The Potential Role of Sodium/Glucose Cotransporter 2 Inhibitors in the Treatment of Cystinuria

The Potential Role of Sodium/Glucose Cotransporter 2 Inhibitors in the Treatment of Cystinuria | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Potential Role of Sodium/Glucose Cotransporter 2 Inhibitors in the Treatment of Cystinuria Wilson Sui, Heiko Yang, Manoj Desai, Thomas Chi, Marshall Stoller This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4706572/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Nov, 2024 Read the published version in Urolithiasis → Version 1 posted 7 You are reading this latest preprint version Abstract Introduction The Maillard reaction is a non-enzymatic reaction between an amino acid and carbohydrate. We hypothesized that continuous washing of cystine stones with glucose could theoretically prevent growth of an existing cystine stone or even reduce its size leading to a decrease in stone events. Sodium/Glucose Cotransporter 2 (SGLT2) inhibitors, well known for inducing glucosuria, were used to test this hypothesis in an initial series of patients. Materials and methods Patients with cystinuria from September 2019 to May 2023 who received off-label dapaglifozin (Farxiga™) were identified. Patients were allowed to continue thiol and alkalinizing agents per standard of care. A symptomatic stone event was defined by stone passage or surgical intervention. Results Ten cystinuric patients were prescribed SGLT2 inhibitors with a median follow up of 13.5 months. Each patients’ historic stone event rate was compared to the event rate while prescribed SGLT2 medication. Overall, 80% of patients experienced fewer or equivalent stone events and half had stable stone volume during therapy. Eight patients had negative cystine capacity at baseline, yet seven experienced fewer stone events while on medication: four experienced no stone growth. One patient was taken off the SGLT2 inhibitor due to an adverse reaction; three others experienced mild, self-resolving effects and yet stayed on the medication. Conclusions Cystinuric patients treated with a SGLT2 inhibitor experienced fewer stone events while on medication compared to their historic rates and exhibited decreased or stable stone growth. There were few medication related side effects. SGLT2 inhibitors may be a promising long-term therapy for patients with cystinuria. Cystinuria Maillard reaction nephrolithiasis Figures Figure 1 Figure 2 Introduction The disulfide bond of cystine, a dimer of the amino acid cysteine, has long been the target of pharmacologic management in patients with cystinuria. Thiol containing medications undergo a thiol exchange reaction to compete with this bond resulting in a drug-cystine complex that is more soluble than cystine. 1–3 These medications however, are associated with severe side effects including liver abnormalities, nephrotic syndrome, blood dyscrasias and skin disorders limiting their use to those who fail dietary or alkali therapy. 4 Since the first report of the use of thiol medications for cystinuria in 1963, there have been no prospective, randomized data for these medications and development of alternative medications for this disease have been limited. 1,4–6 The Maillard reaction, which is a non-enzymatic reaction between the amine of an amino acid and carbohydrate has been widely used in the food industry. While the reaction requires heating, we hypothesized even if a small amount of cysteine/cystine reacts with glucose at body temperature, continuous exposure of cystine stones to glucose could prevent growth of an existing cystine stone and perhaps could reduce its size to facilitate excretion. To this end, the popular class of medications for treatment of diabetes called Sodium/Glucose Cotransporter 2 (SGLT2) inhibitors may be useful. 7–9 These medications block SGLT2, a protein found in the renal proximal tubules which facilitates excretion of glucose into the urine reducing systemic levels; this has been used for many purposes, especially for certain types of diabetes mellitus. Approximately 60–100 grams of glucose are eliminated daily while this medication is therapeutic. Boasting a low-risk safety profile, once daily dosing and cardiovascular and renal benefits, these medications have rapidly grown in popularity. 8,10 Here we present a novel approach to medical management of cystinuria with SGLT2 inhibitors. We hypothesize that the glucosuria and diuretic effects of SGTL2 inhibitors would lead to a Maillard reaction between cysteine/cystine and glucose in the urinary system leading to a reduction in kidney stone events, possible stone dissolution and stabilization of stone growth. Materials and methods Setting and participants Starting in November 2015, the University of California San Francisco (UCSF) Urology Clinic has been enrolling new patients with urinary stone disease into a prospective registry called the Registry for Stones of the Kidney and Ureter (ReSKU). The data points are derived from the EMR notes created by healthcare providers during clinic visits, surgical encounters, and follow-up visits as part of their regular care. The methodology and structure of this registry have been previously described. 11 All individuals participating in ReSKU provide written consent, and the study has received approval from the Committee on Human Research (Protocol 14–14533). Exposure & predictors We performed a retrospective review of consecutive patients with a history of cystinuria who were started on dapafligozin 10mg daily (Farxiga™) off-label from 2019 to May 2023. Patients were counseled that this medication would be used off-label and the risks, benefits and alternatives of this approach were discussed in detail. Given the widespread use of these medications in diabetes, the associated minimal side effect profile and the close clinical monitoring of these patients, we felt the potential benefits outweighed the risks. These patients had previously failed, did not tolerate or did not wish to start a thiol medication. If patients were on a thiol and wished to stop or were previously enrolled in a clinical trial, they were asked to pause these medications for at least 30 days before starting dapafligozin. We additionally extracted demographic and clinical information including past medical history, prior operative procedures. Twenty-four hour urine study (Litholink Corporation, Chicago IL) results were abstracted prior to medication administration and also while on the SGLT2 inhibitor. Outcomes The primary outcome was symptomatic stone events defined by patient report of stone passage or documented surgical intervention. The secondary outcome was silent stone events defined by stone growth. Two trained endourologists reviewed consecutive computed tomography scans and calculated stone growth by the longest stone axis. Baseline size was calculated within 3 months of SGLT2 inhibitor initiation. Final size was calculated at time of last follow up or prior to surgical intervention. Statistical analysis For continuous variables, paired T-tests were used to compare means while chi-square tests were used for categorical variables. All analyses were performed using SPSS™ v27. . Results The SGLT2 inhibitor was prescribed to ten consecutive cystinuric patients in our comprehensive stone clinic. The majority were generally healthy, female (70%), white (90%) with a