Intravascular Hemolysis and Acute Kidney Injury Associated with Pulsed Field Ablation vs. Thermal Ablation in Atrial Fibrillation: A Meta-Analysis

Intravascular Hemolysis and Acute Kidney Injury Associated with Pulsed Field Ablation vs. Thermal Ablation in Atrial Fibrillation: A Meta-Analysis | 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 Short Report Intravascular Hemolysis and Acute Kidney Injury Associated with Pulsed Field Ablation vs. Thermal Ablation in Atrial Fibrillation: A Meta-Analysis Cesar Erazo, Frans Serpa, Gabriel Chagas, Andre Rivera, Esteban Arevalo, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8013252/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 Purpose To evaluate the comparative risk of hemolysis and acute kidney injury (AKI) after pulsed field ablation (PFA) vs. thermal ablation (TA) for atrial fibrillation (AF). Methods Databases were searched through June 2025 for comparative studies reporting hemolysis markers or renal outcomes. Random-effects models estimated risk ratios (RRs) and mean differences (MDs). Results Eight studies (n = 4,307) were included. PFA was not associated with higher AKI risk (RR 2.00, 95% CI 0.51–7.91) or creatinine change (MD 0.02 mg/dL, p = 0.10). LDH was higher (MD + 72 U/L p < 0.001) and haptoglobin lower (MD − 0.60 g/L p < 0.001) with PFA. Conclusions PFA causes greater biochemical hemolysis, but no significant renal injury compared with TA, supporting its favorable renal safety profile. Figures Figure 1 Introduction Pulsed field ablation (PFA) is a non-thermal ablation technique for atrial fibrillation (AF) that creates myocardial-selective lesions by electroporation. Although its safety profile is favorable compared with thermal ablation (TA) [ 1 ], biochemical evidence of intravascular hemolysis resulting in acute kidney injury (AKI) has been reported in post-marketing and comparative studies [ 2 ]. The clinical significance of this observation remains incompletely understood; therefore, we performed a meta-analysis comparing hemolytic and renal outcomes after PFA vs. TA to better contextualize this risk in clinical practice. Methods We searched MEDLINE, Embase, and Cochrane Library (inception–June 2025) for comparative studies of PFA vs. TA (radiofrequency [RFA] or Cryoballoon ablation [CBA]) in AF that reported at least one hemolysis marker (e.g., LDH, haptoglobin) or a renal outcome (change in serum creatinine and AKI). PRISMA flow is shown in Fig. 1 A. Two reviewers screened and extracted data independently; disagreements were resolved by consensus. From each study, we captured design, baseline characteristics, ablation system/catheter, total application, and outcomes. Random-effects models generated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes with 95% confidence intervals (CIs). Heterogeneity was quantified with I². Analyses were performed in RevMan v5.4 and R v4.5.0 ( meta package). Results Study selection The search identified 1,600 records; after removing 323 duplicates, 1,277 titles and abstracts were screened. We excluded 711 non-comparative reports and 187 studies without AKI/hemolysis data; one additional study reported no events or markers. Eight studies met the inclusion criteria (n = 4,307; PFA n = 1,680; TA n = 2,627). Baseline and procedural characteristics Across studies, the mean age ranged from 61 ± 9 to 70 ± 10 years, with men composing 39.1% to 82.7% of participants. Where reported, mean CHA₂DS₂-VASc scores ranged from 1.6 to 3.3, and mean LVEF from 54 ± 6% to 66 ± 7%). PFA applications ranged from 31 ± 3 to 75 ± 29 per case across studies. Meta-analysis outcomes Among eight comparative studies, PFA was not associated with an increased risk of AKI compared with TA (RR 2.00, 95% CI 0.51–7.91; p = 0.32; I²=59%), and there was no significant difference in post-procedural creatinine levels between techniques (MD 0.02 mg/dL, 95% CI 0.00 to 0.05; p = 0.10; I²=3%). PFA was associated with greater biochemical evidence of hemolysis, as indicated by higher LDH (MD + 72.10 U/L, 95% CI 56.48–87.73; p < 0.001; I²=93%) and lower haptoglobin (MD − 0.60 g/L, 95% CI -0.71 to -0.49; p < 0.001; I²=88%) (Fig. 1 B-E). Discussion Our findings suggest that PFA is not associated with an increased