Dapagliflozin did not increase in serum K in advanced CKD in spite of initial eGFR decline

Dapagliflozin did not increase in serum K in advanced CKD in spite of initial eGFR decline | 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 Dapagliflozin did not increase in serum K in advanced CKD in spite of initial eGFR decline Waka Mitani, Yukimasa Iwata, Midori Kobayashi, Shoki Notsu, Madoka Morimoto, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3798021/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 Sodium–glucose cotransporter 2 inhibitors (SGLT2i) exhibit renoprotective effect in patients with chronic kidney disease (CKD) and do not increase serum K levels in the long term. However, it is unknown whether SGLT2i increase serum K levels in patients with advanced CKD in the short term. This study aimed to investigate the impact of SGLT2i on changes in serum K levels in patients with advanced CKD. Data of 127 Japanese patients with CKD who were newly administered 10 mg dapagliflozin in our department between August 2021 and August 2022 were analyzed. Changes in serum K and fractional excretion of K (FEK) were analyzed using multiple regression analysis. Of 127 patients, 41 were excluded. The median age was 67 years, and 70.9% were male. Overall, 24 (27.9%) patients had diabetes mellitus. The median estimated glomerular filtration rate (eGFR), serum K levels, and FEK were 35.4 mL/min/1.73 m 2 , 4.2 mEq/L, and 11.8%, respectively, at the time of dapagliflozin administration. Although eGFR declined to 33.2 mL/min/1.73m 2 from 35.4 mL/min/1.73m 2 after dapagliflozin administration (p<0.001), serum K and FEK levels increase to 4.3 mEq/L and 14.7% after dapagliflozin administration and it was not statistically significant. Dapagliflozin did not increase serum K levels in patients with advanced CKD. Biological sciences/Chemical biology/Metabolic pathways Biological sciences/Physiology Health sciences/Diseases Health sciences/Endocrinology Health sciences/Nephrology Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Chronic kidney disease (CKD) is a global concern, affecting more than 10 million patients in Japan and 700 million worldwide 1)2) . Sodium–glucose cotransporter 2 inhibitors (SGLT2i) such as dapagliflozin have a renoprotective effect 3) with a mechanism that is believed to involve the reduction of intra-glomerular pressure by tubular glomerular feedback 4)−7) . Although SGLT2i have pleiotropic effects and we already reported the effect of dapagliflozin on uric acid dynamics, the mechanism of renal protection has not been fully revealed 8) . Dapagliflozin reportedly does not increase K levels in patients with CKD when taken long term 9)10) . On the other hand, it is unclear whether dapagliflozin increase serum K levels in patients with CKD when taken internally in a short period. Since it has been reported that eGFR decreases in a short period of time after dapagliflozin administration, dapagliflozin seemed to increase K with exacerbation of renal function. Since previous reports stated that SGLT2i increase aldosterone levels, changes in K dynamics after their administration may differ between patients with or without renin-angiotensin system (RAS) inhibitors 11)−13) . This study aimed to investigate the kinetics of K and FEK soon after dapagliflozin administration. Methods Patients This study was conducted in accordance with the Declaration of Helsinki guidelines and approved by the institutional review board of Sakai City Medical Center (No. 23–402). All patients were allowed to opt out of the study. The need for informed consent was waived using our hospital’s opt-out method. This single-center retrospective cohort study included a total of 127 Japanese patients with CKD who were newly administered dapagliflozin 10 mg in our department between August 2021 and August 2022 and were followed up for at least 2 weeks. The duration between dapagliflozin administration and first mesurements of serum K after dapagliflozin administraion was 20.5 [14–28] days. Forty one patients were excluded from the analysis owing to change from other SGLT2i (n = 3) or dapagliflozin dose (n = 3). In addition, patients with changes in the dose of diuretics (n = 14), RAS inhibitors (n = 2), potassium binder (n = 2) and those whose serum K levels was not measured before or after dapagliflozin 10 mg administration (n = 6) were also excluded. Eleven patients with CKD stages 1 and 2 were excluded from the study. Study 1 retrospectively studied, 86 patients (Fig. 1 ). Furthermore, patients whose FEK was not measured before or after dapagliflozin 10 mg administration (n = 37) were excluded from the study. Study 2 included 49 patients. Data collection and definition We collected the data of 86 patients from the electronic medical charts of Sakai City Medical Center, including demographics (sex and age), medications, comorbidities (history of heart failure and diabetes mellitus), and clinical and laboratory variables (blood pressure, pulse rate, serum creatinine, blood urea nitrogen, K, hemoglobin, albumin, FEK, and proteinuria). FEK was calculated as ( \(100\times urine K\times serum creatinine÷serum K÷urine creatinine\) ). The eGFR was estimated using the formula for Japanese people ( \(eGFR [mL/min/1.73 m{2}^{}] =194\times serum creatinine{-1.094}^{}\times age{-0.287}^{}\times 0.739 \left[for females\right]\) ) 14) . Patients were divided into four groups according to their renal function and CKD category (G3 - G5). The definition of changes in K, FEK, and eGFR was ( \(K, FEK and eGFR after dapagliflozin administration-K, FEK and eGFR before dapagliflozin administration\) ). Outcomes This study’s primary and secondary outcomes were changes in serum K levels and FEK after the administration of dapagliflozin 10 mg, respectively. Statistical analyses Continuous variables are presented as medians (interquartile range [IQR]) and were compared using the Kruskal-Wallis test. Categorical variables are presented as numbers and percentages and were compared using Fisher’ s exact test. Changes in serum K levels and FEK were compared using the Wilcoxon signed-rank test and Kruskal-Wallis test. Multiple regression analysis was used to estimate the independent factors associated with changes in serum K levels and FEK. All statistical analyses were performed using EZR software (Saitama Medical Center, Jichi Medical University, Saitama, Japan) 15) . Results Baseline characteristics At the time of the administration of dapagliflozin 