Ketoanalogs supplementation not only retarded kidney function deterioration but also reversed adverse outcomes in patients with advanced chronic kidney disease in a nationwide study

Ketoanalogs supplementation not only retarded kidney function deterioration but also reversed adverse outcomes in patients with advanced chronic kidney disease in a nationwide study | 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 Article Ketoanalogs supplementation not only retarded kidney function deterioration but also reversed adverse outcomes in patients with advanced chronic kidney disease in a nationwide study I Hsueh Lee, Cheng-Jui Lin, Feng-Chi Kuo, Fang-Ju Sun, Shu-O Chiang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5722164/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background and aims: Chronic kidney disease (CKD) is one of the most burdensome health conditions worldwide and necessitates the preservation of kidney function. In recent years, ketoanalogs (KAs) and low-protein diets have been used to treat end-stage renal disease (ESRD). In this study, we used theNational Health Insurance Research Database(NHIRD) of Taiwan to explore the benefits of KAs in clinical practice. Methods: Data on patients with CKD were extracted from the NHIRD for the period 2000–2013. After the data of 7,883 patients were extracted, 1:3 case‒control matching was performed to minimize the differences between KA users and nonusers. A time-dependent Cox regression model and a generalized estimating equation method wereused to examine the clinical effects of KAs in patients with advanced CKD. Results: After 1:3 case‒control matching, the patients were divided into a KA group ( n = 369) and a non-KA group (control, n = 1,107). The patients in the KA group had a longer duration from the time point of CKD diagnosis to ESRD compared with those in the control group (30.9 versus 16.8 months, p < 0.0001). In addition, the patients in the KA group had a lower mortality rate, fewer blood transfusions, and fewer erythropoietin prescriptions per month (mortality rate: 14.6% versus 32.8%, p < 0.01; blood transfusions: 18.9% versus 33.8%, p < 0.01; erythropoietin prescriptions per month: 0.8 versus 1.1, p < 0.01). These results indicated that KAs had a positive effect on patients withCKD. Conclusion: KAs have a major effect on patients with advanced CKD, enabling them to defer dialysis, thereby mitigating their anemia and reducing their mortality risk. Our real-world clinical data demonstrate that low-protein diets and KAs can mitigate the adverse effects of CKD in patients with advanced CKD. Health sciences/Diseases Health sciences/Medical research Health sciences/Nephrology ketoanalogs chronic kidney disease end-stage renal disease National Health Insurance Research Database Figures Figure 1 Figure 2 Figure 3 Introduction Chronic kidney disease (CKD) is a major public health concern, and its global prevalence has reached 13.4% worldwide. This high incidence of CKD contributed to an increase of 41.5% in the rates of mortality between 1990 and 2017 globally. 1 Therefore, more effective strategies are required to mitigate the risk of CKD and slow its progression. Diabetes mellitus (DM) and hypertension (HTN) are the major etiologies of CKD. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for CKD suggest that blood pressure and DM be targeted and individually adjusted. 2 In addition to control of blood sugar and blood pressure, previous KDIGO guidelines have emphasized the importance of dietary intake of nutrients, including protein and sodium, at different stages of CKD. 2 Nutritional status may play a key role in slowing the deterioration of kidney function in patients with CKD. 3,4 Research has also indicated that dietary adjustments and pharmacological interventions may aid in the management of CKD. Recently, low-protein diets (LPDs, 0.6–0.8 g protein/kg) and very-low-protein diets (VLPDs, <0.6 g protein/kg) have been used in clinical practice to control CKD. 3 Multiple studies have indicated that VLPDs have a positive effect on patients with CKD (e.g., by slowing the progression of CKD), although these diets increase the risk of protein-energy wasting syndrome. 3,5–7 Malnutrition may be a consequence of well adherence to low protein diet or reduced daily protein intake in CKD. Li et al . 8 reported that restricted protein intake with ketoanalogs (KAs) supplementation significantly delayed the progression of CKD and prevented the development of malnutrition in patients with CKD. Garneata et al . 9 conducted a clinical trial to compare the effects of LPDs and VLPDs with KAs supplementation on renal outcomes. They reported that, compared with patients who received LPDs, those who received VLPDs with KAs had a considerably lower rate of CKD deterioration and a lower acid load. Although clinical trials indicate that KAs have a positive effect on patients with CKD, no studies have yet confirmed the effectiveness of KAs in real-world practice. KAs have been approved by the National Health Insurance of Taiwan for patients with stage 5 CKD. In this study, we collected and analyzed data from the National Health Insurance Research Database (NHIRD) of Taiwan to evaluate whether KAs can slow the progression of CKD and improve the clinical outcomes of patients with advanced CKD. Materials and Methods Data collection In this retrospective cohort study, we retrieved cause-of-death information from the NHIRD for the period between 2000 and 2013 to determine the benefits of KAs in terms of dialysis outcomes, risk of anemia, blood transfusions, and mortality rate for patients with advanced CKD. We obtained data on a sample of 2.6 million individuals, representative of the general population. The NHIRD includes patient age, sex, date of admission, diagnosis, medical record, prescription record, and date of death, but it does not include nutritional markers, protein intake patterns, or patient biochemistry. This study was approved by the Institutional Review Board of Mackay Memorial Hospital (approval no. 23MMHIS214e). Study population Patients who received a diagnosis of CKD ( International Classification of Diseases, Ninth Revision, Clinical Modification [ ICD-9-CM ] code: 585) between 2000 and 2013 and who visited an outpatient clinic at least twice or were hospitalized were included in the study. Those who were under 18 years of age and whose sex was not mentioned in their records were excluded. The maximum KAs dose that can be obtained without the need for copayment is six tablets. Patients who received KAs, erythropoietin (EPO) injections, dialysis, or blood transfusions before receiving their CKD diagnosis were excluded. According to the Taiwanese National Health Insurance regulations, KAs and EPO injections can be prescribed for patients with CKD whose serum creatinine level is above 6 mg/dL or whose estimated glomerular filtration rate (eGFR) is below 15 mL/min/1.73 m 2 for 3 consecutive months. In clinical practice, physicians tend to provide multidisciplinary CKD education, including education on LPDs, in accordance with the KDIGO guidelines. 2 Blood transfusion is used for different purposes depending on each patient’s needs to improve their clinical outcomes. Figure 1 depicts a flowchart ofthe study population selection process. A total of 8,439 patients, 550 who received KAs and 7,889 who did not receive KAs, were identified from the NHIRD. Each KA user was matched with three non-KA users through 1:3 case‒control matching to minimize the differences and avoid potential confounding between the two groups, with pairing by age, sex, and medications before CKD diagnosis. These medications included statins (ATC code: C10AA), angiotensin-converting enzyme inhibitors (ACEIs, ATC code: C09AA), and angiotensin receptor blockers (ARBs, ATC code: C09CA). A total of 181 patients were excluded from the analysis because they could not be matched. Outcome measurement and definition The primary outcome for this study was the positive effects of KAs, including the legacy effect of KA treatment on dialysis ( International Classification of Diseases, Ninth Revision, Clinical Modification/Procedure Coding System [ ICD-9-CM/PCS ] codes: 39.95 and 54.98). We comprehensively evaluated the risks of all-cause mortality, blood transfusion ( ICD-9-CM/PCS code: 99.0, with the exception of thalassemia [ ICD-9-CM code: 282.4] and leukemia [ ICD-9-CM codes: 204–208]), and anemia (as indicated by a prescription of EPO, ATC codes: B03XA01, B03XA02, and B03XA03). Each KAs user was matched to three non-KAs users (patients with CKD who never received KAs) by age, sex, cardiac disease medication, and use of statins, ACEIs, and ARBs to avoid potential confounders. This 1:3 case–control matching procedure ensured that the influence of comorbidities on our results was controlled (Supplementary Table 1). DM ( ICD-9-CM code: 250), HTN ( ICD-9-CM codes: 401–405), hyperlipidemia ( ICD-9-CM code: 272), atrial fibrillation (AF ICD-9-CM code: 427.31), stroke ( ICD-9-CM codes: 430–438), ischemic heart disease ( ICD-9-CM codes: 410–414), heart failure ( ICD-9-CM code: 428), and peripheral arterial occlusive disease (PAOD, ICD-9-CM codes: 440.0, 440.2, 440.3, 440.8, 440.9, 444.0, 444.8, 444.9, 447.9, and 444.22; ICD-9-CM/PCS codes: 39.7, 38.08, 30.18, 38.38, 38.48, 38.68, 38.88, 39.50, 39.90, 39.25, 39.26, and 39.29) were regarded as comorbidities. Statistical analysis To explore the effect of KAs on patients with advanced CKD, we conducted a within-patient analysis and divided the patients who received KAs into three groups in accordance with their observation period. The first group included patients who received their CKD diagnosis before they were started on KAs, the second group included patients who received their CKD diagnosis while they were on KAs, and the third group included patients who stopped using KAs until the end of the observation period. In the third group, the legacy effect of KAs was examined to determine whether the protective effect of KAs remained even after they were stopped. We used time-dependent covariate Cox regression to evaluate the effectiveness and safety of the treatment while accounting for dialysis, death, and blood transfusion. Patients in the first group who used KAs and those who did not use KAs served as the control group. We established another model to observe the positive effect of KAs. All patients were monitored once they were started on KAs until the end of the study period. Patients who received a diagnosis of CKD before they were started on KAs were regarded as the control group for a within-patient analysis. After designating a control group through 1:3 case–control matching, we conducted chi-square and independent t tests to examine the differences in demographic variables, medications, and comorbidities before matching. We compared these variables after matching by using a generalized estimating equation (GEE) method for a univariate analysis. To analyze numerical binary outcomes-such as