mean age of 45 years (Table 1 ). While taking the SGLT2 inhibitor, seven remained on potassium citrate and no additional stone-related medications. Table 1 Demographic characteristics of the study cohort % (n = 10) Age at medication initiation in years (median, range) 41 (27–71) Sex Male 30 ( 3 ) Female 70 ( 7 ) Race White 90 ( 10 ) Non-white 9 ( 1 ) Past medical history HTN 10 ( 1 ) T2DM 10 ( 1 ) CKD 0 (0) HLD 10 ( 1 ) Anxiety/MDD 30 ( 3 ) Cystinuria-specific history Age at first stone in years (median, range) 19 (6–28) Number of prior stone surgeries (median, range) 10 (5–25) Prior medications for cystinuria Potassium citrate 100 ( 10 ) Tiopronin 80 ( 8 ) Other 20 ( 2 ) Reason for cessation of thiol medication (n = 8) Side effect 75 ( 6 ) Cost 12 ( 1 ) Unknown 12 ( 1 ) The median time on the SGLT2 inhibitor was 13.5 months and overall follow up since enrollment in ReSKU was 64 months (Table 2). While on the SGLT2 inhibitor, seven patients experienced a symptomatic stone event; three of whom underwent surgical intervention. One procedure was due to an acute stone episode while the other two underwent prophylactic treatment due to stone growth. Table 2 Stone events and growth while on SGLT-2 inhibitor Prior to SGLT-2 inhibitor % (n = 10) On SGLT-2 inhibitor % (n = 10) Mean time on medication (months) 12.6 ± 4.1 Citrate utilization 70 ( 7 ) 70 ( 7 ) Stone events Stone event rate per person-years 1.8 1.1 Proportion with fewer stone events on treatment 70 ( 7 ) Surgical event rate per person-years 0.5 0.3 Proportion who underwent surgery on treatment 30 ( 3 ) Stone growth Stone growth (mm) per person-years 7.3 4.8 Proportion with stable stone volume on treatment 50 ( 5 ) The number of stone events were tallied and annualized from the time of registry enrollment through medication initiation and subsequent follow ups. Each patient’s historical stone event rate prior to medication initiation was compared to their stone event rate while on medication expressed as stone events per person year. Seven of ten patients experienced fewer spontaneous stone passage events while taking the SGLT2 inhibitor (Fig. 1 ). Prior to SGLT-2 inhibitor use, the stone event rate per person-year was 1.8 compared to 1.1 while on SGLT-2 inhibitor. The surgical event rate (0.5 surgeries per person year versus 0.3 surgeries per person year) and stone growth (7.3 mm per person year versus 4.8mm per person year) were also improved while on medication compared to their historical values. Importantly, due to small sample size, poisson modeling could not be done to compare stone or surgical events. We therefore performed a comparison of mean stone events per patient. Participants averaged 1.8 ± 1.3 stone events per year prior to initiating the SGLT2 inhibitor compared to 1.2 ± 1.5 stone events per year while taking SGLT2 inhibitors (paired T-test p = 0.313). Half of patients had stable stone volume while on medication while the rest experienced stone growth with a mean stone growth rate of 10mm ± 10.8mm per year (Fig. 2 ). The baseline mean 24-hour urine volumes, quantitative urinary cystine and capacities were 3L, 1000 mg, and − 58mg/L respectively in our cohort (Table 3 ). While on SGLT2 inhibitor, eight patients underwent a repeat 24-hour urine collection which were compared to the baseline studies. There were no significant differences in any of the 24-hour urine analytes except for a significantly higher mean citrate while on medication (719mg ± 254 vs 1172mg ± 649, paired T-test p = 0.03). Interestingly, of the eight patients with negative capacity at baseline, seven had fewer stone events while on medication and four experienced no stone growth while under observation. Only one patient was taken off the SGLT2 inhibitor due to side effects (syncope) while 3 others experienced temporary adverse reactions that resolved spontaneously (nausea, dysuria and lethargy). Table 3. Comparison of 24-hour urine characteristics Baseline On SGLT-2 inhibitor Mean SD Mean SD p-value Volume (L) 3.1 1.0 3.5 1.1 0.206 Cystine (mg) 1000.4 208.7 999.3 342.5 0.965 Capacity (mg/L) -57.9 112.1 -39.5 128.0 0.696 pH 6.9 0.4 6.9 0.5 0.65 Sodium (mmol) 133.3 34.5 173.6 61.2 0.108 Urine Urea Nitrogen (g) 9.4 1.8 10.6 3.9 0.274 PCR (g/kg) 1.0 0.2 1.0 0.2 0.695 Creatinine (mg) 1442.0 354.0 1421.0 475.0 0.888 Calcium (mg) 131.1 53.2 182.5 91.5 0.129 Phosphorus (g) 0.8 0.2 1.0 0.4 0.339 Citrate (mg) 719.0 254.0 1172.0 649.0 0.03 Creatinine (mg) per Kg 17.8 2.7 17.2 4.1 0.795 Calcium (mg) per Kg 1.6 0.7 2.1 1.1 0.277 Supersaturation Cystine 1.1 0.4 1.2 0.5 0.783 Brushite 0.6 0.6 0.5 0.2 0.658 Discussion This retrospective review of ten cystinuric patients who received off-label SGLT2 inhibitors showed 70% of patients experienced fewer stone events after initiating the medication compared to their historic rate. In addition, half of our patients experienced no stone growth while on the medication. The medication was well tolerated with limited adverse effects. Cystine is formed by the oxidation of two cysteine molecules connected by a disulfide bond. The initial management of cystinuria has traditionally relied on aggressive hydration, dietary modifications and alkalinization of urine. 5 Failing these preliminary strategies, targeted medication management has relied solely on the use of thiol (-SH) containing medications targeting the disulfide bond to form a more soluble drug-cysteine complex. Use of these medications however has been limited by side effects such as fatigue, arthritis, mucosal ulcers, liver abnormalities, blood dyscrasias, nephrotic syndrome, and skin rashes. 4,5 These medications are also expensive and require frequent dosing throughout the day limiting patient compliance. Though these medications were first used in treatment of cystinuria in 1963, these substantial limitations have restricted their widespread use and there have not been meaningful advances in alternative medication strategies. We considered a novel approach to treat cystinuria and hypothesized that the Maillard reaction may be an alternative, effective mechanism to impact stone growth and stone recurrence. The biochemical basis for this reaction was initially reported in 1912 when Louis-Camille Maillard was the first to describe that mixtures of amino acids and sugars would become intensely brown with heating; laying the foundation for the understanding of non-enzymatic browning reactions that occur during food preparation. 12 These same reactions occur at body temperature (37 o C) and underly the formation of hemoglobin A1c through glycation of hemoglobin and other advanced-glycation end products (AGEs). 13,14 These AGEs are a heterogeneous group of molecules implicated in diabetes 15,16 and autoimmune or rheumatic diseases. 17,18 As an amino acid, cysteine will also undergo the Maillard reaction when exposed to glucose at physiologic temperatures to form adducts which are expected to be more soluble than cystine. With this hypothetical mechanism to inhibit precipitation of cysteine and possibly induce crystal breakdown leveraging glucosuria, the question was then then how to safely induce this state in our patients. Sodium/Glucose Cotransporter 2 inhibitors block renal glucose reabsorption, leading to a significant increase in glycosuria. 