cba8bdd00bd2","added_by":"auto","created_at":"2026-03-09 16:11:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1496939,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/26c1a329-a955-49ea-a305-f241410c1f86.pdf"},{"id":96251668,"identity":"80a357bc-3949-4fc1-8c71-45bb4764ccce","added_by":"auto","created_at":"2025-11-19 07:39:53","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":197001,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-7849136/v1/3975ff599bd5aade4a30f6d6.docx"}],"financialInterests":"Competing interest reported. Bengt Lindholm has been affiliated with Baxter Healthcare Corporation. Peter Stenvinkel is or has been on scientific advisory boards of REATA, Baxter, GSK, Astra Zeneca, Invizius, Behring, and Vifor and educational advisory boards for Astellas and FMC. Other authors do not declare any conflict of interest.","formattedTitle":"Plasma branched-chain amino acids in chronic kidney disease: Associations with atherogenic lipids and mortality","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBranched-chain amino acids (BCAAs), which include leucine (Leu), isoleucine (Ile), and valine (Val), are essential amino acids that play a crucial role in muscle protein synthesis and energy production. Beyond serving as substrates for protein synthesis, BCAAs act as signaling molecules, stimulating protein synthesis and regulating glucose and lipid metabolism, neurotransmitter and hormone synthesis, and mitochondrial biogenesis, and they have key roles for intestinal health and immunity \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eOn the other hand, high plasma BCAAs concentrations are closely associated with presence and severity of cardiometabolic alterations such as insulin resistance, metabolic syndrome, diabetes mellitus (DM), and obesity, as well as cardiovascular disease (CVD) \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Adipose tissue, a dynamic organ essential for glucose and lipid metabolism, also influences BCAA balance through nutrient storage and lipolysis \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Moreover, associations between BCAAs and metabolic dyslipidemia have been reported and several studies have explored the connections between BCAAs and the lipid profile \u003csup\u003e\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Indeed, recent studies in the general population show that high levels of BCAAs are associated with elevated triglycerides (TG) and reduced high density lipoprotein-cholesterol (HDL-C) levels \u003csup\u003e\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Whereas the connection between BCAAs and the lipid profile is not completely clear, it has been suggested that it is partially mediated by insulin resistance, a common feature in individuals with elevated BCAAs levels, which associates with increased lipolysis and reduced clearance of circulating lipids, contributing to dyslipidemia \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. The finding of a significant association between BCAAs and insulin resistance suggests that BCAAs may play a major role in the modulation of insulin action \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Circulating levels of the BCAAs are significantly higher in obese individuals compared to lean ones \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e and BCAAs have been established as some of the most robust biomarkers for a range of cardiometabolic conditions, including obesity, insulin resistance, type 2 DM, and CVD \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Furthermore, genetic variants linked to dyslipidemia and insulin resistance have been associated with increased concentrations of circulating BCAAs, suggesting that obesity and insulin resistance may drive the obesity-related rise in BCAAs \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eChronic kidney disease (CKD) patients often exhibit insulin resistance and dyslipidemia, along with disturbances in amino acid metabolism, particularly involving BCAAs \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Patients with advanced CKD show decreased levels of plasma and intracellular BCAAs \u003csup\u003e\u003cspan additionalcitationids=\"CR17 CR18 CR19 CR20\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e, likely due to impaired kidney amino acid metabolism and metabolic changes such as acidosis, and malnutrition \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e and often present with elevated levels of TG and low-density lipoprotein cholesterol (LDL-C), decreased HDL-C levels, and altered lipoprotein composition.\u003c/p\u003e\u003cp\u003eWhereas links between BCAAs and lipoproteins have been reported in the general population, the existence of such a linkage in CKD patients has to the best of our knowledge not yet been explored. Therefore, in the present study, we evaluated associations between plasma BCAA concentrations and serum cholesterol, TG, HDL-C, and LDL-C, and estimated the risk of atherogenic dyslipidemia in relation to plasma BCAA levels, in patients with advanced CKD. We used the atherogenic index of plasma (AIP), reflecting the TG to HDL-C ratio, as a biomarker for atherogenic dyslipidemia \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. By considering two atherogenic lipid parameters, AIP provides insights into an individual's risk of atherosclerosis.\u003c/p\u003e\u003cp\u003eWhile high plasma concentrations of BCAAs may be linked to cardiometabolic diseases, low circulating levels of essential nutrients such as BCAAs could potentially have a negative effect on survival. However, the association between BCAAs and mortality risk in CKD remains unclear and has not been conclusively determined. Therefore, we investigated these associations to gain a better understanding of possible links between plasma BCAA concentrations, atherogenic lipids, and clinical outcomes in CKD patients.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy populations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a \u003cem\u003epost hoc\u003c/em\u003e analysis of a cross-sectional study with follow-up data of mortality in a cohort of patients with CKD stage 5 \u003csup\u003e24\u003c/sup\u003e (\u003cstrong\u003eFigure S1)\u003c/strong\u003e. The study conformed to and was conducted in accordance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines\u0026nbsp;\u003csup\u003e25\u003c/sup\u003e. The patients, who were recruited between December 1994 and April 2014, were investigated close to the start of dialysis treatment and were followed for up to five years. Exclusion criteria included age younger than 18 or older than 70 years, signs of overt infection, acute vasculitis, unwillingness to participate, and, for this study, missing BCAA measurement. Of 560 patients included in the cohort, 328 patients (198 (60%) males, median age 54 years, and median estimated glomerular filtration rate (eGFR) 6.3 ml/min per 1.73 m\u003csup\u003e2\u003c/sup\u003e) met the study criteria and were included in the current analyses, see \u003cstrong\u003eTable 1\u003c/strong\u003e. The causes of CKD were diabetic nephropathy (26%), hypertension and kidney vascular disease (21%), chronic glomerulonephritis (25%), and other causes (28%). Most patients (85%) were on\u0026nbsp;antihypertensive medications, 59 (18%) patients were prescribed statins and other commonly used drugs in kidney failure such as erythropoietin, phosphate binders and potassium binders, and 61 (19%) patients received an oral amino acid supplementation.\u003c/p\u003e\n\u003cp\u003eData on BCAAs of 83 healthy subjects (66% males, median age 51 (range 21-80) years) served as comparator for BCAAs in the patient cohort (Supplementary material, \u003cstrong\u003eTable S1\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInformed written consent was obtained from each patient and control subject. The protocol of this study was approved by the Ethics Committee of the Karolinska Institute (EPN) at the Karolinska University Hospital Huddinge, Stockholm, Sweden. The study was conducted in adherence to the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter an overnight fast, venous blood samples were taken for analysis. Plasma and serum were separated and kept frozen at \u0026minus;70\u003csup\u003e◦\u003c/sup\u003eC if not analyzed immediately. Plasma amino acids including BCAAs (Leu, Ile and Val) were measured by reversed-phase high-performance liquid chromatography (HPLC) with fluorometric detection as previously described \u003csup\u003e26\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSerum cholesterol, HDL-C and TG were analyzed by standard enzymatic procedures (Boehringer Mannheim, Mannheim, Germany). High-sensitivity C-reactive protein (hsCRP) was measured by the nephelometry method. Interleukin-6 (IL-6) was measured with ELISA commercial kits (Roche Diagnostics GmbH, Penzberg, Germany). The remaining biochemical analyses were done using routine methods at Karolinska University Hospital at Huddinge. Glomerular filtration rate (GFR) was assessed in the CKD patients as an estimated GFR (eGFR) from serum creatinine levels. Atherogenic index of plasma (AIP) was calculated as the logarithmically transformed ratio of the serum TG to high-density lipoprotein cholesterol (HDL-C) as described in \u003csup\u003e27\u003c/sup\u003e:\u0026nbsp;\u003cimg width=\"125\" height=\"29\" src=\"https://myfiles.space/user_files/58895_8739fc6c57c1c19a/58895_custom_files/img1763380666.png\" alt=\"image\"\u003e\u003cem\u003e.\u003c/em\u003e Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was calculated based on the following equation: Fasting insulin in\u0026nbsp;\u0026mu;U/mL)\u0026times;fasting glucose in mmol/L) \u003cstrong\u003e/\u003c/strong\u003e 22.5. Body mass index (BMI) was calculated as the subject\u0026rsquo;s body weight in kilograms divided by the square of the subject\u0026rsquo;s height in meters (kg/m\u003csup\u003e2\u003c/sup\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome ascertainment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSurvival among the 328 CKD stage 5 patients was measured from the day of examination until death or censoring for kidney transplantation or when they completed the 5-year follow-up period. No patients were lost to follow-up. \u0026nbsp;The median follow-up period was 29.4 (range 0.9\u0026ndash;60) months. Within the 5-year follow-up period, 82 patients (25%) died, of which 52 (63%) were cardiovascular deaths, and 166 patients (51%) underwent transplantation. Cardiovascular deaths were attributed to ischemic heart disease, heart failure, ischemic stroke, peripheral vascular disease, or hemorrhagic stroke.