Do recipient HLA alleles influence HLA Antibody Production in End- stage renal disease (ESRD)? A Scoping Review

Do recipient HLA alleles influence HLA Antibody Production in End- stage renal disease (ESRD)? 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A Scoping Review Ira Puspitawati, Nyoman Kertia, Teguh Triyono, Anastasia Evi Handayaningsih, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7621059/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background Kidney transplantation is the primary choice of renal replacement therapy for patients with end-stage renal disease (ESRD). However, the development of anti-human leukocyte antigen (HLA) antibodies remains a significant immunological barrier to successful transplantation. While sensitization is often linked to previous exposure to alloantigens through pregnancy, transfusion, or prior transplants, the impact of the recipient’s HLA alleles on antibody formation has not been systematically reviewed. Methods A scoping review was conducted in accordance with PRISMA-ScR guidelines. A thorough search of major databases identified 469 studies. After removing duplicates and irrelevant records, 8 observational studies met the inclusion criteria and were included in the qualitative synthesis. The review examined the links between specific HLA alleles and the development of anti-HLA antibodies in ESRD patients. Results The HLA-DR alleles are believed to predict the strength of the alloimmune response, especially HLA-DRB1*01:01, -DRB1*14:01, -DRB1*15:01, -DR4, -DR5, -DR6, -DR52, and -DR53. Additional risk alleles include HLA-A3, -A36, -A66, -B18, and -B42. Conversely, DRB1*07:01, DRB1*11:01, -DRB1*13:01, and -B60 are identified as potentially protective against sensitization. Some studies also report that multi-locus haplotypes (e.g., DR1-B35-A2, DR7-B57-A1) have a stronger predictive value for sensitization risk than individual alleles. One study conducted in China found no significant differences in HLA allele distribution between sensitized and non-sensitized patients, suggesting potential population-based variation. Conclusions This review provides initial evidence that certain HLA alleles, especially at the HLA-DR locus, may influence the risk of anti-HLA antibody development in ESRD patients. Identifying both immunogenic and protective HLA alleles or haplotypes could enable more personalized immunological risk assessments for transplant candidates. Larger, prospective studies across diverse ethnic populations are required to validate these results and enhance transplant outcomes. HLA typing HLA antibodies End-stage renal disease Kidney transplantation Panel reactive antibodies Figures Figure 1 BACKGROUND Kidney transplantation is the primary choice of renal replacement therapy in patients with End-stage renal disease (ESRD). The presence of preexisting antibodies to HLA alloantigens presents a significant challenge in kidney transplantation, as they are strongly linked to hyperacute and acute rejection episodes [ 1 , 2 ]. Sensitization, which triggers the production of anti-HLA antibodies, can develop progressively in patient with the history of pregnancy, blood transfusion, or prior transplantation [ 3 , 4 , 5 , 6 ]. Interestingly, not everyone exposed to non-self HLA antigens develops anti-HLA antibodies. Many multiparous women, transfusion recipients, or transplant patients remain non-sensitized, indicating that other factors, such as immune responsiveness, may affect the likelihood of producing anti-HLA antibodies [ 7 ]. An often overlooked aspect is how the recipient’s HLA genotype influences the immune response. Recent research indicates that the immunogenicity of an HLA mismatch should be viewed in relation to the patient's HLA phenotype, meaning the same donor mismatch may produce varying effects depending on the recipient's HLA types [ 8 ]. The HLA type can influence antigen presentation and T-cell activation. Recipient HLA molecules participate in the indirect allo-recognition pathway, where recipient T cells identify donor-derived peptides presented by self HLA class II molecules on antigen-presenting cells. Reactivity to these donor-derived peptides, especially those in hypervariable regions