death, dialysis, and blood transfusion—we employed time-dependent covariate Cox regression. We utilized a GEE method for numerical data such as monthly dialysis frequency, EPO prescription frequency, and duration from CKD diagnosis to dialysis. We also evaluated the relationship between the dosage of KAs and the prognosis of ESRD, focusing on the positive effect of each additional KAs tablet. We categorized the dosage of KAs either into one to four tablets per day or into five or six tablets per day, and we compared the efficacy of these dosages with that of the control group. Stratified Cox regression was employed to examine the efficacy of KAs in case a patient’s prognosis involved binary data, such as death, dialysis, or blood transfusion. For numerical data—such as monthly dialysis frequency, EPO prescription frequency, and duration from CKD diagnosis to dialysis—we used a GEE method to explore the efficacy of KAs. A two-sided p value less than 0.05 was considered statistically significant. All statistical analyses were conducted using SAS software version 9.4 (SAS Institute, Cary, NC, USA). Results Patient characteristics Figure 1 demonstrates a flowchart of the study population selection process for the period 2000 to 2013. Of all patients, 550 were KAs users, and 7,889 were non-KAs users. Before matching, significant differences were discovered in the distributions of age and comorbidities (DM, AF, ischemic heart disease, and heart failure) between the two groups (Supplementary Table 1). Table 1 presents details on the patients in the KAs group ( n = 369) and non-KAs group ( n = 1,107) after 1:3 case‒control matching. No differences were found in age, sex, ACEI use, ARB use, statin use, or comorbidities between the two groups. In the KAs group, 58.8% of the patients had DM, and 87% of the patients had HTN. Compared with the non-KAs group, the KAs group had a significantly lower mortality rate (14.6% versus 32.8%) and blood transfusion rate (19.2% versus 34.2%). The duration from CKD diagnosis to dialysis was longer in the KAs group than in the non-KAs group, being a median (interquartile range) of 30.9 (10.8–56.6) months in the KAs group and 16.8 (4.4–42.6) months in the non-KAs group. In addition, EPO was less commonly prescribed in the KAs group than in the non-KAs group, with a median (interquartile range) of 0.8 (0.4–1.7) prescriptions per month in the KAs group and 1.1 (0.4–2.9) prescriptions per month in the non-KAs group. Efficacy: Progression of CKD We used dialysis, duration from CKD diagnosis to dialysis, and monthly dialysis frequency as clinical kidney outcomes to evaluate the effect of KAs supplementation. The duration from CKD diagnosis to dialysis significantly differed between the KAs group and non-KAs group (hazard ratio [HR] = 12.38, p < 0.001; Table 2), with the patients taking KAs having a longer duration from CKD diagnosis to dialysis. Compared with the non-KAs group, the KAs group had a significantly lower rate of dialysis (HR = 0.73, p = 0.005). In addition, the frequency of monthly dialysis was significantly lower in the KAs group than in the non-KAs group (HR = −0.33, p < 0.001). Similar results were obtained for dialysis, duration from CKD diagnosis to dialysis, and monthly dialysis frequency in the patients who stopped using KAs and those who did not take KAs (HR = 0.833, p < 0.008; HR = 7.53, p < 0.001; and HR = −0.21, p < 0.001, respectively). The patients who used KAs exhibited improved clinical kidney outcomes across the entire study period. The patients in the KAs group had a longer mean duration to dialysis compared with those in the non-KAs group (mean = 30.9 and 15.8, respectively, p < 0.001, log rank p = 0.001; Figures 2A and 3A). The mean frequency of monthly dialysis was 0.4 in the KA group and 0.8 in the non-KAs group ( p < 0.001, Figure 2B). Efficacy: Mortality and anemia In addition to clinical kidney outcomes, we evaluated the effects of KAs supplementation on the risks of mortality and anemia. The results indicated a significantly lower mean rate of mortality in the KAs group than the control group (14.6% vs. 32.8%, p < 0.001; Table 1). After KAs supplementation was stopped, the rate of mortality was significantly lower in patients who used KAs than in the control group (HR = 0.63, p = 0.001; Table 2). Overall, the rate of mortality was lower in the KAs group than in the control group (log rank p < 0.001, Figure 3C). We explored the effect of KAs supplementation on anemia from two perspectives. As shown in Table 2, the patients who used KAs were more likely to have blood transfusion compared with those who did not (HR = 2.29, p = 0.013). However, throughout the study period, the frequency of blood transfusion was significantly lower in the KAs group than in the control group (HR = 0.35, p < 0.001, log rank p = 0.002; Figure 3B). In addition, the frequency of monthly EPO prescription was significantly lower in the KAs group than in the non-KAs group (HR = −0.84, p < 0.001). No significant difference was discovered between the KAs and control groups in terms of the period of KAs cessation (HR = −0.10, p = 0.73). The mean frequency of monthly EPO prescription was lower in the KAs group than in the non-KAs group (0.8 and 1.1 prescriptions per month, respectively, p < 0.001; Figure 2C). Taken together, these results indicate that KA supplementation can not only alleviate renal anemia but also reduce the likelihood of mortality in patients with advanced CKD. Efficacy: Dose–response effect of KAs and clinical outcomes We examined the effect of KAs supplementation at different dosages (one tablet, one to four tablets, or five or six tablets per day) on the clinical outcomes of patients with CKD (Table 3). Stratified Cox regression was employed to explore the dose–response effect of KAs on the risks of dialysis, mortality, and blood transfusion. In addition, we used a GEE method to examine the dose–response effects of KAs on the monthly dialysis frequency, duration from CKD diagnosis to dialysis, and monthly EPO prescription frequency. The results indicated that the patients who were prescribed five or six KAs tablets per day had more favorable clinical outcomes compared with the control group ( p < 0.05). In addition, patients who were prescribed one to four KAs tablets per day had significantly better kidney function, lower mortality risk, and less severe renal anemia ( p < 0.05). Furthermore, we examined the clinical outcomes of the patients with CKD who were prescribed only one KAs tablet per day. The results indicated that even a single tablet of KAs per day had a significantly positive clinical effect ( p < 0.001). Taken together, our findings indicate that KAs, regardless of their dosage, have a positive effect on patients with CKD. Discussion In this study, we discovered that supplementing an LPD with KAs not only slowed the deterioration of kidney function but also reduced the risk of mortality in patients with advanced CKD. We discovered that the rates of blood transfusion and EPO prescription were significantly lower in the patients who received KAs than in those who did not. Regardless of the number of KA tablets prescribed, the patients who received KAs had more favorable clinical outcomes compared with those who did not receive KAs. Preventing CKD from rapidly progressing to ESRD is regarded as a major public health task worldwide. LPDs and VLPDs with KAs supplementation are typically used for the management of advanced CKD, as recommended by the KDIGO guidelines. 2 Although patients with CKD can be further educated on their condition through multidisciplinary care programs in medical centers across Taiwan, the main concern is whether an LPD or VLPD would cause a nutrient deficiency or exacerbate protein-energy wasting. 11–13 KAs supplementation is a nutritionally safe approach that can substantially delay the deterioration of renal function in patients with advanced CKD. 8.9 Chen et al. 14 argued that KAs supplementation has positive effects on the 5-year mortality rate and incidence of ESRD in patients with stage 5 diabetic kidney disease. However, these positive findings regarding KAs were obtained in research with a rigorous and optimal clinical design; the actual effect of KAs in clinical practice remains unclear. In Taiwan, KAs are covered by the National Health Insurance system for patients with stage 5 CKD. In this study, we extracted the data of patients with advanced CKD who used KAs from the NHIRD for the period 2000–2013 to yield representative results that truly reflect patients’ actual conditions. Our results indicated that KAs supplementation not only extended the duration from CKD diagnosis to dialysis but also reduced the risk of mortality in patients with CKD throughout the study period. We also obtained kidney function and mortality results consistent with those of previous clinical trials. 8,9,14 The benefits of KAs can persist even after the KAs are discontinued. This phenomenon is referred to as the legacy effect and appears to be proportional to the duration and intensity of the initial therapy. Certain medications used in diabetes, lipid lowering, and HTN management have legacy effects. 15 We explored whether KAs supplementation affected the incidence of renal anemia in our nationwide clinical study. Our results indicated that the frequency of monthly EPO prescription was significantly lower in the KAs group than in the control group. In addition, the frequency of blood transfusion was significantly lower after KAs supplementation. Renal anemia is a common complication and a major risk factor for cardiovascular events in patients with CKD. 16–18 The primary cause of anemia in patients with CKD is low production of EPO as CKD progresses. 19 After KAs supplementation, the cardiovascular risk of patients with CKD may decrease because of the amelioration of their anemia. In this study, we discovered that KAs supplementation had a legacy effect and reduced the frequencies of EPO prescription and blood transfusion. We explored the factors underlying the positive effects of KAs supplementation on patients with CKD. The positive effects are speculated to have originated from the preservation of the patients’ eGFR or may have been related to a change in their gut microbiota. Rocchetti et al. 20 reported that KAs reduced the quantity of protein-bound uremic toxins, namely indoxyl sulfate and p -cresyl sulfate, in patients with CKD by altering their gut flora. Chang et al. 21 demonstrated that an LPD with KAs supplementation had a positive effect on the endothelial function of and levels of protein-bound uremic toxins in patients with CKD. Indoxyl sulfate leads to cardiovascular mortality 22 and renal anemia by promoting red blood cell death, resulting in EPO resistance and thereby inhibiting hypoxia-inducible factors; 23 however, the mechanism underlying this process remains unclear. Further prospective studies are required to elucidate a definite mechanism. Further research is required to determine whether KAs have a dose–response effect. In Taiwan, the National Health Insurance system covers the cost of KAs for patients with stage 5 CKD at a maximum dosage of six tablets per day, regardless of a patient’s body weight (one tablet per 5-10 kg body weight per day). Patients with advanced CKD already take many medications every day, and some of them are not willing to take the full dose of KAs. Therefore, physicians usually reduce their patients’ doses to one to six tablets per day depending on the patient’s condition. In this study, we explored the effect of different KAs doses on the clinical outcomes of patients with CKD. Our results indicated that, compared with the control group, the patients who received one to six tablets per day had a significantly longer duration to kidney function deterioration and a lower all-cause mortality rate. Wu et al . 