An Observational Study of SGLT2 Inhibitors and Their Use in Autosomal Dominant Tubulointerstitial Kidney Disease

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Kidd, Adrienne H. Williams, Elhussein A.E. Elhassan, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7482366/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 There are no specific treatments available for autosomal dominant tubulointerstitial kidney disease (ADTKD). As SGLT2 inhibitors have proven effective in other forms of CKD, we performed an observational study to determine their safety and effect on kidney function in ADTKD. Methods We obtained clinical and laboratory data before and after starting an SGLT2 inhibitor on 27 individuals with ADTKD. We created a propensity-matched cohort from a Wake Forest prospective ADTKD observational study. Results Of the 27 individuals, 12 stopped medication prior to one year due to concerns about the (anticipated) acute rise in serum creatinine. There were no adverse effects. The slope of eGFR after SGLT 2 inhibitor initiation was − 2.61 ± 2.58 ml/min/1.73m 2 , which was not significantly different from the eGFR slope prior to initiation of SGLT2 inhibitors (-3.13 ± 5.39 ml/min/1.73 m 2 (p = 0.71)) or from 30 propensity-matched controls (-2.25 ± 2.39 ml/min/1.73 m 2 (p = 0.83)). Hemoglobin and plasma and urine KIM-1 levels did not change after starting SGLT2 inhibitors. Conclusions SGLT2 inhibitors were well tolerated in ADTKD patients. There was neither a rise in hemoglobin levels nor a fall in plasma or urinary KIM-1 levels, suggesting that these agents may not be beneficial in ADTKD. Autosomal Dominant Tubulointerstitial Kidney Disease ADTKD MUC1 UMOD SGLT2 inhibitors Sodium-glucose cotransporter 2 inhibitors Figures Figure 1 Figure 2 INTRODUCTION Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective treatments for patients with diabetic nephropathy 1 and other forms of chronic kidney disease (CKD) 2 , but there is little information available about their use in inherited disorders. It is also unclear if these agents are effective in nonproteinuric CKD. 2 Autosomal dominant tubulointerstitial kidney disease (ADTKD) is the third most common genetic form of inherited kidney disease 3 and is characterized by autosomal dominant inheritance, a bland urinary sediment, and CKD leading to kidney failure at a mean age of 45 years (range 20 to 80 years). 4 The two most common forms of ADTKD are ADTKD- UMOD (due to UMOD pathogenic variants) 5 and ADTKD- MUC1 (due to MUC1 pathogenic variants) 6 . While ADTKD is not associated with proteinuria, ADTKD- UMOD is characterized by increased tubular energy utilization due to increased proximal tubular uptake of sodium and urate. 7 Both ADTKD- UMOD and ADTKD- MUC1 have a strong component of tubulinterstitial fibrosis 8 , which could be targeted by SGLT2 inhibition. 9 At present, there are no treatments available for ADTKD. The purpose of this study was to follow individuals with ADTKD who were started on SGLT2 inhibitors by their healthcare providers and assess patient tolerance and change in estimated glomerular filtration rate (eGFR) over time. We also compared eGFR change with a propensity-matched cohort of participants in the Wake Forest Prospective ADTKD Cohort who were not receiving SGLT2 inhibitors. Materials and Methods All participants signed informed consent to participate in the studies approved by Wake Forest University Health Sciences institutional review board and Beaumont Hospital ethics committee. The Wake Forest Rare Inherited Kidney Disease Team conducted a prospective observational study of participants with genetically diagnosed ADTKD- UMOD or ADTKD- MUC1 beginning in March 2025 and accruing 270 participants (see Table 1 ). Serum creatinine values were assessed at baseline and then at 3-month intervals. Plasma and urine for biomarkers were obtained at baseline and in follow up at three-month intervals and stored in a – 80ºC freezer. Participants filled out a survey every three months, including questions specifically about starting SGLT2 inhibitors. As the study was observational in nature, all decisions regarding starting and stopping medications were made between the participants and their clinical providers. All participants receiving SGLT2 inhibitors received information from their clinical providers prior to starting these agents that there would be an expected decline in eGFR after initiation of therapy, and that this eGFR decline would be reversible. 1 Participants were told that SGLT2 inhibitors were proven beneficial in proteinuric kidney diseases 1 , 2 but not in ADTKD. Beaumont Hospital in Dublin, Ireland has a genetic kidney disease clinic and follows participants longitudinally with ADTKD. 10 Beaumont Hospital investigators were able to identify participants started on SGLT2 inhibitors and provide baseline and follow-up eGFR values. Statistical analysis : Baseline characteristics were calculated using standard statistical techniques with SAS (Cary, NC). In comparisons of the change in eGFR over time, participants were included if they remained on SGLT2 inhibitors for greater than 1 year. For calculation of the eGFR slope prior to initiation of SGLT2 inhibition, we used eGFR data from the prior year. The initial serum creatinine value used to calculate the slope of decline while on SGLT2 inhibition was defined as the serum creatinine value obtained at least three months after therapy initiation in order to account for the initial drop in eGFR when starting SGLT2 inhibitors. 2 , 11 A propensity score was created to match participants who had taken SGLT2 inhibitors with participants not on SGLT2 inhibitors using the PSMATCH optimal algorithm in SAS with a ratio of two controls per case. Samples were matched exactly on sex and ADTKD diagnosis and with the age and eGFR using propensity scores. Four eGFR values per sample were required over a 2-year period to calculate the slope of decline of eGFR for each participant. The differences in the mean eGFR decline for individuals taking SGLT2 inhibitors and individuals not taking SGLT2 inhibitors was evaluated using a paired t-test. The differences in the mean eGFR decline prior to and after starting SGLT2 inhibitors were also evaluated using a paired t-test. Results There were 270 participants followed in the observational study over time (see Fig. 1 and Table 1 ), with 112 (41%) with ADTKD- UMOD and 158 (59%) with ADTKD- MUC1 . 14 of the ADTKD- UMOD participants and 8 of the ADTKD- MUC1 participants started SGLT2 inhibitors. Data was then added on 5 participants from the Irish Cohort (see Fig. 1 and Table 2 ). Table 1 Characteristics of participants in the Wake Forest ADTKD Cohort Observational Study who started versus did not start SGLT2 inhibitors. Cohort participants not starting SGLT2 inhibitors Cohort participants starting SGLT2 inhibitors P-value 1 ADTKD disease type UMOD MUC1 UMOD MUC1 UMOD MUC1 N 144 104 14 8 Age (y) 39.30 ± 14.68 37.37 ± 12.69 40.34 ± 16.89 39.77 ± 10.98 0.82 0.51 Sex (% male) 55 (38%) 35 (34%) 7 (50%) 4 (50%) 0.34 0.37 eGFR (ml/min/1.73m 2 ) at entry into the study 62.29 ± 26.61 61.34 ± 24.47 45.91 ± 17.94 57.94 ± 19.02 0.0019 0.61 1 P value comparing ADTKD subtype participants starting versus not starting SGLT2 inhibitors Table 2 Characteristics of individuals with ADTKD who started SGLT2 inhibitors according to country. US Ireland Total n 22 5 27 ADTKD- UMOD n (%) 14 (64%) 0 14 (52%) ADTKD- MUC1 n (%) 8 (36%) 5 (100%) 13 (48%) Age (y) 1 40.13 ± 14.73 43.79 ± 20.58 40.81 ± 15.57 Sex (%male) 11 (50%) 2 (40%) 13 (48%) eGFR at entry 1 50.29 ± 18.84 47.67 ± 19.49 49.80 ± 18.61 Dapagliflozin, n (%) 11 (50%) 5 (100%) 16 (59%) Empagliflozin, n (%) 11 (50%) 0 11 (41%) 1 mean ± s.d. None of the participants had underlying diabetes or other significant comorbid conditions. None of the participants had proteinuria. Thus, there were 27 individuals with ADTKD who started SGLT2 inhibitors. Of these 27 individuals starting SGLT2 inhibitors, 2 stopped medication prior to one month, 4 stopped medication between 1 and 3 months, and 6 stopped prior to one year of treatment (Fig. 1 ). None of the individuals stopped SGLT2 inhibitors due to urinary tract infections, fungal infections, volume depletion, or ketoacidosis. Table 3 shows characteristics of individuals who stopped versus continued on therapy. Table 3 Comparison of individuals who stopped and did not stop SGLT2 inhibitors. Stopped SGLT 2 inhibitor < 3 months Stopped SGLT2 inhibitor from 3 months to 1 year Did not stop P value N 2 5 20 UMOD n(%) 2 (100%) 3 (50%) 9 (45%) 0.28 1 0 2 (40%) 11(55%) Age at entry 24.58 ± 2.41 41.60 ± 24.61 42.24 ± 13.19 0.49 Age at start of SGLT2i 38.31 ± 8.83 44.57 ± 24.63 50.87 ± 8.83 0.30 Sex (%Male) 0 0.40 0.55 0.27 eGFR at entry 2 39.18 ± 3.67 41.53 ± 12.04 52.93 ± 20.06 0.42 eGFR at start of SGLT2i 2 29.85 ± 3.94 32.24 ± 10.28 37.19 ± 8.83 0.72 % eGFR decline at one month 0.08 ± 0.11 0.08 ± 0.05 0.07 ± 0.11 0.88 Dapagliflozin, n(%) 1(50%) 4 (80%) 0.55 0.52 Empagliflozin, n(%) 1 (50%) 1 (20%) 0.45 1 P value compares the group of individuals who stopped versus did not stop. 2 Mean ± s.d. There were 15 participants with enough data to compare longitudinal changes in eGFR. Table 4 provides characteristics of these patients, and Table 5 provides information on the propensity-matched cohort. Figure 2 shows the change in eGFR over time. Participants had a decline in eGFR at 3 months of 4 ml/min/1.73 m 2 , which was similar to the decline in eGFR observed in other studies. 