of class II molecules, has been associated with acute rejection episodes and the development of chronic rejection [ 9 , 10 ]. Evidences that documented the relationship between recipient HLA typing and the development of anti-HLA antibodies in ESRD patients hasn’t been systematically reviewed. This scoping review aims to fill that gap by identifying HLA alleles that may increase or decrease the risk of sensitization, providing valuable insights into how immunogenetic factors influence the immunobiology of transplantation in ESRD patients. Rationale for conducting a scoping review The relationship between HLA alleles or haplotypes and the development of anti-HLA antibodies in patients with end-stage renal disease (ESRD) or those awaiting kidney transplantation has been extensively studied. However, the existing literature on this subject shows considerable heterogeneity. Research has been carried out across diverse populations, including different ethnic groups and geographical regions, with varying exposures, from specific HLA alleles to broader haplotypes. The outcomes measured also differ, covering several types of anti-HLA antibodies such as panel reactive antibodies (PRA) and donor-specific antibodies (DSA). This extensive variability in populations, exposures, outcomes, study designs, and laboratory methods makes it difficult to synthesize the evidence systematically or to conduct a meta-analysis. Therefore, a scoping review were conducted to comprehensively map the existing literature, identify knowledge gaps, and clarify the breadth and nature of the available evidence. The findings of this scoping review will provide a foundation for future systematic reviews, targeted meta-analyses, or primary research aimed at specific subtopics within this complex field. Objectives To investigate the reported connections between specific HLA alleles and the production of anti-HLA antibodies in ESRD patients. METHODS Three databases — Scopus, PubMed, and ScienceDirect — were searched to identify relevant articles. The systematic search was conducted from March to June 2025. The studies included end-stage renal disease patients and focused on the relationships between HLA alleles and HLA antibody production in these patients. Synthesis involved grouping based on thematic analysis to provide detailed results. Risk of Bias (RoB) assessment was not performed, as this scoping review aimed to map existing evidence on HLA genotypes and antibody production in ESRD rather than evaluate the quality of individual studies. This approach aligns with current guidance for scoping review methodology, adhering to PRISMA-ScR guidelines. Eligibility criteria We include studies examining the relationship between Human Leukocyte Antigen (HLA) alleles and HLA antibody production in patients with end-stage renal disease (ESRD). The inclusion criteria are observational studies—including cross-sectional, case-control, prospective, and retrospective cohort studies—that investigate the link between HLA polymorphisms and HLA antibody production in ESRD patients. We exclude systematic reviews and meta-analyses, case reports/series, reviews, editorials, letters, opinion papers, conference abstracts lacking complete data, animal studies, and non-English publications. Identification of relevant studies We searched the following electronic databases: PubMed, Scopus, ScienceDirect. Study selection Two authors independently reviewed the titles and abstracts of the identified records. We used the web-based application Rayyan ( https://rayyan.qcri.org/welcome ) for screening. Any disagreements between the authors were discussed, and if disagreements persist, third author were invited to find the resolution. We retrieved the full texts of all potentially eligible studies and assess their eligibility independently based on our predefined criteria. We also documented the reasons if a full text were excluded. Extractions A data extraction sheet was created based on the review objectives and piloted with a small set of three included studies to ensure clarity and consistency. Two authors independently collected the following information into a pilot-tested data extraction sheet: study characteristics including