IVIg Monotherapy for Desensitization in Highly Sensitized Kidney Transplant Candidates: Efficacy and Long-Term Outcomes

IVIg Monotherapy for Desensitization in Highly Sensitized Kidney Transplant Candidates: Efficacy and Long-Term Outcomes | 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 IVIg Monotherapy for Desensitization in Highly Sensitized Kidney Transplant Candidates: Efficacy and Long-Term Outcomes Jenaine Oliveira Paixão, Luiz Roberto de Souza Ulisses, Fabiana Agena, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6856706/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Highly sensitized (HS) patients awaiting kidney transplantation often face prolonged waiting times and increased mortality, especially in regions lacking structured organ allocation directed to these patients or desensitization strategies. This study evaluated the efficacy and safety of intravenous immunoglobulin (IVIg) monotherapy for desensitization (DS) in HS patients awaiting deceased donor kidney transplantation. Methods: Thirty-nine sensitized patients on the deceased donor waiting list with > 5 positive T/B-cell complement-dependent cytotoxicity crossmatches (CDC-XM) received IVIg at 2 g/kg/month. Patients were followed for a mean of 58.9 ± 22.9 months. Outcomes included transplantation rates, changes in calculated panel-reactive antibodies (cPRA), donor-specific antibody (DSA) levels, and post-transplant survival. Results: Fourteen patients (35.9%) underwent transplantation, with 64.3% exhibiting detectable DSA. Post-DS waiting time on the WL decreased significantly (75 ± 41 vs. 20 ± 11 months; p < 0.01). IVIg therapy significantly reduced class I cPRA (p = 0.0074), class II cPRA (p = 0.04), total anti-HLA antibodies, and immunodominant DSA levels in transplanted patients (p = 0.03). Transplantation rates were higher among patients prioritized due to dialysis access failure (70% vs. 21%; p 1 DSA at the time of transplantation (p = 0.02). No serious IVIg-related adverse events were observed. Conclusions: IVIg monotherapy is a safe and effective desensitization strategy for HS patients, significantly reducing anti-HLA antibodies and time on WL, thereby facilitating access to deceased donor kidney transplantation. Sensitization Kidney Transplantation Intravenous Immunoglobulin Anti-HLA Antibodies Desensitization 1. Introduction Chronic kidney disease (CKD) represents a growing global public health concern. In Brazil, data from the Brazilian Society of Nephrology reveal a steady increase in the number of patients requiring renal replacement therapy (RRT), from 54,523 in 2009 to approximately 172,585 in 2024, with an annual mortality rate of 16.5%. Despite this, only 19.6% of these patients are enrolled on the kidney transplant waiting list [1]. Among RRT modalities, kidney transplantation offers superior survival rates and quality of life when compared to maintenance dialysis [2]. However, the rising incidence of graft loss has contributed to an expanding population of sensitized patients awaiting retransplantation. In 2024, 5,584 kidney transplants were performed in Brazil, while the estimated annual need stands at approximately 12,510, according to the Brazilian Association of Organ Transplantation (ABTO) [3]. Consequently, median waiting times remain substantially longer than those in many other countries. For example, data from the São Paulo State Health Department (SES-SP) indicate a mean waiting time of 31.7 months between 2002 and 2017 [4]. Patients with preformed anti-HLA antibodies face significantly reduced access to transplantation due to prolonged waiting on the list. Although Brazil’s allocation system prioritizes patients with panel reactive antibody (PRA) levels above 80% by awarding additional points, the absence of comprehensive strategies to increase donor access for highly sensitized individuals perpetuates inequities in transplant access. Pedrosa et al. demonstrated that higher PRA levels are associated with extended waiting times and increased mortality or removal from the waitlist. Specifically, patients with PRA > 98% had a substantially lower likelihood of transplantation compared to non-sensitized candidates (HR: 13.02; p 0–40%, > 90–95%, > 95–98%, and > 98% [4]. High comorbidity burdens among waitlisted patients contribute to elevated mortality, reaching 10% annually in Brazil and 13.12% in São Paulo in 2019 [1]. In the absence of alternative desensitization strategies nationally, our center developed a protocol using intravenous immunoglobulin (IVIg) as monotherapy for severely sensitized candidates with persistent positive crossmatches during the waiting period. 2. Patients and Methods Ethical Approval The study protocol was approved by the Institutional Review Board of our institution. Study Design This retrospective study included 45 sensitized patients listed for deceased donor kidney transplantation. All patients had no available living donor and were considered temporarily ineligible for transplantation due to persistently positive complement-dependent cytotoxicity (CDC) T- and/or B-cell crossmatches while on the waiting list. Six patients were excluded: three who subsequently received compatible living donor transplants and three who received fewer than three consecutive doses of IVIg. Desensitization Protocol Patients received IVIg (5 g vials) at a dose of 2 g/kg/month, administered in two sessions within the same week, typically aligned with hemodialysis (except for peritoneal dialysis patients). Premedication with corticosteroids and antihistamines was administered prior to each infusion. IVIg was provided by the Brazilian Public Health System, and product standardization was not feasible during the study period. No adjunct desensitization agents were available in Brazil at that during the study. Immunological Monitoring HLA typing was performed using the CR-SSP method (LABType SSP, One Lambda, CA, USA). Anti-HLA antibody screening and specificity testing were performed using Luminex-based single antigen bead assays (LABScreen® Single Antigen, One Lambda). PRA class I and II levels and anti-HLA antibody intensities were assessed every three months. Antibodies were categorized based on mean fluorescence intensity (MFI) into five ranges: 10,000. Absolute antibody counts and MFI (mean, median, and total) were recorded. Calculated PRA (cPRA) was not routinely reported during the study period. For patients who underwent transplantation, donor-specific antibodies (DSAs) present at the time of surgery were analyzed. The peak DSA MFI (iDSA-MFI) was compared pre- and post-IVIg. In 14 patients we were able to collected the number of DSAs, iDSA-MFI, and total DSA-MFI. Post-transplant outcomes, including graft function and survival, were recorded. Transplant Procedure and Immunosuppression Transplants were performed using the first available ABO-compatible deceased donor with a negative T- and B-cell CDC crossmatche. All recipients received thymoglobulin (Sanofi-Aventis) at a total dose of 6 mg/kg over 4–7 days. Maintenance immunosuppression included prednisone, tacrolimus, and either mycophenolate mofetil or mycophenolic acid. Allocation and Priority Criteria Brazil's organ allocation system is primarily based on HLA compatibility, prioritizing candidates who have experienced vascular access failure or those who are unable to perform peritoneal dialysis. For these prioritized patients, crossmatching is performed against all ABO-compatible donors, regardless of HLA matching. The effect of this priority status on transplant access and waitlist time was evaluated. Biopsy and Post-Transplant Monitoring Protocol biopsies were performed within two weeks post-transplant (unless contraindicated), in addition to indication biopsies for graft dysfunction or proteinuria. Histological findings were classified per the Banff 2009 criteria [5], including C4d staining via immunofluorescence or immunoperoxidase. All patients received cytomegalovirus (CMV) prophylaxis with IV ganciclovir or oral valganciclovir for three months and sulfamethoxazole-trimethoprim prophylaxis for six months. The mean post-transplant follow-up was 18.2 ± 16.7 months. Assessment of Sensitization and Outcomes PRA class I and II levels were monitored throughout IVIg treatment in patients who remained on the waitlist. Mortality rates and causes of death were documented in both transplanted and non-transplanted cohorts. Factors associated with successful transplantation after IVIg therapy were analyzed by comparing baseline and follow-up characteristics between groups. Statistical Analysis Quantitative variables (e.g., PRA, number and MFI of DSAs) are reported as medians and were compared using the Wilcoxon rank-sum test. Categorical variables (e.g., incidence of rejection or graft loss) are expressed as frequencies and percentages, with comparisons made using Fisher’s exact test. Survival outcomes were analyzed using Kaplan–Meier estimates, with a p-value < 0.05 considered statistically significant. 