10 mg, 27 (31%), 24 (28%), 33 (38%), and 2 (2%) were categorized as having CKD stages 3a, 3b, 4, and 5, respectively (Table 1 ). Patient characteristics and baseline laboratory data for each group are shown in Table 1 . Table 1 Patient characteristics and laboratory data at the time of dapagliflozin 10 mg administration by chronic kidney disease stage All patients n = 86 CKD stage 3a n = 27 CKD stage 3b n = 24 CKD stage 4 n = 33 CKD stage 5 n = 2 p value Male (%) 61 (70.9) 19 (70.4) 21 (87.5) 19 (57.6) 2 (100.0) 0.076 Age 67 [57–77] 62 [53–68] 73 [63–77] 74 [64–79] 56 [47–65] 0.011 Comorbid condition Heart failure (%) 5 (5.8) 0 (0.0) 0 (0.0) 5 (15.2) 0 (0.0) 0.036 Diabetes mellitus (%) 24 (27.9) 7 (25.2) 7 (29.2) 9 (27.3) 0 (0.0) 0.905 Clinical and laboratory variables Systolic blood pressure (mmHg) 134 [122–140] 130 [118–139] 139 [128–144] 135 [122–140] 126 [121–130] 0.195 Diastolic blood pressure (mmHg) 76 [68–80] 80 [73–84] 75 [68–80] 74 [67–78] 70 [67–72] 0.13 Pulse rate (bpm) 78 [70–84] 75 [71–88] 80 [69–83] 78 [70–84] 82 [77–86] 0.805 Creatinine (mg/dL) 1.47 [1.21–1.97] 1.14 [0.98–1.22] 1.47 [1.33–1.58] 2.04 [1.91–2.24] 4.38 [4.25–4.52] < 0.001 Estimated glomerular filtration rate (mL/min/1.73m 2 ) 35.4 [24.7–46.8] 50.7 [47.6–55.1] 37.7 [34.3–42.4] 24.5 [20.3–27.0] 12.5 [11.5–13.5] < 0.001 Blood urea nitrogen (mg/dL) 24 [18–32] 17 [ 15 – 18 ] 23 [21–27] 33 [27–39] 43 [43–43] < 0.001 Potassium (mEq/L) 4.2 [4.0-4.7] 4.0 [3.9–4.3] 4.3 [4.1–4.7] 4.5 [4.0-4.9] 4.4 [4.3–4.4] 0.031 Hemoglobin (g/dL) 12.8 [11.4–14.1] 13.7 [12.8–14.7] 12.5 [10.9–14.5] 12.1 [10.6–13.0] 11.5 [10.8–12.2] 0.001 Albumin (g/dL) 3.9 [3.7–4.1] 4.1 [3.8–4.3] 3.9 [3.8-4.0] 3.8 [3.6-4.0] 3.9 [3.9-4.0] 0.105 Fractional excretion potassium (%) 11.8 [9.42–18.1] 9.62 [7.11–12.7] 9.99 [7.11–15.6] 17.4 [11.8–20.1] 0.002 Urine protein-to-creatinine ratio (g/gCr) 0.40 [0.07–1.57] 0.10 [0.05–0.46] 0.57 [0.07–1.17] 1.05 [0.16–2.38] 3.59 [3.18-4.00] 0.008 Medication Renin-angiotensin system inhibitor (%) 61 (70.9) 18 (66.7) 16 (66.7) 25 (75.8) 2 (100.0) 0.65 Diuretics (%) 20 (23.3) 4 ( 14.8) 6 (25.0) 10 (30.3) 0 ( 0.0) 0.45 The median age was 67 years; 70.9% of the patients were men. Twenty-four (28%) of the patients had diabetes mellitus and all patients were Japanese. The median eGFR was 35.4 mL/min/1.73 m 2 and the median serum K levels was 4.2 mEq/L. There were no significant intergroup differences in the use of RAS inhibitors and diuretics between CKD stages. On the other hands, serum K levels differed significantly between CKD stages. Study 1: Changes in serum K levels by CKD stage In our study, eGFR declined to 33.2 [23.4–43.8] ml/min/1.73 m 2 from 35.4 [25.2–46.8] mL/min/1.73 m 2 after dapagliflozin administration (p < 0.001). Figure 2 a compares the serum K levels before and after dapagliflozin administration. Serum K levels did not significantly increase after dapagliflozin administration (before administration, 4.2 [4.0-4.7] mEq/L vs after administration; 4.3 [4.1–4.6] mEq/L, p = 0.842). Figures 2 b- 2 e shows the group differences in serum K changes by CKD stages. After dapagliflozin administration, serum K levels changed from 4.3 [4.1–4.7] mEq/L to 4.4 [4.2–4.6] mEq/L, 4.0 [3.9–4.3] mEq/L to 4.2 [3.9–4.3] mEq/L, 4.5 [4.0-4.9] mEq/L to 4.5 [4.1–4.8] mEq/L and 4.4 [4.3–4.4] mEq/L to 4.9 [4.6–5.2] mEq/L in CKD stage 3a, 3b, 4 and 5, respectively. The multiple regression analysis revealed that eGFR, serum K levels and changes in eGFR were independently associated with serum K changes (Table 2 ). Table 2 Indicators of rate of changes in serum K levels Univariate analysis Multivariate analysis β p value β p value Estimated glomerular filtration rate (ml/min/1.73m 2 ) -0.089 0.415 -0.225 0.028 Serum potassium (mEq/L) -0.420 < 0.001 -0.475 < 0.001 Renin angiotensin system inhibitor 0.092 0.401 0.123 0.208 Change of estimated glomerular filtration rate (mL/min/1.73m 2 ) -0.205 0.058 -0.227 0.022 There was no significant association between changes in serum K levels and FEK (Fig. 3 ). Study 2: Changes in FEK by CKD stage No significant increase in FEK was observed after versus before dapagliflozin administration (before administration, 12.0 [9.6–18.4]% vs after administration, 14.7 [11.6–17.1]%, p = 0.142) (Fig. 4 a). After dapagliflozin administration, the FEK was changed from 10.1 [9.5–16.1]% to 13.3 [10.4–14.4]%, 10.3 [7.5–12.9]% to 14.0 [9.5–16.4]% and 17.4 [11.9–21.0]% to 17.2 [14.4–23.6]% in patients with CKD stage 3a, 3b and 4, respectively (Figs. 4 b- 4 d). Furthermore, a multiple regression analysis revealed a significant association between FEK and the changes in FEK after dapagliflozin administration (Table 3 ). The amount of changes in serum K levels in patients taking versus not taking RAS inhibitors was 0.68 [-1.80 to 2.97] mEq/L and 1.12 [-0.76 to 3.99] mEq/L, respectively (Fig. 5 ). Table 3 Indicators of rate of changes in fractional excretion of K Univariate analysis Multivariate analysis β p value β p value Estimated glomerular filtration rate (mL/min/1.73m 2 ) 0.037 0.714 -0.086 0.479 FEK (%) -0.253 0.010 -0.303 0.008 Renin angiotensin system inhibitor 0.041 0.684 0.065 0.518 Change of estimated glomerular filtration rate (mL/min/1.73m 2 ) -0.012 0.909 0.026 0.808 Discussion Although RAS inhibitors have renoprotective effect 16)17) , hyperkalemia was often seen in patients with CKD, especially those using RAS inhibitors including mineralocorticoid receptor antagonists. SGLT2i have a renoprotective effect possible through the reduction of intraglomerular pressure by tubuloglomerular feedback 4)−7) . Consequently, eGFR declined and the urinary protein levels decreased. Previous reports already showed that empagliflozin reduced eGFR compared with placebo until 52–76 weeks after its administration 18) . On the other hand, Ferreira et al. reported that serum K levels over time was not significantly different between empagliflozin and placebo in patients with heart failure 10) . Therefore, SGLT2i may prevent the development of hyperkalemia. Similar to previous reports, our study showed that serum K levels did not increase after dapagliflozin administration in patients with advanced CKD in spite of a reduction in renal function. Moreover, our result showed that serum K levels did not increase only in patients whose renal function decreased after dapagliflozin administration (Supplementary Fig. 1). RAS inhibitors increase serum K and lead to serious hyperkalemia in patients with CKD; in fact, hyperkalemia is a contributing factor to RAS