study design, country where the study was conducted, and the features of the populations targeted by the intervention (age, gender, ethnicity). We also record exposure details (types, examination methods), comparison information (if applicable), follow-up duration (if applicable), outcomes (including outcome measures and time-points of assessment), and disclosure of conflicts of interest (COIs). Summary and reporting of the results We categorized data based on the identified exposure categories and the targeted population. The exposure classification will be based on the types of Human Leucocyte Antigen (HLA) typing of patients with end-stage renal disease. We specified which outcomes were assessed and proceed with the analysis steps, including descriptive numerical summaries and qualitative thematic analysis. We present the results and generate the outcome related to the overall purpose or research question. RESULTS A comprehensive literature review initially identified 469 articles. After removing 7 duplicates and excluding 335 irrelevant records, 127 titles and abstracts were screened for relevance. Of these, 95 were excluded for lacking a clear connection between HLA typing and antibody production. Full-text assessments were then performed on the remaining 34 articles, leading to the inclusion of 8 studies that met the criteria for qualitative synthesis. The remaining 26 articles were excluded because they did not align with the specific objectives of the scoping review. The selection process is illustrated in Fig. 1 . The literature search revealed results on the associations between HLA typing and HLA antibody production in patients with end-stage renal disease, summarized in Table 1 . The most frequently reported association was between HLA-DR and antibody production (n = 7), followed by links involving HLA-A and HLA-B (n = 2). Several studies identified antibodies targeting specific HLA antigens, including anti-HLA-A2, A10, A11, A12, A28, BW, B5, B7, B8, B122, B166, and B35. These studies were reported from Brazil, the United Kingdom, the USA, Turkey, the Netherlands, and China. All of these studies were observational [ 11 , 12 , 7 , 13 , 14 , 15 , 16 , 17 ]. Three studies showed that HLA-DR is a significant risk factor for antibody development, Dankers et al., 2004; Fuller et al., 1999; and Papassavas et al., 2002 [ 12 , 13 , 15 ]. HLA-DRB1*01:01 and -DRB1*14:01 were notably linked to higher production of antibodies against common epitopes on HLA-A2 (65–66GK and − 62G), while -DRB1*15:01 was associated with antibodies targeting a private epitope (74H) on the same antigen [ 12 ]. Table 1 Summary Findings Author (Year) Study site Subjects Exposure Outcome Results Saito PK, Yamakawa RH, Aparecida EP, Silva Junior WV, Borelli SD (2014) Brazil 269 patients with chronic renal failure (CRF), renal transplant candidates. The HLA-A2,-A24,-A01,-B44, -B35,-B15, -DRB1*11, -DRB1*04, -DRB1*03 Panel reactive antibody (PRA) The most frequent alleles in CRF patients were the HLA-A02, -A24, -A01, -B44, -B35, -B15, -DRB1*11, -DRB1*04 and -DRB1*03. This study didn't differentiate the frequency of HLA alleles in PRA positive or PRA negative groups. Karahan GE, Kekik C, Oguz FS, Onal AE, Bakkaloğlu H, Çalişkan H, (2010) Turkey 642 ESRD patients preparing for the first transplantation HLA-A3,-B18,-B49, -A66,-B49,-DRB1*07 Panel reactive antibody (PRA) HLA-A3 ( p = 0.018), HLA-A66 ( p = 0.04), HLA-B18 ( p = 0.006), HLA B-49 (p = 0,005) were significantly high in PRA-positive group. HLA-DRB1*07 ( p = 0.02) was significantly high in patients who did not develop any anti-HLA antibodies Papassavas AC, Barnardo MC, Bunce M, Welsh KI, (2002) UK 217 renal transplant patients who received an HLA-A2–mismatched renal graft. HLA-DRB1*01:01,-DRB1*03:01, -DRB1*04:01, -DRB1*07:01, -DRB1*11:01, -DRB1*13:01, -DRB1*14:01, -DRB1*15:01 Production of antibodies against the HLA-A2 The HLA-DRB1-*01:01, -DRB1*-14:01 and DRB1-*1501 alleles had positive correlation with the production of HLA class I–specific antibodies against the HLA-A2 Dankers MK, Roelen DL, Nagelkerke NJ, de Lange P, Persijn GG, Doxiadis II, et al (2004) Netherlands All HLA-DR homozygous Dutch renal transplants patients, registered on the