1 , 2 The slope of eGFR after the initiation of the SGLT2 inhibitors was − 2.61 ± 2.58 ml/min/1.73m 2 . This was not significantly different from the slope of the propensity matched controls (-2.25 ± 2.39 ml/min/1.73 m 2 (p = 0.83)) and not significantly different from the eGFR slope prior to initiation of SGLT2 inhibitors (-3.13 ± 5.39 ml/min/1.73 m 2 (p = 0.71)) (see Table 6 ). There were no differences according to ADTKD sub-type ( see Table 7 ). Table 4 Comparison of laboratory values N Baseline After 1–3 months (first available value) P value from paired t test Hemoglobin (g/dl) 17 11.99 ± 0.90 12.24 ± 1.55 0.61 Plasma Kim-1 12 897.71 ± 2083.82 961.84 ± 2269.83 0.33 Urine Kim-1 12 985.75 ± 1383.68 1682.81 ± 1221.56 0.14 Serum uric acid level 9 5.82 ± 0.94 5.06 ± 1.87 0.12 Table 5 Characteristics of individuals with long-term follow up Overall ADTKD- MUC1 ADTKKD- UMOD P-value N 15 9 6 Male, n (%) 9 (60%) 5 (56%) 4 (66%) 1.0 Age starting SGLT2 inhibitor (years) 51.59 ± 16.68 52.03 ± 18.14 50.92 ± 15.87 0.91 eGFR before start of SGLT2 inhibitors (ml/min/1.73m 2 ) 34.22 ± 10.40 34.28 ± 10.12 34.13 ± 11.79 0.91 eGFR > 40 ml/min/1.73m 2 (n, column percent) 3 (20%) 2 (22%) 1 (17%) 1.0 eGFR 30 to ≤ 40 ml/min/1.73m 2 (n, column percent) 6 (40%) 3 (33%) 3 (50%) eGFR < 30 ml/min/1.73m 2 (n, column percent) and not kidney failure 6 (40%) 4 (44%) 2 (33%) Table 6 Characteristics of individuals receiving SGLT2 inhibitors and the propensity-matched cohort. Cases Matched Controls p-value N 15 30 Age (years) 52.04 ± 16.76 50.38 ± 13.0 0.72 Duration of follow-up 1.35 ± 0.42 1.61 ± 0.58 0.13 eGFR ml/min/1.73m 2 31.87 ± 11.13 36.69 ± 9.90 0.15 Male n (%) 9 (60%) 18 (60%) 1.0 ADTKD Type 9 MUC1 (60%) 18 MUC1 (60%) 1.0 6 UMOD(40%) 12 UMOD (40%) 1.0 Table 7 Comparison in changes of eGFR (ml/min/1.73m 2 ) before and after SGLT2 inhibition and between cases and the propensity-matched controls. Slope of eGFR over time P-value (ref group Cases After) Cases after SGLT2 inhibitor initiation -2.61 ± 2.58 Propensity-matched controls -2.25 ± 2.39 0.83 Cases before SGLT2 inhibitor initiation -3.13 ± 5.39 0.71 There was no significant change in hemoglobin values for 17 individuals who had values pre- and post- SGLT2 inhibitor initiation (see Table 8 ). Plasma and urinary Kim-1 values were widely dispersed. There was an increase in these values, but due to the wide standard deviation this was not statistically significant. The serum uric acid levels showed a non-significant decline. Table 8 Comparison of changes in eGFR (ml/min/1.73m 2 ) according to ADTKD subtype. ADTKD- MUC1 Slope of eGFR over time P-value (ref group Cases After) Cases after SGLT2 inhibitor initiation -3.46 ± 2.83 Propensity-matched controls -2.67 ± 3.47 0.56 Cases before SGLT2 inhibitor initiation -3.06 ± 2.43 0.21 ADTKD- UMOD Slope of eGFR over time P-value (ref group Cases After) Cases after SGLT2 inhibitor initiation -1.33 ± 1.58 Propensity-matched controls -1.93 ± 4.51 0.69 Cases before SGLT2 inhibitor initiation -1.03 ± 1.90 0.36 Discussion SGLT2 inhibitors have been found to be an extremely effective therapy to slow the rate of eGFR decline in participants with diabetic nephropathy 1 and proteinuric CKD. 2 , 12 SGLT2 inhibitors also reduce proteinuria in Alport syndrome. 13 It is unclear whether SGLT2 inhibitors are beneficial in non-proteinuric kidney disease 2 or in genetic disorders autosomal dominant polycystic kidney disease. 14 – 16 Participants with ADTKD suffer from tubulointerstitial kidney disease. Participants with ADTKD- UMOD have increased proximal tubular uptake of sodium and uric acid 17 , with increased energy expenditure of the proximal tubule, providing a potential attractive target for SGLT2 inhibitors. However, as there are a number of potential mechanisms of renal protection with SGLT2 inhibitors 18 , one cannot predict theoretically for which kidney diseases they will be effective. There are numerous obstacles in determining if SGLT2 inhibitors will be effective in ADTKD. First, the patient population is small, and a well-powered prospective randomized trial cannot be carried out. Second, participants with ADTKD do not have proteinuria. SGLT2 inhibitors have been found to be effective in proteinuric kidney disease 2 and also lower proteinuria 13 , a marker of efficacy. Participants with ADTKD do not have proteinuria, and there is no similar biomarker of disease activity. Safety: SGLT2 inhibitors were well-tolerated by participants with ADTKD, with no significant adverse side effects. This is of note, as decreased uromodulin secretion in individuals with ADTKD- UMOD could place them at increased risk of urinary tract infections or genital infections while on SGLT2 inhibitors. 19 There was a high dropout rate due to the expected decline in eGFR after the initiation of therapy. Participants with proteinuric kidney disease may be more likely to stay on SGLT2 inhibitor therapy after the initial eGFR decline because it is anticipated and because large prospective trials have shown that these medications will slow decline in eGFR. While participants with ADTKD were warned that they would have a decline in eGFR, many participants were uncomfortable with this decline, mostly because there was no long-term assurance of benefit as in proteinuric kidney disease trials. There were no significant differences in eGFR decline or other characteristics for participants who stayed on vs. stopped therapy. The initial change in eGFR mirrored that of other SGLT2 inhibitor studies. We also assessed two other endpoints associated with SGLT2 inhibitor efficacy. First, a rise in hemoglobin has been associated with the efficacy of SGLT2 inhibitors. In an analysis by Wanner and colleagues, the 12 week change in hematocrit from baseline was the strongest mediator of beneficial outcomes (99.5% mediation) in participants receiving SGLT2 inhibitors. 20 In our participants we did not find a rise in hemoglobin. Second, declines in urinary Kim-1 levels have been found in participants taking SGLT2 inhibitors 21 , 22 , decreasing 23% (p = 0.05) in a 6 week cross-over trial. 22 . While we have not found an association between plasma Kim-1 levels and kidney survival in our cohort, we did find a rise in Kim-1 levels in our participants. This rise was not significant due to a large standard deviation in these measurements. Increased expression of Kim-1 is associated with worse kidney outcomes in animal models. 23 Conclusions In summary, we were able to show that SGLT2 inhibitors are well tolerated in participants with ADTKD, though the agents were often stopped because of the initial anticipated decline in eGFR and the uncertainty of future benefit. Hemoglobin levels did not rise, and plasma Kim-1 levels did not decline. These findings, together with findings of decreased efficacy in nonproteinuric kidney diseases 12 , were suggestive that these medications may not be effective. On the other hand, participants did have the characteristic eGFR decline with initial therapy that has been associated with future preservation of kidney function. When a biomarker of disease activity is identified in participants with ADTKD, we will reanalyze samples from this study to further look at the potential benefit of these agents. Abbreviations ADTKD autosomal dominant tubulointerstitial kidney disease CKD chronic kidney disease eGFR estimated glomerular filtration rate SGLT2 sodium–glucose cotransporter 2 Declarations Ethics approval and consent to participate This study was approved by the Wake Forest University Health Sciences Institutional Review Board, Winston-Salem, NC, United States, and Beaumont Hospital Ethics Committee, Dublin, Ireland in accordance with the Declaration of Helsinki. All individuals presented in the study provided voluntary, autonomous consent to participate. Consent for publication Not applicable. Clinical trial number Not applicable. Availability of data and materials The datasets generated and analyzed during the current study are not publicly available to protect patient confidentiality. We are very happy to work with any groups interested in studying this condition and providing genetic information that can satisfy their research requests. An anonymized dataset