inhibitor discontinuation. In the current study, SGLT2i did not increase serum K levels in patients with advanced CKD; thus, SGLT2i may be more useful than RAS inhibitors in terms of hyperkalemia. There are some possible mechanisms by which SGLT2i does not increase serum K levels. First, SGLT2i might increase the distal delivery of Na + and water. An increased distal delivery of Na + stimulates distal Na + absorption through epithelial Na channels, which makes the luminal potential more negative and increases K + secretion 19) . However, our results did not show that dapagliflozin increased FEK in patients with CKD. Second, aldosterone is the major mineralocorticoid in humans and plays an important role in regulating kidney K + secretion in the distal nephron. Previous reports stated that SGLT2i may increase serum aldosterone levels 11)−13) . FEK dynamics were not significantly different between patients who were versus were not taking RAS inhibitors. Regardless of RAS inhibitors usage SGLT2i may increase aldosterone levels and prevent hyperkalemia. Third, SGLT2i’s impact on the dynamics of K may be due to an unknown mechanism outside the kidney. Therefore, we found no significant association between changes in K levels and FEK. Further studies are needed to demonstrate the underlying mechanism of SGLT2i’s impact on the dynamics of K. Limitations The present study had some limitations. First, this was a single-center retrospective cohort study with a relatively small sample size. Second, we did not investigate the dietary characteristics of the participants. Third, we did not measure plasma aldosterone levels. Last, because we did not assess difficult endpoints such as end stage kidney disease and CKD progression, we did not determine whether the impact on K dynamics induced by SGLT2i may improve renal outcomes. Conclusion Our results suggest that dapagliflozin did not increase serum K levels in patients with advanced CKD. However, the mechanism by which dapagliflozin impacts on the dynamics of serum K levels has not been fully elucidated, and it is unclear whether this effect can improve renal outcomes. Therefore, further studies are needed to identify the mechanism and impact of SGLT2i on serum K levels. Declarations Competing interests The authors declare no conflicts of interest. Author Contribution W. M., Y. I., M. K., S. N., M. M., and M. Y. were responsible for investigation; Y. I. and M. Y. provided supervision; W. M. and Y. I. wrote the original draft and were responsible for the formal analysis; W. M., Y. I. and M. Y. conceptualized the study and were responsible for project administration and validation; and W. M. and Y. I. were responsible for the study visualization. Data availability All study data are available in the main text or supplementary materials. References Imai, E., et al. Prevalence of chronic kidney disease (CKD) in the Japanese general population predicted by the MDRD equation modified by a Japanese coefficient. Clin Exp Nephrol. 11, 156–163 (2007). GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990–2017: A systematic analysis for the global burden of disease study 2017. Lancet 395, 709–733 (2020). Wanner, C., Inzucchi, S. E, Zinman, B. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med.375, 323–334 (2016). Perkovic, V., et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 380, 2295–2306 (2019). Heerspink, H. J. L., Kosiborod, M., Inzucchi, S. E., Cherney, D. Z. I. Renoprotective effects of sodium-glucose cotransporter-2 inhibitors. Kidney Int. 94, 26–39 (2018). Leoncini, G., et al . SGLT2is and renal protection: From biological mechanisms to real-world clinical benefits. Int J Mol. Sci. 22, 4441 (2021). Patel, D. K., Strong, J. The pleiotropic effects of sodium–glucosecotransporter-2inhibitors: Beyondtheglycemicbenefit. Diabetes Ther. 10, 1771–1792 (2019). Iwata, Y., et al . The effect of dapagliflozin on uric acid excretion and serum uric acid level in advanced CKD. Sci Rep. 13, 4849 (2023). Neuen, B. L., Oshima, M., Perkovic, V., Agarwal, R., Arnott, C., et al . Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial. Eur Heart J. 42, 4891–4901 (2021). Ferreira, J. P., et al. Empagliflozin and serum potassium in heart failure: an analysis from EMPEROR-Pooled. Eur Heart J. 43, 2984–2993 (2022). Scholtes, R. A., et al . Natriuretic effect of two weeks of dapagliflozin treatment in patients with type 2 diabetes and preserved kidney function during standardized sodium intake: results of the DAPASALT Trial. Diabetes Care. 44, 440–447 (2021). Lambers Heerspink, H. J., Zeeuw, D., Wie, L., Leslie, B., List, J. Dapagliflozin: a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 15, 853–862 (2013). Lawler, P. R., et al. Changes in cardiovascular biomarkers associated with the sodium-glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin in patients with chronic kidney disease and type 2 diabetes. Diabetes Care. 44, 45–47 (2021). Matsuo, S., et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 53, 982–992 (2009). Kanda, Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant. 48, 452–458 (2013). Lewis, E. J., et al . Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 345, 851–860 (2001). Brenner, B. M., et al . RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 345, 861–869 (2001). Leoncini, G., et al . SGLT2is and Renal Protection: From Biological Mechanisms to Real-World Clinical Benefits. Int J Mol Sci. 22, 4441 (2021). Packer, M., et al. EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 383, 1413–1424 (2020). Additional Declarations No competing interests reported. Supplementary Files supplymentalyfigure20231218.pdf 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-3798021","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":263541576,"identity":"24a17f0b-6796-45ea-bd38-206a37d6ae26","order_by":0,"name":"Waka 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excretion of K.\u003c/p\u003e","description":"","filename":"figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-3798021/v1/23cccb1a352a5e52db13df3a.png"},{"id":49076817,"identity":"7f3c1562-6c20-4039-8e13-8765ee7b1e11","added_by":"auto","created_at":"2024-01-02 18:46:28","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":196245,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in fractional excretion of K levels at various chronic kidney diseasestages.