Eurotransplant waiting list between 1967 and 2000 (n = 1,317 patients). HLA-DR4,-DR6, -DR52, -DR5, -DR7, -DR52, -DR3, -DR4, -DR53 HLA Antibodies production Risk factor alleles were HLA-DR4, -DR5, -DR6, -DR52, -DR53 Protective factor alleles were HLA-DR1, -DR3, -DR7, -DR53 Heise E, Manning C, Thacker L (2001) US 19.440 kidney allograft recipients HLA-B42, -B53,-A10,-A19, -A36; -DR1,-DR4, -DR7, -B8, -B12, -B40, -A1,-A2,-A11 Panel reactive antibody (PRA) Five allelotypes (HLA-B42,-B53, -A10,-19, -A36) were associated with an increased risk of PRA responses. Nine HLA allelotypes (HLA-DR1,-DR4,-DR7; -B8,-B12,-B40; -A1,-A2,-A11) were associated with a significantly reduced risk of sensitization. Fuller TC, Fuller A (1999) US Sera from both solid organ and bone marrow transplant patients were obtained for purposes of panel-reactive HLA antibody (PRA) screening HLA-DRB1*01:01; -DRB1*03:01 Anti HLA BW4 There are at least two human Ir genes, HLA-DRB1*01:01, -DRB1*03:01, that confer a high risk for both humoral allosensitization and renal allograft failure in situations of HLA-Bw4 incompatibility. Fu Q, Wang C, Zeng W, Liu L (2012) China This study included 383 sensitized patients and 1000 unsensitized patients awaiting kidney transplantation from 2001–2010 HLA-A2,-A11,-A24, -A33, -A26; -B46,-A60,-A13,-A75,-A58,-DR9,-DR15,-DR12, -DR4, -DR14 Panel reactive antibody (PRA) The 5 most frequent HLA alleles in the 2 groups were not different between sensitized and non sensitized groups were HLA-A2,-A11,-A24,-A33,-A26; -B46,-A60,-A13,-A75,-A58; -DR9,-DR15,-DR12,-DR4,-DR14. Lu L, Sun Q (2022) Hunan (China) 347 ESRD patients awaiting renal transplantation in Hunan Province from 2015 to 2019 and 309 healthy individuals. HLA-A2, HLA-B38, HLA-B46, HLA-B60 Panel reactive antibody (PRA) HLA-A2, HLA-B38, and HLA-B46 were significantly higher in the PRA-positive group than in the PRA-negative group (p < 0,05), while HLA-B60 was significantly higher in the PRA-negative group (p < 0,005). DISCUSSION Three key studies (Dankers et al., 2004; Fuller et al., 1999; Papassavas et al., 2002) identified HLA-DR as a major risk factor for developing HLA-specific antibodies. Dankers et al. (2004) found specific links between HLA-DR types and antibody responses. They observed that HLA-DR4 was associated with the production of anti-HLA-A3 antibodies (RR = 2.78, p < 0,05). HLA-DR5 was linked to the production of anti-HLA-A11 (RR = 2.78, p < 0,05), anti-HLA-B5 (RR = 2.28, p < 0,05), anti-HLA-B7 (RR = 2.90, p < 0,001), anti-HLA-B8 (RR = 2.76, p < 0,01), and anti-HLA-B12 (RR = 2.82, p < 0,01). HLA-DR6 was associated with the production of anti-HLA-A10 (RR = 2.47, p < 0,01), anti-HLA-A11 (RR = 2.89, p < 0.01), anti-HLA-A19 (RR = 2.43, p < 0.01), and anti-HLA-B35 (RR = 2.89, p < 0.05). Finally, HLA-DR52 was linked to the production of anti-HLA-A10 and anti-HLA-A1 (RR = 1.76, p < 0.05; RR = 2.42, p < 0.02, respectively) [ 15 ]. Papassavas et al. (2002) found that the HLA-DRB1-*01:01 and -*14:01 alleles had a positive correlation with the production of HLA class I–specific antibodies against the shared HLA-A2 epitopes 65–66GK and 62G, respectively. Conversely, the HLA-DRB1-*1501 allele was positively correlated with the production of antibodies against the private (74H) HLA-A2 epitope [ 12 ]. Fuller et al. (1999) also found associations between HLA-DRB1*01 and *03 and high levels of humoral sensitization, with 73% of patients with anti-HLA-Bw4 antibodies expressing one of these alleles. Saito et al. (2014) identified HLA-DRB1*11, -DRB1*04, and -DRB1*03 as the most common alleles among ESRD cases; however, they did not stratify by PRA positivity [ 11 , 13 ]. Another HLA allele was identified as a risk factor and showed a positive correlation with HLA antibody production. Karahan et al. (2010) found that HLA-A3, -A66, and -B18 were significantly more common in patients who were PRA-positive. There was also a higher prevalence of HLA-B49 within this group, although it did not reach statistical significance [ 14 ]. Heise et al . (2001), in a larger group of 19,440 kidney transplant recipients, demonstrated that HLA-A36, -B42, -A10, and a group consisting of HLA-A19, -A29, -A30, -A31, -A32, -A33, and -A74 were linked