8,9 These inhibitors predominantly target SGLT2, a protein found in the renal proximal tubules. When administered at therapeutic doses, these inhibitors facilitate the excretion of approximately 60–100 grams of glucose per day (equivalent to 40-70mgs of glucose/mL of urine, assuming 1.5Lit of 24h urine volume) in the urine leading to lower systemic levels of glucose. The glucosuria indued by SGLT2 inhibitors is far in excess to the plasma glucose (1.5-2.0mg/mL) in blood of diabetic patients responsible for the formation of hemoglobin A1c through glycation of hemoglobin and other advanced-glycation end products (AGEs) suggesting bimolecular reaction between cystine and glucose should be favored. The enhanced urinary glucose excretion induces an osmotic diuresis that also may promote increased fluid intake. While these medications were initially developed to treat type 2 diabetes, there is a growing body of literature to support its cardiovascular and renal benefits as well. 7,8 While SGLT2 inhibitors are well tolerated and widely prescribed, they do have adverse reactions including polyuria due to diuresis and fungal genital infections. 7 There also may be an increased risk of bacterial urinary tract infections however meta-analyses and observational studies suggest the risk is similar to that of type 2 diabetes. 10,19 Our patients tolerated the medication well with three experiencing self-resolving minor adverse reactions and only one patient discontinuing the treatment due to adverse reaction. No patients experienced perineal or urinary tract infections while on medication. These medications are also well reported to cause weight loss which several of our patients reported as a positive ancillary effect of taking these medications. Urinary citrate excretion was significantly increased in patients while on SGLT2 inhibitors. Citrate reabsorption is tightly regulated by pH such that even small decreases in cellular proximal tubule pH from 7.4 to 7.2 will significantly increase citrate reabsorption whereas alkalosis will limit this reabsorption resulting in increased urinary citrate. 20 Therefore, the increase in urinary citrate we observed may be due to decreases in serum potassium leading to a chronic metabolic alkalosis from SGLT2 inhibitor use leading to increases in urinary citrate. 21 While we did not find any differences in cystine capacity or supersaturation as measured with 24-hour urine collections, sulfhydryl medications are known to cause interference with these measurements in vitro so it is possible imines may have a similar effect. 22 Additionally, we observed a modest increase in voided volume and decrease in capacity though neither was statistically significant. The absolute increase in fluid intake is likely limited as our cystinuria patients already demonstrate excellent hydration. It is possible that in a larger study, these differences would become more apparent. In this context, we hypothesize that SGLT2 inhibitors may be able to induce sufficient levels of glucosuria to inhibit stone growth in patients with cystinuria. In our cohort of patients who received this medication off-label, most experienced fewer symptomatic stone events compared to their own historic event rate and there were few minor side effects from the medication. An alternative mechanism or at least a synergistic aspect of SGLT2 inhibitors is that they induce an osmotic diuresis (due to the increased excretion of both glucose and sodium) which also may have led to increased urinary excretion of cystine and/or encouraged fluid intake. Our study has several important limitations. First, this was a retrospective study with a limited follow up duration on SGLT2 inhibitors. Our patients were managed with standard of care follow up which meant that the follow-up intervals and duration were not as rigid as that of a rigid clinical trial. Nonetheless, our patients had a median of 1 year of follow up while on medication and 64 months overall which points to good patient compliance with rigorous follow up. Second, treating the stone event rate as its own control may introduce healthcare utilization bias as interfacing with the medical system could have led to improved dietary habits which had a major impact on stone event rates. Most patients were typically registered on ReSKU for several years before initiating the SGLT2 inhibitor, so their historic stone event rate was less subject to variations in control of their cystinuria. In addition, most of our patients had a negative cystine capacity at baseline before starting the SGLT2 inhibitor signifying severe disease. Third, patients with cystinuria are known to develop symptomatic calculi in clusters for unknown reasons. It is possible that we captured our patients during a period of quiescence however as stated previously, we had a median follow up of over five years, so this is less likely. Fourth, our overall sample size was small. Yet cystinuria is a rare disease and our practice at UCSF has amassed a large cystinuric patient cohort of at least 60 patients that have enrolled in numerous trials in hopes of finding an alternative to the thiol-type prophylactic medications. Lastly, part of the historic data collected on the stone event rate includes time on clinical trials however all patients had at least 30 days off trial medication prior to starting the SGLT2 inhibitor. In addition, 90% were previously on randomized trials so the effect of these trial medications on their baseline stone rate would have decreased any detectable difference in the event rate on the SGLT2 inhibitor making the difference we captured an underestimate. Conclusions Dapaglifozin (Farxiga™) appears to be a well-tolerated medication for the treatment of cystinuric patients. Most patients experienced fewer stone events and had stable radiographic stone disease on interval imaging. Patients experienced few medication-limiting side effects. The mechanism of action of this medication appears to occur independently of any identifiable findings on twenty-four hour urine analysis aside from an increase in urinary citrate. Conceptualization: Wilson Sui, Marshall Stoller, Manoj Desai; Methodology: Wilson Sui, Heiko Yang, Marshall Stoller; Formal analysis and investigation: Thomas Chi, Wilson Sui, Marshall Stoller; Writing - original draft preparation: Wilson Sui, Marshall Stoller, Manoj Desai; Writing - review and editing: Wilson Sui, Marshall Stoller, Thomas Chi, Heiko Yang, Manoj Desai; Supervision: Thomas Chi, Marshall Stoller Abbreviations AGE advanced-glycation end product EMR electronic medical record ReSKU Registry for Stones of the Kidney and Ureter SGLT2 Sodium/Glucose Cotransporter 2 UCSF University of California, San Francisco Declarations Funding: none Author Contribution Conceptualization: Wilson Sui, Marshall Stoller, Manoj Desai; Methodology: Wilson Sui, Heiko Yang, Marshall Stoller; Formal analysis and investigation: Thomas Chi, Wilson Sui, Marshall Stoller; Writing - original draft preparation: Wilson Sui, Marshall Stoller, Manoj Desai; Writing - review and editing: Wilson Sui, Marshall Stoller, Thomas Chi, Heiko Yang, Manoj Desai; Supervision: Thomas Chi, Marshall Stoller Acknowledgement n/a References Dolin DJ, Asplin JR, Flagel L, Grasso M, Goldfarb DS (2005) Effect of cystine-binding thiol drugs on urinary cystine capacity in patients with cystinuria. 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Rheumatol (Oxford) Mar 46(3):412–416. 