3. Results Demographic and Treatment Characteristics A total of 39 patients who were candidates for deceased donor kidney transplantation underwent the desensitization protocol and received at least three consecutive monthly doses of IVIg at 2 g/kg. All patients had been tested the waiting list (WL) at least five times, consistently demonstrating positive complement-dependent cytotoxicity crossmatch (CDC-XM). The average time on the WL was 91 ± 60 months. IVIg desensitization was well tolerated, with mild adverse effects in 30% of patients and two episodes of hypervolemia associated with infusion. As expected, no increase in infection rates or IVIg-attributable thrombotic events were observed. Most patients were female (26, 66.6%) and Caucasian (24, 61.5%), with a mean age of 47.3 ± 12.2 years. Hemodialysis was the predominant renal replacement therapy modality (36 patients, 92.3%). The most common underlying cause of CKD was chronic glomerulonephritis (9 patients, 23%), and 5 patients (12.8%) were diabetic. Major comorbidities included hypertension (36 patients, 92.3%), secondary hyperparathyroidism (17, 43.5%), coronary artery disease (5, 12.8%), hepatitis B (4, 10.3%), and hepatitis C (8, 20.5%). Twenty patients (51.3%) were granted transplant priority status due to severe and irreversible lack of vascular access for dialysis. All patients had received at least one blood transfusion, and 26 (66.6%) had undergone previous transplantation. Among the 26 female patients, 18 (69.2%) had a history of previous pregnancies. Of the 39 patients included in the deceased donor desensitization protocol, 14 (35.9%) underwent transplantation after a median of 31 months of treatment. The remaining 25 patients (64.1%) did not identify a acceptable donor (negative CDC-XM for both T and B cells) during the observation period of 58.9 ± 22.9 months. Demographic variables were compared between transplanted patients (Group 1) and those who remained on the WL (Group 2), with no significant differences found in age (42.3 ± 12 vs. 49.9 ± 12 years), gender (female: 71.4% vs. 64%), ethnicity (Caucasian: 64.3% vs. 56%), duration of renal replacement therapy (91 ± 62 vs. 97 ± 72 months), dialysis modality (hemodialysis: 92.9% vs. 92%), or ABO blood group distribution. There were also no differences in sensitizing events such as prior blood transfusions (100% in both groups) or previous transplantation (71.4% vs. 84%). However, among women, a significantly higher proportion of those who were transplanted had previous pregnancies compared to those who remained on the WL (50% vs. 7%, p < 0.05). The mean number of IVIg doses administered was 13.87 ± 11.03. At the last evaluation, patients who were transplanted received fewer doses (8 ± 4) than those who remained on the WL (17 ± 12, p = 0.026). Immunological Results To explore the mechanisms by which IVIg facilitated transplant access, we analyzed anti-HLA antibody profiles separately for class I and class II specificities. The mean panel reactive antibody (PRA) levels at the beginning of desensitization were 78 ± 26 for class I and 74 ± 27 for class II. Significant reductions were observed after treatment for both class I PRA (from 78.4 ± 26.0 to 69.5 ± 31.2, p = 0.0074) and class II PRA (from 74.4 ± 27.5 to 61.8 ± 36.3, p < 0.005), especially in patients who received a higher number of IVIg infusions (Table 1). The impact of the desensitization on the MFI in transplanted and in not transplanted patients is shown in the table 2. When assessing the strength of anti-HLA antibodies by mean fluorescence intensity (MFI), a significant reduction was seen in category A antibodies (MFI ≤ 1500), which decreased from 10.7 to 3.7 (p 5000), which declined from 16.9 to 13.2 (p < 0.005). No significant changes were observed in categories B, C, or E. At the time of transplantation, donor-specific antibodies (DSA) against HLA-A, -B, and -DR loci were evaluated. The mean HLA A, B, DR mismatch was 3.78 ± 1.88. One patient received a fully matched graft (zero A, B, DR mismatches). Among the 14 transplanted patients, 9 (64.3%) had detectable DSA at transplantation. In this subgroup, the mean MFI of immunodominant DSA (iDSA) decreased significantly following desensitization (from 3615 ± 1514 to 2020 ± 1299, p < 0.05) (Figure 1). One patient experienced an increase in anti-DR1 MFI from <1000 to 4000, although this remained below the threshold for clinical concern at the start of the protocol. Clinical Outcomes The transplant rate among desensitized patients was 35.9% over a mean follow-up of 58.9 ± 22.9 months. These patients had been on the WL for a mean of 91 ± 60 months (median 71 months, range 27–242 months). The median time from desensitization to transplantation was 19 months (range 17.5–50 months). Among the ten priority patients who underwent transplantation, the duration of dialysis significantly decreased following desensitization, reducing from 87.2 ± 48.5 months to 18.3 ± 7.9 months (p < 0.004). In contrast, for non-priority patients, the decrease did not reach statistical significance, with dialysis duration changing from 81.2 ± 74.2 months to 37.0 ± 19.1 months (p = 0.29). Transplant Outcomes The mean follow-up time after transplantation was 54.6 ± 20.7 months. Overall survival did not differ significantly between transplanted and non-transplanted patients (71.4% vs. 77%, p = 0.32). The 3-year patient survival was 78.6%, and the 3-year death-censored graft survival was 76.4%. The most common cause of graft loss was patient death, primarily from infections often related to dialysis access. BK virus nephropathy was the second leading cause of graft failure. Donor kidneys had a mean cold ischemia time of 28.2 ± 3.8 hours. Delayed graft function, defined as the need for dialysis within the first post-transplant week, occurred in 85.7% of patients, which is usually 60-70% in Brazil. No machine perfusion was used. The mean donor age was 45 years, and 64% of donors died from stroke. The rate of antibody-mediated rejection (ABMR) was 35.7%, with all cases occurring within the first post-transplant year. These episodes were treated with plasma exchange, rituximab, and IVIg. Eight of the nine patients with ABMR had DSA at the time of transplantation. ABMR occurred only in patients with two or more DSA (p = 0.02), while none of the patients with only one DSA developed rejection. ABMR did not impact long-term graft function (eGFR: 53.8 ± 26.6 vs. 36.1 ± 22.6 mL/min/1.73 m², p = 0.21) or graft survival (40% vs. 33.3%, p = 0.81). Only one patient experienced graft loss due to chronic ABMR after 51 months. 