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData are expressed as number (percentage) or median (interquartile range, IQR). Statistical significance was set at the level of P \u0026lt; 0.05. Comparisons between two groups were assessed with the non-parametric Wilcoxon test for continuous variables and Chi-square test (\u003cem\u003e\u0026chi;\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e) for nominal variables. When comparing more than two groups we applied the non-parametric Kruskal-Walli\u0026rsquo;s test for continuous variables and\u0026nbsp;\u003cem\u003e\u0026chi;\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003etest for nominal variables. Non-parametric Spearman rank correlation analysis was used to determine associations between variables.\u0026nbsp;Multivariate linear regression analysis with stepwise backward selection of variables was used to determine the predictors of total and individual BCAAs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRestricted cubic spline curve analysis was performed to assess the associations between total BCAA and valine concentrations (as continuous variables) and the risk of all-cause mortality and cardiovascular mortality. Fine-Gray competing-risk regression analysis models with kidney transplantation as a competing risk were used to estimate the sub-distribution hazard ratio (sHR) with 95% confidence interval (95% CI) to quantify the association of total and individual BCAAs, expressed as tertiles, with mortality risk. Statistical analyses were performed using statistical software Stata Now 18.5 (Stata Corporation, College Station, TX, USA) and Statistical Analysis Systems (SAS) SAS 9.4 level 1 M8 (SAS Campus Drive, Cary, NC, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eCharacteristics of the CKD patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 328 CKD patients (198 males and 130 females) with a median (IQR) age of 54 (43 \u0026ndash; 63) years were included in the study (\u003cstrong\u003eTable 1)\u003c/strong\u003e. Their median eGFR was 6.3 (4.9 \u0026ndash; 7.9) ml/min/1.73\u0026nbsp;m\u003csup\u003e2\u003c/sup\u003e, 104 (32%) had DM and 111 (34%) had CVD. Moreover, Table 1 shows glucose-related parameters, plasma lipid profile including AIP, and total and individual BCAAs, for all patients and when patients are divided into tertiles of total BCAAs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBCAAs in patients and controls\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePlasma concentrations of total (T-BCAA) and individual BCAAs were significantly lower in CKD patients compared to healthy controls (\u003cstrong\u003eFig. 1\u0026nbsp;\u003c/strong\u003eand \u003cstrong\u003eTable S1\u003c/strong\u003e), except for Ile, for which the difference did not reach statistical significance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBCAAs in different CKD patient groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe plasma concentrations of T-BCAA (\u003cstrong\u003eFig. S2\u003c/strong\u003e) and the three individual BCAAs (\u003cstrong\u003eTable S2\u003c/strong\u003e) were higher (all p\u0026lt;0.0001) in male patients compared to female patients. Similarly, plasma concentrations of total BCAAs (T-BCAA) and the three individual BCAAs were significantly higher in healthy males compared to healthy females (\u003cstrong\u003eFig. S3\u003c/strong\u003e). However, the plasma BCAA concentrations did not differ significantly between CKD patients with and without DM, CVD, and statin treatment, respectively (\u003cstrong\u003eFig. S2\u003c/strong\u003e). Moreover, the concentrations of BCAAs did not differ significantly between 61 patients (19%) who received amino acid supplementation and those who did not\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e(\u003cstrong\u003eTable S3\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssociations of BCAAs with lipid profile\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe individual BCAAs were strongly correlated with each other and with lipid components (\u003cstrong\u003eTable 2)\u003c/strong\u003e. TG was positively and significantly correlated with T-BCAA and Val. Moreover, HDL-C was negatively and significantly correlated with T-BCAA, Val, Ile, and Leu. Similarly, AIP, Lp(a), and Apo-A were negatively and significantly correlated with T-BCAA, Val, and Ile, but not with Leu. Serum cholesterol, LDL-C, and Apo-B did not show significant associations with T-BCAA or individual BCAAs.\u003c/p\u003e\n\u003cp\u003eTo further explore links between AIP and BCAAs, we divided the patients into AIP tertiles and compared the concentration of T-BCAA and individual BCAAs between the AIP tertiles. The high AIP tertile had significantly higher levels of T-BCAA, Val and Ile, but not Leu, compared to the low tertile (\u003cstrong\u003eFig. 2\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe association between BCAAs and atherogenic lipids was further investigated by multivariate linear regression analysis to determine variables independently associated with BCAAs (\u003cstrong\u003eTable 3\u003c/strong\u003e). In a model including age, sex, DM, CVD, BMI, AIP and plasma insulin, higher AIP, higher plasma insulin and male sex emerged as independent predictors of plasma T-BCAA concentration, whereas age, DM and BMI were not significantly associated with T-BCAA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssociations of BCAA with glucose-related factors and inflammatory biomarkers\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs shown in \u003cstrong\u003eTable 4\u003c/strong\u003e, blood glucose, plasma insulin and HOMA-IR were positively and significantly correlated with T-BCAA and Val, and HbA1c was inversely and significantly correlated with Leu.\u003c/p\u003e\n\u003cp\u003eTNF-\u0026alpha; correlated inversely with T-BCAA, Val, and Leu (Table 4). Other inflammatory markers such as WBC, hsCRP, IL-6, IL-10, IL-18, ICAM-1, VCAM-1, and 8-OHdG were not significantly correlated with the concentrations of BCAAs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBCAAs and mortality\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe associations of low and middle tertiles vs. high tertile of T-BCAA and individual BCAAs with cardiovascular and all-cause mortality were investigated using competing-risk regression analysis models, adjusted for age, sex, DM, CVD, eGFR, BMI, AIP, serum albumin and plasma insulin (\u003cstrong\u003eFig 3\u003c/strong\u003e and \u003cstrong\u003eTable S4)\u003c/strong\u003e. The low T-BCAA tertile was associated with increased risk of cardiovascular mortality (sub-hazard ratio [sHR] 2.37, 95% confidence interval [CI], 1.08 - 5.21) and the low tertile of valine was associated with higher risk of both all-cause mortality (sHR 2.05, 95% CI 1.10\u0026ndash;3.79) and cardiovascular mortality (sHR 2.46, 95% CI 1.15\u0026ndash;5.26).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRestricted cubic spline curve analysis showed that lower\u0026nbsp;plasma concentrations of T-BCAA and Val, as continuous variables,\u0026nbsp;were\u0026nbsp;associated with increased 5-year all-cause and cardiovascular mortality risk (\u003cstrong\u003eFig. 4\u003c/strong\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study provides several important insights into the complex relationship between BCAAs, atherogenic lipids and mortality risk in patients with advanced CKD. Their plasma concentrations of BCAAs, which were lower than in healthy individuals, were inversely associated with increased cardiovascular mortality, and lower Val concentration was associated with increased both all-cause and cardiovascular mortality risk. Finally, higher plasma BCAA levels were positively associated with TG and AIP, and inversely associated with HDL-C, Apo-A, and Lp(a).\u003c/p\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eBCAAs in different CKD groups\u003c/h2\u003e\u003cp\u003eDuring CKD, abnormalities in BCAA metabolism occur due to the reduced kidney contribution to amino acid metabolism, compounded by declining kidney function and the accumulation of uremic toxins, which disrupt whole body nitrogen metabolism. Previous studies have demonstrated that patients with advanced CKD, including those undergoing hemodialysis (HD) or peritoneal dialysis, exhibit reduced levels of essential amino acids, including BCAAs \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. In our study, BCAA levels were significantly lower in the CKD patients compared to a group of healthy individuals. The precise cause of lower BCAA levels in CKD remains unclear. It is plausible that the combination of impaired kidney amino acid metabolism, effects of uremic toxins, nutritional deficits, muscle wasting, metabolic stress, inflammation, and the process of adapting to kidney failure all contribute to the lower plasma amino acid concentrations.\u003c/p\u003e\u003cp\u003eOur findings also revealed strong intercorrelations among plasma concentrations of BCAAs in CKD patients, consistent with findings by Ikeda \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e28\u003c/sup\u003e in both HD patients and healthy older individuals and by Luo \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e29\u003c/sup\u003e in patients with hypertension-attributed CKD. These observations support previous explanations that attributed the strong correlation among BCAAs to shared metabolic enzymes \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eFurthermore, in CKD patients and in healthy controls, BCAA concentrations were significantly higher in males compared to females, consistent with previous findings in HD patients and healthy individuals \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. The higher levels of BCAAs in males may be attributed to differences in muscle mass, hormone status, and body fat distribution, all of which affect amino acid metabolism differently between sexes.