10.1093/rheumatology/kel076 Li D, Wang T, Shen S, Fang Z, Dong Y, Tang H (2017) Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors: A meta-analysis of randomized controlled trials. Diabetes Obes Metab Mar 19(3):348–355. 10.1111/dom.12825 Zuckerman JM, Assimos DG (2009) Hypocitraturia: pathophysiology and medical management. Rev Urol Summer 11(3):134–144 Neuen BL, Oshima M, Agarwal R et al (2022) Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Hyperkalemia in People With Type 2 Diabetes: A Meta-Analysis of Individual Participant Data From Randomized, Controlled Trials. Circulation . May 10. ;145(19):1460–1470. 10.1161/CIRCULATIONAHA.121.057736 Nakagawa Y, Asplin JR, Goldfarb DS, Parks JH, Coe FL (2000) Clinical use of cystine supersaturation measurements. J Urol Nov 164(5):1481–1485 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 26 Nov, 2024 Read the published version in Urolithiasis → Version 1 posted Editorial decision: Revision requested 07 Oct, 2024 Reviews received at journal 18 Sep, 2024 Reviewers agreed at journal 09 Sep, 2024 Reviewers invited by journal 09 Sep, 2024 Editor assigned by journal 11 Jul, 2024 Submission checks completed at journal 11 Jul, 2024 First submitted to journal 08 Jul, 2024 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4706572","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":329523307,"identity":"7134253f-3187-4435-a62b-9eeb7152617d","order_by":0,"name":"Wilson Sui","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIiWNgGAWjYFACxgYGBgMLIIP5AJCQkCFWiwSQwZYA0sJDrFUgLTwGIBZhLfIzkhuYeQok7Pmlez6/ulFjwcPAfvjoBnxaDG4kArUYSCTOnHN2m3XOMaDDeNLSbuDVIgHUkmMgkWBwI3ebcQ4bUIsEjxleLfIzIFrsDW7kPDPO+UeEFoYbEC2MG27kMD/ObSNCi8GZhw2H/4D8MiPNjDm3T4KHjZBf5NvTHz6c8cfGnl8i+fHnnG91cvzsh4/hdxgQHIDSbBJgkpByZMD8gRTVo2AUjIJRMHIAAD2/QdFFmsp9AAAAAElFTkSuQmCC","orcid":"","institution":"University of California San Francisco","correspondingAuthor":true,"prefix":"","firstName":"Wilson","middleName":"","lastName":"Sui","suffix":""},{"id":329523308,"identity":"46afde9f-b054-4de7-b32c-a41c36c2bc19","order_by":1,"name":"Heiko Yang","email":"","orcid":"","institution":"University of California San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Heiko","middleName":"","lastName":"Yang","suffix":""},{"id":329523312,"identity":"063c4bfa-96ad-4bf5-a3ed-df3a80297816","order_by":2,"name":"Manoj Desai","email":"","orcid":"","institution":"Liliac Therapeutics Inc.","correspondingAuthor":false,"prefix":"","firstName":"Manoj","middleName":"","lastName":"Desai","suffix":""},{"id":329523314,"identity":"ee17df5e-863a-46b2-933d-94a8dd4b0034","order_by":3,"name":"Thomas Chi","email":"","orcid":"","institution":"University of California San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Chi","suffix":""},{"id":329523318,"identity":"8806c5bd-2eeb-416f-8244-695e2b9b98a3","order_by":4,"name":"Marshall Stoller","email":"","orcid":"","institution":"University of California San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Marshall","middleName":"","lastName":"Stoller","suffix":""}],"badges":[],"createdAt":"2024-07-08 15:14:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4706572/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4706572/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00240-024-01666-0","type":"published","date":"2024-11-26T15:57:28+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62218138,"identity":"7a806fb7-fc4e-4204-82c0-075e35e1bbbd","added_by":"auto","created_at":"2024-08-11 12:00:24","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":42850,"visible":true,"origin":"","legend":"\u003cp\u003eIndividual patient stone event rate per year before and while on SGLT2\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4706572/v1/c1b30028475ab894dae53b38.png"},{"id":62217109,"identity":"a92ed723-18ad-41d1-8480-515da24ac7c4","added_by":"auto","created_at":"2024-08-11 11:52:24","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":20674,"visible":true,"origin":"","legend":"\u003cp\u003eIndividual patient stone growth (in mm) at baseline and while on SGLT2 inhibitor. Asterix (*) denotes patient underwent stone surgery because of stone growth or due to a symptomatic event.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4706572/v1/fc31cfda85febff10f4b26cd.png"},{"id":70382416,"identity":"ae661797-37a9-4457-aa48-16d5dc48e106","added_by":"auto","created_at":"2024-12-02 16:26:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":461734,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4706572/v1/b0398991-b7b7-4b47-bba6-14c737a27323.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Potential Role of Sodium/Glucose Cotransporter 2 Inhibitors in the Treatment of Cystinuria","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe disulfide bond of cystine, a dimer of the amino acid cysteine, has long been the target of pharmacologic management in patients with cystinuria. Thiol containing medications undergo a thiol exchange reaction to compete with this bond resulting in a drug-cystine complex that is more soluble than cystine.\u003csup\u003e1\u0026ndash;3\u003c/sup\u003e These medications however, are associated with severe side effects including liver abnormalities, nephrotic syndrome, blood dyscrasias and skin disorders limiting their use to those who fail dietary or alkali therapy.\u003csup\u003e4\u003c/sup\u003e Since the first report of the use of thiol medications for cystinuria in 1963, there have been no prospective, randomized data for these medications and development of alternative medications for this disease have been limited.\u003csup\u003e1,4\u0026ndash;6\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe Maillard reaction, which is a non-enzymatic reaction between the amine of an amino acid and carbohydrate has been widely used in the food industry. While the reaction requires heating, we hypothesized even if a small amount of cysteine/cystine reacts with glucose at body temperature, continuous exposure of cystine stones to glucose could prevent growth of an existing cystine stone and perhaps could reduce its size to facilitate excretion. To this end, the popular class of medications for treatment of diabetes called Sodium/Glucose Cotransporter 2 (SGLT2) inhibitors may be useful.\u003csup\u003e7\u0026ndash;9\u003c/sup\u003e These medications block SGLT2, a protein found in the renal proximal tubules which facilitates excretion of glucose into the urine reducing systemic levels; this has been used for many purposes, especially for certain types of diabetes mellitus. Approximately 60\u0026ndash;100 grams of glucose are eliminated daily while this medication is therapeutic. Boasting a low-risk safety profile, once daily dosing and cardiovascular and renal benefits, these medications have rapidly grown in popularity.\u003csup\u003e8,10\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHere we present a novel approach to medical management of cystinuria with SGLT2 inhibitors. We hypothesize that the glucosuria and diuretic effects of SGTL2 inhibitors would lead to a Maillard reaction between cysteine/cystine and glucose in the urinary system leading to a reduction in kidney stone events, possible stone dissolution and stabilization of stone growth.