4. Discussion This study describes the outcomes of a desensitization protocol using intravenous immunoglobulin (IVIg) as monotherapy in highly sensitized patients with persistently positive CDC crossmatches while awaiting kidney transplantation. To our knowledge, this is the largest single-center Brazilian cohort to report on IVIg monotherapy in a public health system setting, reflecting a real-world strategy implemented in the absence of adjunct therapies such as rituximab, plasmapheresis, or bortezomib. Our results demonstrate that IVIg was safe and moderately effective, allowing 35.9% of patients to undergo deceased donor transplantation (50% in patints on priority) with favorable short-to medium-term graft and patient outcomes. Importantly, IVIg was well tolerated, and no increase in infection or thromboembolic events were observed, aligning with existing literature that supports the safety profile of IVIg in transplantation [6,7]. A notable strength of this protocol lies in its accessibility and feasibility within the constraints of a public health system. In contrast to more complex and risky DS regimens employed in North America and Europe - which often involve combinations of plasmapheresis, rituximab, proteasome inhibitors, or complement blockers - our approach utilized a widely available immunomodulatory agent, delivering measurable immunological benefit in an underserved population. From an immunological standpoint, we observed a reduction in PRA levels and anti-HLA antibody intensity in several patients, especially among those who subsequently underwent transplantation. Although the protocol did not universally eliminate donor-specific antibodies (DSAs), the downregulation of immune activation may have contributed to to achieving negative CM outcomes over time. This aligns with the proposed mechanisms of IVIg, including Fc receptor blockade, cytokine modulation, and expansion of regulatory T cells [8,9]. Despite these encouraging findings, the overall transplantation rate remained below 40%, underscoring the persistent challenges faced by highly sensitized candidates, since there was no special allocation systems for sensitized patients in our country. Notably, the median desensitization period exceeded two years, highlighting the need for more proactive and individualized strategies. In this regard, future integration of virtual crossmatch platforms and refined epitope-based matching could enhance access to acceptable donors and optimize the timing of transplantation. One particularly original implication of our study is the potential repurposing of IVIg not only as a desensitization tool but also as a bridge strategy—maintaining sensitized patients in a “transplant-ready” immunological state until access to a compatible donor is achieved. Also, decreasing anti-HLA ab in these patients, may help us to find faster a living donor when on paired exchange programs.This concept may be especially relevant in low- and middle-income countries, where access to biologics remains limited and resource optimization is essential. It is also important to consider the psychological and systemic impact of prolonged time on dialysis, which contribute to increased mortality and withdrawal from the waitlist. By demonstrating that desensitization with IVIg can modify immunological barriers and allow transplantation in a subset of patients, our study supports the implementation of easy, scalable strategies that may promote equity in transplant access. Limitations This study is limited by its retrospective nature and small sample size. Additionally, cPRA and detailed DSA quantification were not always available at baseline. The lack of a control group limits comparisons with untreated sensitized patients, although our findings provide valuable insight into outcomes in a previously excluded population. Future Directions It is essential to emphasize that, for highly sensitized patients, multiple public policies should be implemented to increase their access to transplantation: expanding the donor pool, prioritizing equitable access compared to non-sensitized patients, implementing permissive antigen programs, and establishing paired donation programs. Nevertheless, highly sensitized patients in many countries still do not have these policies available. Despite the implementation of these measures, many sensitized patients will still require desensitization procedures. Future studies should evaluate the addition of cost-effective immunomodulatory agents—such as low-dose rituximab or IL-6 inhibitors—in combination with IVIg, especially in patients with persistent high-strength DSAs. Moreover, incorporating personalized immunological risk stratification using artificial intelligence and machine learning may enable tailored desensitization protocols that maximize efficacy while minimizing toxicity and cost. Abbreviations HS Highly Sensitized IVIg Intravenous Immunoglobulin DS Desensitization CDC XM-Complement-Dependent Cytotoxicity Crossmatches cPRA Calculated Panel-Reactive Antibodies DSA Donor-Specific Antibody ABMR Antibody-Mediated Rejection CKD Chronic Kidney Disease RRT Renal Replacement Therapy SES SP-São Paulo State Health Department MFI Mean Fluorescence Intensity CMV Cytomegalovirus iDSA Immunodominant Donor-Specific Antibodies eGFR Estimated Glomerular Filtration Rate Declarations Ethics approval and consent to participate: This study was conducted in accordance with the principles of the Declaration of Helsinki. The study was approved by the Ethics Committee for the Analysis of Research Projects (CAPPesq) of the Hospital das Clínicas of the Faculty of Medicine of the University of São Paulo under number 1.629.278, on July 8, 2016. Consent for publication: not applicable. Availability of data and materials: The data and materials generated during this study are available to the research community under the following conditions: Data Sharing Policy: The datasets supporting the findings of this study are available on request. Data access: Interested researchers can obtain access to the data by contacting the corresponding author. Contact Information: For further inquiries regarding data or materials, please contact: Jenaine Oliveira Paixão Email address: [email protected] Affiliation: Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil. Competing Interests: I declare that the authors have no competing interests as defined by BMC, or other interests that might be perceived to influence the results and/or discussion reported in this paper. Funding: no funding. Authors’ contributions: J.P. wrote the main manuscript text and performed the data analysis. G.B., N.P., and H.R. conducted the immunological tests. L.U. and F.A. assisted with data collection from electronic medical records. M.C. and E.D. supervised the manuscript writing and data analysis. All authors reviewed and approved the final manuscript. Acknowledgements We would like to thank the Clinical Research Group of the Renal Transplantation Service at Hospital das Clínicas, University of São Paulo, for their valuable contributions to this study. References Sociedade Brasileira de Nefrologia. Censo Brasileiro de Diálise 2024 [Internet]. Available at: www.sbn.org.br. Accessed on: March 2, 2025. Port FK, Wolfe RA, Mauger EA, Berling DP, Jiang K. 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Aguirre AR, Souza PS, Agena F, et al. Vale a pena transplantar o paciente sensibilizado? Uma análise retrospectiva unicêntrica de 1002 transplantes consecutivos. J Bras Transpl. 2016;19(3):60–6. Orandi BJ, Luo X, Massie AB, et al. Survival benefit with kidney transplants from HLA-incompatible live donors. N Engl J Med. 2016;374(10):940–50. Orandi BJ, Garonzik-Wang JM, Massie AB, et al. Quantifying the risk of incompatible kidney transplantation: a multicenter study. Am J Transpl. 2014;14(7):1573–80. Associação Brasileira de Transplantes de Órgãos. Registro Brasileiro de Transplantes 2019 [Internet]. Disponível em: www.abto.org.br. Acesso em: 12 mar 2020. Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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Paixão","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+0lEQVRIiWNgGAWjYBACxgYgkQBiMYOIChCDuYEULWdADEb8WtAMaIMbgxswt/ce/PBwh00efzuP4YeP82qj+duBWn5UbMNtbs+5ZInEM2nFEofZkiVnbjueO+MwYwNjz5nbuLXMyDGQSGw7nNhwmPmANO+2Y7kNQC3MjG14tMx/Y/wjse1/4vzDjM2/eeccy51PUMsMHjOgLQcSNxxmPibN21CTu4Gglp4cM4vEtuRiw8NsaZYzjh3I3QjUchCfXwzbzxjf/Nlmlyd3/ozxjQ81dbnzzh8++OBHBR4tDRA6Aco/DCYP4FQPBPIMqFrq8CkeBaNgFIyCEQoAGuJezW2wGPoAAAAASUVORK5CYII=","orcid":"","institution":"University of São Paulo","correspondingAuthor":true,"prefix":"","firstName":"Jenaine","middleName":"Oliveira","lastName":"Paixão","suffix":""},{"id":511518408,"identity":"533340a7-05a4-4fd2-a217-29e84e260f52","order_by":1,"name":"Luiz Roberto de Souza Ulisses","email":"","orcid":"","institution":"University of São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Luiz","middleName":"Roberto de Souza","lastName":"Ulisses","suffix":""},{"id":511518409,"identity":"4fbd56e0-1e1e-4e7c-aa3d-064b541c19db","order_by":2,"name":"Fabiana Agena","email":"","orcid":"","institution":"University of São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Fabiana","middleName":"","lastName":"Agena","suffix":""},{"id":511518410,"identity":"93507026-75f7-488d-959b-f9f3eb5e98d5","order_by":3,"name":"Gislene