analyzed in the study will be available from the European Genome-Phenome Archive (EGA-archive.org), with request for data access. Competing Interests AJB has received compensation as follows: advisory board, Horizon Pharma; speaker, Natera; author, UpToDate; advisor, First Faculty of Medicine, Charles University; royalty; Sail Bio; patent for UMOD genetic diagnosis. PJC has received funding from Astra Zeneca, Boehringer, Hansa, and medical advisory board fees. KOK, AHW, EAEE, AT, LM, AK, MVR, MJC, MZ, and SK have nothing to disclose. Author’s contributions Conceptualization: AJB; Data curation: KOK, EAEE, AT, LM, AK; Formal analysis: AJB, KOK, AHW; Funding acquisition: AJB, SK; Investigation: KOK, AT, LM, EAEE; Methodology: AJB, KOK, EAEE, MZ, SK, PJC; Project Administration: KOK, AT; Resources: KOK, AHW, EAEE, AT, LM, AK; Software: KOK, AHW, AT, AK; Supervision: AJB, SK, PJC; Validation: KOK, AHW; Visualization: AJB, KOK, AHW; Writing-original draft: AJB, KOK, AHW, EAEE, SK, PJC; Writing-review & editing: KOK, AHW, EAEE, AT, LM, AK, MVR, MJC, MZ, SK, PJC and AJB. Funding AJB was funded by NIH-NIDDK R21 DK106584, CKD Biomarkers Consortium Pilot and Feasibility Studies Program funded by the NIH-NIDDK (U01 DK103225), the Slim Health Foundation, the Black-Brogan Foundation, the Rassmuss Foundation, Soli Deo Gloria. REDCap is supported through a National Center for Advancing Translational Sciences Wake Forest University School of Medicine Clinical and Translational Science Award (UL1TR004929). SK and colleagues were supported by the Ministry of Education, Youth and Sports of the Czech Republic through projects LUAUS24087 and MULTIOMICS_CZ (Programme Johannes Amos Comenius, Ministry of Education, Youth and Sports of the Czech Republic,//ID Project CZ.02.01.01/00/23_020/0008540) – Co-funded by the European Union. EAEE reports funds from the Royal College of Surgeons in Ireland. Acknowledgements The authors thank all individuals who participated in this study. Special thanks to Victoria Robins, RN, BSN for her work on this study. References Wanner C, Inzucchi SE, Lachin JM et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 7/28/2016 2016;375(4):323–34. Not in File. 10.1056/NEJMoa1515920 [doi]. Heerspink HJL, Stefansson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med Oct. 2020;8(15):1436–46. 10.1056/NEJMoa2024816 . Devuyst O, Olinger E, Weber S, et al. Autosomal dominant tubulointerstitial kidney disease. Nat Rev Dis Primers Sep. 2019;5(1):60. 10.1038/s41572-019-0109-9 . Olinger E, Hofmann P, Kidd K, et al. Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease due to mutations in UMOD and MUC1. Kidney Int May. 2020;22. 10.1016/j.kint.2020.04.038 . Hart TC, Gorry MC, Hart PS, et al. Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genet. 2002;12/2002(12):882–92. Not in File. Kirby A, Gnirke A, Jaffe DB, et al. Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing. Nat Genet Mar. 2013;45(3):299–303. 10.1038/ng.2543 . Kidd K, Vylet'al P, Schaeffer C, et al. Genetic and Clinical Predictors of Age of ESKD in Individuals With Autosomal Dominant Tubulointerstitial Kidney Disease Due to UMOD Mutations. Kidney Int Rep Sep. 2020;5(9):1472–85. 10.1016/j.ekir.2020.06.029 . Vylet'al P, Kublova M, Kalbacova M et al. Alterations of uromodulin biology: a common denominator of the genetically heterogeneous FJHN/MCKD syndrome. Kidney Int . 9/2006. 2006;70(6):1155–1169. Not in File. doi:5001728 [pii];10.1038/sj.ki.5001728 [doi]. Vallon V. State-of-the-Art-Review: Mechanisms of Action of SGLT2 Inhibitors and Clinical Implications. Am J Hypertens Oct. 2024;14(11):841–52. 10.1093/ajh/hpae092 . Cormican S, Connaughton DM, Kennedy C, et al. Autosomal dominant tubulointerstitial kidney disease (ADTKD) in Ireland. Ren Fail Nov. 2019;41(1):832–41. 10.1080/0886022X.2019.1655452 . Vonesh E, Tighiouart H, Ying J, et al. Mixed-effects models for slope-based endpoints in clinical trials of chronic kidney disease. Stat Med Sep. 2019;30(22):4218–39. 10.1002/sim.8282 . Group E-KC, Herrington WG, Staplin N, et al. Long-Term Effects of Empagliflozin in Patients with Chronic Kidney Disease. 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Clinical characterization of a family with a mutation in the uromodulin (Tamm-Horsfall glycoprotein) gene. Kidney Int . 7/2003. 2003;64(1):36–42. Not in File. doi:kid081 [pii];10.1046/j.1523-1755.2003.00081.x [doi]. Bailey CJ, Day C, Bellary S. Renal Protection with SGLT2 Inhibitors: Effects in Acute and Chronic Kidney Disease. Curr Diab Rep Jan. 2022;22(1):39–52. 10.1007/s11892-021-01442-z . Liu J, Li L, Li S, et al. Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: a systematic review and meta-analysis. Sci Rep Jun. 2017;6(1):2824. 10.1038/s41598-017-02733-w . Wanner C, Nangaku M, Kraus BJ, et al. How do SGLT2 inhibitors protect the kidney? A mediation analysis of the EMPA-REG OUTCOME trial. Nephrol Dial Transplant Aug. 2024;30(9):1504–13. 10.1093/ndt/gfae032 . Satirapoj B, Korkiatpitak P, Supasyndh O. Effect of sodium-glucose cotransporter 2 inhibitor on proximal tubular function and injury in patients with type 2 diabetes: a randomized controlled trial. Clin Kidney J Jun. 2019;12(3):326–32. 10.1093/ckj/sfy122 . Dekkers CCJ, Petrykiv S, Laverman GD, Cherney DZ, Gansevoort RT, Heerspink HJL. Effects of the SGLT-2 inhibitor dapagliflozin on glomerular and tubular injury markers. Diabetes Obes Metab Aug. 2018;20(8):1988–93. 10.1111/dom.13301 . Humphreys BD, Xu F, Sabbisetti V, et al. Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis. J Clin Invest Sep. 2013;123(9):4023–35. 10.1172/JCI45361 . Additional Declarations Competing interest reported. AJB has received compensation as follows: advisory board, Horizon Pharma; speaker, Natera; author, UpToDate; advisor, First Faculty of Medicine, Charles University; royalty; Sail Bio; patent for UMOD genetic diagnosis. PJC has received funding from Astra Zeneca, Boehringer, Hansa, and medical advisory board fees. KOK, AHW, EAEE, AT, LM, AK, MVR, MJC, MZ, and SK have nothing to disclose. 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-7482366","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":519517505,"identity":"dd576afd-ca51-4762-a27b-3dba5c3bb2c6","order_by":0,"name":"Kendrah O. Kidd","email":"","orcid":"","institution":"Wake Forest School University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Kendrah","middleName":"O.","lastName":"Kidd","suffix":""},{"id":519517506,"identity":"11ca1482-2ebc-4967-9a5e-7ec782ce41f1","order_by":1,"name":"Adrienne H. 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Choi","email":"","orcid":"","institution":"MedStar Georgetown University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"J.","lastName":"Choi","suffix":""},{"id":519517513,"identity":"1ced2519-b01c-4782-b135-3642c92510c2","order_by":8,"name":"Martina Zivna","email":"","orcid":"","institution":"Charles University","correspondingAuthor":false,"prefix":"","firstName":"Martina","middleName":"","lastName":"Zivna","suffix":""},{"id":519517514,"identity":"eb3f4ebd-1a30-4121-9615-dc234050a929","order_by":9,"name":"Stanislav Kmoch","email":"","orcid":"","institution":"Charles University","correspondingAuthor":false,"prefix":"","firstName":"Stanislav","middleName":"","lastName":"Kmoch","suffix":""},{"id":519517515,"identity":"89b75956-e524-4c17-b067-91013f64044c","order_by":10,"name":"Peter J. Conlon","email":"","orcid":"","institution":"Beaumont Hospital","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"J.","lastName":"Conlon","suffix":""},{"id":519517516,"identity":"6cddb6a3-9457-46d6-ad8a-468df8e0b1fe","order_by":11,"name":"Anthony J. Bleyer","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA90lEQVRIiWNgGAWjYDACCeYGECXHwMDGwAxkyDBIAEkevFoYwVqMYVp4eIjVkthAtBb+2Y2Nj3kq7qVvOH4s8XFBhR2PvXQD44O3bXgsuXOw2ZjnTHHuhjNph41nnEnm4ZE5wGw4F48WhhuJbdK8bQm52w6kgxjMQIclsAEZuHXI30hs/837LyHd7PxzEKMepIX9Nz4tBkBbmHkbEhLMbqQdAzIOg21hxqfFEOgXyTnHEgz333iWLM1z7DgPz41EoMg53Frkbjcf/PCmJkFesj/N8DNPTbUc+4xkoEgZHu8DARNaLEBiCi9g/EFQySgYBaNgFIxoAAAHrFC40z0wHwAAAABJRU5ErkJggg==","orcid":"","institution":"Wake Forest School University of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Anthony","middleName":"J.","lastName":"Bleyer","suffix":""}],"badges":[],"createdAt":"2025-08-28 17:08:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7482366/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7482366/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":92185595,"identity":"dda2718c-9155-4f80-b839-af66e3d01abc","added_by":"auto","created_at":"2025-09-25 14:10:42","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":52925,"visible":true,"origin":"","legend":"","description":"","filename":"SGLT2i02Sep2025clean.docx","url":"https://assets-eu.researchsquare.com/files/rs-7482366/v1/a9fe37a45a86fafd3d892c15.docx"},{"id":92185591,"identity":"2a6f5624-e96c-4ecb-8568-b2bf3f1d99f5","added_by":"auto","created_at":"2025-09-25 