\u003c/p\u003e\u003cp\u003eMany studies have reported a close association between elevated BCAA levels and the development of insulin resistance, DM, and hypertension \u003csup\u003e\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e–\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. However, the concentrations of BCAAs in CKD patients with DM or hypertension in our study did not significantly differ from those without these conditions. We did observe, however, significant associations between BCAA levels and both blood glucose and plasma insulin concentrations, suggesting a link between BCAAs and glucose regulation.. Although there was a trend towards a positive association with HbA1c, it did not reach statistical significance, except for leucine, which showed a significant association with HbA1c. This suggests that BCAAs may play a role in metabolic processes related to glucose and insulin regulation, although the precise nature of these relationships requires further investigation.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eAssociations BCAAs with lipid profile\u003c/h2\u003e\u003cp\u003eA novel and intriguing finding in our study is the specific correlation between BCAA levels and lipid profiles. To our knowledge, this is the first study to examine the association between plasma BCAA concentrations and the circulating lipid profile in CKD patients. Although BCAA levels in our cohort were lower than those typically observed in healthy individuals, they were still positively associated with atherogenic lipids, as indicated by the Atherogenic Index of Plasma (AIP), a composite biomarker derived from the ratio of TG to HDL-C. Consistent with previous studies in non-kidney disease populations \u003csup\u003e\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e–\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e, we found that BCAA concentrations were significantly positively correlated with TG and AIP, and negatively correlated with HDL-C, Apo-A, and Lp (a). Interestingly, no significant correlation was observed between BCAA levels and total cholesterol or LDL-C concentrations.\u003c/p\u003e\u003cp\u003eBCAAs are crucial in protein synthesis and energy metabolism and have been shown to regulate both glucose and lipid metabolism \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. The interaction between BCAAs and lipids involves complex metabolic pathways, where BCAAs influence enzymes and signalling pathways critical for lipid synthesis and breakdown \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. Although BCAAs are primarily metabolized in skeletal muscle, their catabolism is linked to the production of acyl-CoA intermediates that can enter lipid synthesis pathways \u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e, potentially leading to increased production of specific lipids. Low BCAA levels, as in CKD, may impair the regulation of these pathways, resulting in lipid accumulation in the bloodstream. Additionally, BCAAs may influence lipid transport by affecting lipoprotein levels, including those responsible for carrying cholesterol and triglycerides \u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. This interaction may contribute to dyslipidemia, further highlighting the complex role of BCAAs in lipid metabolism and cardiovascular risk. In CKD patients, the combination of dysregulated lipid metabolism and low BCAA levels may create a perfect storm for increased cardiovascular risk. This occurs through mechanisms including the promotion of atherogenesis, enhanced insulin resistance, chronic inflammation, oxidative stress, muscle wasting, and endothelial dysfunction \u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eAssociations of BCAAs with glucose-related factors\u003c/h2\u003e\u003cp\u003eMany studies have reported a close association between elevated BCAA levels and the development of insulin resistance, DM, and hypertension \u003csup\u003e\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e–\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. However, in our study, BCAA concentrations in CKD patients with DM or hypertension did not significantly differ from those without these conditions. Insulin resistance is a common and early feature of kidney failure, regardless of diabetes status. In this study, we observed significant associations between BCAA levels and both blood glucose and plasma insulin concentrations, suggesting a potential link between BCAAs and glucose regulation. Moreover, the HOMA-IR was positively and significantly correlated with T-BCAA and valine concentrations. These findings imply that BCAAs may play a role in metabolic processes related to glucose and insulin regulation, although the precise nature of these relationships warrants further investigation. It is important to consider that the nature and direction of these associations may differ in individuals with CKD compared to those without. Notably, metabolomics work by Newgard et al. \u003csup\u003e11, 13, 14\u003c/sup\u003e reported strong associations between elevated circulating BCAA levels and the development of insulin resistance, type 2 diabetes mellitus, and related metabolic disorders. Their study demonstrated that a metabolic signature characterized by increased BCAAs and related metabolites was closely linked to insulin resistance and impaired glucose metabolism, suggesting a contributory role of BCAAs in the pathogenesis of metabolic disease. Further research is needed to elucidate the mechanisms through which BCAAs influence glucose homeostasis in CKD and to determine how these pathways may differ from those established in non-CKD populations.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003eAssociations of BCAAs with inflammatory markers\u003c/h2\u003e\u003cp\u003eOur study did not find significant associations between total or individual BCAAs and inflammatory markers such as CRP or IL-6. However, there was a significant negative association between TNF-α and total BCAAs, Val, and Ile, but not Leu. Inflammatory cytokines like TNF-α and IL-6 modulate BCAA metabolism and are key mediators of muscle protein breakdown, altering circulating amino acid levels, including BCAAs. TNF-α, in particular, promotes muscle protein catabolism via the ubiquitin-proteasome pathway, contributing to elevated BCAA levels and systemic metabolic disturbances \u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. TNF-α, IL-1β, and IL-6 are central pro-inflammatory cytokines that drive myofibrillar protein degradation, inhibit protein synthesis, and lead to muscle atrophy. TNF-α also stimulates reactive oxygen species (ROS) production via the mitochondrial electron transport chain, activating NF-κB, which further enhances the ubiquitin-proteasome system, accelerating muscle protein breakdown and atrophy \u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. TNF-α is produced by various cells, including macrophages, lymphocytes, and skeletal muscle cells, and contributes to local and systemic inflammation upon binding to its receptors \u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. In CKD patients and those on hemodialysis, persistent activation of innate and adaptive immunity results in \"inflammaging,\" a state of chronic low-grade inflammation \u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. Simultaneously, BCAAs may exacerbate inflammation by directly activating NF-κB in inflammatory cells, leading to increased production of IL-6 and TNF-α \u003csup\u003e43\u003c/sup\u003e. Thus, TNF-α contributes to muscle wasting and altered amino acid levels, while BCAAs may further promote inflammation by enhancing cytokine production.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003eBCAAs and mortality\u003c/h2\u003e\u003cp\u003eIn our study, we observed that individuals in the low tertile of Val levels, compared to those in the high tertile, had an increased risk of cardiovascular and all-cause mortality. Additionally, lower levels of total BCAAs were linked to higher cardiovascular mortality risk but not to all-cause mortality risk. While in our study, no significant associations were found between Ile or Leu and neither cardiovascular nor all-cause mortality, a recent study by Luo et al. \u003csup\u003e29\u003c/sup\u003e reported that in hypertensive individuals with advanced non-diabetic CKD, higher levels of Val, Leu, and Ile were associated with reduced cardiovascular mortality, with higher levels of Leu and Ile, but not Val, also being linked to lower all-cause mortality.\u003c/p\u003e\u003cp\u003ePrevious studies in non-kidney disease populations have yielded inconsistent results. For instance, a meta-analysis by Teymoori et al. \u003csup\u003e44\u003c/sup\u003e, which included nine cohort studies and one case–control study, found no association between total or individual BCAAs and the risk of all-cause mortality. On the other hand, Fung et al. \u003csup\u003e45\u003c/sup\u003e demonstrated a U-shaped relationship between BCAA levels and mortality in older individuals with hypertension and/or diabetes mellitus, with both high and low BCAA levels being associated with increased mortality. In contrast, among individuals without these conditions \u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e, higher BCAA levels were associated with improved survival. Moreover, the LURIC study \u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e found that elevated BCAA levels in a Caucasian population were associated with a reduced long-term risk of both all-cause and cardiovascular mortality, with this relationship persisting regardless of obesity and/or diabetes status. The study by Deelen et al. \u003csup\u003e47\u003c/sup\u003e further supported these findings, showing that higher levels of Val and Ile were associated with decreased mortality. Moreover, in a recent study Li et al \u003csup\u003e48\u003c/sup\u003e reported that lower total BCAA levels were associated with increased all-cause mortality in patients with liver cirrhosis.\u003c/p\u003e\u003cp\u003eOur study is so far the most comprehensive exploration of the relationship between BCAAs, lipid profiles, and mortality risk among individuals with advanced CKD, with a relatively large sample size, detailed phenotyping and inclusion of age- and sex-matched controls for comparative analysis of BCAA concentrations. Additionally, no patients were lost to follow-up. However, some limitations should be considered when interpreting our findings. First, as this is an observational study, causality cannot be established. Second, BCAAs were measured only at the study's outset. Third, unmeasured confounders may have influenced the results, despite our efforts to account for potential confounders such as age, sex, BMI, DM, CVD, eGFR, plasma insulin, atherogenic lipids, and inflammation. Finally, the lack of detailed dietary information for CKD patients that potentially may influence circulating BCAA levels limits our ability to fully account for dietary contributions. However, previous studies suggest that metabolic alterations in CKD often outweigh the effects of diet, indicating that the observed changes in BCAA levels are likely driven primarily by the disease itself.