24 argued that prescribing more than 5.5 tablets of KAs per day has a positive effect on patients with CKD. Further research is required to identify the reason for these discrepancies between studies from the same country. We speculate that these discrepancies are attributable to the use of the NHIRD at different time points. In this study, we adopted a longer time frame than those used in previous studies. Therefore, regardless of the dose of KAs prescribed for patients with CKD, these patients had favorable clinical outcomes. Despite our novel findings regarding the effects of KAs on patients with CKD, this study has several limitations. First, LPDs were introduced to patients with CKD by their physician. In the NHIRD, the nutritional markers or characteristics of the proteins administered to these patients were not clarified. In addition, we could not determine whether the patients received animal- or plant-based proteins, and we were unable to confirm whether the KAs sand non-KAs groups actually complied with their physicians’ LPD recommendations. Second, KAs were prescribed at outpatient clinics for patients who met the criteria for stage 5 CKD. We could not confirm whether each patient regularly took their KAs pills. To the best of our knowledge, no objective parameter is yet available for examining the drug compliance of these patients. Third, this was a retrospective study. Although we adopted 1:3 case–control matching to minimize the differences between the KAs and non-KAs groups, these patients had certain factors, such as the timing of blood transfusion, that may have influenced their clinical course. Fourth, we were unable to identify the cause of the legacy effect of KA supplementation. Finally, no laboratory data were available for this study, and we were unable to evaluate the effect of KAs on the renal function or other biochemical parameters of the two groups. Conclusion Overall, this nationwide clinical study of real-world data confirms the positive effect of KA supplementation on the kidney function and overall mortality risk of patients with advanced CKD. Patients receiving KAs may require less blood transfusion and EPO prescription. Further prospective research is required to address the aforementioned limitations. Declarations Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflicts of interest The authors have no conflicts of interest to declare. Author contributions Cheng-Jui Lin: Conceptualization; Shu-O Chiang: Formal Analysis; I Hsueh Lee, Cheng-Jui Lin, Fang-Ju Sun, and Shu-O Chiang: Investigation; Shu-O Chiang: Methodology; Cheng-Jui Lin and Feng-Chi Kuo: Supervision; I Hsueh Lee: Writing—Original Draft; Cheng-Jui Lin: Writing-Review & Editing. Data availability The data that support the findings of this study are available from Taiwan’s Ministry of Health and Welfare but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Taiwan’s Ministry of Health and Welfare. References Kovesdy CP. Epidemiology of chronic kidney disease: an update 2022. 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J Cachexia Sarcopenia Muscle 2018;9(2):235-45. doi: 10.1002/jcsm.12264 [published Online First: 20171102] Watanabe S. Low-protein diet for the prevention of renal failure. Proc Jpn Acad Ser B Phys Biol Sci 2017;93(1):1-9. doi: 10.2183/pjab.93.001 Ko GJ, Kalantar-Zadeh K. How important is dietary management in chronic kidney disease progression? A role for low protein diets. Korean J Intern Med 2021;36(4):795-806. doi: 10.3904/kjim.2021.197 [published Online First: 20210622] Chen HY, Sun CY, Lee CC, et al. KAs supplements reduce mortality in patients with pre-dialysis advanced diabetic kidney disease: A nationwide population-based study. Clin Nutr 2021;40(6):4149-60. doi: 10.1016/j.clnu.2021.01.045 [published Online First: 20210206] Wander GS, Bansal M. Legacy effect in medicine-the expanding horizon! Indian Heart J. 2018 Nov-Dec;70(6):769-771. Hanna RM, Streja E, Kalantar-Zadeh K. Burden of Anemia in Chronic Kidney Disease: Beyond Erythropoietin. Adv Ther 2021;38(1):52-75. doi: 10.1007/s12325-020-01524-6 [published Online First: 20201029] Ku E, Del Vecchio L, Eckardt KU, et al. Novel anemia therapies in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2023;104(4):655-80. doi: 10.1016/j.kint.2023.05.009 [published Online First: 20230524] Toft G, Heide-Jorgensen U, van Haalen H, et al. Anemia and clinical outcomes in patients with non-dialysis dependent or dialysis dependent severe chronic kidney disease: a Danish population-based study. J Nephrol 2020;33(1):147-56. doi: 10.1007/s40620-019-00652-9 [published Online First: 20191005] Fishbane S, Spinowitz B. Update on Anemia in ESRD and Earlier Stages of CKD: Core Curriculum 2018. Am J Kidney Dis 2018;71(3):423-35. doi: 10.1053/j.ajkd.2017.09.026 [published Online First: 20180111] Rocchetti MT, et al. Ketoanalogs’ Effects on Intestinal Microbiota Modulation and Uremic Toxins Serum Levels in Chronic Kidney Disease. J Clin Med. 2021 18;10:840. Chang G, Shih HM, Pan CF, et al. Effect of Low Protein Diet Supplemented with Ketoanalogs on Endothelial Function and Protein-Bound Uremic Toxins in Patients with Chronic Kidney Disease. Biomedicines 2023, 11, 1312. Barreto FC, et al. European Uremic Toxin Work Group (EUTox). Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin J Am Soc Nephrol. 2009;4:1551-8. Hamza E et al. Uremic Toxins Affect Erythropoiesis during the Course of Chronic Kidney Disease: A Review. Cells 2020, 9, 2039. Wu CH, Yang YW, Hung SC, et al. KAss supplementation decreases dialysis and mortality risk in patients with anemic advanced chronic kidney disease. PLoS One 2017;12(5):e0176847. doi: 10.1371/journal.pone.0176847 [published Online First: 20170505] Tables Table 1. Demographics, medications, and clinical parameters of the KAs and non-KAs groups before CKD diagnosis (matched). Characteristics KAs (n=369) Non-KAs (n=1,107) p n % n % Age (years) 18–44 22 6.0 66 6.0 -- 45–64 195 52.9 585 52.9 ≥65 152 41.2 456 41.2 Mean, SD 61.1 11.3 61.1 11.3 -- Sex (male) 187 50.7 561 50.7 -- Medications before CKD diagnosis Statins 162 43.9 486 43.9 -- ACEIs 286 77.5 858 77.5 -- ARBs 195 52.9 585 52.9 -- Comorbidities before CKD diagnosis a DM 217 58.8 655 59.2 0.8845 HTN 321 87.0 942 85.1 0.246 Hyperlipidemia 202 54.7 595 53.8 0.667 AF 4 1.1 23 2.1 0.195 Stroke 105 28.5 262 23.7 0.060 Ischemic heart disease 143 38.8 438 39.6 0.770 Heart failure 62 16.8 203 18.3 0.491 PAOD 45 12.2 116 10.5 0.347 Clinical parameters a Mortality 54 14.6 363 32.8 <0.001** Blood transfusion 70 18.9 374 33.8 <0.001** Dialysis 369 100.0 1107 100.0 -- Monthly dialysis frequency b 0.4 0.2-0.8 0.8 0.4-1.0 <0.001** Duration from CKD diagnosis to dialysis (months) b 30.9 10.8-56.6 16.8 4.4-42.6 <0.001** EPO injection 369 100.0 1107 100.0 -- Monthly EPO prescription frequency b 0.8 0.4-1.7 1.1 0.4-2.9 <0.001** a Analyzed using a univariate GEE method. b Presented as medians and interquartile ranges. Table 2. Effects of KAs on the clinical outcomes of patients with CKD. Outcomes of CKD During KA use (1) After KA cessation (2) Entire course (1 + 2) c HR (95% CI) p HR (95% CI) p HR (95% CI) p Mortality a -- -- 0.63 (0.47-0.84) 0.001** 0.63 (0.47-0.84) 0.001** Blood transfusion a 2.29 (1.18-4.44) 0.013** 0.28 (0.20-0.40) <0.001** 0.35 (0.25–0.48) <0.001** Dialysis a 0.73 (0.58-0.91) 0.005** 0.83 (0.72-0.95) 0.008** 0.80 (0.71–0.91) <0.001** Monthly dialysis frequency b -0.33 (-0.42 – -0.23) <0.001** -0.21 (-0.28 – -0.13) <0.001** -0.24 (-0.30 – -0.17) <0.001** Duration from CKD diagnosis to dialysis (months) b 12.38 (5.42-19.35) <0.001** 7.53 (3.67-11.39) 0.001** 8.74 (5.24–12.25) <0.001** Monthly EPO prescription frequency b -0.84 (-1.29 – -0.39) <0.001** -0.10(-0.64-0.45) 0.730 -0.46 (-0.84 – -0.09) 0.015* The reference group comprised the control group and KAs group at the immortal time points. a Analyzed using time-dependent Cox regression. KAs supplementation and KAs cessation were defined as 1 and 2, respectively, in the regression model, and the reference group was defined as 0. * p < 0.05, ** p < 0.01. b Analyzed using a GEE method. Values are presented as regression coefficients and 95% CIs. * p < 0.05, ** p < 0.01. c After KAs supplementation (1 + 2). In time-dependent Cox regression, the data obtained after KAs supplementation pertained to the KAs group. Table 3. Dose‒response relationship between KAs supplementation and clinical outcomes in patients with CKD. Prognosis in CKD Per one tablet Control group ( n = 1,107) One to four tablets ( n = 272, 73.7%) Five or six tablets ( n = 97, 26.3%) HR (95% CI) p HR HR (95% CI) p HR (95% CI) p Mortality a 0.87 (0.80-0.94) <0.001** 1.00 0.61 (0.43-0.87) 0.005** 0.45 (0.25-0.80) 0.006** Blood transfusion a 0.89 (0.83-0.95) <0.001** 1.00 0.67 (0.49-0.92) 0.013* 0.53 (0.31-0.89) 0.017* Dialysis a 0.92 (0.88-0.95) <0.001** 1.00 0.68 (0.57-0.81) <0.001** 0.69 (0.52-0.92) 0.012* Monthly dialysis frequency b -0.06 (-0.07 – -0.04) <0.001** 0.00 -0.24 (-0.31 – -0.16) <0.001** -0.26 (-0.35 – -0.17) <0.001** Duration from CKD diagnosis to dialysis (months) b 1.81 (1.01-2.61) <0.001** 0.00 7.45 (3.60-11.31) 0.0001** 8.77 (2.94-14.61) 0.003** Monthly EPO prescription frequency b -0.12(-0.18- -0.07) <0.001** 0.00 -0.58 (-0.82- -0.34) <0.001** -0.56 (-0.90- -0.23) 0.001** a Analyzed using stratified Cox regression. * p < 0.05, ** p < 0.01. b Analyzed using a GEE method. Values are presented as regression coefficients and 95% CIs. * p < 0.05, ** p < 0.01. Additional Declarations No competing interests reported. Supplementary Files SupplementaryTable1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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-5722164","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":405145164,"identity":"bf231fda-0ffa-4599-9819-f4337a290102","order_by":0,"name":"I Hsueh Lee","email":"","orcid":"","institution":"Pingtung Christian Hospital","correspondingAuthor":false,"prefix":"","firstName":"I","middleName":"Hsueh","lastName":"Lee","suffix":""},{"id":405145165,"identity":"3d1ad581-a9dc-4499-9879-68f1001a5f06","order_by":1,"name":"Cheng-Jui