\u003c/p\u003e","description":"","filename":"figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-3798021/v1/4789dbf456997252c5510d0c.png"},{"id":49076819,"identity":"8e6bf2df-7e04-4bf3-a038-548b22dab3f6","added_by":"auto","created_at":"2024-01-02 18:46:28","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":74155,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in fractional excretion of K levels of patients taking versus not taking renin-angiotensin system inhibitors\u003c/p\u003e","description":"","filename":"figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-3798021/v1/24d2ad8f0deedfe59e5f6ae9.png"},{"id":49698244,"identity":"b171e776-7652-4efd-8a79-4992d5ee8cae","added_by":"auto","created_at":"2024-01-16 15:37:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":636622,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3798021/v1/3b5f2478-0ee4-40c5-b46a-82333df31098.pdf"},{"id":49076818,"identity":"17fb3d8f-68c3-433f-9de0-0d0b4e439630","added_by":"auto","created_at":"2024-01-02 18:46:28","extension":"pdf","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":387538,"visible":true,"origin":"","legend":"","description":"","filename":"supplymentalyfigure20231218.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3798021/v1/d2516b069b46d12ab3b24fd9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Dapagliflozin did not increase in serum K in advanced CKD in spite of initial eGFR decline","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChronic kidney disease (CKD) is a global concern, affecting more than 10\u0026nbsp;million patients in Japan and 700\u0026nbsp;million worldwide\u003csup\u003e1)2)\u003c/sup\u003e. Sodium\u0026ndash;glucose cotransporter 2 inhibitors (SGLT2i) such as dapagliflozin have a renoprotective effect\u003csup\u003e3)\u003c/sup\u003e with a mechanism that is believed to involve the reduction of intra-glomerular pressure by tubular glomerular feedback\u003csup\u003e4)\u0026minus;7)\u003c/sup\u003e. Although SGLT2i have pleiotropic effects and we already reported the effect of dapagliflozin on uric acid dynamics, the mechanism of renal protection has not been fully revealed\u003csup\u003e8)\u003c/sup\u003e. Dapagliflozin reportedly does not increase K levels in patients with CKD when taken long term\u003csup\u003e9)10)\u003c/sup\u003e. On the other hand, it is unclear whether dapagliflozin increase serum K levels in patients with CKD when taken internally in a short period. Since it has been reported that eGFR decreases in a short period of time after dapagliflozin administration, dapagliflozin seemed to increase K with exacerbation of renal function. Since previous reports stated that SGLT2i increase aldosterone levels, changes in K dynamics after their administration may differ between patients with or without renin-angiotensin system (RAS) inhibitors\u003csup\u003e11)\u0026minus;13)\u003c/sup\u003e. This study aimed to investigate the kinetics of K and FEK soon after dapagliflozin administration.\u003c/p\u003e \u003cp\u003eMethods\u003c/p\u003e \u003cp\u003ePatients\u003c/p\u003e \u003cp\u003e This study was conducted in accordance with the Declaration of Helsinki guidelines and approved by the institutional review board of Sakai City Medical Center (No. 23\u0026ndash;402). All patients were allowed to opt out of the study. The need for informed consent was waived using our hospital\u0026rsquo;s opt-out method.\u003c/p\u003e \u003cp\u003eThis single-center retrospective cohort study included a total of 127 Japanese patients with CKD who were newly administered dapagliflozin 10 mg in our department between August 2021 and August 2022 and were followed up for at least 2 weeks. The duration between dapagliflozin administration and first mesurements of serum K after dapagliflozin administraion was 20.5 [14\u0026ndash;28] days. Forty one patients were excluded from the analysis owing to change from other SGLT2i (n\u0026thinsp;=\u0026thinsp;3) or dapagliflozin dose (n\u0026thinsp;=\u0026thinsp;3). In addition, patients with changes in the dose of diuretics (n\u0026thinsp;=\u0026thinsp;14), RAS inhibitors (n\u0026thinsp;=\u0026thinsp;2), potassium binder (n\u0026thinsp;=\u0026thinsp;2) and those whose serum K levels was not measured before or after dapagliflozin 10 mg administration (n\u0026thinsp;=\u0026thinsp;6) were also excluded. Eleven patients with CKD stages 1 and 2 were excluded from the study.\u003c/p\u003e \u003cp\u003eStudy 1 retrospectively studied, 86 patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Furthermore, patients whose FEK was not measured before or after dapagliflozin 10 mg administration (n\u0026thinsp;=\u0026thinsp;37) were excluded from the study. Study 2 included 49 patients.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eData collection and definition\u003c/p\u003e \u003cp\u003eWe collected the data of 86 patients from the electronic medical charts of Sakai City Medical Center, including demographics (sex and age), medications, comorbidities (history of heart failure and diabetes mellitus), and clinical and laboratory variables (blood pressure, pulse rate, serum creatinine, blood urea nitrogen, K, hemoglobin, albumin, FEK, and proteinuria). FEK was calculated as (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(100\\times urine K\\times serum creatinine\u0026divide;serum K\u0026divide;urine creatinine\\)\u003c/span\u003e\u003c/span\u003e). The eGFR was estimated using the formula for Japanese people (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(eGFR [mL/min/1.73 m{2}^{}] =194\\times serum creatinine{-1.094}^{}\\times age{-0.287}^{}\\times 0.739 \\left[for females\\right]\\)\u003c/span\u003e\u003c/span\u003e)\u003csup\u003e14)\u003c/sup\u003e. Patients were divided into four groups according to their renal function and CKD category (G3 - G5). The definition of changes in K, FEK, and eGFR was (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(K, FEK and eGFR after dapagliflozin administration-K, FEK and eGFR before dapagliflozin administration\\)\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOutcomes\u003c/p\u003e \u003cp\u003eThis study\u0026rsquo;s primary and secondary outcomes were changes in serum K levels and FEK after the administration of dapagliflozin 10 mg, respectively.\u003c/p\u003e \u003cp\u003eStatistical analyses\u003c/p\u003e \u003cp\u003eContinuous variables are presented as medians (interquartile range [IQR]) and were compared using the Kruskal-Wallis test. Categorical variables are presented as numbers and percentages and were compared using Fisher\u0026rsquo; s exact test. Changes in serum K levels and FEK were compared using the Wilcoxon signed-rank test and Kruskal-Wallis test. Multiple regression analysis was used to estimate the independent factors associated with changes in serum K levels and FEK.