14:10:42","extension":"json","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":12880,"visible":true,"origin":"","legend":"","description":"","filename":"759b184305804dd083b0710338ea3dfb.json","url":"https://assets-eu.researchsquare.com/files/rs-7482366/v1/bd5e7f759fcb754557534d19.json"},{"id":92186040,"identity":"01a2b88a-8954-41f3-a3be-d3d279c981be","added_by":"auto","created_at":"2025-09-25 14:18:42","extension":"xml","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":95624,"visible":true,"origin":"","legend":"","description":"","filename":"759b184305804dd083b0710338ea3dfb1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7482366/v1/2aa442df2d4efa380356e118.xml"},{"id":92186039,"identity":"6edbbf61-00bc-4f1b-acea-c96d00033e22","added_by":"auto","created_at":"2025-09-25 14:18:42","extension":"pptx","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":38992,"visible":true,"origin":"","legend":"","description":"","filename":"Figure127Aug2025.pptx","url":"https://assets-eu.researchsquare.com/files/rs-7482366/v1/c57a01860a60463960af3431.pptx"},{"id":92185594,"identity":"7aaead17-16f9-43bd-b851-8fbb67ff8658","added_by":"auto","created_at":"2025-09-25 14:10:42","extension":"pptx","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":46466,"visible":true,"origin":"","legend":"","description":"","filename":"Figure227aug2025.pptx","url":"https://assets-eu.researchsquare.com/files/rs-7482366/v1/b3eebd63733c73dbe38a2636.pptx"},{"id":92185596,"identity":"b867c33e-ed72-44c5-80bb-4214b0c80630","added_by":"auto","created_at":"2025-09-25 14:10:42","extension":"xml","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":93567,"visible":true,"origin":"","legend":"","description":"","filename":"759b184305804dd083b0710338ea3dfb1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7482366/v1/04f6d22cbf8f70fe4928b0ba.xml"},{"id":92185598,"identity":"b8989089-e845-4464-8232-3d6026ad1841","added_by":"auto","created_at":"2025-09-25 14:10:42","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":103016,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7482366/v1/8ccbe25ec1397ad545e62fcb.html"},{"id":92185590,"identity":"8828055c-69dc-4065-a229-190aa0095810","added_by":"auto","created_at":"2025-09-25 14:10:42","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":592215,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow diagram\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7482366/v1/32453ea0db4b89db69b7439d.jpg"},{"id":92185592,"identity":"77103cde-5918-4300-a429-a99ad07d0286","added_by":"auto","created_at":"2025-09-25 14:10:42","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":492689,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChange in eGFR over time.\u003c/strong\u003e Mean values for each time point are only provided if there were more than 3 measurements for that time point. The eGFR decline of 4 ml/min/1.73m2 seen at 3 months was similar to prior studies of SGLT2 inhibitors.\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7482366/v1/708bd57977ad1c94f5b6665e.jpg"},{"id":92699030,"identity":"1e8478d9-d94c-48c8-a9de-0a36d801bbd8","added_by":"auto","created_at":"2025-10-03 07:46:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1946506,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7482366/v1/74c6ff62-9259-4c3c-852b-babe00120ddd.pdf"}],"financialInterests":"Competing interest reported. AJB has received compensation as follows: advisory board, Horizon Pharma; speaker, Natera; author, UpToDate; advisor, First Faculty of Medicine, Charles University; royalty; Sail Bio; patent for UMOD genetic diagnosis. PJC has received funding from Astra Zeneca, Boehringer, Hansa, and medical advisory board fees. KOK, AHW, EAEE, AT, LM, AK, MVR, MJC, MZ, and SK have nothing to disclose.","formattedTitle":"An Observational Study of SGLT2 Inhibitors and Their Use in Autosomal Dominant Tubulointerstitial Kidney Disease","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eSodium-glucose cotransporter 2 (SGLT2) inhibitors are effective treatments for patients with diabetic nephropathy\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e and other forms of chronic kidney disease (CKD)\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e, but there is little information available about their use in inherited disorders. It is also unclear if these agents are effective in nonproteinuric CKD.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eAutosomal dominant tubulointerstitial kidney disease (ADTKD) is the third most common genetic form of inherited kidney disease\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e and is characterized by autosomal dominant inheritance, a bland urinary sediment, and CKD leading to kidney failure at a mean age of 45 years (range 20 to 80 years).\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e The two most common forms of ADTKD are ADTKD-\u003cem\u003eUMOD\u003c/em\u003e (due to \u003cem\u003eUMOD\u003c/em\u003e pathogenic variants)\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e and ADTKD-\u003cem\u003eMUC1\u003c/em\u003e (due to \u003cem\u003eMUC1\u003c/em\u003e pathogenic variants)\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. While ADTKD is not associated with proteinuria, ADTKD-\u003cem\u003eUMOD\u003c/em\u003e is characterized by increased tubular energy utilization due to increased proximal tubular uptake of sodium and urate.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Both ADTKD-\u003cem\u003eUMOD\u003c/em\u003e and ADTKD-\u003cem\u003eMUC1\u003c/em\u003e have a strong component of tubulinterstitial fibrosis\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e, which could be targeted by SGLT2 inhibition.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e At present, there are no treatments available for ADTKD.\u003c/p\u003e\u003cp\u003eThe purpose of this study was to follow individuals with ADTKD who were started on SGLT2 inhibitors by their healthcare providers and assess patient tolerance and change in estimated glomerular filtration rate (eGFR) over time. We also compared eGFR change with a propensity-matched cohort of participants in the Wake Forest Prospective ADTKD Cohort who were not receiving SGLT2 inhibitors.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e All participants signed informed consent to participate in the studies approved by Wake Forest University Health Sciences institutional review board and Beaumont Hospital ethics committee.\u003c/p\u003e\u003cp\u003eThe Wake Forest Rare Inherited Kidney Disease Team conducted a prospective observational study of participants with genetically diagnosed ADTKD-\u003cem\u003eUMOD\u003c/em\u003e or ADTKD-\u003cem\u003eMUC1\u003c/em\u003e beginning in March 2025 and accruing 270 participants (see Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Serum creatinine values were assessed at baseline and then at 3-month intervals. Plasma and urine for biomarkers were obtained at baseline and in follow up at three-month intervals and stored in a \u0026ndash; 80\u0026ordm;C freezer. Participants filled out a survey every three months, including questions specifically about starting SGLT2 inhibitors. As the study was observational in nature, all decisions regarding starting and stopping medications were made between the participants and their clinical providers.\u003c/p\u003e\u003cp\u003eAll participants receiving SGLT2 inhibitors received information from their clinical providers prior to starting these agents that there would be an expected decline in eGFR after initiation of therapy, and that this eGFR decline would be reversible.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Participants were told that SGLT2 inhibitors were proven beneficial in proteinuric kidney diseases\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e but not in ADTKD.\u003c/p\u003e\u003cp\u003eBeaumont Hospital in Dublin, Ireland has a genetic kidney disease clinic and follows participants longitudinally with ADTKD.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Beaumont Hospital investigators were able to identify participants started on SGLT2 inhibitors and provide baseline and follow-up eGFR values.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eStatistical analysis\u003c/span\u003e: Baseline characteristics were calculated using standard statistical techniques with SAS (Cary, NC). In comparisons of the change in eGFR over time, participants were included if they remained on SGLT2 inhibitors for greater than 1 year. For calculation of the eGFR slope prior to initiation of SGLT2 inhibition, we used eGFR data from the prior year. The initial serum creatinine value used to calculate the slope of decline while on SGLT2 inhibition was defined as the serum creatinine value obtained at least three months after therapy initiation in order to account for the initial drop in eGFR when starting SGLT2 inhibitors.