Lin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAArElEQVRIiWNgGAWjYBACPmYgIVHBwGBAtBY2sJYzcC1E6GQDEYxtJGlh5z34wXLetmhzBuZjH78w/ElsIOwwvmQJyW23c3c2sCXPlmEwIEYLjxkDSMuGAzzGzBIMBrlEaplDupYGiBbGD0RqMZaQOAbUcpgtmZnBwLieoBZ+/jOGnyVqgFqONx9m/FEhZ0xIBxgAvQAigYiH2DQA9AKU8YNIHaNgFIyCUTCyAAAB4TJsJN8kdgAAAABJRU5ErkJggg==","orcid":"","institution":"Mackay Memorial Hospital","correspondingAuthor":true,"prefix":"","firstName":"Cheng-Jui","middleName":"","lastName":"Lin","suffix":""},{"id":405145166,"identity":"076e55db-6d81-4eca-a604-d1072a2fa253","order_by":2,"name":"Feng-Chi Kuo","email":"","orcid":"","institution":"Taitung Mackey Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Feng-Chi","middleName":"","lastName":"Kuo","suffix":""},{"id":405145167,"identity":"e2c83473-e7c6-45a7-bf20-fc9db156aa41","order_by":3,"name":"Fang-Ju Sun","email":"","orcid":"","institution":"Mackay Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fang-Ju","middleName":"","lastName":"Sun","suffix":""},{"id":405145168,"identity":"a2b3788e-6620-4cd8-8556-bbc71690e50e","order_by":4,"name":"Shu-O Chiang","email":"","orcid":"","institution":"National Defense Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Shu-O","middleName":"","lastName":"Chiang","suffix":""}],"badges":[],"createdAt":"2024-12-27 14:23:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5722164/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5722164/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":75308496,"identity":"5ac617a6-b671-481c-b0a4-e9cbc4d2789a","added_by":"auto","created_at":"2025-02-03 08:47:53","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":227222,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the\u003cstrong\u003e \u003c/strong\u003estudy population selection process for the period 2000 to 2013.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5722164/v1/9070b925a30265efc818b057.jpeg"},{"id":75308487,"identity":"d2700c97-d33a-4309-88f2-d0796a0a7f02","added_by":"auto","created_at":"2025-02-03 08:47:52","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":31719,"visible":true,"origin":"","legend":"\u003cp\u003eBoxplot of the GEE analysis of the KAs and non-KAs groups: (A) monthly duration from CKD diagnosis to dialysis,(B) monthly dialysis frequency, and(C) monthly EPO prescription frequency.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5722164/v1/9c0a15b6809df60c21c73d4e.jpg"},{"id":75308493,"identity":"6988bf44-0a8f-4401-b7f7-8e32207eda71","added_by":"auto","created_at":"2025-02-03 08:47:53","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":187148,"visible":true,"origin":"","legend":"\u003cp\u003eTime-dependent survival curves of the KAs and non-KAs groups: (A) duration from CKD diagnosis to dialysis, (B) blood transfusion after CKD diagnosis, and (C) cumulative mortality rate after CKD diagnosis. The blue dotted line represents the KAs group, and the red line represents the non-KAs group.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-5722164/v1/135c8b4be53d8bd8b44975d8.png"},{"id":79413665,"identity":"c87c538d-6bf4-4a07-83e2-175def345296","added_by":"auto","created_at":"2025-03-28 06:47:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1095353,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5722164/v1/4762a9fa-d45d-449f-8da5-3fd304112631.pdf"},{"id":75308512,"identity":"3d4530fe-2127-4c8b-900a-840cf031fa38","added_by":"auto","created_at":"2025-02-03 08:47:54","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18052,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5722164/v1/eccd1859291e762765250cff.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Ketoanalogs supplementation not only retarded kidney function deterioration but also reversed adverse outcomes in patients with advanced chronic kidney disease in a nationwide study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChronic kidney disease (CKD) is a major public health concern, and its global prevalence has reached 13.4% worldwide. This high incidence of CKD contributed to an increase of 41.5% in the rates of\u0026nbsp;mortality between 1990 and 2017 globally.\u003csup\u003e1\u003c/sup\u003e Therefore, more effective strategies are required to\u0026nbsp;mitigate\u0026nbsp;the\u0026nbsp;risk\u0026nbsp;of CKD and slow its progression.\u003c/p\u003e\n\u003cp\u003eDiabetes mellitus (DM) and hypertension (HTN) are the major etiologies of CKD. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for CKD suggest that blood pressure and DM be targeted and individually adjusted.\u003csup\u003e2\u003c/sup\u003e In addition to control of blood sugar and blood pressure, previous KDIGO guidelines have emphasized the importance of dietary intake of nutrients, including protein and sodium, at different stages of CKD.\u003csup\u003e2\u003c/sup\u003e Nutritional status may play a key role in slowing the deterioration of kidney function in patients with CKD.\u003csup\u003e3,4\u003c/sup\u003e Research has also indicated that dietary adjustments and pharmacological interventions may aid in the management of CKD. Recently, low-protein diets (LPDs, 0.6\u0026ndash;0.8 g protein/kg) and very-low-protein diets (VLPDs, \u0026lt;0.6 g protein/kg) have been used in clinical practice to control CKD.\u003csup\u003e3\u003c/sup\u003e Multiple studies have indicated that VLPDs have a positive effect on patients with CKD (e.g., by slowing the progression of CKD), although these diets increase the risk of protein-energy wasting syndrome.\u003csup\u003e3,5\u0026ndash;7\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eMalnutrition may be a consequence of well adherence to low protein diet or reduced daily protein intake in CKD. Li \u003cem\u003eet al\u003c/em\u003e.\u003csup\u003e8\u003c/sup\u003e reported that restricted protein intake with ketoanalogs (KAs) supplementation significantly delayed the progression of CKD and prevented the development of malnutrition in patients with CKD.\u003csup\u003e\u0026nbsp;\u003c/sup\u003eGarneata \u003cem\u003eet al\u003c/em\u003e.\u003csup\u003e9\u003c/sup\u003e conducted a clinical trial to compare the effects of LPDs and VLPDs with KAs supplementation on renal outcomes. They reported that, compared with patients who received LPDs, those who received VLPDs with KAs had a considerably lower rate of CKD deterioration and a lower acid load.\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAlthough clinical trials indicate that KAs have a positive effect on patients with CKD, no studies have yet confirmed the effectiveness of KAs in real-world practice. KAs have been approved by the National Health Insurance of Taiwan for patients with stage 5 CKD. In this study, we collected and analyzed data from the National Health Insurance Research Database (NHIRD) of Taiwan to evaluate whether KAs can slow the progression of CKD and improve the clinical outcomes of patients with advanced CKD.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eData collection\u003c/p\u003e\n\u003cp\u003eIn this retrospective cohort study, we retrieved cause-of-death information from the NHIRD for the period between 2000 and 2013 to determine the benefits of KAs in terms of dialysis outcomes, risk of anemia, blood transfusions, and mortality rate for patients with advanced CKD. We obtained data on a sample of 2.6 million individuals, representative of the general population. The NHIRD includes patient age, sex, date of admission, diagnosis, medical record, prescription record, and date of death, but it does not include nutritional markers, protein intake patterns, or patient biochemistry. This study was approved by the Institutional Review Board of Mackay Memorial Hospital (approval no. 23MMHIS214e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStudy population\u003c/p\u003e\n\u003cp\u003ePatients who received a diagnosis of CKD (\u003cem\u003eInternational Classification of Diseases, Ninth Revision, Clinical Modification\u003c/em\u003e [\u003cem\u003eICD-9-CM\u003c/em\u003e] code: 585) between 2000 and 2013 and who visited an outpatient clinic at least twice or were hospitalized were included in the study. Those who were under 18 years of age and whose sex was not mentioned in their records were excluded. The maximum KAs dose that can be obtained without the need for copayment is six tablets. Patients who received KAs, erythropoietin (EPO) injections, dialysis, or blood transfusions before receiving their CKD diagnosis were excluded.\u003c/p\u003e\n\u003cp\u003eAccording to the Taiwanese National Health Insurance regulations, KAs and EPO injections can be prescribed for patients with CKD whose serum creatinine level is above 6 mg/dL or whose estimated glomerular filtration rate (eGFR) is below 15 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e for 3 consecutive months. In clinical practice, physicians tend to provide multidisciplinary CKD education, including education on LPDs, in accordance with the KDIGO guidelines.\u003csup\u003e2\u003c/sup\u003e Blood transfusion is used for different purposes depending on each patient’s needs to improve their clinical outcomes.\u003c/p\u003e\n\u003cp\u003eFigure 1 depicts\u0026nbsp;a flowchart ofthe study population selection process. A total of\u0026nbsp;8,439 patients, 550 who received KAs and 7,889 who did not receive KAs, were identified from the NHIRD. Each KA user was matched with three non-KA users through 1:3 case‒control matching to minimize the differences and avoid potential confounding between the two groups, with pairing by age, sex, and medications before CKD diagnosis. These medications included statins (ATC code: C10AA), angiotensin-converting enzyme inhibitors (ACEIs, ATC code: C09AA), and angiotensin receptor blockers (ARBs, ATC code: C09CA). A total of 181 patients were excluded from the analysis because they could not be matched.\u003c/p\u003e\n\u003cp\u003eOutcome measurement and definition\u003c/p\u003e\n\u003cp\u003eThe primary outcome for this study was the positive effects of KAs, including the legacy effect of KA treatment on dialysis (\u003cem\u003eInternational Classification of Diseases, Ninth Revision, Clinical Modification/Procedure Coding System\u003c/em\u003e [\u003cem\u003eICD-9-CM/PCS\u003c/em\u003e] codes: 39.95 and 54.98). We comprehensively evaluated the risks of all-cause mortality, blood transfusion (\u003cem\u003eICD-9-CM/PCS\u003c/em\u003e code: 99.0, with the exception of thalassemia [\u003cem\u003eICD-9-CM\u003c/em\u003e code: 282.4] and leukemia [\u003cem\u003eICD-9-CM\u003c/em\u003e codes: 204–208]), and anemia (as indicated by a prescription of EPO, ATC codes: B03XA01, B03XA02, and B03XA03).