\u003c/p\u003e \u003cp\u003eAll statistical analyses were performed using EZR software (Saitama Medical Center, Jichi Medical University, Saitama, Japan)\u003csup\u003e15)\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eBaseline characteristics\u003c/p\u003e \u003cp\u003eAt the time of the administration of dapagliflozin 10 mg, 27 (31%), 24 (28%), 33 (38%), and 2 (2%) were categorized as having CKD stages 3a, 3b, 4, and 5, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Patient characteristics and baseline laboratory data for each group are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics and laboratory data at the time of dapagliflozin 10 mg administration by chronic kidney disease stage\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll patients\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;86\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCKD stage 3a\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;27\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCKD stage 3b\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;24\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCKD stage 4\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;33\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCKD stage 5\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61 (70.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (70.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (87.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19 (57.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.076\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67 [57\u0026ndash;77]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62 [53\u0026ndash;68]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73 [63\u0026ndash;77]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e74 [64\u0026ndash;79]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e56 [47\u0026ndash;65]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eComorbid condition\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart failure (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (5.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (15.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes mellitus (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (27.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (25.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (29.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 (27.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.905\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClinical and laboratory variables\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystolic blood pressure (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e134 [122\u0026ndash;140]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e130 [118\u0026ndash;139]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e139 [128\u0026ndash;144]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e135 [122\u0026ndash;140]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e126 [121\u0026ndash;130]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.195\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiastolic blood pressure (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76 [68\u0026ndash;80]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80 [73\u0026ndash;84]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e75 [68\u0026ndash;80]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e74 [67\u0026ndash;78]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e70 [67\u0026ndash;72]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePulse rate (bpm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78 [70\u0026ndash;84]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75 [71\u0026ndash;88]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e80 [69\u0026ndash;83]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e78 [70\u0026ndash;84]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e82 [77\u0026ndash;86]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.805\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.47 [1.21\u0026ndash;1.97]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.14 [0.98\u0026ndash;1.22]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.47 [1.33\u0026ndash;1.58]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.04 [1.91\u0026ndash;2.24]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.38 [4.25\u0026ndash;4.52]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstimated glomerular filtration rate (mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35.4 [24.7\u0026ndash;46.8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50.7 [47.6\u0026ndash;55.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37.7 [34.3\u0026ndash;42.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24.5 [20.3\u0026ndash;27.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12.5 [11.5\u0026ndash;13.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood urea nitrogen (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 [18\u0026ndash;32]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 [\u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 [21\u0026ndash;27]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e33 [27\u0026ndash;39]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e43 [43\u0026ndash;43]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePotassium (mEq/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.2 [4.0-4.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.0 [3.9\u0026ndash;4.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.3 [4.1\u0026ndash;4.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.5 [4.0-4.9]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.4 [4.3\u0026ndash;4.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.031\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12.8 [11.4\u0026ndash;14.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.7 [12.8\u0026ndash;14.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.5 [10.9\u0026ndash;14.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.1 [10.6\u0026ndash;13.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11.5 [10.8\u0026ndash;12.2]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumin (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.9 [3.7\u0026ndash;4.