to an increased risk of PRA. Logistic regression analysis indicated that HLA-A36 was an independent risk factor, while -A10 showed marginal significance; however, group -B53 and -A19 were not statistically significant [ 7 ]. Fu et al. (2012) found no statistically significant difference in the frequency of the most common HLA types between sensitized and non-sensitized subjects in a study of patients from Guangzhou, China [ 16 ]. Finally, certain HLA alleles may provide protection against sensitization. Karahan et al. (2010) observed that HLA-DRB1*07 was significantly more common in patients who experienced sensitization events without developing anti-HLA antibodies and might have a protective effect [ 14 ]. Papassavas et al. (2002) studied 217 renal transplant patients who received an HLA-A2–mismatched renal graft. They found that five HLA-DRB1 alleles (-DRB1*01:01, -DRB1*07:01, -DRB1*11:01, -DRB1*13:01, and -DRB1*14:01) showed a tendency toward a negative correlation with the development of HLA class I-specific antibodies against the HLA-A2 group of epitopes [ 12 ]. Dankers et al. (2004) also reported that certain HLA alleles might provide a protective effect against developing anti-HLA antibodies. Specifically, the presence of HLA-DR1 and -DR3 was linked to a significantly lower frequency of antibody formation. Individuals with HLA-DR1 showed notably lower rates of antibodies against HLA-A3 (RR = 0.001, p < 0.05) and HLA-A11 (RR = 0.001, p < 0.02) compared to those with other HLA-DR alleles. Similarly, the presence of HLA-DR3 was associated with reduced antibody responses to HLA-A1 (RR = 0.003, p < 0.05), HLA-A3 (RR = 0.28, p < 0.05), HLA-B5 (RR = 0.30, p < 0.02), and HLA-B35 (RR = 0.18, p < 0.05) ) [ 15 ]. A study by Heise et al. (2001) reported findings consistent with those of Papassavas et al. (2002), showing that HLA-DR1 and -DR7 are linked to a decreased risk of sensitization and subsequent production of anti-HLA antibodies [ 7 ]. Other HLA alleles identified as potentially protective included HLA-DR4, -A1, -A2, -A11, -B8, -B12, and -B40. Among these, HLA-DR1, -DR4, -DR7, -B12, -A1, and -A2 were independently associated with protection against sensitization. Additionally, a specific HLA allele—HLA-B60—was identified by Lu, Long et al. as significantly protective against HLA antibody production (RR = 0.475, p = 0.0036) [ 17 ]. Heise et al. (2001) also examined combinations of HLA-DR, -B, and -A alleles to identify haplotypes or genotypes that might be linked to an increased or decreased risk of sensitization. Using stepwise logistic regression analysis, five genotype combinations were identified as providing a protective effect: DR1-B35-A3, DR1-B35-A2, DR1-B44-A2, DR4-B44-A2, and DR7-B57-A1, each with a relative risk (RR) ranging from 0.63 to 0.83, which indicates an average risk reduction of 27%. Conversely, six allele combinations were associated with a higher risk of sensitization: DR2-B44-A2, DR2-B53-A2, DR3-B8-A1, DR3-B42-A30, DR6-B42-A30, and DR11-B53-A30, with RRs between 1.48 and 2.76, reflecting an average 70% increase in risk. These results provide strong evidence that genes within the HLA region, especially at the DR locus, greatly influence the anti-HLA panel reactive antibody (PRA) response. Significantly, the effect of DR-B-A allele combinations on PRA risk was about twice as large as that of individual alleles alone, highlighting the critical role of HLA-DR in affecting sensitization [ 7 ]. It’s important to note that not all studies found statistically significant links. For example, Fu et al. (2012) reported no meaningful difference in HLA allele distribution between sensitized and non-sensitized groups in a Chinese cohort. This indicates that population-specific factors and other non-HLA immune or environmental factors may influence the results [ 16 ]. This scoping review emphasizes the important role of specific HLA alleles and haplotypes in affecting the production of anti-HLA antibodies among patients with end-stage renal disease (ESRD). Most of the included studies showed strong links between HLA-DR alleles and increased sensitization, with additional contributions from HLA-A and HLA-B loci. Notably, the most frequently reported associations