\u003c/p\u003e\u003c/div\u003e"},{"header":"Summary and conclusion","content":"\u003cp\u003eIn patients with CKD stage 5, plasma concentrations of total and individual BCAAs were lower than in age- and sex matched healthy controls, lower in females than in males, and inversely correlated with TNF-α. Whereas higher levels of BCAAs were associated with an atherogenic lipid profile including higher AIP and glucose-related factors including HOMA-IR, competing risk regression analysis showed that lower levels of total BCAAs and valine were associated with increased cardiovascular mortality risk and lower plasma valine concentration was associated also with higher all-cause mortality risk.\u003c/p\u003e\u003cp\u003eThese results provide insights into the intricate relationships between BCAA levels, lipid profiles, glucose-related compounds, inflammatory markers, and mortality in CKD patients and underscore the role of BCAAs in modulating cardiovascular risk and mortality in the context of CKD. While our study highlights significant associations, it also raises questions about the causality and clinical implications of these findings, and the underlying mechanisms remain complex and warrant further investigation. Further research, particularly longitudinal studies and interventional trials is needed to clarify the role of BCAAs in CKD in relation to metabolic alterations, progression of underlying disease and patient outcomes. Understanding these relationships could potentially contribute to new therapeutic strategies aimed at improving the prognosis for CKD patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all patients and healthy subjects who participated in present study, and those who carried out the extensive clinical and laboratory work at the clinical investigational unit and the Renal Laboratory at Department of Renal Medicine, Karolinska University Hospital Huddinge. Baxter Novum is the result of a grant from Baxter Healthcare to Karolinska Institutet. The study also benefited from support from Martin Rind Foundation, Heart and Lung Foundation, Njurfonden, and Westmans Foundation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBengt Lindholm has been affiliated with Baxter Healthcare Corporation. Peter Stenvinkel is or has been on scientific advisory boards of REATA, Baxter, GSK, Astra Zeneca, Invizius, Behring, and Vifor and educational advisory boards for Astellas and FMC. Other authors do not declare any conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCredit Authorship Contribution Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMohamed E Suliman: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Visualization, and Writing \u0026ndash; original draft, Writing - review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003eAbdul Rashid Qureshi: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Visualization, and Writing \u0026ndash; original draft.\u003c/p\u003e\n\u003cp\u003eDario Troise: Formal analysis and Writing \u0026ndash; original draft and review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003eQianying Zhang: Formal analysis and Writing \u0026ndash; original draft and review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003ePeter Barany: Patient recruitment, Investigation, Methodology, Writing - review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003eOlof Heimb\u0026uuml;rger: Patient recruitment, Investigation, Methodology, Writing - review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003ePeter Stenvinkel: Investigation, Methodology, Funding acquisition, Project administration, Resources, Writing - review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003eBengt Lindholm: Conceptualization, Funding acquisition, Project administration, Resources,\u003c/p\u003e\n\u003cp\u003eSupervision, and Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003eAll authors have read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e: Data described in the manuscript, code book, and analytic code will be made available upon request pending application to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary Data:\u0026nbsp;\u003c/strong\u003eSupplementary data to this article can be found online at\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eNie C, He T, Zhang W, Zhang G, Ma X. Branched Chain Amino Acids: Beyond Nutrition Metabolism. \u003cem\u003eInt J Mol Sci \u003c/em\u003e2018; \u003cstrong\u003e19\u003c/strong\u003e(4). e-pub ahead of print 20180323; doi: 10.3390/ijms19040954\u003c/li\u003e\n\u003cli\u003eHolecek M. Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements. \u003cem\u003eNutr Metab (Lond) \u003c/em\u003e2018; \u003cstrong\u003e15: \u003c/strong\u003e33. e-pub ahead of print 20180503; doi: 10.1186/s12986-018-0271-1\u003c/li\u003e\n\u003cli\u003eBatch BC, Hyland K, Svetkey LP. Branch chain amino acids: biomarkers of health and disease. \u003cem\u003eCurr Opin Clin Nutr Metab Care \u003c/em\u003e2014; \u003cstrong\u003e17\u003c/strong\u003e(1)\u003cstrong\u003e: \u003c/strong\u003e86-89. doi: 10.1097/MCO.0000000000000010\u003c/li\u003e\n\u003cli\u003eGannon NP, Schnuck JK, Vaughan RA. BCAA metabolism and insulin sensitivity\u0026ndash;dysregulated by metabolic status? \u003cem\u003eMolecular nutrition \u0026amp; food research \u003c/em\u003e2018; \u003cstrong\u003e62\u003c/strong\u003e(6)\u003cstrong\u003e: \u003c/strong\u003e1700756. \u003c/li\u003e\n\u003cli\u003eYang P, Hu W, Fu Z, Sun L, Zhou Y, Gong Y\u003cem\u003e et al.\u003c/em\u003e The positive association of branched-chain amino acids and metabolic dyslipidemia in Chinese Han population. \u003cem\u003eLipids Health Dis \u003c/em\u003e2016; \u003cstrong\u003e15: \u003c/strong\u003e120. e-pub ahead of print 20160725; doi: 10.1186/s12944-016-0291-7\u003c/li\u003e\n\u003cli\u003eHamaya R, Mora S, Lawler PR, Cook NR, Ridker PM, Buring JE\u003cem\u003e et al.\u003c/em\u003e Association of Plasma Branched-Chain Amino Acid With Biomarkers of Inflammation and Lipid Metabolism in Women. \u003cem\u003eCirc Genom Precis Med \u003c/em\u003e2021; \u003cstrong\u003e14\u003c/strong\u003e(4)\u003cstrong\u003e: \u003c/strong\u003ee003330. e-pub ahead of print 20210715; doi: 10.1161/CIRCGEN.121.003330\u003c/li\u003e\n\u003cli\u003eFukushima K, Harada S, Takeuchi A, Kurihara A, Iida M, Fukai K\u003cem\u003e et al.\u003c/em\u003e Association between dyslipidemia and plasma levels of branched-chain amino acids in the Japanese population without diabetes mellitus. \u003cem\u003eJ Clin Lipidol \u003c/em\u003e2019; \u003cstrong\u003e13\u003c/strong\u003e(6)\u003cstrong\u003e: \u003c/strong\u003e932-939 e932. e-pub ahead of print 20190911; doi: 10.1016/j.jacl.2019.09.002\u003c/li\u003e\n\u003cli\u003eWang FH, Liu J, Deng QJ, Qi Y, Wang M, Wang Y\u003cem\u003e et al.\u003c/em\u003e Association between plasma essential amino acids and atherogenic lipid profile in a Chinese population: A cross-sectional study. \u003cem\u003eAtherosclerosis \u003c/em\u003e2019; \u003cstrong\u003e286: \u003c/strong\u003e7-13. e-pub ahead of print 20190425; doi: 10.1016/j.atherosclerosis.2019.04.225\u003c/li\u003e\n\u003cli\u003eYamaguchi N, Mahbub MH, Takahashi H, Hase R, Ishimaru Y, Sunagawa H\u003cem\u003e et al.\u003c/em\u003e Plasma free amino acid profiles evaluate risk of metabolic syndrome, diabetes, dyslipidemia, and hypertension in a large Asian population. \u003cem\u003eEnviron Health Prev Med \u003c/em\u003e2017; \u003cstrong\u003e22\u003c/strong\u003e(1)\u003cstrong\u003e: \u003c/strong\u003e35. e-pub ahead of print 20170407; doi: 10.1186/s12199-017-0642-7\u003c/li\u003e\n\u003cli\u003eYamakado M, Nagao K, Imaizumi A, Tani M, Toda A, Tanaka T\u003cem\u003e et al.\u003c/em\u003e Plasma Free Amino Acid Profiles Predict Four-Year Risk of Developing Diabetes, Metabolic Syndrome, Dyslipidemia, and Hypertension in Japanese Population. \u003cem\u003eSci Rep \u003c/em\u003e2015; \u003cstrong\u003e5: \u003c/strong\u003e11918. e-pub ahead of print 20150709; doi: 10.1038/srep11918\u003c/li\u003e\n\u003cli\u003eNewgard CB. Interplay between lipids and branched-chain amino acids in development of insulin resistance. \u003cem\u003eCell Metab \u003c/em\u003e2012; \u003cstrong\u003e15\u003c/strong\u003e(5)\u003cstrong\u003e: \u003c/strong\u003e606-614. doi: 10.1016/j.cmet.2012.01.024\u003c/li\u003e\n\u003cli\u003eLu J, Xie G, Jia W, Jia W. Insulin resistance and the metabolism of branched-chain amino acids. \u003cem\u003eFront Med \u003c/em\u003e2013; \u003cstrong\u003e7\u003c/strong\u003e(1)\u003cstrong\u003e: \u003c/strong\u003e53-59. e-pub ahead of print 20130206; doi: 10.1007/s11684-013-0255-5\u003c/li\u003e\n\u003cli\u003eNewgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF\u003cem\u003e et al.\u003c/em\u003e A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. \u003cem\u003eCell Metab \u003c/em\u003e2009; \u003cstrong\u003e9\u003c/strong\u003e(4)\u003cstrong\u003e: \u003c/strong\u003e311-326. doi: 10.1016/j.cmet.2009.02.002\u003c/li\u003e\n\u003cli\u003eWhite PJ, McGarrah RW, Herman MA, Bain JR, Shah SH, Newgard CB. Insulin action, type 2 diabetes, and branched-chain amino acids: a two-way street. \u003cem\u003eMolecular metabolism \u003c/em\u003e2021; \u003cstrong\u003e52: \u003c/strong\u003e101261. \u003c/li\u003e\n\u003cli\u003eWang Q, Holmes MV, Davey Smith G, Ala-Korpela M. Genetic Support for a Causal Role of Insulin Resistance on Circulating Branched-Chain Amino Acids and Inflammation. \u003cem\u003eDiabetes Care \u003c/em\u003e2017; \u003cstrong\u003e40\u003c/strong\u003e(12)\u003cstrong\u003e: \u003c/strong\u003e1779-1786. e-pub ahead of print 20171018; doi: 10.2337/dc17-1642\u003c/li\u003e\n\u003cli\u003eCano NJ, Fouque D, Leverve XM. Application of branched-chain amino acids in human pathological states: renal failure. \u003cem\u003eJ Nutr \u003c/em\u003e2006; \u003cstrong\u003e136\u003c/strong\u003e(1 Suppl)\u003cstrong\u003e: \u003c/strong\u003e299S-307S. doi: 10.1093/jn/136.1.299S\u003c/li\u003e\n\u003cli\u003eAlvestrand A, F\u0026uuml;rst P, Bergstr\u0026ouml;m J. Intracellular amino acids in uremia. \u003cem\u003eKidney international. Supplement \u003c/em\u003e1983; \u003cstrong\u003e16: \u003c/strong\u003eS9-16. \u003c/li\u003e\n\u003cli\u003eBergstr\u0026ouml;m J, Alvestrand A, F\u0026uuml;rst P. Plasma and muscle free amino acids in maintenance hemodialysis patients without protein malnutrition. \u003cem\u003eKidney international \u003c/em\u003e1990; \u003cstrong\u003e38\u003c/strong\u003e(1)\u003cstrong\u003e: \u003c/strong\u003e108-114. \u003c/li\u003e\n\u003cli\u003eLindholm B, Alvestrand A, F\u0026uuml;rst P, Bergstr\u0026ouml;m J. Plasma and muscle free amino acids during continuous ambulatory peritoneal dialysis. \u003cem\u003eKidney international \u003c/em\u003e1989; \u003cstrong\u003e35\u003c/strong\u003e(5)\u003cstrong\u003e: \u003c/strong\u003e1219-1226. \u003c/li\u003e\n\u003cli\u003eJones MR, Kopple JD. Valine metabolism in normal and chronically uremic man. \u003cem\u003eAm J Clin Nutr \u003c/em\u003e1978; \u003cstrong\u003e31\u003c/strong\u003e(9)\u003cstrong\u003e: \u003c/strong\u003e1660-1664. doi: 10.1093/ajcn/31.9.1660\u003c/li\u003e\n\u003cli\u003eQureshi AR, Alvestrand A, Danielsson A, Divino-Filho JC, Gutierrez A, Lindholm B\u003cem\u003e et al.