\u003c/p\u003e\n\u003cp\u003eEach KAs user was matched to three non-KAs users (patients with CKD who never received KAs) by age, sex, cardiac disease medication, and use of statins, ACEIs, and ARBs to avoid potential confounders. This 1:3 case–control matching procedure ensured that the influence of comorbidities on our results was controlled (Supplementary Table 1). DM (\u003cem\u003eICD-9-CM\u003c/em\u003e code: 250), HTN (\u003cem\u003eICD-9-CM\u003c/em\u003e codes: 401–405), hyperlipidemia (\u003cem\u003eICD-9-CM\u003c/em\u003e code: 272), atrial fibrillation (AF \u003cem\u003eICD-9-CM\u003c/em\u003e code: 427.31), stroke (\u003cem\u003eICD-9-CM\u003c/em\u003e codes: 430–438), ischemic heart disease (\u003cem\u003eICD-9-CM\u003c/em\u003e codes: 410–414), heart failure (\u003cem\u003eICD-9-CM\u003c/em\u003e code: 428), and peripheral arterial occlusive disease (PAOD, \u003cem\u003eICD-9-CM\u003c/em\u003e codes: 440.0, 440.2, 440.3, 440.8, 440.9, 444.0, 444.8, 444.9, 447.9, and 444.22; \u003cem\u003eICD-9-CM/PCS\u003c/em\u003e codes: 39.7, 38.08, 30.18, 38.38, 38.48, 38.68, 38.88, 39.50, 39.90, 39.25, 39.26, and 39.29) were regarded as comorbidities.\u003c/p\u003e\n\u003cp\u003eStatistical analysis\u003c/p\u003e\n\u003cp\u003eTo explore the effect of KAs on patients with advanced CKD, we conducted a within-patient analysis and divided the patients who received KAs into three groups in accordance with their observation period. The first group included patients who received their CKD diagnosis before they were started on KAs, the second group included patients who received their CKD diagnosis while they were on KAs, and the third group included patients who stopped using KAs until the end of the observation period. In the third group, the legacy effect of KAs was examined to determine whether the protective effect of KAs remained even after they were stopped. We used time-dependent covariate Cox regression to evaluate the effectiveness and safety of the treatment while accounting for dialysis, death, and blood transfusion. Patients in the first group who used KAs and those who did not use KAs served as the control group. We established another model to observe the positive effect of KAs. All patients were monitored once they were started on KAs until the end of the study period. Patients who received a diagnosis of CKD before they were started on KAs were regarded as the control group for a within-patient analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAfter designating a control group through 1:3 case–control matching, we conducted chi-square and independent \u003cem\u003et\u003c/em\u003e tests to examine the differences in demographic variables, medications, and comorbidities before matching. We compared these variables after matching by using a generalized estimating equation (GEE) method for a univariate analysis. To analyze numerical binary outcomes-such as death, dialysis, and blood transfusion—we employed time-dependent covariate Cox regression. We utilized a GEE method for numerical data such as monthly dialysis frequency, EPO prescription frequency, and duration from CKD diagnosis to dialysis.\u003c/p\u003e\n\u003cp\u003eWe also evaluated the relationship between the dosage of KAs and the prognosis of ESRD, focusing on the positive effect of each additional KAs tablet. We categorized the dosage of KAs either into one to four tablets per day or into five or six tablets per day, and we compared the efficacy of these dosages with that of the control group. Stratified Cox regression was employed to examine the efficacy of KAs in case a patient’s prognosis involved binary data, such as death, dialysis, or blood transfusion. For numerical data—such as monthly dialysis frequency, EPO prescription frequency, and duration from CKD diagnosis to dialysis—we used a GEE method to explore the efficacy of KAs. A two-sided \u003cem\u003ep\u003c/em\u003e value less than 0.05 was considered statistically significant. All statistical analyses were conducted using SAS software version 9.4 (SAS Institute, Cary, NC, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003ePatient characteristics\u003c/p\u003e\n\u003cp\u003eFigure 1 demonstrates a flowchart of the study population selection process for the period 2000 to 2013. Of all patients, 550 were KAs users, and 7,889 were non-KAs users. Before matching, significant differences were discovered in the distributions of age and comorbidities (DM, AF, ischemic heart disease, and heart failure) between the two groups (Supplementary Table 1). Table 1 presents details on the patients in the KAs group (\u003cem\u003en\u003c/em\u003e = 369) and non-KAs group (\u003cem\u003en\u003c/em\u003e = 1,107) after 1:3 case‒control matching. No differences were found in age, sex, ACEI use, ARB use, statin use, or comorbidities between the two groups. In the KAs group, 58.8% of the patients had DM, and 87% of the patients had HTN. Compared with the non-KAs group, the KAs group had a significantly lower mortality rate (14.6% versus 32.8%) and blood transfusion rate (19.2% versus 34.2%). The duration from CKD diagnosis to dialysis was longer in the KAs group than in the non-KAs group, being a median (interquartile range) of 30.9 (10.8–56.6) months in the KAs group and 16.8 (4.4–42.6) months in the non-KAs group. In addition, EPO was less commonly prescribed in the KAs group than in the non-KAs group, with a median (interquartile range) of 0.8 (0.4–1.7) prescriptions per month in the KAs group and 1.1 (0.4–2.9) prescriptions per month in the non-KAs group.\u003c/p\u003e\n\u003cp\u003eEfficacy: Progression of CKD\u003c/p\u003e\n\u003cp\u003eWe used dialysis, duration from CKD diagnosis to dialysis, and monthly dialysis frequency as clinical kidney outcomes to evaluate the effect of KAs supplementation. The duration from CKD diagnosis to dialysis significantly differed between the KAs group and non-KAs group (hazard ratio [HR] = 12.38, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.001; Table 2), with the patients taking KAs having a longer duration from CKD diagnosis to dialysis. Compared with the non-KAs group, the KAs group had a significantly lower rate of dialysis (HR = 0.73, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.005). In addition, the frequency of monthly dialysis was significantly lower in the KAs group than in the non-KAs group (HR = −0.33, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.001). Similar results were obtained for dialysis, duration from CKD diagnosis to dialysis, and monthly dialysis frequency in the patients who stopped using KAs and those who did not take KAs (HR = 0.833, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.008; HR = 7.53, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.001; and HR = −0.21, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.001, respectively). The patients who used KAs exhibited improved clinical kidney outcomes across the entire study period. The patients in the KAs group had a longer mean duration to dialysis compared with those in the non-KAs group (mean = 30.9 and 15.8, respectively, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.001, log rank \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.001; Figures 2A and 3A). The mean frequency of monthly dialysis was 0.4 in the KA group and 0.8 in the non-KAs group (\u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.001, Figure 2B).\u003c/p\u003e\n\u003cp\u003eEfficacy: Mortality and anemia\u003c/p\u003e\n\u003cp\u003eIn addition to clinical kidney outcomes, we evaluated the effects of KAs supplementation on the risks of mortality and anemia. The results indicated a significantly lower mean rate of mortality in the KAs group than the control group (14.6% vs. 32.8%, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001; Table 1). After KAs supplementation was stopped, the rate of mortality was significantly lower in patients who used KAs than in the control group (HR = 0.63, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.001; Table 2). Overall, the rate of mortality was lower in the KAs group than in the control group (log rank \u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.001, Figure 3C).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe explored the effect of KAs supplementation on anemia from two perspectives. As shown in Table 2, the patients who used KAs were more likely to have blood transfusion compared with those who did not (HR = 2.29, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.013). However, throughout the study period, the frequency of blood transfusion was significantly lower in the KAs group than in the control group (HR = 0.35, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.001, log rank \u003cem\u003ep\u003c/em\u003e = 0.002; Figure 3B). In addition, the frequency of monthly EPO prescription was significantly lower in the KAs group than in the non-KAs group (HR = −0.84, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.001). No significant difference was discovered between the KAs and control groups in terms of the period of KAs cessation (HR = −0.10, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.73). The mean frequency of monthly EPO prescription was lower in the KAs group than in the non-KAs group (0.8 and 1.1 prescriptions per month, respectively, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.001; Figure 2C). Taken together, these results indicate that KA supplementation can not only alleviate renal anemia but also reduce the likelihood of mortality in patients with advanced CKD.\u003c/p\u003e\n\u003cp\u003eEfficacy: Dose–response effect of KAs and clinical outcomes\u003c/p\u003e\n\u003cp\u003eWe examined the effect of KAs supplementation at different dosages (one tablet, one to four tablets, or five or six tablets per day) on the clinical outcomes of patients with CKD (Table 3). Stratified Cox regression was employed to explore the dose–response effect of KAs on the risks of dialysis, mortality, and blood transfusion. In addition, we used a GEE method to examine the dose–response effects of KAs on the monthly dialysis frequency, duration from CKD diagnosis to dialysis, and monthly EPO prescription frequency. The results indicated that the patients who were prescribed five or six KAs tablets per day had more favorable clinical outcomes compared with the control group (\u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05). In addition, patients who were prescribed one to four KAs tablets per day had significantly better kidney function, lower mortality risk, and less severe renal anemia (\u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05). Furthermore, we examined the clinical outcomes of the patients with CKD who were prescribed only one KAs tablet per day. The results indicated that even a single tablet of KAs per day had a significantly positive clinical effect (\u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.001). Taken together, our findings indicate that KAs, regardless of their dosage, have a positive effect on patients with CKD.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we discovered that supplementing an LPD with KAs not only slowed the deterioration of kidney function but also reduced the risk of mortality in patients with advanced CKD. We discovered that the rates of blood transfusion and EPO prescription were significantly lower in the patients who received KAs than in those who did not. Regardless of the number of KA tablets prescribed, the patients who received KAs had more favorable clinical outcomes compared with those who did not receive KAs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePreventing CKD from rapidly progressing to ESRD is regarded as a major public health task worldwide. LPDs and VLPDs with KAs supplementation are typically used for the management of advanced CKD, as recommended by the KDIGO guidelines.