involved HLA-DRB1 alleles, highlighting the importance of HLA class II molecules in the immune response. CONCLUSIONS This scoping review highlights the crucial role of recipient HLA typing in influencing the risk of developing anti-HLA antibodies in patients with end-stage renal disease (ESRD). Most of the included studies demonstrated a strong association between specific HLA-DR alleles, such as DRB1*01:01, DRB1*14:01, DRB1*15:01, HLA-DRB1*01:01, -DRB1*03:01, HLA-DR4, -DR5, -DR6, -DR52, -DR53, and increased sensitization. Conversely, several HLA alleles were repeatedly and consistently associated with reduced sensitization risk in some studies, such as HLA-DRB1*07 and HLA-DR1. These findings collectively indicate that individual and combined HLA genotypes significantly influence alloimmune responses in ESRD patients. Recognizing these genetic factors can improve sensitization risk assessment and enable more personalized immunological monitoring in kidney transplants. However, additional research—including prospective, multi-ethnic cohort studies—is necessary to confirm these links and evaluate their impact on clinical practice and transplant outcomes. Declarations Ethics approval and consent to participate Not applicable, as this study is a scoping review of previously published literature and did not involve human participants or animals. Consent for publication Not applicable, as this study is a scoping review based on previously published literature and did not include individual patient data. Competing interests The authors declare that they have no competing interests. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Author Contribution I.P., T.T. developed the study concept, designed the review protocol, and provided overall supervision. I.P., A.E.H. constructed and implemented the search strategy across databases. I.P., T.T and K.H. independently screened titles/abstracts, assessed full texts, and piloted the data extraction sheet. I.P., A.E.H. performed data charting, summarized evidence, and prepared figures/tables. I.P., TT., and N.K. critically interpreted the findings and revised the manuscript for its important intellectual content. All authors read, contributed, and approved the final manuscript. Acknowledgements Not applicable. Data Availability All data generated or analysed during this study are included in this published article. References Kissmeyer-Nielsen F, Olsen S, Petersen VP, Fjeldborg O. Hyperacute rejection of kidney allografts, associated with pre-existing humoral antibodies against donor cells. Lancet. 1966;2:662–5. Halloran PF, Wadgymar A, Ritchie S, Falk J, Solez K, et al. The significance of the anti-class I antibody response. I. Clinical and pathologic features of anti-class I-mediated rejection. Transplantation. 1990;49:85–91. Van Rood JJ, Eernisse JG, Van Leeuwen A. Leucocyte antibodies in sera from pregnant women. Nature. 1958;181:1735–6. Higgins R, Lowe D, Daga S, Hathaway M, Williams C, Lam FT, et al. 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The humoral immune response against an HLA class I allodeterminant correlates with the HLA-DR phenotype of the responder. Transplantation. 1999;68(2):173–82. 10.1097/00007890-199907270-00002 . Karahan GE, Kekik C, Oguz FS, Onal AE, Bakkaloğlu H, Calişkan YK, et al. Association of HLA phenotypes of end-stage renal disease patients preparing for first transplantation with anti-HLA antibody status. Ren Fail. 2010;32(3):380–3. 10.3109/08860221003615803 . Dankers MK, Roelen DL, Nagelkerke NJ, de Lange P, Persijn GG, Doxiadis II, et al. The HLA-DR phenotype of the responder is predictive of humoral response against HLA class I antigens. Hum Immunol. 2004;65(1):13–9. 10.1016/j.humimm.2003.09.017 . Fu Q, Wang C, Zeng W, Liu L. The correlation of HLA allele frequencies and HLA antibodies in sensitized kidney transplantation candidates. Transpl Proc. 2012;44(1):217–21. 10.1016/j.transproceed.2011.12.041 . Lu L, Sun Q. Association of end-stage renal disease with HLA phenotypes and panel reactive antibodies in patients awaiting renal transplantation in Hunan Province. Clin Transpl. 2022;36(3):e24251. 