Oliveira Bezerra","email":"","orcid":"","institution":"Heart Institute of University of São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Gislene","middleName":"Oliveira","lastName":"Bezerra","suffix":""},{"id":511518411,"identity":"5a11973a-a432-4aeb-a64b-f7421617dd42","order_by":4,"name":"Helcio Rodrigues","email":"","orcid":"","institution":"Heart Institute of University of São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Helcio","middleName":"","lastName":"Rodrigues","suffix":""},{"id":511518412,"identity":"21549646-3a8a-4a45-95bf-413ed621b77d","order_by":5,"name":"Nicolas Panajotopolous","email":"","orcid":"","institution":"Heart Institute of University of São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Nicolas","middleName":"","lastName":"Panajotopolous","suffix":""},{"id":511518413,"identity":"7a2dbb19-0351-461e-932a-fc2706709feb","order_by":6,"name":"Elias David-Neto","email":"","orcid":"","institution":"University of São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Elias","middleName":"","lastName":"David-Neto","suffix":""},{"id":511518414,"identity":"d8552016-a109-4eac-8f5b-52ee43120652","order_by":7,"name":"Maria Cristina Ribeiro de Castro","email":"","orcid":"","institution":"University of São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Cristina Ribeiro","lastName":"de Castro","suffix":""}],"badges":[],"createdAt":"2025-06-09 17:53:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6856706/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6856706/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91214376,"identity":"db615821-d695-4370-ade3-55ea86ed6b3f","added_by":"auto","created_at":"2025-09-12 19:01:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":411280,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6856706/v1/2eb2111e-552d-4d9f-a3da-c864c0108bff.pdf"},{"id":90815987,"identity":"c86f01a4-fff9-4d2c-90d4-7eb188e826fa","added_by":"auto","created_at":"2025-09-08 13:11:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":48515,"visible":true,"origin":"","legend":"","description":"","filename":"DSIVIGTable1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6856706/v1/c58eaf1471ed17d6b43e5808.pdf"},{"id":90815989,"identity":"2e90ac2a-7e6f-4570-835c-a3361db7f8d1","added_by":"auto","created_at":"2025-09-08 13:11:55","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":46543,"visible":true,"origin":"","legend":"","description":"","filename":"DSIVIGTable2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6856706/v1/0f5688f87502adce0b709fd1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"IVIg Monotherapy for Desensitization in Highly Sensitized Kidney Transplant Candidates: Efficacy and Long-Term Outcomes","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eChronic kidney disease (CKD) represents a growing global public health concern. In Brazil, data from the Brazilian Society of Nephrology reveal a steady increase in the number of patients requiring renal replacement therapy (RRT), from 54,523 in 2009 to approximately 172,585 in 2024, with an annual mortality rate of 16.5%. Despite this, only 19.6% of these patients are enrolled on the kidney transplant waiting list [1].\u003c/p\u003e\u003cp\u003eAmong RRT modalities, kidney transplantation offers superior survival rates and quality of life when compared to maintenance dialysis [2]. However, the rising incidence of graft loss has contributed to an expanding population of sensitized patients awaiting retransplantation. In 2024, 5,584 kidney transplants were performed in Brazil, while the estimated annual need stands at approximately 12,510, according to the Brazilian Association of Organ Transplantation (ABTO) [3]. Consequently, median waiting times remain substantially longer than those in many other countries. For example, data from the S\u0026atilde;o Paulo State Health Department (SES-SP) indicate a mean waiting time of 31.7 months between 2002 and 2017 [4].\u003c/p\u003e\u003cp\u003ePatients with preformed anti-HLA antibodies face significantly reduced access to transplantation due to prolonged waiting on the list. Although Brazil\u0026rsquo;s allocation system prioritizes patients with panel reactive antibody (PRA) levels above 80% by awarding additional points, the absence of comprehensive strategies to increase donor access for highly sensitized individuals perpetuates inequities in transplant access. Pedrosa et al. demonstrated that higher PRA levels are associated with extended waiting times and increased mortality or removal from the waitlist. Specifically, patients with PRA\u0026thinsp;\u0026gt;\u0026thinsp;98% had a substantially lower likelihood of transplantation compared to non-sensitized candidates (HR: 13.02; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with progressive waitlist attrition observed in PRA strata\u0026thinsp;\u0026gt;\u0026thinsp;0\u0026ndash;40%, \u0026gt;\u0026thinsp;90\u0026ndash;95%, \u0026gt;\u0026thinsp;95\u0026ndash;98%, and \u0026gt;\u0026thinsp;98% [4].\u003c/p\u003e\u003cp\u003eHigh comorbidity burdens among waitlisted patients contribute to elevated mortality, reaching 10% annually in Brazil and 13.12% in S\u0026atilde;o Paulo in 2019 [1]. In the absence of alternative desensitization strategies nationally, our center developed a protocol using intravenous immunoglobulin (IVIg) as monotherapy for severely sensitized candidates with persistent positive crossmatches during the waiting period.\u003c/p\u003e"},{"header":"2. Patients and Methods","content":"\u003cp\u003eEthical Approval\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Institutional Review Board of our institution.\u003c/p\u003e\n\u003cp\u003eStudy Design\u003c/p\u003e\n\u003cp\u003eThis retrospective study included 45 sensitized patients listed for deceased donor kidney transplantation. All patients had no available living donor and were considered temporarily ineligible for transplantation due to persistently positive complement-dependent cytotoxicity (CDC) T- and/or B-cell crossmatches while on the waiting list. Six patients were excluded: three who subsequently received compatible living donor transplants and three who received fewer than three consecutive doses of IVIg.\u003c/p\u003e\n\u003cp\u003eDesensitization Protocol\u003c/p\u003e\n\u003cp\u003ePatients received IVIg (5 g vials) at a dose of 2 g/kg/month, administered in two sessions within the same week, typically aligned with hemodialysis (except for peritoneal dialysis patients). Premedication with corticosteroids and antihistamines was administered prior to each infusion. IVIg was provided by the Brazilian Public Health System, and product standardization was not feasible during the study period. No adjunct desensitization agents were available in Brazil at that during the study.\u003c/p\u003e\n\u003cp\u003eImmunological Monitoring\u003c/p\u003e\n\u003cp\u003eHLA typing was performed using the CR-SSP method (LABType SSP, One Lambda, CA, USA). Anti-HLA antibody screening and specificity testing were performed using Luminex-based single antigen bead assays (LABScreen® Single Antigen, One Lambda). PRA class I and II levels and anti-HLA antibody intensities were assessed every three months. Antibodies were categorized based on mean fluorescence intensity (MFI) into five ranges: \u0026lt;1500, 1500–2499, 2500–4999, 5000–10,000, and \u0026gt;10,000. Absolute antibody counts and MFI (mean, median, and total) were recorded. Calculated PRA (cPRA) was not routinely reported during the study period.\u003c/p\u003e\n\u003cp\u003eFor patients who underwent transplantation, donor-specific antibodies (DSAs) present at the time of surgery were analyzed. The peak DSA MFI (iDSA-MFI) was compared pre- and post-IVIg. In 14 patients we were able to collected the number of DSAs, iDSA-MFI, and total DSA-MFI. Post-transplant outcomes, including graft function and survival, were recorded.\u003c/p\u003e\n\u003cp\u003eTransplant Procedure and Immunosuppression\u003c/p\u003e\n\u003cp\u003eTransplants were performed using the first available ABO-compatible deceased donor with a negative T- and B-cell CDC crossmatche. All recipients received thymoglobulin (Sanofi-Aventis) at a total dose of 6 mg/kg over 4–7 days. Maintenance immunosuppression included prednisone, tacrolimus, and either mycophenolate mofetil or mycophenolic acid.