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e A propensity score was created to match participants who had taken SGLT2 inhibitors with participants not on SGLT2 inhibitors using the PSMATCH optimal algorithm in SAS with a ratio of two controls per case. Samples were matched exactly on sex and ADTKD diagnosis and with the age and eGFR using propensity scores. Four eGFR values per sample were required over a 2-year period to calculate the slope of decline of eGFR for each participant. The differences in the mean eGFR decline for individuals taking SGLT2 inhibitors and individuals not taking SGLT2 inhibitors was evaluated using a paired t-test. The differences in the mean eGFR decline prior to and after starting SGLT2 inhibitors were also evaluated using a paired t-test.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThere were 270 participants followed in the observational study over time (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), with 112 (41%) with ADTKD-\u003cem\u003eUMOD\u003c/em\u003e and 158 (59%) with ADTKD-\u003cem\u003eMUC1\u003c/em\u003e. 14 of the ADTKD-\u003cem\u003eUMOD\u003c/em\u003e participants and 8 of the ADTKD-\u003cem\u003eMUC1\u003c/em\u003e participants started SGLT2 inhibitors. Data was then added on 5 participants from the Irish Cohort (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\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\u003eCharacteristics of participants in the Wake Forest ADTKD Cohort Observational Study who started versus did not start SGLT2 inhibitors.\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=\"left\" 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\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eCohort participants not starting SGLT2 inhibitors\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eCohort participants starting SGLT2 inhibitors\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003eP-value\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eADTKD disease type\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eUMOD\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eMUC1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eUMOD\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eMUC1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eUMOD\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cem\u003eMUC1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e144\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e104\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e8\u003c/p\u003e\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\u003eAge (y)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e39.30\u0026thinsp;\u0026plusmn;\u0026thinsp;14.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e37.37\u0026thinsp;\u0026plusmn;\u0026thinsp;12.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e40.34\u0026thinsp;\u0026plusmn;\u0026thinsp;16.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e39.77\u0026thinsp;\u0026plusmn;\u0026thinsp;10.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.51\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex (% male)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e55 (38%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e35 (34%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7 (50%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4 (50%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.37\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eeGFR (ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e) at entry into the study\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e62.29\u0026thinsp;\u0026plusmn;\u0026thinsp;26.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e61.34\u0026thinsp;\u0026plusmn;\u0026thinsp;24.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e45.91\u0026thinsp;\u0026plusmn;\u0026thinsp;17.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e57.94\u0026thinsp;\u0026plusmn;\u0026thinsp;19.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.0019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.61\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003eP value comparing ADTKD subtype participants starting versus not starting SGLT2 inhibitors\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\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\u003eCharacteristics of individuals with ADTKD who started SGLT2 inhibitors according to country.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUS\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIreland\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTotal\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003en\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e27\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eADTKD-\u003cem\u003eUMOD\u003c/em\u003e n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14 (64%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14 (52%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eADTKD-\u003cem\u003eMUC1\u003c/em\u003e n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (36%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13 (48%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (y) \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e40.13\u0026thinsp;\u0026plusmn;\u0026thinsp;14.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e43.79\u0026thinsp;\u0026plusmn;\u0026thinsp;20.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e40.81\u0026thinsp;\u0026plusmn;\u0026thinsp;15.57\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex (%male)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (50%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (40%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13 (48%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eeGFR at entry\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e50.29\u0026thinsp;\u0026plusmn;\u0026thinsp;18.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e47.67\u0026thinsp;\u0026plusmn;\u0026thinsp;19.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e49.80\u0026thinsp;\u0026plusmn;\u0026thinsp;18.61\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDapagliflozin, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (50%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16 (59%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEmpagliflozin, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (50%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11 (41%)\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\u003csup\u003e1\u003c/sup\u003emean \u0026plusmn; s.d.\u003c/p\u003e\u003cp\u003eNone of the participants had underlying diabetes or other significant comorbid conditions. None of the participants had proteinuria. Thus, there were 27 individuals with ADTKD who started SGLT2 inhibitors.\u003c/p\u003e\u003cp\u003eOf these 27 individuals starting SGLT2 inhibitors, 2 stopped medication prior to one month, 4 stopped medication between 1 and 3 months, and 6 stopped prior to one year of treatment (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). None of the individuals stopped SGLT2 inhibitors due to urinary tract infections, fungal infections, volume depletion, or ketoacidosis. Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows characteristics of individuals who stopped versus continued on therapy.\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\u003eComparison of individuals who stopped and did not stop SGLT2 inhibitors.\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=\"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=\"char\" char=\".\" 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\" colname=\"c2\"\u003e\u003cp\u003eStopped SGLT 2 inhibitor\u0026thinsp;\u0026lt;\u0026thinsp;3 months\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStopped SGLT2 inhibitor from 3 months to 1 year\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDid not stop\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\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\u003eN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUMOD n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (50%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 (45%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0.28\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (40%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11(55%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge at entry\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e24.58\u0026thinsp;\u0026plusmn;\u0026thinsp;2.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e41.60\u0026thinsp;\u0026plusmn;\u0026thinsp;24.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e42.24\u0026thinsp;\u0026plusmn;\u0026thinsp;13.