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.1 [3.8\u0026ndash;4.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.9 [3.8-4.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.8 [3.6-4.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.9 [3.9-4.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.105\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFractional excretion potassium (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.8 [9.42\u0026ndash;18.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.62 [7.11\u0026ndash;12.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.99 [7.11\u0026ndash;15.6]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17.4 [11.8\u0026ndash;20.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrine protein-to-creatinine ratio (g/gCr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.40 [0.07\u0026ndash;1.57]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.10 [0.05\u0026ndash;0.46]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.57 [0.07\u0026ndash;1.17]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.05 [0.16\u0026ndash;2.38]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.59 [3.18-4.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMedication\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenin-angiotensin system inhibitor (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61 (70.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25 (75.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiuretics (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (23.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 ( 14.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10 (30.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 ( 0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe median age was 67 years; 70.9% of the patients were men. Twenty-four (28%) of the patients had diabetes mellitus and all patients were Japanese. The median eGFR was 35.4 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e and the median serum K levels was 4.2 mEq/L. There were no significant intergroup differences in the use of RAS inhibitors and diuretics between CKD stages. On the other hands, serum K levels differed significantly between CKD stages.\u003c/p\u003e \u003cp\u003eStudy 1: Changes in serum K levels by CKD stage\u003c/p\u003e \u003cp\u003eIn our study, eGFR declined to 33.2 [23.4\u0026ndash;43.8] ml/min/1.73 m\u003csup\u003e2\u003c/sup\u003e from 35.4 [25.2\u0026ndash;46.8] mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e after dapagliflozin administration (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea compares the serum K levels before and after dapagliflozin administration. Serum K levels did not significantly increase after dapagliflozin administration (before administration, 4.2 [4.0-4.7] mEq/L vs after administration; 4.3 [4.1\u0026ndash;4.6] mEq/L, p\u0026thinsp;=\u0026thinsp;0.842).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigures \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb-\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ee shows the group differences in serum K changes by CKD stages. After dapagliflozin administration, serum K levels changed from 4.3 [4.1\u0026ndash;4.7] mEq/L to 4.4 [4.2\u0026ndash;4.6] mEq/L, 4.0 [3.9\u0026ndash;4.3] mEq/L to 4.2 [3.9\u0026ndash;4.3] mEq/L, 4.5 [4.0-4.9] mEq/L to 4.5 [4.1\u0026ndash;4.8] mEq/L and 4.4 [4.3\u0026ndash;4.4] mEq/L to 4.9 [4.6\u0026ndash;5.2] mEq/L in CKD stage 3a, 3b, 4 and 5, respectively.\u003c/p\u003e \u003cp\u003eThe multiple regression analysis revealed that eGFR, serum K levels and changes in eGFR were independently associated with serum K changes (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIndicators of rate of changes in serum K levels\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eUnivariate analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eβ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eβ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstimated glomerular filtration rate (ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.089\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.415\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.225\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.028\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum potassium (mEq/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.420\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.475\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenin angiotensin system inhibitor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.092\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.401\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.123\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.208\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange of estimated glomerular filtration rate (mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.205\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.058\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.227\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThere was no significant association between changes in serum K levels and FEK (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eStudy 2: Changes in FEK by CKD stage\u003c/p\u003e \u003cp\u003eNo significant increase in FEK was observed after versus before dapagliflozin administration (before administration, 12.0 [9.6\u0026ndash;18.4]% vs after administration, 14.7 [11.6\u0026ndash;17.1]%, p\u0026thinsp;=\u0026thinsp;0.142) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAfter dapagliflozin administration, the FEK was changed from 10.1 [9.5\u0026ndash;16.1]% to 13.3 [10.4\u0026ndash;14.4]%, 10.3 [7.5\u0026ndash;12.9]% to 14.0 [9.5\u0026ndash;16.4]% and 17.4 [11.9\u0026ndash;21.0]% to 17.2 [14.4\u0026ndash;23.6]% in patients with CKD stage 3a, 3b and 4, respectively (Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb-\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ed).