\u003c/p\u003e\n\u003cp\u003eAllocation and Priority Criteria\u003c/p\u003e\n\u003cp\u003eBrazil's organ allocation system is primarily based on HLA compatibility, prioritizing candidates who have experienced vascular access failure or those who are unable to perform peritoneal dialysis. For these \u0026nbsp;prioritized patients, crossmatching is performed against all ABO-compatible donors, regardless of HLA matching. The effect of this priority status on transplant access and waitlist time was evaluated.\u003c/p\u003e\n\u003cp\u003eBiopsy and Post-Transplant Monitoring\u003c/p\u003e\n\u003cp\u003eProtocol biopsies were performed within two weeks post-transplant (unless contraindicated), in addition to indication biopsies for graft dysfunction or proteinuria. Histological findings were classified per the Banff 2009 criteria [5], including C4d staining via immunofluorescence or immunoperoxidase. All patients received cytomegalovirus (CMV) prophylaxis with IV ganciclovir or oral valganciclovir for three months and sulfamethoxazole-trimethoprim prophylaxis for six months. The mean post-transplant follow-up was 18.2\u0026nbsp;±\u0026nbsp;16.7 months.\u003c/p\u003e\n\u003cp\u003eAssessment of Sensitization and Outcomes\u003c/p\u003e\n\u003cp\u003ePRA class I and II levels were monitored throughout IVIg treatment in patients who remained on the waitlist. Mortality rates and causes of death were documented in both transplanted and non-transplanted cohorts. Factors associated with successful transplantation after IVIg therapy were analyzed by comparing baseline and follow-up characteristics between groups.\u003c/p\u003e\n\u003cp\u003eStatistical Analysis\u003c/p\u003e\n\u003cp\u003eQuantitative variables (e.g., PRA, number and MFI of DSAs) are reported as medians and were compared using the Wilcoxon rank-sum test. Categorical variables (e.g., incidence of rejection or graft loss) are expressed as frequencies and percentages, with comparisons made using Fisher’s exact test. Survival outcomes were analyzed using Kaplan–Meier estimates, with a p-value \u0026lt; 0.05 considered statistically significant.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003eDemographic and Treatment Characteristics\u003c/p\u003e\n\u003cp\u003eA total of 39 patients who were candidates for deceased donor kidney transplantation underwent the desensitization protocol and received at least three consecutive monthly doses of IVIg at 2 g/kg. All patients had been tested the waiting list (WL) at least five times, consistently demonstrating positive complement-dependent cytotoxicity crossmatch (CDC-XM). The average time on the WL was 91\u0026nbsp;±\u0026nbsp;60 months. IVIg desensitization was well tolerated, with mild adverse effects in 30% of patients and two episodes of hypervolemia associated with infusion. As expected, no increase in infection rates or IVIg-attributable thrombotic events were\u0026nbsp;observed.\u003c/p\u003e\n\u003cp\u003eMost patients were female (26, 66.6%) and Caucasian (24, 61.5%), with a mean age of 47.3\u0026nbsp;±\u0026nbsp;12.2 years. Hemodialysis was the predominant renal replacement therapy modality (36 patients, 92.3%). The most common underlying cause of CKD was chronic glomerulonephritis (9 patients, 23%), and 5 patients (12.8%) were diabetic. Major comorbidities included hypertension (36 patients, 92.3%), secondary hyperparathyroidism (17, 43.5%), coronary artery disease (5, 12.8%), hepatitis B (4, 10.3%), and hepatitis C (8, 20.5%). Twenty patients (51.3%) were granted transplant priority status due to severe and irreversible lack of vascular access for dialysis.\u003c/p\u003e\n\u003cp\u003eAll patients had received at least one blood transfusion, and 26 (66.6%) had undergone previous transplantation. Among the 26 female patients, 18 (69.2%) had a history of previous pregnancies.\u003c/p\u003e\n\u003cp\u003eOf the 39 patients included in the deceased donor desensitization protocol, 14 (35.9%) underwent transplantation after a median of 31 months of treatment. The remaining 25 patients (64.1%) did not identify a acceptable donor (negative CDC-XM for both T and B cells) during the observation period of 58.9\u0026nbsp;±\u0026nbsp;22.9 months.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDemographic variables were compared between transplanted patients (Group 1) and those who remained on the WL (Group 2), with no significant differences found in age (42.3\u0026nbsp;±\u0026nbsp;12 vs. 49.9\u0026nbsp;±\u0026nbsp;12 years), gender (female: 71.4% vs. 64%), ethnicity (Caucasian: 64.3% vs. 56%), duration of renal replacement therapy (91\u0026nbsp;±\u0026nbsp;62 vs. 97\u0026nbsp;±\u0026nbsp;72 months), dialysis modality (hemodialysis: 92.9% vs. 92%), or ABO blood group distribution.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere were also no differences in sensitizing events such as prior blood transfusions (100% in both groups) or previous transplantation (71.4% vs. 84%). However, among women, a significantly higher proportion of those who were transplanted had previous pregnancies compared to those who remained on the WL (50% vs. 7%, p \u0026lt; 0.05).\u003c/p\u003e\n\u003cp\u003eThe mean number of IVIg doses administered was 13.87\u0026nbsp;±\u0026nbsp;11.03. At the last evaluation, patients who were transplanted received fewer doses (8\u0026nbsp;±\u0026nbsp;4) than those who remained on the WL (17\u0026nbsp;±\u0026nbsp;12, p = 0.026).\u003c/p\u003e\n\u003cp\u003eImmunological Results\u003c/p\u003e\n\u003cp\u003eTo explore the mechanisms by which IVIg facilitated transplant access, we analyzed anti-HLA antibody profiles separately for class I and class II specificities. The mean panel reactive antibody (PRA) levels at the beginning of desensitization were 78\u0026nbsp;±\u0026nbsp;26 for class I and 74\u0026nbsp;±\u0026nbsp;27 for class II.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSignificant reductions were observed after treatment for both class I PRA (from 78.4\u0026nbsp;±\u0026nbsp;26.0 to 69.5\u0026nbsp;±\u0026nbsp;31.2, p = 0.0074) and class II PRA (from 74.4\u0026nbsp;±\u0026nbsp;27.5 to 61.8 ±\u0026nbsp;36.3, p \u0026lt; 0.005), especially in patients who received a higher number of IVIg infusions (Table 1).\u003c/p\u003e\n\u003cp\u003eThe impact of the desensitization on the MFI in transplanted and in not transplanted patients is shown in the table 2.\u003c/p\u003e\n\u003cp\u003eWhen assessing the strength of anti-HLA antibodies by mean fluorescence intensity (MFI), a significant reduction was seen in category A antibodies (MFI\u0026nbsp;≤ 1500), which decreased from 10.7 to 3.7 (p \u0026lt; 0.005), and in category D antibodies (MFI \u0026gt; 5000), which declined from 16.9 to 13.2 (p \u0026lt; 0.005). No significant changes were observed in categories B, C, or E.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt the time of transplantation, donor-specific antibodies (DSA) against HLA-A, -B, and -DR loci were evaluated. The mean HLA A, B, DR mismatch was 3.78\u0026nbsp;±\u0026nbsp;1.88. One patient received a fully matched graft (zero A, B, DR mismatches).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAmong the 14 transplanted patients, 9 (64.3%) had detectable DSA at transplantation. In this subgroup, the mean MFI of immunodominant DSA (iDSA) decreased significantly following desensitization (from 3615\u0026nbsp;±\u0026nbsp;1514 to 2020\u0026nbsp;±\u0026nbsp;1299, p \u0026lt; 0.05) (Figure 1). One patient experienced an increase in anti-DR1 MFI from \u0026lt;1000 to 4000, although this remained below the threshold for clinical concern at the start of the protocol.\u003c/p\u003e\n\u003cp\u003eClinical Outcomes\u003c/p\u003e\n\u003cp\u003eThe transplant rate among desensitized patients was 35.9% over a mean follow-up of 58.9\u0026nbsp;±\u0026nbsp;22.9 months. These patients had been on the WL for a mean of 91\u0026nbsp;±\u0026nbsp;60 months (median 71 months, range 27–242 months). The median time from desensitization to transplantation was 19 months (range 17.5–50 months). Among the ten priority patients who underwent transplantation, the duration of dialysis significantly decreased following desensitization, reducing from 87.2\u0026nbsp;±\u0026nbsp;48.5 months to 18.3\u0026nbsp;±\u0026nbsp;7.9 months (p \u0026lt; 0.004). In contrast, for non-priority patients, the decrease did not reach statistical significance, with dialysis duration changing from 81.2\u0026nbsp;±\u0026nbsp;74.2 months to 37.0\u0026nbsp;±\u0026nbsp;19.1 months (p = 0.29).