risk of adverse renal outcomes, such as AKI or significant changes in serum creatinine, compared with TA. Despite greater elevations in biochemical markers of intravascular hemolysis with PFA, these changes did not translate into worse renal outcomes. The hemolysis observed with PFA is most consistent with pore formation in red blood cell membranes caused by electroporation. This leads to ionic imbalance, swelling, and rupture of the cells [ 3 ]. In theory, hemolysis could contribute to AKI through tubular obstruction by heme, direct injury to kidney cells, and renal vasoconstriction [ 4 ]. However, in our analysis, creatinine changes were mild and not significant, and clinically evident AKI was rare. Alterations to renal function appear to follow a dose–response relationship, with the number of pulses acting as the principal determinant. In the single-arm study by Martinez et al., pulse count was the only strong predictor of creatinine rise, with an increase of about 0.004 mg/dL per pulse [ 5 ]. This means that approximately 129–140 pulses would be needed to produce a clinically relevant 0.3 mg/dL increase in creatinine. In our comparative data, PFA dosing was usually below these thresholds, which may explain why AKI was infrequent despite consistent biochemical evidence of hemolysis. Our meta-analysis provides a contemporary pooled evaluation of the comparative renal outcomes of PFA vs. TA. Limitations should be noted. The studies included in our analysis differed in design, patient populations, ablation protocols, biomarker definitions, and timing of measurements, which may have introduced variability. Although no significant difference in AKI risk was observed based on the available data, the wide confidence intervals and high heterogeneity warrant cautious interpretation, as a clinically meaningful effect cannot be excluded. Conclusion This meta-analysis suggests that the use of PFA for AF ablation is associated with greater intravascular hemolysis without a resultant increase in AKI compared with TA techniques. These findings support the renal safety of PFA; however, the observed hemolysis pattern warrants identification of high-risk patients for close monitoring, continued investigation into preventive strategies, and ongoing technological advancement to mitigate these risks. Further analysis of real-world data and large prospective studies with standardized outcome definitions are needed to validate these findings, clarify the risks, and inform preventive strategies. Declarations Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflicts of Interest: The authors declare that they have no conflicts of interest relevant to this manuscript. Ethical Approval: This article is a meta-analysis of previously published studies and does not contain any studies with human participants or animals performed by any of the authors. Author Contributions: CE and GC performed data extraction and analysis. FS and AR assisted with methodology, and review. EA and JA contributed to data validation. KPT supervised the study and reviewed the final manuscript. References de Campos MCAV, Moraes VRY, Daher RF, et al. Pulsed-field ablation versus thermal ablation for atrial fibrillation: A meta-analysis. Heart Rhythm O. 2024;2 5:385–95. https://doi.org/10.1016/j.hroo.2024.04.012 . Ekanem E, Neuzil P, Reichlin T, et al. Safety of pulsed field ablation in more than 17,000 patients with atrial fibrillation in the MANIFEST-17K study. Nat Med. 2024;30:2020–9. https://doi.org/10.1038/s41591-024-03114-3 . Kinosita K, Tsong TY. Voltage-induced pore formation and hemolysis of human erythrocytes. Biochim Biophys Acta. 1977;471:227–42. https://doi.org/10.1016/0005-2736(77)90252-8 . Dvanajscak Z, Walker PD, Cossey LN, et al. Hemolysis-associated hemoglobin cast nephropathy results from a range of clinicopathologic disorders. Kidney Int. 2019;96:1400–7. https://doi.org/10.1016/j.kint.2019.08.026 . Martinez J, Challapalli M, Hutchinson M, et al. Renal safety of high-dose pulsed field ablation of atrial fibrillation: A prospective real-world analysis. Heart Rhythm. 2025. https://doi.org/10.1016/j.hrthm.2025.07.026 . Additional Declarations No competing interests reported. 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. 