\u003csup\u003e2\u003c/sup\u003e Although patients with CKD can be further educated on their condition through multidisciplinary care programs in medical centers across Taiwan, the main concern is whether an LPD or VLPD would cause a nutrient deficiency or exacerbate protein-energy wasting.\u003csup\u003e11\u0026ndash;13\u0026nbsp;\u003c/sup\u003eKAs supplementation is a nutritionally safe approach that can substantially delay the deterioration of renal function in patients with advanced CKD.\u003csup\u003e8.9\u003c/sup\u003e Chen \u003cem\u003eet al.\u003c/em\u003e\u003csup\u003e14\u003c/sup\u003e argued that KAs supplementation has positive effects on the 5-year mortality rate and incidence of ESRD in patients with stage 5 diabetic kidney disease.\u003csup\u003e\u0026nbsp;\u003c/sup\u003eHowever, these positive findings regarding KAs were obtained in research with a rigorous and optimal clinical design; the actual effect of KAs in clinical practice remains unclear.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn Taiwan, KAs are covered by the National Health Insurance system for patients with stage 5 CKD. In this study, we extracted the data of patients with advanced CKD who used KAs from the NHIRD for the period 2000\u0026ndash;2013 to yield representative results that truly reflect patients\u0026rsquo; actual conditions. Our results indicated that KAs supplementation not only extended the duration from CKD diagnosis to dialysis but also reduced the risk of mortality in patients with CKD throughout the study period. We also obtained kidney function and mortality results consistent with those of previous clinical trials.\u003csup\u003e8,9,14\u003c/sup\u003e The benefits of KAs can\u0026nbsp;persist even after the KAs are discontinued. This phenomenon\u0026nbsp;is referred to as the legacy effect and appears to be proportional to the duration and intensity of the initial therapy. Certain medications used in diabetes, lipid lowering, and HTN management have legacy effects.\u003csup\u003e15\u003c/sup\u003e We explored whether KAs supplementation affected the incidence of renal anemia in our nationwide clinical study. Our results indicated that the frequency of monthly EPO prescription was significantly lower in the KAs group than in the control group. In addition, the frequency of blood transfusion was significantly lower after KAs supplementation. Renal anemia is a common complication and a major risk factor for cardiovascular events in patients with CKD.\u003csup\u003e16\u0026ndash;18\u003c/sup\u003e The primary cause of anemia in patients with CKD is low production of EPO as CKD progresses.\u003csup\u003e19\u003c/sup\u003e After KAs supplementation, the cardiovascular risk of patients with CKD may decrease because of the amelioration of their anemia.\u003c/p\u003e\n\u003cp\u003eIn this study, we discovered that KAs supplementation had a legacy effect and reduced the frequencies of EPO prescription and blood transfusion. We explored the factors underlying the positive effects of KAs supplementation on patients with CKD. The positive effects are speculated to have originated from the preservation of the patients\u0026rsquo; eGFR or may have been related to a change in their gut microbiota. Rocchetti \u003cem\u003eet al.\u003c/em\u003e\u003csup\u003e20\u003c/sup\u003e reported that KAs reduced the quantity of protein-bound uremic toxins, namely indoxyl sulfate and \u003cem\u003ep\u003c/em\u003e-cresyl sulfate, in patients with CKD by altering their gut flora. Chang \u003cem\u003eet al.\u003c/em\u003e\u003csup\u003e21\u003c/sup\u003e demonstrated that an LPD with KAs supplementation had a positive effect on the endothelial function of and levels of protein-bound uremic toxins in patients with CKD. Indoxyl sulfate leads to cardiovascular mortality\u003csup\u003e22\u003c/sup\u003e and renal anemia by promoting red blood cell death, resulting in EPO resistance and thereby inhibiting hypoxia-inducible factors;\u003csup\u003e23\u003c/sup\u003e however, the mechanism underlying this process remains unclear. Further prospective studies are required to elucidate a definite mechanism.\u003c/p\u003e\n\u003cp\u003eFurther research is required to determine whether KAs have a dose\u0026ndash;response effect. In Taiwan, the National Health Insurance system covers the cost of KAs for patients with stage 5 CKD at a maximum dosage of six tablets per day, regardless of a patient\u0026rsquo;s body weight (one tablet per 5-10 kg body weight per day). Patients with advanced CKD already take many medications every day, and some of them are not willing to take the full dose of KAs. Therefore, physicians usually reduce their patients\u0026rsquo; doses to one to six tablets per day depending on the patient\u0026rsquo;s condition. In this study, we explored the effect of different KAs doses on the clinical outcomes of patients with CKD. Our results indicated that, compared with the control group, the patients who received one to six tablets per day had a significantly longer duration to kidney function deterioration and a lower all-cause mortality rate. Wu \u003cem\u003eet al\u003c/em\u003e.\u003csup\u003e24\u003c/sup\u003e argued that prescribing more than 5.5 tablets of KAs per day has a positive effect on patients with CKD. Further research is required to identify the reason for these discrepancies between studies from the same country. We speculate that these discrepancies are attributable to the use of the NHIRD at different time points. In this study, we adopted a longer time frame than those used in previous studies. Therefore, regardless of the dose of KAs prescribed for patients with CKD, these patients had favorable clinical outcomes.\u003c/p\u003e\n\u003cp\u003eDespite our novel findings regarding the effects of KAs on patients with CKD, this study has several limitations. First, LPDs were introduced to patients with CKD by their physician. In the NHIRD, the nutritional markers or characteristics of the proteins administered to these patients were not clarified. In addition, we could not determine whether the patients received animal- or plant-based proteins, and we were unable to confirm whether the KAs sand non-KAs groups actually complied with their physicians\u0026rsquo; LPD recommendations. Second, KAs were prescribed at outpatient clinics for patients who met the criteria for stage 5 CKD. We could not confirm whether each patient regularly took their KAs pills. To the best of our knowledge, no objective parameter is yet available for examining the drug compliance of these patients. Third, this was a retrospective study. Although we adopted 1:3 case\u0026ndash;control matching to minimize the differences between the KAs and non-KAs groups, these patients had certain factors, such as the timing of blood transfusion, that may have influenced their clinical course. Fourth, we were unable to identify the cause of the legacy effect of KA supplementation. Finally, no laboratory data were available for this study, and we were unable to evaluate the effect of KAs on the renal function or other biochemical parameters of the two groups.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOverall, this nationwide clinical study of real-world data confirms the positive effect of KA supplementation on the kidney function and overall mortality risk of patients with advanced CKD. Patients receiving KAs may require less blood transfusion and EPO prescription. Further prospective research is required to address the aforementioned limitations.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCheng-Jui Lin: Conceptualization; Shu-O Chiang: Formal Analysis; I Hsueh Lee, Cheng-Jui Lin, Fang-Ju Sun, and Shu-O Chiang: Investigation; Shu-O Chiang: Methodology; Cheng-Jui Lin and Feng-Chi Kuo: Supervision; I Hsueh Lee: Writing\u0026mdash;Original Draft; Cheng-Jui Lin: Writing-Review \u0026amp; Editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from Taiwan\u0026rsquo;s Ministry of Health and Welfare but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Taiwan\u0026rsquo;s Ministry of Health and Welfare.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKovesdy CP. Epidemiology of chronic kidney disease: an update 2022. Kidney Int Suppl (2011) 2022;12(1):7-11. doi: 10.1016/j.kisu.2021.11.003 [published Online First: 20220318]\u003c/li\u003e\n\u003cli\u003eKDIGO 2012 Clinical Practice Guideline for the Evaluation and Managementof Chronic Kidney Disease\u003c/li\u003e\n\u003cli\u003eIkizler TA, Burrowes JD, Byham-Gray LD, et al. KDOQI Clinical Practice Guideline for Nutrition in CKD: 2020 Update. Am J Kidney Dis 2020;76(3 Suppl 1):S1-S107. doi: 10.1053/j.ajkd.2020.05.006\u003c/li\u003e\n\u003cli\u003eMacLaughlin HL, Friedman AN, Ikizler TA. Nutrition in Kidney Disease: Core Curriculum 2022. Am J Kidney Dis 2022;79(3):437-49. doi: 10.1053/j.ajkd.2021.05.024 [published Online First: 20211201]\u003c/li\u003e\n\u003cli\u003eCupisti A, Gallieni M, Avesani CM, et al. Medical Nutritional Therapy for Patients with Chronic Kidney Disease not on Dialysis: The Low Protein Diet as a Medication. J Clin Med 2020;9(11) doi: 10.3390/jcm9113644 [published Online First: 20201112]\u003c/li\u003e\n\u003cli\u003eDi Micco L, Di Lullo L, Bellasi A, et al. Very Low Protein Diet for Patients with Chronic Kidney Disease: Recent Insights. J Clin Med 2019;8(5) doi: 10.3390/jcm8050718 [published Online First: 20190520]\u003c/li\u003e\n\u003cli\u003eKalantar-Zadeh K, Fouque D. Nutritional Management of Chronic Kidney Disease. N Engl J Med 2017;377(18):1765-76. doi: 10.1056/NEJMra1700312\u003c/li\u003e\n\u003cli\u003eLi A, Lee HY, Lin YC. The Effect of KAss on Chronic Kidney Disease Deterioration: A Meta-Analysis. Nutrients 2019;11(5) doi: 10.3390/nu11050957 [published Online First: 20190426]\u003c/li\u003e\n\u003cli\u003eGarneata L, Stancu A, Dragomir D, et al. KAs-Supplemented Vegetarian Very Low-Protein Diet and CKD Progression. J Am Soc Nephrol 2016;27(7):2164-76. doi: 10.1681/ASN.2015040369 [published Online First: 20160128]\u003c/li\u003e\n\u003cli\u003eSuissa S. Immortal time bias in observational studies of drug effects. Pharmacoepidemiol Drug Saf 2007;16(3):241-9. doi: 10.1002/pds.1357\u003c/li\u003e\n\u003cli\u003eRhee CM, Ahmadi SF, Kovesdy CP, et al. Low-protein diet for conservative management of chronic kidney disease: a systematic review and meta-analysis of controlled trials. J Cachexia Sarcopenia Muscle 2018;9(2):235-45. doi: 10.1002/jcsm.12264 [published Online First: 20171102]\u003c/li\u003e\n\u003cli\u003eWatanabe S. Low-protein diet for the prevention of renal failure. Proc Jpn Acad Ser B Phys Biol Sci 2017;93(1):1-9. doi: 10.2183/pjab.93.001\u003c/li\u003e\n\u003cli\u003eKo GJ, Kalantar-Zadeh K. How important is dietary management in chronic kidney disease progression? A role for low protein diets. Korean J Intern Med 2021;36(4):795-806. doi: 10.3904/kjim.2021.197 [published Online First: 20210622]\u003c/li\u003e\n\u003cli\u003eChen HY, Sun CY, Lee CC, et al. KAs supplements reduce mortality in patients with pre-dialysis advanced diabetic kidney disease: A nationwide population-based study. Clin Nutr 2021;40(6):4149-60. doi: 10.1016/j.clnu.2021.01.045 [published Online First: 20210206]\u003c/li\u003e\n\u003cli\u003eWander GS, Bansal M. Legacy effect in medicine-the expanding horizon! Indian Heart J. 2018 Nov-Dec;70(6):769-771.