\u003c/p\u003e\n\u003cp\u003eTransplant Outcomes\u003c/p\u003e\n\u003cp\u003eThe mean follow-up time after transplantation was 54.6\u0026nbsp;±\u0026nbsp;20.7 months. Overall survival did not differ significantly between transplanted and non-transplanted patients (71.4% vs. 77%, p = 0.32). The 3-year patient survival was 78.6%, and the 3-year death-censored graft survival was 76.4%. The most common cause of graft loss was patient death, primarily from infections often related to dialysis access. BK virus nephropathy was the second leading cause of graft failure.\u003c/p\u003e\n\u003cp\u003eDonor kidneys had a mean cold ischemia time of 28.2\u0026nbsp;±\u0026nbsp;3.8 hours. Delayed graft function, defined as the need for dialysis within the first post-transplant week, occurred in 85.7% of patients, which is usually 60-70% in Brazil. No machine perfusion was used. The mean donor age was 45 years, and 64% of donors died from stroke.\u003c/p\u003e\n\u003cp\u003eThe rate of antibody-mediated rejection (ABMR) was 35.7%, with all cases occurring within the first post-transplant year. These episodes were treated with plasma exchange, rituximab, and IVIg. Eight of the nine patients with ABMR had DSA at the time of transplantation. ABMR occurred only in patients with two or more DSA (p = 0.02), while none of the patients with only one DSA developed rejection. ABMR did not impact long-term graft function (eGFR: 53.8\u0026nbsp;±\u0026nbsp;26.6 vs. 36.1\u0026nbsp;±\u0026nbsp;22.6 mL/min/1.73 m², p = 0.21) or graft survival (40% vs. 33.3%, p = 0.81). Only one patient experienced graft loss due to chronic ABMR after 51 months.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis study describes the outcomes of a desensitization protocol using intravenous immunoglobulin (IVIg) as monotherapy in highly sensitized patients with persistently positive CDC crossmatches while awaiting kidney transplantation. To our knowledge, this is the largest single-center Brazilian cohort to report on IVIg monotherapy in a public health system setting, reflecting a real-world strategy implemented in the absence of adjunct therapies such as rituximab, plasmapheresis, or bortezomib.\u003c/p\u003e\n\u003cp\u003eOur results demonstrate that IVIg was safe and moderately effective, allowing 35.9% of patients to undergo deceased donor transplantation (50% in patints on priority) with favorable short-to medium-term graft and patient outcomes. Importantly, IVIg was well tolerated, and no increase in infection or thromboembolic events were observed, aligning with existing literature that supports the safety profile of IVIg in transplantation [6,7].\u003c/p\u003e\n\u003cp\u003eA notable strength of this protocol lies in its accessibility and feasibility within the constraints of a public health system. In contrast to more complex and risky DS regimens employed in North America and Europe - which often involve combinations of plasmapheresis, rituximab, proteasome inhibitors, or complement blockers - our approach utilized a widely available immunomodulatory agent, delivering measurable immunological benefit in an underserved population.\u003c/p\u003e\n\u003cp\u003eFrom an immunological standpoint, we observed a reduction in PRA levels and anti-HLA antibody intensity in several patients, especially among those who subsequently underwent transplantation. Although the protocol did not universally eliminate donor-specific antibodies (DSAs), the downregulation of immune activation may have contributed to to achieving negative CM outcomes over time. This aligns with the proposed mechanisms of IVIg, including Fc receptor blockade, cytokine modulation, and expansion of regulatory T cells [8,9].\u003c/p\u003e\n\u003cp\u003eDespite these encouraging findings, the overall transplantation rate remained below 40%, underscoring the persistent challenges faced by highly sensitized candidates, since there was no special allocation systems for sensitized patients in our country. Notably, the median desensitization period exceeded two years, highlighting the need for more proactive and individualized strategies. In this regard, future integration of virtual crossmatch platforms and refined epitope-based matching could enhance access to acceptable donors and optimize the timing of transplantation.\u003c/p\u003e\n\u003cp\u003eOne particularly original implication of our study is the potential repurposing of IVIg not only as a desensitization tool but also as a bridge strategy—maintaining sensitized patients in a\u0026nbsp;“transplant-ready” immunological state until access to a compatible donor is achieved. Also, decreasing anti-HLA ab in these patients, may help us to find faster a living donor when on paired exchange programs.This concept may be especially relevant in low- and middle-income countries, where access to biologics remains limited and resource optimization is essential.\u003c/p\u003e\n\u003cp\u003eIt is also important to consider the psychological and systemic impact of prolonged time on dialysis, which contribute to increased mortality and withdrawal from the waitlist. By demonstrating that desensitization with IVIg can modify immunological barriers and allow transplantation in a subset of patients, our study supports the implementation of easy, scalable strategies that may promote equity in transplant access.\u003c/p\u003e\n\u003cp\u003eLimitations\u003c/p\u003e\n\u003cp\u003eThis study is limited by its retrospective nature and small sample size. Additionally, cPRA and detailed DSA quantification were not always available at baseline. The lack of a control group limits comparisons with untreated sensitized patients, although our findings provide valuable insight into outcomes in a previously excluded population.\u003c/p\u003e\n\u003cp\u003eFuture Directions\u003c/p\u003e\n\u003cp\u003eIt is essential to emphasize that, for highly sensitized patients, multiple public policies should be implemented to increase their access to transplantation: expanding the donor pool, prioritizing equitable access compared to non-sensitized patients, implementing permissive antigen programs, and establishing paired donation programs. Nevertheless, highly sensitized patients in many countries still do not have these policies available.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDespite the implementation of these measures, many sensitized patients will still require desensitization procedures. Future studies should evaluate the addition of cost-effective immunomodulatory agents—such as low-dose rituximab or IL-6 inhibitors—in combination with IVIg, especially in patients with persistent high-strength DSAs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMoreover, incorporating personalized immunological risk stratification using artificial intelligence and machine learning may enable tailored desensitization protocols that maximize efficacy while minimizing toxicity and cost.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHighly Sensitized\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIVIg\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eIntravenous Immunoglobulin\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDesensitization\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCDC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eXM-Complement-Dependent Cytotoxicity Crossmatches\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ecPRA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCalculated Panel-Reactive Antibodies\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDSA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDonor-Specific Antibody\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eABMR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAntibody-Mediated Rejection\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCKD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eChronic Kidney Disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRRT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRenal Replacement Therapy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSES\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSP-S\u0026atilde;o Paulo State Health Department\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMFI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMean Fluorescence Intensity\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCMV\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCytomegalovirus\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eiDSA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eImmunodominant Donor-Specific Antibodies\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eeGFR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eEstimated Glomerular Filtration Rate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate:\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the principles of the Declaration of Helsinki. The study was approved by the Ethics Committee for the Analysis of Research Projects (CAPPesq) of the Hospital das Clínicas of the Faculty of Medicine of the University of São Paulo under number 1.629.278, on July 8, 2016.