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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-8013252","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":543048849,"identity":"4d214b20-6cda-4e30-8dbb-5922ad6d5c98","order_by":0,"name":"Cesar Erazo","email":"","orcid":"","institution":"Cleveland Clinic","correspondingAuthor":false,"prefix":"","firstName":"Cesar","middleName":"","lastName":"Erazo","suffix":""},{"id":543048850,"identity":"d1c2fa32-cad6-4896-9570-d7042d6edad9","order_by":1,"name":"Frans Serpa","email":"","orcid":"","institution":"University of Texas Southwestern Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Frans","middleName":"","lastName":"Serpa","suffix":""},{"id":543048851,"identity":"7141d12c-6f5f-4875-9bd0-cf95701bb0b7","order_by":2,"name":"Gabriel Chagas","email":"","orcid":"","institution":"Cleveland Clinic","correspondingAuthor":false,"prefix":"","firstName":"Gabriel","middleName":"","lastName":"Chagas","suffix":""},{"id":543048852,"identity":"6ee7b53d-9ec4-424c-bd00-5728e3141b42","order_by":3,"name":"Andre Rivera","email":"","orcid":"","institution":"Universidade Nove de Julho","correspondingAuthor":false,"prefix":"","firstName":"Andre","middleName":"","lastName":"Rivera","suffix":""},{"id":543048857,"identity":"fa3ec45a-ac8b-4934-a853-a211b8677d73","order_by":4,"name":"Esteban Arevalo","email":"","orcid":"","institution":"Loma Linda University","correspondingAuthor":false,"prefix":"","firstName":"Esteban","middleName":"","lastName":"Arevalo","suffix":""},{"id":543048859,"identity":"0a1b38b0-7ede-446d-84ce-12c7f86aad74","order_by":5,"name":"Jose Aguilera","email":"","orcid":"","institution":"University of Missouri-Kansas City","correspondingAuthor":false,"prefix":"","firstName":"Jose","middleName":"","lastName":"Aguilera","suffix":""},{"id":543048860,"identity":"5b9574e8-9bc7-4b98-b39d-d3e7f18feb89","order_by":6,"name":"Kamala P. Tamirisa","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+klEQVRIiWNgGAWjYJCCAwwGDAwSINYDBhsgydh4AJ9yHhQtCQxpIC0NBLWAAVTLYai9eIA9++nEwxUFdfKS7acTPyTUnLdb234YaEuNTTROW3hyNxw8Y3DYcDZP7maJhGO3k7edSQRqOZaW24DTYUAtDQYHGOcBGRIJbLeTzQ4AtTA2HMathf8tSEud/Tz+t5t/JPw7l2x2/iEBLRJgW5gTZ0vkbpNIbDtgZ3aDkC03wLYcTp454+02i8S+5ASzG0BbEvD4hb0/d/PHhj91tjPO526+8eGbnb3Z+fSHDz7U2ODUggESwSoTiFUOAvakKB4Fo2AUjIKRAQAjLWpr7hgEgwAAAABJRU5ErkJggg==","orcid":"","institution":"Texas Cardiac Arrhythmia Institute","correspondingAuthor":true,"prefix":"","firstName":"Kamala","middleName":"P.","lastName":"Tamirisa","suffix":""}],"badges":[],"createdAt":"2025-11-02 21:38:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8013252/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8013252/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":95841567,"identity":"3cd3d4e9-c6d9-4715-aa4d-e7b8fd52d7df","added_by":"auto","created_at":"2025-11-13 14:17:57","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":774994,"visible":true,"origin":"","legend":"","description":"","filename":"FinalPFAJICE.docx","url":"https://assets-eu.researchsquare.com/files/rs-8013252/v1/142c718a5276eca427f042f7.docx"},{"id":95841566,"identity":"6401d39e-5b95-4abb-b226-1e04b8c77870","added_by":"auto","created_at":"2025-11-13 14:17:57","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":7332,"visible":true,"origin":"","legend":"","description":"","filename":"11c03f96372d4fa1aeada793d22c2a2d.json","url":"https://assets-eu.researchsquare.com/files/rs-8013252/v1/a71412c8b1a0102635dc3785.json"},{"id":95841571,"identity":"f2546b1f-066b-41d5-b87c-eb279a8b5af6","added_by":"auto","created_at":"2025-11-13 14:17:57","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":21419,"visible":true,"origin":"","legend":"","description":"","filename":"11c03f96372d4fa1aeada793d22c2a2d1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8013252/v1/456fd21261d3a8183fb922b8.xml"},{"id":96239634,"identity":"f3fb093f-b3e5-48cf-8b05-235f4127c173","added_by":"auto","created_at":"2025-11-19 07:07:13","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":186978,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8013252/v1/609e9b1dde1bd345b770de5a.png"},{"id":95841569,"identity":"809ace7e-11bb-47ce-b18a-034a6346445f","added_by":"auto","created_at":"2025-11-13 