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eSetting and participants\u003c/p\u003e \u003cp\u003eStarting in November 2015, the University of California San Francisco (UCSF) Urology Clinic has been enrolling new patients with urinary stone disease into a prospective registry called the Registry for Stones of the Kidney and Ureter (ReSKU). The data points are derived from the EMR notes created by healthcare providers during clinic visits, surgical encounters, and follow-up visits as part of their regular care. The methodology and structure of this registry have been previously described.\u003csup\u003e11\u003c/sup\u003e All individuals participating in ReSKU provide written consent, and the study has received approval from the Committee on Human Research (Protocol 14\u0026ndash;14533).\u003c/p\u003e \u003cp\u003eExposure \u0026amp; predictors\u003c/p\u003e \u003cp\u003eWe performed a retrospective review of consecutive patients with a history of cystinuria who were started on dapafligozin 10mg daily (Farxiga\u0026trade;) off-label from 2019 to May 2023. Patients were counseled that this medication would be used off-label and the risks, benefits and alternatives of this approach were discussed in detail. Given the widespread use of these medications in diabetes, the associated minimal side effect profile and the close clinical monitoring of these patients, we felt the potential benefits outweighed the risks. These patients had previously failed, did not tolerate or did not wish to start a thiol medication. If patients were on a thiol and wished to stop or were previously enrolled in a clinical trial, they were asked to pause these medications for at least 30 days before starting dapafligozin. We additionally extracted demographic and clinical information including past medical history, prior operative procedures. Twenty-four hour urine study (Litholink Corporation, Chicago IL) results were abstracted prior to medication administration and also while on the SGLT2 inhibitor.\u003c/p\u003e \u003cp\u003eOutcomes\u003c/p\u003e \u003cp\u003eThe primary outcome was symptomatic stone events defined by patient report of stone passage or documented surgical intervention. The secondary outcome was silent stone events defined by stone growth. Two trained endourologists reviewed consecutive computed tomography scans and calculated stone growth by the longest stone axis. Baseline size was calculated within 3 months of SGLT2 inhibitor initiation. Final size was calculated at time of last follow up or prior to surgical intervention.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eFor continuous variables, paired T-tests were used to compare means while chi-square tests were used for categorical variables. All analyses were performed using SPSS\u0026trade; v27.\u003c/p\u003e \u003cp\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe SGLT2 inhibitor was prescribed to ten consecutive cystinuric patients in our comprehensive stone clinic. The majority were generally healthy, female (70%), white (90%) with a mean age of 45 years (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). While taking the SGLT2 inhibitor, seven remained on potassium citrate and no additional stone-related medications.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eDemographic characteristics of the study cohort\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e% (n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge at medication initiation in years (median, range)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41 (27\u0026ndash;71)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSex\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30 (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70 (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRace\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWhite\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e90 (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNon-white\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePast medical history\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHTN\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT2DM\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCKD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHLD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAnxiety/MDD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30 (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCystinuria-specific history\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge at first stone in years (median, range)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19 (6\u0026ndash;28)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNumber of prior stone surgeries (median, range)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (5\u0026ndash;25)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePrior medications for cystinuria\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePotassium citrate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100 (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTiopronin\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e80 (\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOther\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eReason for cessation of thiol medication (n\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSide effect\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e75 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCost\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnknown\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eThe median time on the SGLT2 inhibitor was 13.5 months and overall follow up since enrollment in ReSKU was 64 months (Table\u0026nbsp;2). While on the SGLT2 inhibitor, seven patients experienced a symptomatic stone event; three of whom underwent surgical intervention. One procedure was due to an acute stone episode while the other two underwent prophylactic treatment due to stone growth.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable\u0026nbsp;2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eStone events and growth while on SGLT-2 inhibitor\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePrior to SGLT-2 inhibitor\u003c/p\u003e\n\u003cp\u003e% (n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOn SGLT-2 inhibitor\u003c/p\u003e\n\u003cp\u003e% (n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMean time on medication (months)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCitrate utilization\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70 (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70 (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eStone events\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eStone event rate per person-years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eProportion with fewer stone events on treatment\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70 (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSurgical event rate per person-years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eProportion who underwent surgery on treatment\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30 (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eStone growth\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eStone growth (mm) per person-years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.8\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eProportion with stable stone volume on treatment\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50 (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\n\u003cp\u003eThe number of stone events were tallied and annualized from the time of registry enrollment through medication initiation and subsequent follow ups. Each patient\u0026rsquo;s historical stone event rate prior to medication initiation was compared to their stone event rate while on medication expressed as stone events per person year. Seven of ten patients experienced fewer spontaneous stone passage events while taking the SGLT2 inhibitor (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Prior to SGLT-2 inhibitor use, the stone event rate per person-year was 1.8 compared to 1.1 while on SGLT-2 inhibitor. The surgical event rate (0.5 surgeries per person year versus 0.3 surgeries per person year) and stone growth (7.3 mm per person year versus 4.8mm per person year) were also improved while on medication compared to their historical values. Importantly, due to small sample size, poisson modeling could not be done to compare stone or surgical events.