\u003c/li\u003e\n\u003cli\u003eHanna RM, Streja E, Kalantar-Zadeh K. Burden of Anemia in Chronic Kidney Disease: Beyond Erythropoietin. Adv Ther 2021;38(1):52-75. doi: 10.1007/s12325-020-01524-6 [published Online First: 20201029]\u003c/li\u003e\n\u003cli\u003eKu E, Del Vecchio L, Eckardt KU, et al. Novel anemia therapies in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2023;104(4):655-80. doi: 10.1016/j.kint.2023.05.009 [published Online First: 20230524]\u003c/li\u003e\n\u003cli\u003eToft G, Heide-Jorgensen U, van Haalen H, et al. Anemia and clinical outcomes in patients with non-dialysis dependent or dialysis dependent severe chronic kidney disease: a Danish population-based study. J Nephrol 2020;33(1):147-56. doi: 10.1007/s40620-019-00652-9 [published Online First: 20191005]\u003c/li\u003e\n\u003cli\u003eFishbane S, Spinowitz B. Update on Anemia in ESRD and Earlier Stages of CKD: Core Curriculum 2018. Am J Kidney Dis 2018;71(3):423-35. doi: 10.1053/j.ajkd.2017.09.026 [published Online First: 20180111]\u003c/li\u003e\n\u003cli\u003eRocchetti MT, et al. Ketoanalogs\u0026rsquo; Effects on Intestinal Microbiota Modulation and Uremic Toxins Serum Levels in Chronic Kidney Disease. J Clin Med. 2021 18;10:840.\u003c/li\u003e\n\u003cli\u003eChang G, Shih HM, Pan CF, et al. Effect of Low Protein Diet Supplemented with Ketoanalogs on Endothelial Function and Protein-Bound Uremic Toxins in Patients with Chronic Kidney Disease. Biomedicines 2023, 11, 1312.\u003c/li\u003e\n\u003cli\u003eBarreto FC, et al. European Uremic Toxin Work Group (EUTox). Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin J Am Soc Nephrol. 2009;4:1551-8.\u003c/li\u003e\n\u003cli\u003eHamza E et al. Uremic Toxins Affect Erythropoiesis during the Course of Chronic Kidney Disease: A Review. Cells 2020, 9, 2039.\u003c/li\u003e\n\u003cli\u003eWu CH, Yang YW, Hung SC, et al. KAss supplementation decreases dialysis and mortality risk in patients with anemic advanced chronic kidney disease. PLoS One 2017;12(5):e0176847. doi: 10.1371/journal.pone.0176847 [published Online First: 20170505]\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Demographics, medications, and clinical parameters of the KAs and non-KAs groups before CKD diagnosis (matched).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"630\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 20.1096%;\"\u003e\n \u003cp\u003eKAs\u003c/p\u003e\n \u003cp\u003e(n=369)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 20.1096%;\"\u003e\n \u003cp\u003eNon-KAs\u003c/p\u003e\n \u003cp\u003e(n=1,107)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003e18\u0026ndash;44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e6.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e6.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e--\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003e45\u0026ndash;64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e195\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e52.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e585\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e52.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003e\u0026ge;65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e152\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e41.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e456\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e41.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eMean, SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e61.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e11.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e61.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e11.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e--\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eSex (male)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e187\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e50.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e561\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e50.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e--\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eMedications before CKD diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eStatins\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e162\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e43.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e486\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e43.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e--\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eACEIs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e286\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e77.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e858\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e77.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e--\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eARBs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e195\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e52.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e585\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e52.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e--\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eComorbidities before CKD diagnosis\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eDM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e217\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e58.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e655\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e59.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e0.8845\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eHTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e321\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e87.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e942\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e85.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e0.246\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eHyperlipidemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e202\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e54.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e595\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e53.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e0.667\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eAF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e2.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e0.195\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eStroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e28.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e262\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e23.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e0.060\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eIschemic heart disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e38.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e438\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e39.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e0.770\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eHeart failure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e16.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e203\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e18.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e0.491\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003ePAOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e12.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e116\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e10.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e0.347\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eClinical parameters\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eMortality\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e14.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e363\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e32.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eBlood transfusion\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e18.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e374\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e33.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eDialysis\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e369\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e100.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e1107\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e100.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e--\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eMonthly dialysis frequency\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e0.2-0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e0.4-1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eDuration from CKD diagnosis to dialysis (months)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e30.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e10.8-56.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e16.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e4.4-42.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eEPO injection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e369\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e100.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e1107\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e100.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8387%;\"\u003e\n \u003cp\u003e--\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8684%;\"\u003e\n \u003cp\u003eMonthly EPO prescription frequency\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.7574%;\"\u003e\n \u003cp\u003e0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.19%;\"\u003e\n \u003cp\u003e0.4-1.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.4061%;\"\u003e\n \u003cp\u003e1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.5413%;\"\u003e\n \u003cp\u003e0.4-2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.8387%;\"\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\u003e\u003csup\u003ea\u003c/sup\u003eAnalyzed using a univariate GEE method.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003ePresented as medians and interquartile ranges.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003eEffects of KAs on the clinical outcomes of patients with CKD.