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.49\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge at start of SGLT2i\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38.31\u0026thinsp;\u0026plusmn;\u0026thinsp;8.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e44.57\u0026thinsp;\u0026plusmn;\u0026thinsp;24.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e50.87\u0026thinsp;\u0026plusmn;\u0026thinsp;8.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.30\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex (%Male)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.27\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eeGFR at entry\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e39.18\u0026thinsp;\u0026plusmn;\u0026thinsp;3.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e41.53\u0026thinsp;\u0026plusmn;\u0026thinsp;12.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e52.93\u0026thinsp;\u0026plusmn;\u0026thinsp;20.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.42\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eeGFR at start of SGLT2i\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e29.85\u0026thinsp;\u0026plusmn;\u0026thinsp;3.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e32.24\u0026thinsp;\u0026plusmn;\u0026thinsp;10.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e37.19\u0026thinsp;\u0026plusmn;\u0026thinsp;8.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.72\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e% eGFR decline at one month\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.88\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDapagliflozin, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1(50%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (80%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0.52\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEmpagliflozin, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (50%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (20%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\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\u003e\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003eP value compares the group of individuals who stopped versus did not stop.\u003c/p\u003e\u003cp\u003e\u003csup\u003e2\u003c/sup\u003eMean \u0026plusmn; s.d.\u003c/p\u003e\u003cp\u003eThere were 15 participants with enough data to compare longitudinal changes in eGFR. Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e provides characteristics of these patients, and Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e provides information on the propensity-matched cohort. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the change in eGFR over time. Participants had a decline in eGFR at 3 months of 4 ml/min/1.73 m\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e, which was similar to the decline in eGFR observed in other studies.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e The slope of eGFR after the initiation of the SGLT2 inhibitors was \u0026minus;\u0026thinsp;2.61\u0026thinsp;\u0026plusmn;\u0026thinsp;2.58 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e. This was not significantly different from the slope of the propensity matched controls (-2.25\u0026thinsp;\u0026plusmn;\u0026thinsp;2.39 ml/min/1.73 m\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e (p\u0026thinsp;=\u0026thinsp;0.83)) and not significantly different from the eGFR slope prior to initiation of SGLT2 inhibitors (-3.13\u0026thinsp;\u0026plusmn;\u0026thinsp;5.39 ml/min/1.73 m\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e (p\u0026thinsp;=\u0026thinsp;0.71)) (see Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). There were no differences according to ADTKD sub-type (\u003cb\u003esee\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparison of laboratory values\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=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" 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\" colname=\"c2\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBaseline\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAfter 1\u0026ndash;3 months (first available value)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP value from paired t test\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHemoglobin (g/dl)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e11.99\u0026thinsp;\u0026plusmn;\u0026thinsp;0.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e12.24\u0026thinsp;\u0026plusmn;\u0026thinsp;1.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.61\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlasma Kim-1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e897.71\u0026thinsp;\u0026plusmn;\u0026thinsp;2083.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e961.84\u0026thinsp;\u0026plusmn;\u0026thinsp;2269.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.33\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrine Kim-1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e985.75\u0026thinsp;\u0026plusmn;\u0026thinsp;1383.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e1682.81\u0026thinsp;\u0026plusmn;\u0026thinsp;1221.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.14\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSerum uric acid level\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e5.82\u0026thinsp;\u0026plusmn;\u0026thinsp;0.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e5.06\u0026thinsp;\u0026plusmn;\u0026thinsp;1.87\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.12\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\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristics of individuals with long-term follow up\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=\"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=\"char\" char=\".\" 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\" colname=\"c2\"\u003e\u003cp\u003eOverall\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eADTKD-\u003cem\u003eMUC1\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eADTKKD-\u003cem\u003eUMOD\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\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\u003eN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9 (60%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (56%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (66%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge starting SGLT2 inhibitor (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e51.59\u0026thinsp;\u0026plusmn;\u0026thinsp;16.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e52.03\u0026thinsp;\u0026plusmn;\u0026thinsp;18.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e50.92\u0026thinsp;\u0026plusmn;\u0026thinsp;15.87\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.91\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eeGFR before start of SGLT2 inhibitors (ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34.22\u0026thinsp;\u0026plusmn;\u0026thinsp;10.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e34.28\u0026thinsp;\u0026plusmn;\u0026thinsp;10.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e34.13\u0026thinsp;\u0026plusmn;\u0026thinsp;11.79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.91\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eeGFR\u0026thinsp;\u0026gt;\u0026thinsp;40 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e (n, column percent)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (20%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (22%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (17%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e1.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eeGFR 30 to \u0026le;\u0026thinsp;40 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e (n, column percent)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (40%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (33%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (50%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eeGFR\u0026thinsp;\u0026lt;\u0026thinsp;30 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e (n, column percent) and not kidney failure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (40%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (44%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (33%)\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\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristics of individuals receiving SGLT2 inhibitors and the propensity-matched cohort.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\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\u003eCases\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMatched Controls\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\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\u003eN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e52.04\u0026thinsp;\u0026plusmn;\u0026thinsp;16.