\u003c/p\u003e \u003cp\u003eFurthermore, a multiple regression analysis revealed a significant association between FEK and the changes in FEK after dapagliflozin administration (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The amount of changes in serum K levels in patients taking versus not taking RAS inhibitors was 0.68 [-1.80 to 2.97] mEq/L and 1.12 [-0.76 to 3.99] mEq/L, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIndicators of rate of changes in fractional excretion of K\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eUnivariate analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eβ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eβ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstimated glomerular filtration rate (mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.037\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.714\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.086\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.479\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFEK (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.253\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.303\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenin angiotensin system inhibitor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.041\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.684\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.065\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.518\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange of estimated glomerular filtration rate (mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.909\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.808\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAlthough RAS inhibitors have renoprotective effect\u003csup\u003e16)17)\u003c/sup\u003e, hyperkalemia was often seen in patients with CKD, especially those using RAS inhibitors including mineralocorticoid receptor antagonists.\u003c/p\u003e \u003cp\u003eSGLT2i have a renoprotective effect possible through the reduction of intraglomerular pressure by tubuloglomerular feedback\u003csup\u003e4)\u0026minus;7)\u003c/sup\u003e. Consequently, eGFR declined and the urinary protein levels decreased.\u003c/p\u003e \u003cp\u003ePrevious reports already showed that empagliflozin reduced eGFR compared with placebo until 52\u0026ndash;76 weeks after its administration\u003csup\u003e18)\u003c/sup\u003e. On the other hand, Ferreira et al. reported that serum K levels over time was not significantly different between empagliflozin and placebo in patients with heart failure\u003csup\u003e10)\u003c/sup\u003e. Therefore, SGLT2i may prevent the development of hyperkalemia. Similar to previous reports, our study showed that serum K levels did not increase after dapagliflozin administration in patients with advanced CKD in spite of a reduction in renal function. Moreover, our result showed that serum K levels did not increase only in patients whose renal function decreased after dapagliflozin administration (Supplementary Fig.\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eRAS inhibitors increase serum K and lead to serious hyperkalemia in patients with CKD; in fact, hyperkalemia is a contributing factor to RAS inhibitor discontinuation. In the current study, SGLT2i did not increase serum K levels in patients with advanced CKD; thus, SGLT2i may be more useful than RAS inhibitors in terms of hyperkalemia.\u003c/p\u003e \u003cp\u003eThere are some possible mechanisms by which SGLT2i does not increase serum K levels. First, SGLT2i might increase the distal delivery of Na\u0026thinsp;+\u0026thinsp;and water. An increased distal delivery of Na\u0026thinsp;+\u0026thinsp;stimulates distal Na\u0026thinsp;+\u0026thinsp;absorption through epithelial Na channels, which makes the luminal potential more negative and increases K\u0026thinsp;+\u0026thinsp;secretion\u003csup\u003e19)\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, our results did not show that dapagliflozin increased FEK in patients with CKD.\u003c/p\u003e \u003cp\u003eSecond, aldosterone is the major mineralocorticoid in humans and plays an important role in regulating kidney K\u0026thinsp;+\u0026thinsp;secretion in the distal nephron. Previous reports stated that SGLT2i may increase serum aldosterone levels\u003csup\u003e11)\u0026minus;13)\u003c/sup\u003e. FEK dynamics were not significantly different between patients who were versus were not taking RAS inhibitors. Regardless of RAS inhibitors usage SGLT2i may increase aldosterone levels and prevent hyperkalemia.\u003c/p\u003e \u003cp\u003eThird, SGLT2i\u0026rsquo;s impact on the dynamics of K may be due to an unknown mechanism outside the kidney. Therefore, we found no significant association between changes in K levels and FEK.\u003c/p\u003e \u003cp\u003eFurther studies are needed to demonstrate the underlying mechanism of SGLT2i\u0026rsquo;s impact on the dynamics of K.\u003c/p\u003e \u003cp\u003eLimitations\u003c/p\u003e \u003cp\u003eThe present study had some limitations. First, this was a single-center retrospective cohort study with a relatively small sample size. Second, we did not investigate the dietary characteristics of the participants. Third, we did not measure plasma aldosterone levels. Last, because we did not assess difficult endpoints such as end stage kidney disease and CKD progression, we did not determine whether the impact on K dynamics induced by SGLT2i may improve renal outcomes.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur results suggest that dapagliflozin did not increase serum K levels in patients with advanced CKD.\u003c/p\u003e \u003cp\u003eHowever, the mechanism by which dapagliflozin impacts on the dynamics of serum K levels has not been fully elucidated, and it is unclear whether this effect can improve renal outcomes. Therefore, further studies are needed to identify the mechanism and impact of SGLT2i on serum K levels.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eW. M., Y. I., M. K., S. N., M. M., and M. Y. were responsible for investigation; Y. I. and M. Y. provided supervision; W. M. and Y. I. wrote the original draft and were responsible for the formal analysis; W. M., Y. I. and M. Y. conceptualized the study and were responsible for project administration and validation; and W. M. and Y. I. were responsible for the study visualization.\u003c/p\u003e\u003ch2\u003eData availability\u003c/h2\u003e \u003cp\u003eAll study data are available in the main text or supplementary materials.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eImai, E., \u003cem\u003eet al.\u003c/em\u003e Prevalence of chronic kidney disease (CKD) in the Japanese general population predicted by the MDRD equation modified by a Japanese coefficient. Clin Exp Nephrol. 11, 156\u0026ndash;163 (2007).