14:17:57","extension":"xml","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":20548,"visible":true,"origin":"","legend":"","description":"","filename":"11c03f96372d4fa1aeada793d22c2a2d1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8013252/v1/a977d672a165eb74eb4f1493.xml"},{"id":96239778,"identity":"d7af5189-ed74-43e3-87cf-71cc110fa03b","added_by":"auto","created_at":"2025-11-19 07:07:38","extension":"html","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":24461,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8013252/v1/1d5b0564d00165b44e6520f3.html"},{"id":95841572,"identity":"b262a2b0-883a-42df-bdba-002f89a16e17","added_by":"auto","created_at":"2025-11-13 14:17:57","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1100437,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow and pooled analyses of renal and hemolytic outcomes comparing pulsed field ablation (PFA) with thermal ablation (TA). (A) Study selection. (B) Pooled risk ratio for AKI. (C) Mean difference in serum creatinine. (D) Mean difference in LDH. (E) Mean difference in haptoglobin. AKI = acute kidney injury; LDH = lactate dehydrogenase; MD = mean difference; RR = risk ratio; CI = confidence interval.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8013252/v1/4b386ecead7832699463256d.jpeg"},{"id":96254373,"identity":"74622ff4-72b3-421c-9ed5-0d389e068f73","added_by":"auto","created_at":"2025-11-19 07:46:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1449814,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8013252/v1/563dfa55-502d-4a0f-bc52-bc5d5047183b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Intravascular Hemolysis and Acute Kidney Injury Associated with Pulsed Field Ablation vs. Thermal Ablation in Atrial Fibrillation: A Meta-Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePulsed field ablation (PFA) is a non-thermal ablation technique for atrial fibrillation (AF) that creates myocardial-selective lesions by electroporation. Although its safety profile is favorable compared with thermal ablation (TA) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], biochemical evidence of intravascular hemolysis resulting in acute kidney injury (AKI) has been reported in post-marketing and comparative studies [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The clinical significance of this observation remains incompletely understood; therefore, we performed a meta-analysis comparing hemolytic and renal outcomes after PFA vs. TA to better contextualize this risk in clinical practice.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe searched MEDLINE, Embase, and Cochrane Library (inception\u0026ndash;June 2025) for comparative studies of PFA vs. TA (radiofrequency [RFA] or Cryoballoon ablation [CBA]) in AF that reported at least one hemolysis marker (e.g., LDH, haptoglobin) or a renal outcome (change in serum creatinine and AKI). PRISMA flow is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA. Two reviewers screened and extracted data independently; disagreements were resolved by consensus.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFrom each study, we captured design, baseline characteristics, ablation system/catheter, total application, and outcomes. Random-effects models generated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes with 95% confidence intervals (CIs). Heterogeneity was quantified with I\u0026sup2;. Analyses were performed in RevMan v5.4 and R v4.5.0 (\u003cem\u003emeta\u003c/em\u003e package).\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003eStudy selection\u003c/h2\u003e\u003cp\u003eThe search identified 1,600 records; after removing 323 duplicates, 1,277 titles and abstracts were screened. We excluded 711 non-comparative reports and 187 studies without AKI/hemolysis data; one additional study reported no events or markers. Eight studies met the inclusion criteria (n\u0026thinsp;=\u0026thinsp;4,307; PFA n\u0026thinsp;=\u0026thinsp;1,680; TA n\u0026thinsp;=\u0026thinsp;2,627).