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e50.38\u0026thinsp;\u0026plusmn;\u0026thinsp;13.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.72\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDuration of follow-up\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.35\u0026thinsp;\u0026plusmn;\u0026thinsp;0.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.61\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eeGFR ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e31.87\u0026thinsp;\u0026plusmn;\u0026thinsp;11.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e36.69\u0026thinsp;\u0026plusmn;\u0026thinsp;9.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.15\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9 (60%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18 (60%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eADTKD Type\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9 MUC1 (60%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18 MUC1 (60%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 UMOD(40%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 UMOD (40%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.0\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\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab7\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparison in changes of eGFR (ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e) before and after SGLT2 inhibition and between cases and the propensity-matched controls.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\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\u003eSlope of eGFR over time\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eP-value (ref group Cases After)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCases after SGLT2 inhibitor initiation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e-2.61\u0026thinsp;\u0026plusmn;\u0026thinsp;2.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePropensity-matched controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e-2.25\u0026thinsp;\u0026plusmn;\u0026thinsp;2.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.83\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCases before SGLT2 inhibitor initiation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e-3.13\u0026thinsp;\u0026plusmn;\u0026thinsp;5.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.71\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 change in hemoglobin values for 17 individuals who had values pre- and post- SGLT2 inhibitor initiation (see Table\u0026nbsp;\u003cspan refid=\"Tab8\" class=\"InternalRef\"\u003e8\u003c/span\u003e). Plasma and urinary Kim-1 values were widely dispersed. There was an increase in these values, but due to the wide standard deviation this was not statistically significant. The serum uric acid levels showed a non-significant decline.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab8\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 8\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparison of changes in eGFR (ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e) according to ADTKD subtype.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eADTKD-\u003cem\u003eMUC1\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSlope of eGFR over time\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eP-value (ref group Cases After)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCases after SGLT2 inhibitor initiation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-3.46\u0026thinsp;\u0026plusmn;\u0026thinsp;2.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePropensity-matched controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-2.67\u0026thinsp;\u0026plusmn;\u0026thinsp;3.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCases before SGLT2 inhibitor initiation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-3.06\u0026thinsp;\u0026plusmn;\u0026thinsp;2.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.21\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eADTKD-\u003cem\u003eUMOD\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSlope of eGFR over time\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eP-value (ref group Cases After)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCases after SGLT2 inhibitor initiation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-1.33\u0026thinsp;\u0026plusmn;\u0026thinsp;1.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePropensity-matched controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-1.93\u0026thinsp;\u0026plusmn;\u0026thinsp;4.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.69\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCases before SGLT2 inhibitor initiation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-1.03\u0026thinsp;\u0026plusmn;\u0026thinsp;1.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.36\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSGLT2 inhibitors have been found to be an extremely effective therapy to slow the rate of eGFR decline in participants with diabetic nephropathy\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e and proteinuric CKD.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e SGLT2 inhibitors also reduce proteinuria in Alport syndrome.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eIt is unclear whether SGLT2 inhibitors are beneficial in non-proteinuric kidney disease\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e or in genetic disorders autosomal dominant polycystic kidney disease.\u003csup\u003e\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eParticipants with ADTKD suffer from tubulointerstitial kidney disease. Participants with ADTKD-\u003cem\u003eUMOD\u003c/em\u003e have increased proximal tubular uptake of sodium and uric acid\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e, with increased energy expenditure of the proximal tubule, providing a potential attractive target for SGLT2 inhibitors. However, as there are a number of potential mechanisms of renal protection with SGLT2 inhibitors\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, one cannot predict theoretically for which kidney diseases they will be effective.\u003c/p\u003e\u003cp\u003eThere are numerous obstacles in determining if SGLT2 inhibitors will be effective in ADTKD. First, the patient population is small, and a well-powered prospective randomized trial cannot be carried out. Second, participants with ADTKD do not have proteinuria. SGLT2 inhibitors have been found to be effective in proteinuric kidney disease\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e and also lower proteinuria\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e, a marker of efficacy. Participants with ADTKD do not have proteinuria, and there is no similar biomarker of disease activity.\u003c/p\u003e\u003cp\u003eSafety: SGLT2 inhibitors were well-tolerated by participants with ADTKD, with no significant adverse side effects. This is of note, as decreased uromodulin secretion in individuals with ADTKD-\u003cem\u003eUMOD\u003c/em\u003e could place them at increased risk of urinary tract infections or genital infections while on SGLT2 inhibitors.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e There was a high dropout rate due to the expected decline in eGFR after the initiation of therapy. Participants with proteinuric kidney disease may be more likely to stay on SGLT2 inhibitor therapy after the initial eGFR decline because it is anticipated and because large prospective trials have shown that these medications will slow decline in eGFR. While participants with ADTKD were warned that they would have a decline in eGFR, many participants were uncomfortable with this decline, mostly because there was no long-term assurance of benefit as in proteinuric kidney disease trials. There were no significant differences in eGFR decline or other characteristics for participants who stayed on vs. stopped therapy.\u003c/p\u003e\u003cp\u003eThe initial change in eGFR mirrored that of other SGLT2 inhibitor studies. We also assessed two other endpoints associated with SGLT2 inhibitor efficacy. First, a rise in hemoglobin has been associated with the efficacy of SGLT2 inhibitors. In an analysis by Wanner and colleagues, the 12 week change in hematocrit from baseline was the strongest mediator of beneficial outcomes (99.5% mediation) in participants receiving SGLT2 inhibitors.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e In our participants we did not find a rise in hemoglobin. Second, declines in urinary Kim-1 levels have been found in participants taking SGLT2 inhibitors\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e, decreasing 23% (p\u0026thinsp;=\u0026thinsp;0.05) in a 6 week cross-over trial.