\u003c/p\u003e\n\u003cp\u003eConsent for publication: not applicable.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials:\u003c/p\u003e\n\u003cp\u003eThe data and materials generated during this study are available to the research community under the following conditions:\u003c/p\u003e\n\u003cp\u003eData Sharing Policy: The datasets supporting the findings of this study are available on request. Data access: Interested researchers can obtain access to the data by contacting the corresponding author.\u003c/p\u003e\n\u003cp\u003eContact Information: For further inquiries regarding data or materials, please contact:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJenaine Oliveira Paixão\u003c/p\u003e\n\u003cp\u003eEmail address: [email protected]\u003c/p\u003e\n\u003cp\u003eAffiliation: Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil.\u003c/p\u003e\n\u003cp\u003eCompeting Interests:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eI declare that the authors have no competing interests as defined by BMC, or other interests that might be perceived to influence the results and/or discussion reported in this paper.\u003c/p\u003e\n\u003cp\u003eFunding: no funding.\u003c/p\u003e\n\u003cp\u003eAuthors’ contributions:\u003c/p\u003e\n\u003cp\u003eJ.P. wrote the main manuscript text and performed the data analysis.\u003c/p\u003e\n\u003cp\u003eG.B., N.P., and H.R. conducted the immunological tests.\u003c/p\u003e\n\u003cp\u003eL.U. and F.A. assisted with data collection from electronic medical records.\u003c/p\u003e\n\u003cp\u003eM.C. and E.D. supervised the manuscript writing and data analysis.\u003c/p\u003e\n\u003cp\u003eAll authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eWe would like to thank the Clinical Research Group of the Renal Transplantation Service at Hospital das Clínicas, University of São Paulo, for their valuable contributions to this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSociedade Brasileira de Nefrologia. Censo Brasileiro de Di\u0026aacute;lise 2024 [Internet]. Available at: www.sbn.org.br. Accessed on: March 2, 2025.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePort FK, Wolfe RA, Mauger EA, Berling DP, Jiang K. Comparison of survival probabilities for dialysis patient vs cadaveric renal transplant recipients. JAMA. 1993;270(11):1339\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAssocia\u0026ccedil;\u0026atilde;o Brasileira de Transplantes de \u0026Oacute;rg\u0026atilde;os. Registro Brasileiro de Transplantes 2020 [Internet]. Dispon\u0026iacute;vel em: www.abto.org.br. Acesso em: 12 out. 2020.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePerosa M, Ferreira GF, Modelli LG, et al. Disparity in the access to kidney transplantation for sensitized patients in the state of Sao Paulo-Brazil. Transpl Immunol. 2021;68:101441.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSis B, Mengel M, Haas M, et al. Banff '09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups. Am J Transpl. 2010;10(3):464\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJordan SC, Tyan D, Stablein D, et al. Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial. J Am Soc Nephrol. 2004;15(12):3256\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJordan SC, Vo AA. Desensitization offers hope to highly HLA-sensitized patients for a longer life expectancy after incompatible kidney transplant. Am J Kidney Dis. 2012;59(5):758\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJordan SC, Vo AA, Peng A, Toyoda M, Tyan D. Intravenous gamma globulin (IVIG): a novel approach to improve transplant rates and outcomes in highly HLA-sensitized patients. Am J Transpl. 2006;6(3):459\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSethi S, Choi J, Toyoda M, Vo AA, Peng A, Jordan SC. Desensitization: overcoming the immunologic barriers to transplantation. J Immunol Res. 2017; 2017:6804678.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJordan SC, Vo A, Bunnapradist S, et al. Intravenous immune globulin treatment inhibits crossmatch positivity and allows for successful transplantation of incompatible organs in living-donor and cadaver recipients. Transplantation. 2003;76(4):631\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGlotz D, Antoine C, Julia P, et al. Desensitization and subsequent kidney transplantation of patients using intravenous immunoglobulins (IVIg). Am J Transpl. 2002;2(8):758\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJordan SC, Cunningham-Rundles C, McEwan R. Utility of intravenous gammaglobulin in kidney transplantation: efficacy, safety, and cost implications. Am J Transpl. 2003;3(6):653\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMontgomery RA, Lonze BE, King KE, et al. Desensitization in HLA-incompatible kidney recipients and survival. N Engl J Med. 2011;365(4):318\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZachary AA, Lucas DP, Montgomery RA, Leffell MS. Rituximab prevents an anamnestic response in patients with cryptic sensitization to HLA. Transplantation. 2013;95(4):701\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVo AA, Lukovsky M, Toyoda M, et al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Engl J Med. 2008;359(3):242\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVo AA, Choi J, Cisneros K, et al. Benefits of rituximab combined with intravenous immunoglobulin for desensitization in kidney transplant recipients. Transplantation. 2014;98(3):312\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVo AA, Peng A, Toyoda M, et al. Use of intravenous immune globulin and rituximab for desensitization of highly HLA-sensitized patients awaiting kidney transplantation. Transplantation. 2010;89(9):1095\u0026ndash;102.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWoodle ES, Shields AR, Ejaz NS, et al. Prospective iterative trial of proteasome inhibitor-based desensitization. Am J Transpl. 2015;15(1):101\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJeong JC, Jambaldorj E, Kwon HY, et al. Desensitization using bortezomib and high-dose immunoglobulin increases rate of deceased donor kidney transplantation. Med (Baltim). 2016;95(5):e2635.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVo AA, Choi J, Kim I, et al. A phase I/II trial of the interleukin-6 receptor-specific humanized monoclonal antibody (tocilizumab) plus intravenous immunoglobulin in difficult-to-desensitize patients. Transplantation. 2015;99(11):2356\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJordan SC, Lorant T, Kjellman C, et al. IgG endopeptidase in highly sensitized patients undergoing transplantation. N Engl J Med. 2017;377(5):442\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchwartz J, Winters JL, Padmanabhan A, et al. Guidelines on the use of therapeutic apheresis in clinical practice\u0026mdash;evidence-based approach from the writing committee of the American Society for Apheresis: the sixth special issue. J Clin Apher. 2013;28(3):145\u0026ndash;284.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMontgomery RA. Renal transplantation across HLA and ABO antibody barriers: integrating paired donation into desensitization protocols. Am J Transpl. 