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eBaseline and procedural characteristics\u003c/h3\u003e\n\u003cp\u003eAcross studies, the mean age ranged from 61\u0026thinsp;\u0026plusmn;\u0026thinsp;9 to 70\u0026thinsp;\u0026plusmn;\u0026thinsp;10 years, with men composing 39.1% to 82.7% of participants. Where reported, mean CHA₂DS₂-VASc scores ranged from 1.6 to 3.3, and mean LVEF from 54\u0026thinsp;\u0026plusmn;\u0026thinsp;6% to 66\u0026thinsp;\u0026plusmn;\u0026thinsp;7%). PFA applications ranged from 31\u0026thinsp;\u0026plusmn;\u0026thinsp;3 to 75\u0026thinsp;\u0026plusmn;\u0026thinsp;29 per case across studies.\u003c/p\u003e\n\u003ch3\u003eMeta-analysis outcomes\u003c/h3\u003e\n\u003cp\u003eAmong eight comparative studies, PFA was not associated with an increased risk of AKI compared with TA (RR 2.00, 95% CI 0.51\u0026ndash;7.91; p\u0026thinsp;=\u0026thinsp;0.32; I\u0026sup2;=59%), and there was no significant difference in post-procedural creatinine levels between techniques (MD 0.02 mg/dL, 95% CI 0.00 to 0.05; p\u0026thinsp;=\u0026thinsp;0.10; I\u0026sup2;=3%). PFA was associated with greater biochemical evidence of hemolysis, as indicated by higher LDH (MD\u0026thinsp;+\u0026thinsp;72.10 U/L, 95% CI 56.48\u0026ndash;87.73; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; I\u0026sup2;=93%) and lower haptoglobin (MD \u0026minus;\u0026thinsp;0.60 g/L, 95% CI -0.71 to -0.49; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; I\u0026sup2;=88%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB-E).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur findings suggest that PFA is not associated with an increased risk of adverse renal outcomes, such as AKI or significant changes in serum creatinine, compared with TA. Despite greater elevations in biochemical markers of intravascular hemolysis with PFA, these changes did not translate into worse renal outcomes.\u003c/p\u003e\u003cp\u003eThe hemolysis observed with PFA is most consistent with pore formation in red blood cell membranes caused by electroporation. This leads to ionic imbalance, swelling, and rupture of the cells [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In theory, hemolysis could contribute to AKI through tubular obstruction by heme, direct injury to kidney cells, and renal vasoconstriction [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, in our analysis, creatinine changes were mild and not significant, and clinically evident AKI was rare.\u003c/p\u003e\u003cp\u003eAlterations to renal function appear to follow a dose\u0026ndash;response relationship, with the number of pulses acting as the principal determinant. In the single-arm study by Martinez et al., pulse count was the only strong predictor of creatinine rise, with an increase of about 0.004 mg/dL per pulse [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. This means that approximately 129\u0026ndash;140 pulses would be needed to produce a clinically relevant 0.3 mg/dL increase in creatinine. In our comparative data, PFA dosing was usually below these thresholds, which may explain why AKI was infrequent despite consistent biochemical evidence of hemolysis.\u003c/p\u003e\u003cp\u003eOur meta-analysis provides a contemporary pooled evaluation of the comparative renal outcomes of PFA vs. TA. Limitations should be noted. The studies included in our analysis differed in design, patient populations, ablation protocols, biomarker definitions, and timing of measurements, which may have introduced variability. Although no significant difference in AKI risk was observed based on the available data, the wide confidence intervals and high heterogeneity warrant cautious interpretation, as a clinically meaningful effect cannot be excluded.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis meta-analysis suggests that the use of PFA for AF ablation is associated with greater intravascular hemolysis without a resultant increase in AKI compared with TA techniques. These findings support the renal safety of PFA; however, the observed hemolysis pattern warrants identification of high-risk patients for close monitoring, continued investigation into preventive strategies, and ongoing technological advancement to mitigate these risks. Further analysis of real-world data and large prospective studies with standardized outcome definitions are needed to validate these findings, clarify the risks, and inform preventive strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflicts of interest relevant to this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis article is a meta-analysis of previously published studies and does not contain any studies with human participants or animals performed by any of the authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCE and GC performed data extraction and analysis. FS and AR assisted with methodology, and review. EA and JA contributed to data validation. KPT supervised the study and reviewed the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ede Campos MCAV, Moraes VRY, Daher RF, et al. Pulsed-field ablation versus thermal ablation for atrial fibrillation: A meta-analysis. Heart Rhythm O. 2024;2 5:385\u0026ndash;95. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.hroo.2024.04.012\u003c/span\u003e\u003cspan address=\"10.1016/j.hroo.2024.04.012\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEkanem E, Neuzil P, Reichlin T, et al. Safety of pulsed field ablation in more than 17,000 patients with atrial fibrillation in the MANIFEST-17K study. Nat Med. 2024;30:2020\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41591-024-03114-3\u003c/span\u003e\u003cspan address=\"10.1038/s41591-024-03114-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKinosita K, Tsong TY. Voltage-induced pore formation and hemolysis of human erythrocytes. Biochim Biophys Acta. 1977;471:227\u0026ndash;42. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/0005-2736(77)90252-8\u003c/span\u003e\u003cspan address=\"10.1016/0005-2736(77)90252-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDvanajscak Z, Walker PD, Cossey LN, et al. Hemolysis-associated hemoglobin cast nephropathy results from a range of clinicopathologic disorders. Kidney Int. 2019;96:1400\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.kint.2019.08.026\u003c/span\u003e\u003cspan address=\"10.1016/j.kint.2019.08.026\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMartinez J, Challapalli M, Hutchinson M, et al. Renal safety of high-dose pulsed field ablation of atrial fibrillation: A prospective real-world analysis. Heart Rhythm. 2025. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.hrthm.2025.07.026\u003c/span\u003e\u003cspan address=\"10.1016/j.hrthm.2025.07.026\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8013252/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8013252/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eTo evaluate the comparative risk of hemolysis and acute kidney injury (AKI) after pulsed field ablation (PFA) vs. thermal ablation (TA) for atrial fibrillation (AF).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eDatabases were searched through June 2025 for comparative studies reporting hemolysis markers or renal outcomes. Random-effects models estimated risk ratios (RRs) and mean differences (MDs).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eEight studies (n\u0026thinsp;=\u0026thinsp;4,307) were included. PFA was not associated with higher AKI risk (RR 2.00, 95% CI 0.51\u0026ndash;7.91) or creatinine change (MD 0.02 mg/dL, p\u0026thinsp;=\u0026thinsp;0.10). LDH was higher (MD\u0026thinsp;+\u0026thinsp;72 U/L p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and haptoglobin lower (MD \u0026minus;\u0026thinsp;0.60 g/L p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) with PFA.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003ePFA causes greater biochemical hemolysis, but no significant renal injury compared with TA, supporting its favorable renal safety profile.\u003c/p\u003e","manuscriptTitle":"Intravascular Hemolysis and Acute Kidney Injury Associated with Pulsed Field Ablation vs. Thermal Ablation in Atrial Fibrillation: A Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-13 14:17:52","doi":"10.21203/rs.3.rs-8013252/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":"0f799ec9-63eb-4cd1-8c62-d4cd4311017f","owner":[],"postedDate":"November 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-17T00:23:13+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-13 14:17:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8013252","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8013252","identity":"rs-8013252","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}