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. While we have not found an association between plasma Kim-1 levels and kidney survival in our cohort, we did find a rise in Kim-1 levels in our participants. This rise was not significant due to a large standard deviation in these measurements. Increased expression of Kim-1 is associated with worse kidney outcomes in animal models.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn summary, we were able to show that SGLT2 inhibitors are well tolerated in participants with ADTKD, though the agents were often stopped because of the initial anticipated decline in eGFR and the uncertainty of future benefit. Hemoglobin levels did not rise, and plasma Kim-1 levels did not decline. These findings, together with findings of decreased efficacy in nonproteinuric kidney diseases\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, were suggestive that these medications may not be effective. On the other hand, participants did have the characteristic eGFR decline with initial therapy that has been associated with future preservation of kidney function. When a biomarker of disease activity is identified in participants with ADTKD, we will reanalyze samples from this study to further look at the potential benefit of these agents.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eADTKD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eautosomal dominant tubulointerstitial kidney disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCKD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003echronic kidney disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eeGFR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eestimated glomerular filtration rate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSGLT2\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003esodium\u0026ndash;glucose cotransporter 2\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Wake Forest University Health Sciences Institutional Review Board, Winston-Salem, NC, United States, and Beaumont Hospital Ethics Committee, Dublin, Ireland in accordance with the Declaration of Helsinki. All individuals presented in the study provided voluntary, autonomous consent to participate.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analyzed during the current study are not publicly available to protect patient confidentiality. \u0026nbsp;We are very happy to work with any groups interested in studying this condition and providing genetic information that can satisfy their research requests. An anonymized dataset analyzed in the study will be available from the European Genome-Phenome Archive (EGA-archive.org), with request for data access.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAJB has received compensation as follows: \u0026nbsp;advisory board, Horizon Pharma; speaker, Natera; author, UpToDate; advisor, First Faculty of Medicine, Charles University; royalty; Sail Bio; patent for \u003cem\u003eUMOD\u0026nbsp;\u003c/em\u003egenetic diagnosis. PJC has received funding from Astra Zeneca, Boehringer, Hansa, and medical advisory board fees. KOK, AHW, EAEE, AT, LM, AK, MVR, MJC, MZ, and SK have nothing to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor’s contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: AJB; Data curation: KOK, EAEE, AT, LM, AK; Formal analysis: AJB, KOK, AHW; Funding acquisition: AJB, SK; Investigation: KOK, AT, LM, EAEE; Methodology: AJB, KOK, EAEE, MZ, SK, PJC; Project Administration: KOK, AT; Resources: KOK, AHW, EAEE, AT, LM, AK; Software: KOK, AHW, AT, AK; Supervision: AJB, SK, PJC; Validation: KOK, AHW; Visualization: AJB, KOK, AHW; Writing-original draft: AJB, KOK, AHW, EAEE, SK, PJC; Writing-review \u0026amp; editing: KOK, AHW, EAEE, AT, LM, AK, MVR, MJC, MZ, SK, PJC and AJB.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;AJB was funded by NIH-NIDDK R21 DK106584, CKD Biomarkers Consortium Pilot and Feasibility Studies Program funded by the NIH-NIDDK (U01 DK103225), the Slim Health Foundation, the Black-Brogan Foundation, the Rassmuss Foundation, Soli Deo Gloria. \u0026nbsp; REDCap is supported through a National Center for Advancing Translational Sciences Wake Forest University School of Medicine Clinical and Translational Science Award (UL1TR004929). \u0026nbsp;SK and colleagues were supported by the Ministry of Education, Youth and Sports of the Czech Republic through projects LUAUS24087 and MULTIOMICS_CZ (Programme Johannes Amos Comenius, Ministry of Education, Youth and Sports of the Czech Republic,//ID Project CZ.02.01.01/00/23_020/0008540) – Co-funded by the European Union. EAEE reports funds from the Royal College of Surgeons in Ireland.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank all individuals who participated in this study. Special thanks to Victoria Robins, RN, BSN for her work on this study.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWanner C, Inzucchi SE, Lachin JM et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 7/28/2016 2016;375(4):323\u0026ndash;34. Not in File. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa1515920\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa1515920\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [doi].\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHeerspink HJL, Stefansson BV, Correa-Rotter R, et al. 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Effects of the SGLT-2 inhibitor dapagliflozin on glomerular and tubular injury markers. Diabetes Obes Metab Aug. 2018;20(8):1988\u0026ndash;93. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/dom.13301\u003c/span\u003e\u003cspan address=\"10.1111/dom.13301\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHumphreys BD, Xu F, Sabbisetti V, et al. Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis. J Clin Invest Sep. 2013;123(9):4023\u0026ndash;35. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1172/JCI45361\u003c/span\u003e\u003cspan address=\"10.1172/JCI45361\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":true,"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":"Autosomal Dominant Tubulointerstitial Kidney Disease, ADTKD, MUC1, UMOD, SGLT2 inhibitors, Sodium-glucose cotransporter 2 inhibitors","lastPublishedDoi":"10.21203/rs.3.rs-7482366/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7482366/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eThere are no specific treatments available for autosomal dominant tubulointerstitial kidney disease (ADTKD). As SGLT2 inhibitors have proven effective in other forms of CKD, we performed an observational study to determine their safety and effect on kidney function in ADTKD.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe obtained clinical and laboratory data before and after starting an SGLT2 inhibitor on 27 individuals with ADTKD. We created a propensity-matched cohort from a Wake Forest prospective ADTKD observational study.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eOf the 27 individuals, 12 stopped medication prior to one year due to concerns about the (anticipated) acute rise in serum creatinine. There were no adverse effects. The slope of eGFR after SGLT 2 inhibitor initiation was \u0026minus;\u0026thinsp;2.61\u0026thinsp;\u0026plusmn;\u0026thinsp;2.58 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e, which was not significantly different from the eGFR slope prior to initiation of SGLT2 inhibitors (-3.13\u0026thinsp;\u0026plusmn;\u0026thinsp;5.39 ml/min/1.73 m\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e (p\u0026thinsp;=\u0026thinsp;0.71)) or from 30 propensity-matched controls (-2.25\u0026thinsp;\u0026plusmn;\u0026thinsp;2.39 ml/min/1.73 m\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e (p\u0026thinsp;=\u0026thinsp;0.83)). Hemoglobin and plasma and urine KIM-1 levels did not change after starting SGLT2 inhibitors.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eSGLT2 inhibitors were well tolerated in ADTKD patients. There was neither a rise in hemoglobin levels nor a fall in plasma or urinary KIM-1 levels, suggesting that these agents may not be beneficial in ADTKD.\u003c/p\u003e","manuscriptTitle":"An Observational Study of SGLT2 Inhibitors and Their Use in Autosomal Dominant Tubulointerstitial Kidney Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-25 14:10:38","doi":"10.21203/rs.3.rs-7482366/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":"f79d44f1-d22e-48d4-a5f0-e2304e94cd09","owner":[],"postedDate":"September 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-03T07:38:44+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-25 14:10:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7482366","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7482366","identity":"rs-7482366","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}