\u003c/p\u003e\n\u003cp\u003eWe therefore performed a comparison of mean stone events per patient. Participants averaged 1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3 stone events per year prior to initiating the SGLT2 inhibitor compared to 1.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5 stone events per year while taking SGLT2 inhibitors (paired T-test p\u0026thinsp;=\u0026thinsp;0.313). Half of patients had stable stone volume while on medication while the rest experienced stone growth with a mean stone growth rate of 10mm\u0026thinsp;\u0026plusmn;\u0026thinsp;10.8mm per year (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThe baseline mean 24-hour urine volumes, quantitative urinary cystine and capacities were 3L, 1000 mg, and \u0026minus;\u0026thinsp;58mg/L respectively in our cohort (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). While on SGLT2 inhibitor, eight patients underwent a repeat 24-hour urine collection which were compared to the baseline studies. There were no significant differences in any of the 24-hour urine analytes except for a significantly higher mean citrate while on medication (719mg\u0026thinsp;\u0026plusmn;\u0026thinsp;254 vs 1172mg\u0026thinsp;\u0026plusmn;\u0026thinsp;649, paired T-test p\u0026thinsp;=\u0026thinsp;0.03). Interestingly, of the eight patients with negative capacity at baseline, seven had fewer stone events while on medication and four experienced no stone growth while under observation. Only one patient was taken off the SGLT2 inhibitor due to side effects (syncope) while 3 others experienced temporary adverse reactions that resolved spontaneously (nausea, dysuria and lethargy).\u003c/p\u003e\n\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003cstrong\u003eTable 3. \u003c/strong\u003eComparison of 24-hour urine characteristics\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Taba\" border=\"1\"\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eBaseline\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eOn SGLT-2 inhibitor\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMean\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMean\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ep-value\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVolume (L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.206\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCystine (mg)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1000.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e208.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e999.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e342.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.965\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCapacity (mg/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-57.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e112.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-39.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e128.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.696\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003epH\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.65\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSodium (mmol)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e133.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e173.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e61.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.108\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUrine Urea Nitrogen (g)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.274\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePCR (g/kg)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.695\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCreatinine (mg)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1442.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e354.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1421.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e475.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.888\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCalcium (mg)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e131.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e53.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e182.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e91.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.129\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePhosphorus (g)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.339\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCitrate (mg)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e719.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e254.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1172.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e649.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.03\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCreatinine (mg) per Kg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.795\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCalcium (mg) per Kg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.277\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSupersaturation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCystine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.783\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBrushite\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.658\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis retrospective review of ten cystinuric patients who received off-label SGLT2 inhibitors showed 70% of patients experienced fewer stone events after initiating the medication compared to their historic rate. In addition, half of our patients experienced no stone growth while on the medication. The medication was well tolerated with limited adverse effects.\u003c/p\u003e \u003cp\u003eCystine is formed by the oxidation of two cysteine molecules connected by a disulfide bond. The initial management of cystinuria has traditionally relied on aggressive hydration, dietary modifications and alkalinization of urine.\u003csup\u003e5\u003c/sup\u003e Failing these preliminary strategies, targeted medication management has relied solely on the use of thiol (-SH) containing medications targeting the disulfide bond to form a more soluble drug-cysteine complex. Use of these medications however has been limited by side effects such as fatigue, arthritis, mucosal ulcers, liver abnormalities, blood dyscrasias, nephrotic syndrome, and skin rashes.