\u003c/em\u003e Factors predicting malnutrition in hemodialysis patients: a cross-sectional study. \u003cem\u003eKidney Int \u003c/em\u003e1998; \u003cstrong\u003e53\u003c/strong\u003e(3)\u003cstrong\u003e: \u003c/strong\u003e773-782. doi: 10.1046/j.1523-1755.1998.00812.x\u003c/li\u003e\n\u003cli\u003eKopple JD, Kalantar-Zadeh K, Mehrotra R. Risks of chronic metabolic acidosis in patients with chronic kidney disease. \u003cem\u003eKidney Int Suppl \u003c/em\u003e2005; (95)\u003cstrong\u003e: \u003c/strong\u003eS21-27. doi: 10.1111/j.1523-1755.2005.09503.x\u003c/li\u003e\n\u003cli\u003eNiroumand S, Khajedaluee M, Khadem-Rezaiyan M, Abrishami M, Juya M, Khodaee G\u003cem\u003e et al.\u003c/em\u003e Atherogenic Index of Plasma (AIP): A marker of cardiovascular disease. \u003cem\u003eMed J Islam Repub Iran \u003c/em\u003e2015; \u003cstrong\u003e29: \u003c/strong\u003e240. e-pub ahead of print 20150725; \u003c/li\u003e\n\u003cli\u003eStenvinkel P, Heimburger O, Paultre F, Diczfalusy U, Wang T, Berglund L\u003cem\u003e et al.\u003c/em\u003e Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. \u003cem\u003eKidney Int \u003c/em\u003e1999; \u003cstrong\u003e55\u003c/strong\u003e(5)\u003cstrong\u003e: \u003c/strong\u003e1899-1911. doi: 10.1046/j.1523-1755.1999.00422.x\u003c/li\u003e\n\u003cli\u003eVon Elm E, Altman DG, Egger M, Pocock SJ, G\u0026oslash;tzsche PC, Vandenbroucke JP\u003cem\u003e et al.\u003c/em\u003e The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies. \u003cem\u003eInternational journal of surgery \u003c/em\u003e2014; \u003cstrong\u003e12\u003c/strong\u003e(12)\u003cstrong\u003e: \u003c/strong\u003e1495-1499. \u003c/li\u003e\n\u003cli\u003eSuliman ME, Anderstam B, Bergstrom J. Evidence of taurine depletion and accumulation of cysteinesulfinic acid in chronic dialysis patients. \u003cem\u003eKidney Int \u003c/em\u003e1996; \u003cstrong\u003e50\u003c/strong\u003e(5)\u003cstrong\u003e: \u003c/strong\u003e1713-1717. doi: 10.1038/ki.1996.490\u003c/li\u003e\n\u003cli\u003eDobiasova M, Frohlich J. [The new atherogenic plasma index reflects the triglyceride and HDL-cholesterol ratio, the lipoprotein particle size and the cholesterol esterification rate: changes during lipanor therapy]. \u003cem\u003eVnitr Lek \u003c/em\u003e2000; \u003cstrong\u003e46\u003c/strong\u003e(3)\u003cstrong\u003e: \u003c/strong\u003e152-156. \u003c/li\u003e\n\u003cli\u003eIkeda H. Cross-correlation of plasma concentrations of branched-chain amino acids: A comparison between healthy participants and patients with chronic kidney disease. \u003cem\u003eClin Nutr ESPEN \u003c/em\u003e2020; \u003cstrong\u003e38: \u003c/strong\u003e201-210. e-pub ahead of print 20200521; doi: 10.1016/j.clnesp.2020.04.014\u003c/li\u003e\n\u003cli\u003eLuo S, Surapaneni A, Rebholz CM, Appel LJ, Coresh J, Grams ME. Circulating Branched-Chain Amino Acids, Incident Cardiovascular Disease, and Mortality in the African American Study of Kidney Disease and Hypertension. \u003cem\u003eCirc Genom Precis Med \u003c/em\u003e2023; \u003cstrong\u003e16\u003c/strong\u003e(1)\u003cstrong\u003e: \u003c/strong\u003ee003729. e-pub ahead of print 20230130; doi: 10.1161/CIRCGEN.122.003729\u003c/li\u003e\n\u003cli\u003eBrosnan JT, Brosnan ME. Branched-chain amino acids: enzyme and substrate regulation. \u003cem\u003eJ Nutr \u003c/em\u003e2006; \u003cstrong\u003e136\u003c/strong\u003e(1 Suppl)\u003cstrong\u003e: \u003c/strong\u003e207S-211S. doi: 10.1093/jn/136.1.207S\u003c/li\u003e\n\u003cli\u003eCuomo P, Capparelli R, Iannelli A, Iannelli D. Role of Branched-Chain Amino Acid Metabolism in Type 2 Diabetes, Obesity, Cardiovascular Disease and Non-Alcoholic Fatty Liver Disease. \u003cem\u003eInt J Mol Sci \u003c/em\u003e2022; \u003cstrong\u003e23\u003c/strong\u003e(8). e-pub ahead of print 20220413; doi: 10.3390/ijms23084325\u003c/li\u003e\n\u003cli\u003eAlqudah A, Qnais E, Wedyan M, Awali A, Bseiso Y, Gammoh O. Amino acid profiles: exploring their diagnostic and pathophysiological significance in hypertension. \u003cem\u003eMol Biol Rep \u003c/em\u003e2024; \u003cstrong\u003e51\u003c/strong\u003e(1)\u003cstrong\u003e: \u003c/strong\u003e200. e-pub ahead of print 20240125; doi: 10.1007/s11033-023-09107-8\u003c/li\u003e\n\u003cli\u003eBloomgarden Z. Diabetes and branched-chain amino acids: What is the link? \u003cem\u003eJ Diabetes \u003c/em\u003e2018; \u003cstrong\u003e10\u003c/strong\u003e(5)\u003cstrong\u003e: \u003c/strong\u003e350-352. e-pub ahead of print 20180213; doi: 10.1111/1753-0407.12645\u003c/li\u003e\n\u003cli\u003eChoi BH, Hyun S, Koo S-H. The role of BCAA metabolism in metabolic health and disease. \u003cem\u003eExperimental \u0026amp; Molecular Medicine \u003c/em\u003e2024\u003cstrong\u003e: \u003c/strong\u003e1-8. \u003c/li\u003e\n\u003cli\u003eZhang S, Zeng X, Ren M, Mao X, Qiao S. Novel metabolic and physiological functions of branched chain amino acids: a review. \u003cem\u003eJournal of animal science and biotechnology \u003c/em\u003e2017; \u003cstrong\u003e8: \u003c/strong\u003e1-12. \u003c/li\u003e\n\u003cli\u003eGalli A, Arunagiri A, Dule N, Castagna M, Marciani P, Perego C. Cholesterol redistribution in pancreatic \u0026beta;-cells: a flexible path to regulate insulin secretion. \u003cem\u003eBiomolecules \u003c/em\u003e2023; \u003cstrong\u003e13\u003c/strong\u003e(2)\u003cstrong\u003e: \u003c/strong\u003e224. \u003c/li\u003e\n\u003cli\u003eGai Z, Wang T, Visentin M, Kullak-Ublick GA, Fu X, Wang Z. Lipid Accumulation and Chronic Kidney Disease. \u003cem\u003eNutrients \u003c/em\u003e2019; \u003cstrong\u003e11\u003c/strong\u003e(4). e-pub ahead of print 20190328; doi: 10.3390/nu11040722\u003c/li\u003e\n\u003cli\u003eSandri M. Signaling in muscle atrophy and hypertrophy. \u003cem\u003ePhysiology \u003c/em\u003e2008; \u003cstrong\u003e23\u003c/strong\u003e(3)\u003cstrong\u003e: \u003c/strong\u003e160-170. \u003c/li\u003e\n\u003cli\u003eWang DT, Yin Y, Yang YJ, Lv PJ, Shi Y, Lu L\u003cem\u003e et al.\u003c/em\u003e Resveratrol prevents TNF-alpha-induced muscle atrophy via regulation of Akt/mTOR/FoxO1 signaling in C2C12 myotubes. \u003cem\u003eInt Immunopharmacol \u003c/em\u003e2014; \u003cstrong\u003e19\u003c/strong\u003e(2)\u003cstrong\u003e: \u003c/strong\u003e206-213. e-pub ahead of print 20140215; doi: 10.1016/j.intimp.2014.02.002\u003c/li\u003e\n\u003cli\u003eZhou J, Liu B, Liang C, Li Y, Song YH. Cytokine Signaling in Skeletal Muscle Wasting. \u003cem\u003eTrends Endocrinol Metab \u003c/em\u003e2016; \u003cstrong\u003e27\u003c/strong\u003e(5)\u003cstrong\u003e: \u003c/strong\u003e335-347. e-pub ahead of print 20160326; doi: 10.1016/j.tem.2016.03.002\u003c/li\u003e\n\u003cli\u003eJofre R, Rodriguez-Benitez P, Lopez-Gomez JM, Perez-Garcia R. Inflammatory syndrome in patients on hemodialysis. \u003cem\u003eJ Am Soc Nephrol \u003c/em\u003e2006; \u003cstrong\u003e17\u003c/strong\u003e(12 Suppl 3)\u003cstrong\u003e: \u003c/strong\u003eS274-280. doi: 10.1681/ASN.2006080926\u003c/li\u003e\n\u003cli\u003eHernandez-Segura A, Nehme J, Demaria M. Hallmarks of Cellular Senescence. \u003cem\u003eTrends Cell Biol \u003c/em\u003e2018; \u003cstrong\u003e28\u003c/strong\u003e(6)\u003cstrong\u003e: \u003c/strong\u003e436-453. e-pub ahead of print 20180221; doi: 10.1016/j.tcb.2018.02.001\u003c/li\u003e\n\u003cli\u003eZhenyukh O, Civantos E, Ruiz-Ortega M, Sanchez MS, Vazquez C, Peiro C\u003cem\u003e et al.\u003c/em\u003e High concentration of branched-chain amino acids promotes oxidative stress, inflammation and migration of human peripheral blood mononuclear cells via mTORC1 activation. \u003cem\u003eFree Radic Biol Med \u003c/em\u003e2017; \u003cstrong\u003e104: \u003c/strong\u003e165-177. e-pub ahead of print 20170113; doi: 10.1016/j.freeradbiomed.2017.01.009\u003c/li\u003e\n\u003cli\u003eTeymoori F, Ahmadirad H, Jahromi MK, Mokhtari E, Farhadnejad H, Mohammadzadeh M\u003cem\u003e et al.\u003c/em\u003e Serum branched amino acids and the risk of all-cause mortality: a meta-analysis and systematic review. \u003cem\u003eAmino Acids \u003c/em\u003e2023; \u003cstrong\u003e55\u003c/strong\u003e(11)\u003cstrong\u003e: \u003c/strong\u003e1475-1486. e-pub ahead of print 20230919; doi: 10.1007/s00726-023-03329-7\u003c/li\u003e\n\u003cli\u003eFung E, Ng KH, Kwok T, Lui L-T, Palaniswamy S, Chan Q\u003cem\u003e et al.\u003c/em\u003e Divergent Survival Outcomes Associated with Elevated Branched-Chain Amino Acid Levels among Older Adults with or without Hypertension and Diabetes: A Validated, Prospective, Longitudinal Follow-Up Study. \u003cem\u003eBiomolecules \u003c/em\u003e2023; \u003cstrong\u003e13\u003c/strong\u003e(8)\u003cstrong\u003e: \u003c/strong\u003e1252. \u003c/li\u003e\n\u003cli\u003eMoissl AP, Lorkowski S, Meinitzer A, Pilz S, Scharnagl H, Delgado GE\u003cem\u003e et al.\u003c/em\u003e Association of branched-chain amino acids with mortality-the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. \u003cem\u003eiScience \u003c/em\u003e2023; \u003cstrong\u003e26\u003c/strong\u003e(4)\u003cstrong\u003e: \u003c/strong\u003e106459. e-pub ahead of print 20230321; doi: 10.1016/j.isci.2023.106459\u003c/li\u003e\n\u003cli\u003eDeelen J, Kettunen J, Fischer K, van der Spek A, Trompet S, Kastenmuller G\u003cem\u003e et al.