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990\u0026ndash;2017: A systematic analysis for the global burden of disease study 2017. Lancet 395, 709\u0026ndash;733 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWanner, C., Inzucchi, S. E, Zinman, B. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med.375, 323\u0026ndash;334 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerkovic, V., \u003cem\u003eet al.\u003c/em\u003e Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 380, 2295\u0026ndash;2306 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHeerspink, H. J. L., Kosiborod, M., Inzucchi, S. E., Cherney, D. Z. I. Renoprotective effects of sodium-glucose cotransporter-2 inhibitors. Kidney Int. 94, 26\u0026ndash;39 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeoncini, G., \u003cem\u003eet al\u003c/em\u003e. SGLT2is and renal protection: From biological mechanisms to real-world clinical benefits. Int J Mol. Sci. 22, 4441 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePatel, D. K., Strong, J. The pleiotropic effects of sodium\u0026ndash;glucosecotransporter-2inhibitors: Beyondtheglycemicbenefit. Diabetes Ther. 10, 1771\u0026ndash;1792 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIwata, Y., \u003cem\u003eet al\u003c/em\u003e. The effect of dapagliflozin on uric acid excretion and serum uric acid level in advanced CKD. Sci Rep. 13, 4849 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNeuen, B. L., Oshima, M., Perkovic, V., Agarwal, R., Arnott, C., \u003cem\u003eet al\u003c/em\u003e. Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial. Eur Heart J. 42, 4891\u0026ndash;4901 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerreira, J. P., \u003cem\u003eet al.\u003c/em\u003e Empagliflozin and serum potassium in heart failure: an analysis from EMPEROR-Pooled. Eur Heart J. 43, 2984\u0026ndash;2993 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScholtes, R. A., \u003cem\u003eet al\u003c/em\u003e. Natriuretic effect of two weeks of dapagliflozin treatment in patients with type 2 diabetes and preserved kidney function during standardized sodium intake: results of the DAPASALT Trial. Diabetes Care. 44, 440\u0026ndash;447 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLambers Heerspink, H. J., Zeeuw, D., Wie, L., Leslie, B., List, J. Dapagliflozin: a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 15, 853\u0026ndash;862 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLawler, P. R., \u003cem\u003eet al.\u003c/em\u003e Changes in cardiovascular biomarkers associated with the sodium-glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin in patients with chronic kidney disease and type 2 diabetes. Diabetes Care. 44, 45\u0026ndash;47 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsuo, S., \u003cem\u003eet al.\u003c/em\u003e Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 53, 982\u0026ndash;992 (2009).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKanda, Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant. 48, 452\u0026ndash;458 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLewis, E. J., \u003cem\u003eet al\u003c/em\u003e. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 345, 851\u0026ndash;860 (2001).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrenner, B. M., \u003cem\u003eet al\u003c/em\u003e. RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 345, 861\u0026ndash;869 (2001).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeoncini, G., \u003cem\u003eet al\u003c/em\u003e. SGLT2is and Renal Protection: From Biological Mechanisms to Real-World Clinical Benefits. Int J Mol Sci. 22, 4441 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePacker, M., \u003cem\u003eet al.\u003c/em\u003e EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 383, 1413\u0026ndash;1424 (2020).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3798021/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3798021/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSodium–glucose cotransporter 2 inhibitors (SGLT2i) exhibit renoprotective effect in patients with chronic kidney disease (CKD) and do not increase serum K levels in the long term. However, it is unknown whether SGLT2i increase serum K levels in patients with advanced CKD in the short term. This study aimed to investigate the impact of SGLT2i on changes in serum K levels in patients with advanced CKD.\u003c/p\u003e\n\u003cp\u003eData of 127 Japanese patients with CKD who were newly administered 10 mg dapagliflozin in our department between August 2021 and August 2022 were analyzed. Changes in serum K and fractional excretion of K (FEK) were analyzed using multiple regression analysis.\u003c/p\u003e\n\u003cp\u003eOf 127 patients, 41 were excluded.\u003c/p\u003e\n\u003cp\u003eThe median age was 67 years, and 70.9% were male. Overall, 24 (27.9%) patients had diabetes mellitus. The median estimated glomerular filtration rate (eGFR), serum K levels, and FEK were 35.4 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e, 4.2 mEq/L, and 11.8%, respectively, at the time of dapagliflozin administration. Although eGFR declined to 33.2 mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e from 35.4 mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e after dapagliflozin administration (p\u0026lt;0.001), serum K and FEK levels increase to 4.3 mEq/L and 14.7% after dapagliflozin administration and it was not statistically significant.\u003c/p\u003e\n\u003cp\u003eDapagliflozin did not increase serum K levels in patients with advanced CKD.\u003c/p\u003e","manuscriptTitle":"Dapagliflozin did not increase in serum K in advanced CKD in spite of initial eGFR decline","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-02 18:46:23","doi":"10.21203/rs.3.rs-3798021/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":"b300d2c3-2469-4071-a169-378fa759cbb1","owner":[],"postedDate":"January 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":27795890,"name":"Biological sciences/Chemical biology/Metabolic pathways"},{"id":27795891,"name":"Biological sciences/Physiology"},{"id":27795892,"name":"Health sciences/Diseases"},{"id":27795893,"name":"Health sciences/Endocrinology"},{"id":27795894,"name":"Health sciences/Nephrology"}],"tags":[],"updatedAt":"2024-01-16T15:29:16+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-02 18:46:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3798021","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3798021","identity":"rs-3798021","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}