\u003csup\u003e4,5\u003c/sup\u003e These medications are also expensive and require frequent dosing throughout the day limiting patient compliance. Though these medications were first used in treatment of cystinuria in 1963, these substantial limitations have restricted their widespread use and there have not been meaningful advances in alternative medication strategies.\u003c/p\u003e \u003cp\u003eWe considered a novel approach to treat cystinuria and hypothesized that the Maillard reaction may be an alternative, effective mechanism to impact stone growth and stone recurrence. The biochemical basis for this reaction was initially reported in 1912 when Louis-Camille Maillard was the first to describe that mixtures of amino acids and sugars would become intensely brown with heating; laying the foundation for the understanding of non-enzymatic browning reactions that occur during food preparation.\u003csup\u003e12\u003c/sup\u003e These same reactions occur at body temperature (37\u003csup\u003eo\u003c/sup\u003eC) and underly the formation of hemoglobin A1c through glycation of hemoglobin and other advanced-glycation end products (AGEs).\u003csup\u003e13,14\u003c/sup\u003e These AGEs are a heterogeneous group of molecules implicated in diabetes\u003csup\u003e15,16\u003c/sup\u003e and autoimmune or rheumatic diseases.\u003csup\u003e17,18\u003c/sup\u003e As an amino acid, cysteine will also undergo the Maillard reaction when exposed to glucose at physiologic temperatures to form adducts which are expected to be more soluble than cystine. With this hypothetical mechanism to inhibit precipitation of cysteine and possibly induce crystal breakdown leveraging glucosuria, the question was then then how to safely induce this state in our patients.\u003c/p\u003e \u003cp\u003eSodium/Glucose Cotransporter 2 inhibitors block renal glucose reabsorption, leading to a significant increase in glycosuria.\u003csup\u003e8,9\u003c/sup\u003e These inhibitors predominantly target SGLT2, a protein found in the renal proximal tubules. When administered at therapeutic doses, these inhibitors facilitate the excretion of approximately 60\u0026ndash;100 grams of glucose per day (equivalent to 40-70mgs of glucose/mL of urine, assuming 1.5Lit of 24h urine volume) in the urine leading to lower systemic levels of glucose. The glucosuria indued by SGLT2 inhibitors is far in excess to the plasma glucose (1.5-2.0mg/mL) in blood of diabetic patients responsible for the formation of hemoglobin A1c through glycation of hemoglobin and other advanced-glycation end products (AGEs) suggesting bimolecular reaction between cystine and glucose should be favored. The enhanced urinary glucose excretion induces an osmotic diuresis that also may promote increased fluid intake. While these medications were initially developed to treat type 2 diabetes, there is a growing body of literature to support its cardiovascular and renal benefits as well.\u003csup\u003e7,8\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWhile SGLT2 inhibitors are well tolerated and widely prescribed, they do have adverse reactions including polyuria due to diuresis and fungal genital infections.\u003csup\u003e7\u003c/sup\u003e There also may be an increased risk of bacterial urinary tract infections however meta-analyses and observational studies suggest the risk is similar to that of type 2 diabetes.\u003csup\u003e10,19\u003c/sup\u003e Our patients tolerated the medication well with three experiencing self-resolving minor adverse reactions and only one patient discontinuing the treatment due to adverse reaction. No patients experienced perineal or urinary tract infections while on medication. These medications are also well reported to cause weight loss which several of our patients reported as a positive ancillary effect of taking these medications.\u003c/p\u003e \u003cp\u003eUrinary citrate excretion was significantly increased in patients while on SGLT2 inhibitors. Citrate reabsorption is tightly regulated by pH such that even small decreases in cellular proximal tubule pH from 7.4 to 7.2 will significantly increase citrate reabsorption whereas alkalosis will limit this reabsorption resulting in increased urinary citrate.\u003csup\u003e20\u003c/sup\u003e Therefore, the increase in urinary citrate we observed may be due to decreases in serum potassium leading to a chronic metabolic alkalosis from SGLT2 inhibitor use leading to increases in urinary citrate.\u003csup\u003e21\u003c/sup\u003e While we did not find any differences in cystine capacity or supersaturation as measured with 24-hour urine collections, sulfhydryl medications are known to cause interference with these measurements \u003cem\u003ein vitro\u003c/em\u003e so it is possible imines may have a similar effect.\u003csup\u003e22\u003c/sup\u003e Additionally, we observed a modest increase in voided volume and decrease in capacity though neither was statistically significant. The absolute increase in fluid intake is likely limited as our cystinuria patients already demonstrate excellent hydration. It is possible that in a larger study, these differences would become more apparent.\u003c/p\u003e \u003cp\u003eIn this context, we hypothesize that SGLT2 inhibitors may be able to induce sufficient levels of glucosuria to inhibit stone growth in patients with cystinuria. In our cohort of patients who received this medication off-label, most experienced fewer symptomatic stone events compared to their own historic event rate and there were few minor side effects from the medication. An alternative mechanism or at least a synergistic aspect of SGLT2 inhibitors is that they induce an osmotic diuresis (due to the increased excretion of both glucose and sodium) which also may have led to increased urinary excretion of cystine and/or encouraged fluid intake.\u003c/p\u003e \u003cp\u003eOur study has several important limitations. First, this was a retrospective study with a limited follow up duration on SGLT2 inhibitors. Our patients were managed with standard of care follow up which meant that the follow-up intervals and duration were not as rigid as that of a rigid clinical trial. Nonetheless, our patients had a median of 1 year of follow up while on medication and 64 months overall which points to good patient compliance with rigorous follow up. Second, treating the stone event rate as its own control may introduce healthcare utilization bias as interfacing with the medical system could have led to improved dietary habits which had a major impact on stone event rates. Most patients were typically registered on ReSKU for several years before initiating the SGLT2 inhibitor, so their historic stone event rate was less subject to variations in control of their cystinuria. In addition, most of our patients had a negative cystine capacity at baseline before starting the SGLT2 inhibitor signifying severe disease. Third, patients with cystinuria are known to develop symptomatic calculi in clusters for unknown reasons. It is possible that we captured our patients during a period of quiescence however as stated previously, we had a median follow up of over five years, so this is less likely. Fourth, our overall sample size was small. Yet cystinuria is a rare disease and our practice at UCSF has amassed a large cystinuric patient cohort of at least 60 patients that have enrolled in numerous trials in hopes of finding an alternative to the thiol-type prophylactic medications. Lastly, part of the historic data collected on the stone event rate includes time on clinical trials however all patients had at least 30 days off trial medication prior to starting the SGLT2 inhibitor. In addition, 90% were previously on randomized trials so the effect of these trial medications on their baseline stone rate would have decreased any detectable difference in the event rate on the SGLT2 inhibitor making the difference we captured an underestimate.