\u003c/em\u003e A metabolic profile of all-cause mortality risk identified in an observational study of 44,168 individuals. \u003cem\u003eNat Commun \u003c/em\u003e2019; \u003cstrong\u003e10\u003c/strong\u003e(1)\u003cstrong\u003e: \u003c/strong\u003e3346. e-pub ahead of print 20190820; doi: 10.1038/s41467-019-11311-9\u003c/li\u003e\n\u003cli\u003eLi Y, Chvatal-Medina M, Trillos-Almanza MC, Connelly MA, Moshage H, Bakker SJL\u003cem\u003e et al.\u003c/em\u003e Branched-chain amino acids and all-cause mortality in patients with liver cirrhosis, and the onset of diabetes in liver transplant recipients. \u003cem\u003eEur J Clin Invest \u003c/em\u003e2025\u003cstrong\u003e: \u003c/strong\u003ee70096. e-pub ahead of print 20250710; doi: 10.1111/eci.70096\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e. Baseline characteristics of all CKD stage 5 patients and when divided into tertiles based on plasma concentration of total branched-chain amino acids (BCAAs).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient characteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBCAAs\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eFirst tertile\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBCAAs\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMiddle tertile\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBCAAs\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eThird tertile\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eNumber\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e328\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e109\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e111\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e54 (43 \u0026ndash; 63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e56 (47-63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e53 (44-63.)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e52 (42-64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eMales, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e198 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e49 (45%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e69 (63%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e80 (72%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eDM, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e104 (32%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e32 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e37 (34%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e35 (32%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eCVD, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e111 (34%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e38 (35%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e36 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e37 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e24 (22- 27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e24 (22-27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e24 (22-28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e24 (22-28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eeGFR, ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e6.4 (5.0-8.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e6.3 (5.0-8.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e6.6 (5.1-7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e6.5 (5.0-8.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eCRP, mg/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e5.0 (2.0-15.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e4.0 (1.6-15.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e4.8 (2.0-15.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e5.7 (2.6-14.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.71\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 274px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGlucose-related parameters\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eHbA1c, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e5.1 (4.5 \u0026ndash; 6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e5.0 (4.4-5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e5.1 (4.4-6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e5.1 (4.6-6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eBlood glucose, mmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e5.4 (4.8-6.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e5.3 (4.7-5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e5.3 (4.8-7.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e5.5 (5.0-7.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003ePlasma insulin, mU/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e16 (11 \u0026ndash; 29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e14 (11-22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e16 (10-27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e18 (11-29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eHOMA-IR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e3.9 (2.5-7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e3.3 (2.4-5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e4.7 (2.4-7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e4.4 (2.9-9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 274px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlasma lipid profile\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eTriglycerides, mmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e1.9 (1.3-2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.8 (1.2-2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.9 (1.4-2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e2.0 (1.4-2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eTotal cholesterol, mmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e5.2 (4.4-6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e5.5 (4.5-6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e5.3 (4.4-6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e4.9 (4.1-6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eHDL-C, mmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e1.2 (0.9-1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.4 (1.0-1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.1 (0.9-1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1.1 (0.8-1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eLDL-C, mmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e3.1 (2.2-4.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e3.0 (2.2-4.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e3.2 (2.3-4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e2.9 (2.0-4.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eAIP, ratio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e0.4 (0.0-1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.2 (-0.2-0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.5 (0.0-1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0.5 (0.1-1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eLipoprotein(a), nmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e213 (91-499)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e212 (85-596)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e271 (113-562)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e180 (64-381)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eApolipoprotein-A, g/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e1.3 (1.1-1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.4 (1.2-1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.2 (1.1-1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1.2 (1.0-1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eApolipoprotein-B, g/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e1.0 (0.8-1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.1 (0.8-1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.1 (0.8-1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1.0 (0.8-1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlasma BCAAs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eTotal BCAAs\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003emmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e281 (232-329)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e219 (191-232)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e281 (263-291)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e356 (328-397)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eValine\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003emmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e152 (126 \u0026ndash; 179)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e112 (96-129)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e152 (140-163)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e195 (174-231)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eIsoleucine\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003emmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e56 (43-68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e41 (35-50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e57 (49-65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e69 (58-85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eLeucine\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003emmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e67 (54-84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e54 (46-62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e72 (58-81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e88 (68-108)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eData presented as median (IQR, interquartile range). Abbreviations: DM, diabetes mellitus; CVD, cardiovascular disease; BMI, body mass index; eGFR, estimated glomerular filtration rate; CRP, C-reactive protein; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; AIP, atherogenic index of plasma; BCAAs, branched-chain amino acids.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e. Spearman rank correlation matrix of branched chain amino acids and lipid profile in 328 CKD stage 5 patients.