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"945\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 284px;\"\u003e\n \u003cp\u003eOutcomes of CKD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 208px;\"\u003e\n \u003cp\u003eDuring KA use (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 208px;\"\u003e\n \u003cp\u003eAfter KA cessation (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 208px;\"\u003e\n \u003cp\u003eEntire course (1 + 2)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 132px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 132px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 132px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003eMortality\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e--\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e--\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.63 (0.47-0.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.63 (0.47-0.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003eBlood transfusion\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.29 (1.18-4.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.013**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.28 (0.20-0.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.35 (0.25\u0026ndash;0.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003eDialysis\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.73 (0.58-0.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.005**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.83 (0.72-0.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.008**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.80 (0.71\u0026ndash;0.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003eMonthly dialysis frequency\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e-0.33 (-0.42 \u0026ndash; -0.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e-0.21 (-0.28 \u0026ndash; -0.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e-0.24 (-0.30 \u0026ndash; -0.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003eDuration from CKD diagnosis to dialysis (months)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e12.38 (5.42-19.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e7.53 (3.67-11.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e8.74 (5.24\u0026ndash;12.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 284px;\"\u003e\n \u003cp\u003eMonthly EPO prescription frequency\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e-0.84 (-1.29 \u0026ndash; -0.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e-0.10(-0.64-0.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.730\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e-0.46 (-0.84 \u0026ndash; -0.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.015*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eThe reference group comprised the control group and KAs group at the immortal time points.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eAnalyzed using time-dependent Cox regression. KAs supplementation and KAs cessation were defined as 1 and 2, respectively, in the regression model, and the reference group was defined as 0. \u003csup\u003e*\u003c/sup\u003e\u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05, \u003csup\u003e**\u003c/sup\u003e\u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.01.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003eAnalyzed using a GEE method. Values are presented as regression coefficients and 95% CIs. \u003csup\u003e*\u003c/sup\u003e\u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05, \u003csup\u003e**\u003c/sup\u003e\u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.01.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ec\u003c/sup\u003eAfter KAs supplementation (1 + 2). In time-dependent Cox regression, the data obtained after KAs supplementation pertained to the KAs group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Dose‒response relationship between KAs supplementation and clinical outcomes in patients with CKD.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"952\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 252px;\"\u003e\n \u003cp\u003ePrognosis in CKD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003ePer one tablet\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003eControl group\u003c/p\u003e\n \u003cp\u003e(\u003cem\u003en\u003c/em\u003e = 1,107)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003eOne to four tablets\u003c/p\u003e\n \u003cp\u003e(\u003cem\u003en\u003c/em\u003e = 272, 73.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 190px;\"\u003e\n \u003cp\u003eFive or six tablets\u003c/p\u003e\n \u003cp\u003e(\u003cem\u003en\u003c/em\u003e = 97, 26.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eMortality\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e0.87 (0.80-0.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.61 (0.43-0.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e0.005**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e0.45 (0.25-0.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.006**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eBlood transfusion\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e0.89 (0.83-0.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.67 (0.49-0.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e0.013*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e0.53 (0.31-0.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.017*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eDialysis\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e0.92 (0.88-0.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.68 (0.57-0.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e0.69 (0.52-0.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.012*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eMonthly dialysis frequency\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e-0.06 (-0.07 \u0026ndash; -0.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e-0.24 (-0.31 \u0026ndash; -0.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e-0.26 (-0.35 \u0026ndash; -0.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eDuration from CKD diagnosis to dialysis (months)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e1.81 (1.01-2.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e7.45 (3.60-11.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e0.0001**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e8.77 (2.94-14.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.003**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 252px;\"\u003e\n \u003cp\u003eMonthly EPO prescription frequency\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e-0.12(-0.18- -0.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e-0.58 (-0.82- -0.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e\u0026lt;0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e-0.56 (-0.90- -0.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eAnalyzed using stratified Cox regression. \u003csup\u003e*\u003c/sup\u003e\u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05, \u003csup\u003e**\u003c/sup\u003e\u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.01.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003eAnalyzed using a GEE method. Values are presented as regression coefficients and 95% CIs. \u003csup\u003e*\u003c/sup\u003e\u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05, \u003csup\u003e**\u003c/sup\u003e\u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.01.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"ketoanalogs, chronic kidney disease, end-stage renal disease, National Health Insurance Research Database","lastPublishedDoi":"10.21203/rs.3.rs-5722164/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5722164/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground and aims: \u003c/strong\u003eChronic kidney disease (CKD) is one of the most burdensome health conditions worldwide and necessitates the preservation of kidney function. In recent years, ketoanalogs (KAs) and low-protein diets have been used to treat end-stage renal disease (ESRD). In this study, we used theNational Health Insurance Research Database(NHIRD) of Taiwan to explore the benefits of KAs in clinical practice.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eData on patients with CKD were extracted from the NHIRD for the period 2000–2013. After the data of 7,883 patients were extracted, 1:3 case‒control matching was performed to minimize the differences between KA users and nonusers. A time-dependent Cox regression model and a generalized estimating equation method wereused to examine the clinical effects of KAs in patients with advanced CKD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e After 1:3 case‒control matching, the patients were divided into a KA group (\u003cem\u003en\u003c/em\u003e = 369) and a non-KA group (control, \u003cem\u003en\u003c/em\u003e = 1,107). The patients in the KA group had a longer duration from the time point of CKD diagnosis to ESRD compared with those in the control group (30.9 versus 16.8 months, \u003cem\u003ep \u003c/em\u003e\u0026lt; 0.0001). In addition, the patients in the KA group had a lower mortality rate, fewer blood transfusions, and fewer erythropoietin prescriptions per month (mortality rate: 14.6% versus 32.8%, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01; blood transfusions: 18.9% versus 33.8%,\u003cem\u003e p \u003c/em\u003e\u0026lt; 0.01; erythropoietin prescriptions per month: 0.8 versus 1.1, \u003cem\u003ep \u003c/em\u003e\u0026lt; 0.01). These results indicated that KAs had a positive effect on patients withCKD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eKAs have a major effect on patients with advanced CKD, enabling them to defer dialysis, thereby mitigating their anemia and reducing their mortality risk. Our real-world clinical data demonstrate that low-protein diets and KAs can mitigate the adverse effects of CKD in patients with advanced CKD.\u003c/p\u003e","manuscriptTitle":"Ketoanalogs supplementation not only retarded kidney function deterioration but also reversed adverse outcomes in patients with advanced chronic kidney disease in a nationwide study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-03 08:47:47","doi":"10.21203/rs.3.rs-5722164/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"40510cff-6e98-4550-b28f-ea081cde0be4","owner":[],"postedDate":"February 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":43196021,"name":"Health sciences/Diseases"},{"id":43196022,"name":"Health sciences/Medical research"},{"id":43196023,"name":"Health sciences/Nephrology"}],"tags":[],"updatedAt":"2025-03-28T06:38:56+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-03 08:47:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5722164","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5722164","identity":"rs-5722164","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}