2010;10(3):449\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDuquesnoy RJ. The antibody response to an HLA mismatch: a model for no self-discrimination in relation to HLA epitope immunogenicity. Int J Immunogenet. 2012;39(1):1\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHeidt S, Haasnoot GW, Witvliet MD, Claas FHJ. Kidney allocation based on proven acceptable antigens results in superior graft survival in highly sensitized patients. Kidney Int. 2018;93(2):491\u0026ndash;500.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUnited Network for Organ Sharing (UNOS). Kidney Allocation System (KAS) [Internet]. Dispon\u0026iacute;vel em: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://optn.transplant.hrsa.gov/media/1178/kas_report_06-2015.pdf\u003c/span\u003e\u003cspan address=\"https://optn.transplant.hrsa.gov/media/1178/kas_report_06-2015.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Acesso em: 18 mar 2018.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUnited Network for Organ Sharing (UNOS). OPTN policies [Internet]. Dispon\u0026iacute;vel em: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf#nameddest=Policy_08\u003c/span\u003e\u003cspan address=\"https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf#nameddest=Policy_08\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Acesso em: 18 Mar. 2018.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBrasil. mar. Lei n\u0026ordm; 9.434, de 4 de fevereiro de 1997. [Internet]. Dispon\u0026iacute;vel em: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.saude.pr.gov.br/arquivos/File/centraldetransplantes/Lei9434.pdf\u003c/span\u003e\u003cspan address=\"http://www.saude.pr.gov.br/arquivos/File/centraldetransplantes/Lei9434.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Acesso em: 18 2018.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUlisses LRS, Paix\u0026atilde;o JO, Agena F, et al. Desensitization using IVIG alone for living-donor kidney transplant: impact on donor-specific antibodies. J Bras Nefrol. 2022;44(4):527\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHoup JA, Schillinger KP, Eckstein AJ, et al. Casting a smaller net into a bigger donor pool: a single center\u0026rsquo;s experience with the new kidney allocation system. Hum Immunol. 2017;78(1):49\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlachkar M, Lonze BE, Zachary AA, et al. Infusion of high-dose intravenous immunoglobulin fails to lower the strength of human leukocyte antigen antibodies in highly sensitized patients. Transplantation. 2012;94(2):165\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJordan SC, Vo A, Bunnapradist S, et al. Intravenous immune globulin treatment inhibits crossmatch positivity and allows for successful transplantation of incompatible organs in living-donor and cadaver recipients. Transplantation. 2003;76(4):631\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNair V, Sawinski D, Akalin E, et al. Effect of high-dose intravenous immunoglobulin on anti-HLA antibodies in sensitized kidney transplant candidates. Clin Transpl. 2012;26(3):E261\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLefaucheur C, Loupy A, Hill GS, et al. Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation. J Am Soc Nephrol. 2010;21(8):1398\u0026ndash;406.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLefaucheur C, Viglietti D, Bentlejewski C, et al. IgG donor-specific anti-HLA antibody subclasses and kidney allograft antibody-mediated injury. J Am Soc Nephrol. 2016;27(1):293\u0026ndash;304.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVo AA, Aubert O, Haas M, et al. Clinical relevance of posttransplant DSAs in patients receiving desensitization for HLA-incompatible kidney transplantation. Transplantation. 2019;103(12):2666\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDavid-Neto E, Souza PS, Panajotopoulos N, et al. The impact of pretransplant donor-specific antibodies on graft outcome in renal transplantation: a six-year follow-up study. Clin (Sao Paulo). 2012;67(4):355\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAguirre AR, Souza PS, Agena F, et al. Vale a pena transplantar o paciente sensibilizado? Uma an\u0026aacute;lise retrospectiva unic\u0026ecirc;ntrica de 1002 transplantes consecutivos. J Bras Transpl. 2016;19(3):60\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOrandi BJ, Luo X, Massie AB, et al. Survival benefit with kidney transplants from HLA-incompatible live donors. N Engl J Med. 2016;374(10):940\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOrandi BJ, Garonzik-Wang JM, Massie AB, et al. Quantifying the risk of incompatible kidney transplantation: a multicenter study. Am J Transpl. 2014;14(7):1573\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAssocia\u0026ccedil;\u0026atilde;o Brasileira de Transplantes de \u0026Oacute;rg\u0026atilde;os. Registro Brasileiro de Transplantes 2019 [Internet]. Dispon\u0026iacute;vel em: www.abto.org.br. Acesso em: 12 mar 2020.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Sensitization, Kidney Transplantation, Intravenous Immunoglobulin, Anti-HLA Antibodies, Desensitization","lastPublishedDoi":"10.21203/rs.3.rs-6856706/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6856706/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e\u003cp\u003eHighly sensitized (HS) patients awaiting kidney transplantation often face prolonged waiting times and increased mortality, especially in regions lacking structured organ allocation directed to these patients or desensitization strategies. This study evaluated the efficacy and safety of intravenous immunoglobulin (IVIg) monotherapy for desensitization (DS) in HS patients awaiting deceased donor kidney transplantation.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e\u003cp\u003eThirty-nine sensitized patients on the deceased donor waiting list with \u0026gt;\u0026thinsp;5 positive T/B-cell complement-dependent cytotoxicity crossmatches (CDC-XM) received IVIg at 2 g/kg/month. Patients were followed for a mean of 58.9\u0026thinsp;\u0026plusmn;\u0026thinsp;22.9 months. Outcomes included transplantation rates, changes in calculated panel-reactive antibodies (cPRA), donor-specific antibody (DSA) levels, and post-transplant survival.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e\u003cp\u003eFourteen patients (35.9%) underwent transplantation, with 64.3% exhibiting detectable DSA. Post-DS waiting time on the WL decreased significantly (75\u0026thinsp;\u0026plusmn;\u0026thinsp;41 vs. 20\u0026thinsp;\u0026plusmn;\u0026thinsp;11 months; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). IVIg therapy significantly reduced class I cPRA (p\u0026thinsp;=\u0026thinsp;0.0074), class II cPRA (p\u0026thinsp;=\u0026thinsp;0.04), total anti-HLA antibodies, and immunodominant DSA levels in transplanted patients (p\u0026thinsp;=\u0026thinsp;0.03). Transplantation rates were higher among patients prioritized due to dialysis access failure (70% vs. 21%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.003). Three-year patient survival was 78.6%, and death-censored graft survival was 76.4%. Antibody-mediated rejection (ABMR) occurred only in recipients with \u0026gt;\u0026thinsp;1 DSA at the time of transplantation (p\u0026thinsp;=\u0026thinsp;0.02). No serious IVIg-related adverse events were observed.\u003c/p\u003e\u003ch2\u003eConclusions:\u003c/h2\u003e\u003cp\u003eIVIg monotherapy is a safe and effective desensitization strategy for HS patients, significantly reducing anti-HLA antibodies and time on WL, thereby facilitating access to deceased donor kidney transplantation.\u003c/p\u003e","manuscriptTitle":"IVIg Monotherapy for Desensitization in Highly Sensitized Kidney Transplant Candidates: Efficacy and Long-Term Outcomes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-08 13:11:50","doi":"10.21203/rs.3.rs-6856706/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":"662cddaf-4b87-4f46-9166-adc5906c5935","owner":[],"postedDate":"September 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-12T18:53:35+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-08 13:11:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6856706","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6856706","identity":"rs-6856706","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}