\u003c/p\u003e\n\u003ctable style=\"border-collapse: collapse;border: none;width: 636px;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 40.05pt;border: 1pt solid black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:40.05pt;border-top:solid black 1.0pt;border-left:none;border-bottom:dotted black 1.0pt;border-right:solid black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eBCAAs\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:40.05pt;border-top:solid black 1.0pt;border-left:none;border-bottom:dotted black 1.0pt;border-right:solid black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eVal\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:40.05pt;border-top:solid black 1.0pt;border-left:none;border-bottom:dotted black 1.0pt;border-right:solid black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eIle\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:40.1pt;border-top:solid black 1.0pt;border-left:none;border-bottom:dotted black 1.0pt;border-right:solid black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eLeu\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:40.1pt;border-top:solid black 1.0pt;border-left:none;border-bottom:dotted black 1.0pt;border-right:solid black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eTG\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:40.1pt;border-top:solid black 1.0pt;border-left:none;border-bottom:dotted black 1.0pt;border-right:solid black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eHDL\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:40.1pt;border-top:solid black 1.0pt;border-left:none;border-bottom:dotted black 1.0pt;border-right:solid black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eAIP\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:40.1pt;border-top:solid black 1.0pt;border-left:none;border-bottom:dotted black 1.0pt;border-right:solid black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eChol\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:40.1pt;border-top:solid black 1.0pt;border-left:none;border-bottom:dotted black 1.0pt;border-right:solid black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eLDL\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:40.1pt;border-top:solid black 1.0pt;border-left:none;border-bottom:dotted black 1.0pt;border-right:solid black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eLp(a)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:40.1pt;border-top:solid black 1.0pt;border-left:none;border-bottom:dotted black 1.0pt;border-right:solid black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eApo-A\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:40.05pt;border-top:none;border-left:solid black 1.0pt;border-bottom:solid black 1.0pt;border-right:dotted black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eVal\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(217, 226, 243);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.93\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(251, 228, 213);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:40.05pt;border-top:none;border-left:solid black 1.0pt;border-bottom:solid black 1.0pt;border-right:dotted black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eIle\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(217, 226, 243);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.73\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:40.05pt;border-top:none;border-left:none;border-bottom:dotted black 1.0pt;border-right:dotted black 1.0pt;background:#D9E2F3;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.59\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(251, 228, 213);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:40.05pt;border-top:none;border-left:solid black 1.0pt;border-bottom:solid black 1.0pt;border-right:dotted black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eLeu\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(217, 226, 243);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.63\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(217, 226, 243);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.40\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(217, 226, 243);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.29\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(251, 228, 213);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:40.05pt;border-top:none;border-left:solid black 1.0pt;border-bottom:solid black 1.0pt;border-right:dotted black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eTG\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.13\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;a\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.15\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;b\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.08\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.02\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(251, 228, 213);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:40.05pt;border-top:none;border-left:solid black 1.0pt;border-bottom:solid black 1.0pt;border-right:dotted black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eHDL\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.26\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.24\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.24\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.15\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;b\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.45\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(251, 228, 213);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:40.05pt;border-top:none;border-left:solid black 1.0pt;border-bottom:solid black 1.0pt;border-right:dotted black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eAIP\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.22\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;c\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.22\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;c\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.17\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;b\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.10\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.89\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.79\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(251, 228, 213);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:40.05pt;border-top:none;border-left:solid black 1.0pt;border-bottom:solid black 1.0pt;border-right:dotted black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eChol\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.08\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.05\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.05\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.10\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.41\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.11\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.22\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;c\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(251, 228, 213);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:40.05pt;border-top:none;border-left:solid black 1.0pt;border-bottom:solid black 1.0pt;border-right:dotted black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eLDL\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.02\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.01\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.02\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.05\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.29\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.09\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.23\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;c\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.91\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(251, 228, 213);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:40.05pt;border-top:none;border-left:solid black 1.0pt;border-bottom:solid black 1.0pt;border-right:dotted black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eLp(a)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.12\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;a\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.13\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;a\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.10\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.05\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.08\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.15\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;b\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.13\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;a\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.12\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;a\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.11\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(251, 228, 213);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:40.05pt;border-top:none;border-left:solid black 1.0pt;border-bottom:solid black 1.0pt;border-right:dotted black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eApo-A\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.23\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;c\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.24\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.21\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;c\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.07\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.25\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.75\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.53\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.26\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.09\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.12\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;a\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(251, 228, 213);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:40.05pt;border-top:none;border-left:solid black 1.0pt;border-bottom:solid black 1.0pt;border-right:dotted black 1.0pt;padding:0cm 5.4pt 0cm 5.4pt;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eApo-B\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.02\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.01\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.05pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.04\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(226, 239, 217);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.02\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.46\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e-0.18\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;b\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.39\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.84\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.87\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;d\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.12\u003c/span\u003e\u003csup\u003e\u003cspan style=\"color:black;\"\u003e\u0026nbsp;a\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 40.1pt;border-top: none;border-left: none;border-bottom: 1pt dotted black;border-right: 1pt dotted black;background: rgb(231, 230, 230);padding: 0cm 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0cm;margin-right:0cm;margin-bottom:0cm;margin-left:0cm;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.08\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eSignificance levels: a\u0026lt;0.05, b\u0026lt;0.01, c\u0026lt;0.001 and d\u0026lt;0.0001.