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eDapaglifozin (Farxiga\u0026trade;) appears to be a well-tolerated medication for the treatment of cystinuric patients. Most patients experienced fewer stone events and had stable radiographic stone disease on interval imaging. Patients experienced few medication-limiting side effects. The mechanism of action of this medication appears to occur independently of any identifiable findings on twenty-four hour urine analysis aside from an increase in urinary citrate.\u003c/p\u003e \u003cp\u003eConceptualization: Wilson Sui, Marshall Stoller, Manoj Desai; Methodology: Wilson Sui, Heiko Yang, Marshall Stoller; Formal analysis and investigation: Thomas Chi, Wilson Sui, Marshall Stoller; Writing - original draft preparation: Wilson Sui, Marshall Stoller, Manoj Desai; Writing - review and editing: Wilson Sui, Marshall Stoller, Thomas Chi, Heiko Yang, Manoj Desai; Supervision: Thomas Chi, Marshall Stoller\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAGE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eadvanced-glycation end product\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEMR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eelectronic medical record\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eReSKU\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRegistry for Stones of the Kidney and Ureter\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/Glucose Cotransporter 2\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUCSF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eUniversity of California, San Francisco\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003enone\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eConceptualization: Wilson Sui, Marshall Stoller, Manoj Desai; Methodology: Wilson Sui, Heiko Yang, Marshall Stoller; Formal analysis and investigation: Thomas Chi, Wilson Sui, Marshall Stoller; Writing - original draft preparation: Wilson Sui, Marshall Stoller, Manoj Desai; Writing - review and editing: Wilson Sui, Marshall Stoller, Thomas Chi, Heiko Yang, Manoj Desai; Supervision: Thomas Chi, Marshall Stoller\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003en/a\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDolin DJ, Asplin JR, Flagel L, Grasso M, Goldfarb DS (2005) Effect of cystine-binding thiol drugs on urinary cystine capacity in patients with cystinuria. 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J Urol Nov 164(5):1481\u0026ndash;1485\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"urolithiasis","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ures","sideBox":"Learn more about [Urolithiasis](http://link.springer.com/journal/240)","snPcode":"240","submissionUrl":"https://submission.nature.com/new-submission/240/3","title":"Urolithiasis","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Cystinuria, Maillard reaction, nephrolithiasis","lastPublishedDoi":"10.21203/rs.3.rs-4706572/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4706572/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Introduction\nThe Maillard reaction is a non-enzymatic reaction between an amino acid and carbohydrate. We hypothesized that continuous washing of cystine stones with glucose could theoretically prevent growth of an existing cystine stone or even reduce its size leading to a decrease in stone events. Sodium/Glucose Cotransporter 2 (SGLT2) inhibitors, well known for inducing glucosuria, were used to test this hypothesis in an initial series of patients.\nMaterials and methods\nPatients with cystinuria from September 2019 to May 2023 who received off-label dapaglifozin (Farxiga™) were identified. Patients were allowed to continue thiol and alkalinizing agents per standard of care. A symptomatic stone event was defined by stone passage or surgical intervention.\nResults\nTen cystinuric patients were prescribed SGLT2 inhibitors with a median follow up of 13.5 months. Each patients’ historic stone event rate was compared to the event rate while prescribed SGLT2 medication. Overall, 80% of patients experienced fewer or equivalent stone events and half had stable stone volume during therapy. Eight patients had negative cystine capacity at baseline, yet seven experienced fewer stone events while on medication: four experienced no stone growth. One patient was taken off the SGLT2 inhibitor due to an adverse reaction; three others experienced mild, self-resolving effects and yet stayed on the medication.\nConclusions\nCystinuric patients treated with a SGLT2 inhibitor experienced fewer stone events while on medication compared to their historic rates and exhibited decreased or stable stone growth. There were few medication related side effects. SGLT2 inhibitors may be a promising long-term therapy for patients with cystinuria. ","manuscriptTitle":"The Potential Role of Sodium/Glucose Cotransporter 2 Inhibitors in the Treatment of Cystinuria","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-11 11:52:20","doi":"10.21203/rs.3.rs-4706572/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-10-07T07:39:36+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-18T15:39:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"200316703932605521873380433303640623713","date":"2024-09-09T15:24:02+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-09T13:32:24+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-11T04:22:57+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-11T04:22:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"Urolithiasis","date":"2024-07-08T15:13:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"urolithiasis","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ures","sideBox":"Learn more about [Urolithiasis](http://link.springer.com/journal/240)","snPcode":"240","submissionUrl":"https://submission.nature.com/new-submission/240/3","title":"Urolithiasis","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"964a26b0-ba6b-4251-b88e-8e14cc124eb6","owner":[],"postedDate":"August 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-02T16:01:43+00:00","versionOfRecord":{"articleIdentity":"rs-4706572","link":"https://doi.org/10.1007/s00240-024-01666-0","journal":{"identity":"urolithiasis","isVorOnly":false,"title":"Urolithiasis"},"publishedOn":"2024-11-26 15:57:28","publishedOnDateReadable":"November 26th, 2024"},"versionCreatedAt":"2024-08-11 11:52:20","video":"","vorDoi":"10.1007/s00240-024-01666-0","vorDoiUrl":"https://doi.org/10.1007/s00240-024-01666-0","workflowStages":[]},"version":"v1","identity":"rs-4706572","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4706572","identity":"rs-4706572","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}