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAbbreviations: BCAAs, branched-chain amino acids; Val, valine; Ile, isoleucine; Leu, leucine; TG, triglycerides; HDL, high-density lipoprotein-cholesterol; AIP, atherogenic index of plasma; Chol, cholesterol; LDL, low-density lipoprotein-cholesterol; Lp(a), lipoprotein (a); Apo-A, Apolipoprotein A; Apo-B, Apolipoprotein B.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Predictors of 1-standard deviation (SD) increase of plasma concentrations of total (T-BCAAs) and individual branched-chain amino acids in 328 CKD 5 patients.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"643\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT-BCAAs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eValine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIsoleucine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLeucine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eBeta\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eBeta\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eBeta\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eBeta\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e1-SD of age, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e-0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e-0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e-0.019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e-0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eSex, F vs. M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e-0.258\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e-0.215\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e-0.253\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.163\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003ePresence of DM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e-0.020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.090\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003ePresence of CVD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e-0.067\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e-0.075\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e-0.102\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.189\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e1-SD of BMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.050\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.070\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e1-SD of AIP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.153\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.177\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.031\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003ens\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e1-SD of plasma insulin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.127\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.099\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.097\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.113\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eMultivariate linear regression analysis with stepwise backward selection of variables. The model including sex, age, diabetes mellitus (DM), cardiovascular disease (CVD), body mass index (BMI), plasma insulin and atherogenic index of plasma (AIP). AIP is a ratio of the log of TG to HDL-C. ns= non-significant.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTable 4.\u003c/strong\u003e Correlation between plasma concentrations of total (T-BCAA) and individual BCAAs with glucose-related parameters, estimated glomerular filtration rate (eGFR) and tumor necrosis factor-\u0026alpha;\u0026nbsp;(TNF-\u0026alpha;) in 328 CKD 5 patients.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT-BCAA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIle\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLeu\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHbA1c\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0.17\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGlucose\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.12\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.12\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInsulin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.12\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.14\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHOMA-IR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.17\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.20\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eeGFR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.15\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.18\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTNF-\u0026alpha;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e-0.15\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e-0.14\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e-0.18\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"amino-acids","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"amac","sideBox":"Learn more about [Amino Acids](http://link.springer.com/journal/726)","snPcode":"726","submissionUrl":"https://submission.nature.com/new-submission/726/3","title":"Amino Acids","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Branched-chain amino acids, lipid profile, inflammation, chronic kidney disease, mortality","lastPublishedDoi":"10.21203/rs.3.rs-7849136/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7849136/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eBranched-chain amino acids (BCAAs) are essential nutrients that promote muscle protein anabolism but also associate with cardiometabolic diseases; however, their role in chronic kidney disease (CKD) remains unclear. We investigated plasma BCAA levels and their associations with metabolic parameters and survival in CKD patients.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003ePlasma BCAA levels, along with clinical and laboratory parameters, were measured in 328 patients with CKD stage 5 (median age 54 years, 60% males). BCAA concentrations in 83 healthy individuals (median age 51 years, 66% males) served as comparators. Multivariate linear regression analysis was employed to identify predictors of BCAA levels. Competing risk regression analysis was conducted to assess 5-year risk of all-cause and cardiovascular mortality in relation to total and individual BCAAs (valine, isoleucine, and leucine).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003ePlasma BCAA levels were lower compared to healthy individuals (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and positively associated with triglycerides and the atherogenic index of plasma, while inversely associated with high density lipoprotein-cholesterol (HDL-C), Apo-A, and Lp (a). After adjustments for confounders, low vs. high tertile of total BCAAs associated with increased risk of cardiovascular mortality (sub-hazard ratio [sHR] 2.37, 95% confidence interval [CI], 1.08\u0026ndash;5.21) and low tertile of valine associated with higher risk of both all-cause mortality (sHR 2.05, 95% CI 1.10\u0026ndash;3.79) and cardiovascular mortality (sHR 2.46, 95% CI 1.15\u0026ndash;5.26).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eIn CKD, higher levels of BCAAs associated with an atherogenic lipid profile while lower BCAAs levels associated with increased cardiovascular mortality risk, and low valine was associated with higher both all-cause and cardiovascular mortality risk. Monitoring and potentially modulating BCAA levels could have prognostic or therapeutic implications in advanced CKD.\u003c/p\u003e","manuscriptTitle":"Plasma branched-chain amino acids in chronic kidney disease: Associations with atherogenic lipids and mortality","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-18 08:31:18","doi":"10.21203/rs.3.rs-7849136/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-04T09:15:12+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-04T02:38:04+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-01T18:53:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"296291577733769947560188786467223970149","date":"2025-11-17T17:20:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"35111215438444657740344981047017428684","date":"2025-11-08T17:04:22+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-05T15:20:30+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-14T13:43:15+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-14T13:36:07+00:00","index":"","fulltext":""},{"type":"submitted","content":"Amino Acids","date":"2025-10-13T12:34:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"amino-acids","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"amac","sideBox":"Learn more about [Amino Acids](http://link.springer.com/journal/726)","snPcode":"726","submissionUrl":"https://submission.nature.com/new-submission/726/3","title":"Amino Acids","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"56f2299b-f48b-4ded-8332-92c104459c8b","owner":[],"postedDate":"November 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-09T16:08:05+00:00","versionOfRecord":{"articleIdentity":"rs-7849136","link":"https://doi.org/10.1007/s00726-026-03511-7","journal":{"identity":"amino-acids","isVorOnly":false,"title":"Amino Acids"},"publishedOn":"2026-03-08 15:59:22","publishedOnDateReadable":"March 8th, 2026"},"versionCreatedAt":"2025-11-18 08:31:18","video":"","vorDoi":"10.1007/s00726-026-03511-7","vorDoiUrl":"https://doi.org/10.1007/s00726-026-03511-7","workflowStages":[]},"version":"v1","identity":"rs-7849136","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7849136","identity":"rs-7849136","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}