10.1111/ctr.14251 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 16 Oct, 2025 Reviewers invited by journal 16 Oct, 2025 Editor invited by journal 19 Sep, 2025 Editor assigned by journal 17 Sep, 2025 Submission checks completed at journal 17 Sep, 2025 First submitted to journal 15 Sep, 2025 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-7621059","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":535928781,"identity":"b5da19c1-aa85-4cac-8353-1bf12806da91","order_by":0,"name":"Ira 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Mada","correspondingAuthor":false,"prefix":"","firstName":"Nyoman","middleName":"","lastName":"Kertia","suffix":""},{"id":535928783,"identity":"59f9174b-5cd2-48ff-b9aa-59b6f95d5642","order_by":2,"name":"Teguh Triyono","email":"","orcid":"","institution":"Universitas Gadjah Mada","correspondingAuthor":false,"prefix":"","firstName":"Teguh","middleName":"","lastName":"Triyono","suffix":""},{"id":535928784,"identity":"530ded95-5571-4aa8-a71d-3a197c92eb78","order_by":3,"name":"Anastasia Evi Handayaningsih","email":"","orcid":"","institution":"Universitas Gadjah Mada","correspondingAuthor":false,"prefix":"","firstName":"Anastasia","middleName":"Evi","lastName":"Handayaningsih","suffix":""},{"id":535928785,"identity":"b217fe82-b4b8-46b1-ba4a-3b54277da352","order_by":4,"name":"Kristia Hermawan","email":"","orcid":"","institution":"Universitas Gadjah Mada","correspondingAuthor":false,"prefix":"","firstName":"Kristia","middleName":"","lastName":"Hermawan","suffix":""}],"badges":[],"createdAt":"2025-09-15 13:23:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7621059/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7621059/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":94824373,"identity":"9ec21382-97a1-478a-9733-3fcc33a740ee","added_by":"auto","created_at":"2025-10-31 06:48:56","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":96294,"visible":true,"origin":"","legend":"","description":"","filename":"16092025FINManuskripIraPuspitawati.docx","url":"https://assets-eu.researchsquare.com/files/rs-7621059/v1/833af79e38280092c618aee0.docx"},{"id":94760145,"identity":"4db609ec-bd48-47db-a3ab-1394b5b3ff08","added_by":"auto","created_at":"2025-10-30 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11:54:26","extension":"html","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":67831,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7621059/v1/4c8136a6cfd9ed8395643c2f.html"},{"id":94823268,"identity":"d205e400-8de3-482a-81b1-2960c2fdf89c","added_by":"auto","created_at":"2025-10-31 06:46:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":58344,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Scoping Review\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7621059/v1/b7fa693aae72e3f28e3d9633.png"},{"id":94827322,"identity":"df5fdfb1-e160-4f02-8217-8b740469b6ed","added_by":"auto","created_at":"2025-10-31 06:57:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":648899,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7621059/v1/f4d2e957-7e7c-4186-a0a2-5acff8d00e27.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Do recipient HLA alleles influence HLA Antibody Production in End- stage renal disease (ESRD)? A Scoping Review","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eKidney transplantation is the primary choice of renal replacement therapy in patients with End-stage renal disease (ESRD). The presence of preexisting antibodies to HLA alloantigens presents a significant challenge in kidney transplantation, as they are strongly linked to hyperacute and acute rejection episodes [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Sensitization, which triggers the production of anti-HLA antibodies, can develop progressively in patient with the history of pregnancy, blood transfusion, or prior transplantation [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Interestingly, not everyone exposed to non-self HLA antigens develops anti-HLA antibodies. Many multiparous women, transfusion recipients, or transplant patients remain non-sensitized, indicating that other factors, such as immune responsiveness, may affect the likelihood of producing anti-HLA antibodies [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. An often overlooked aspect is how the recipient\u0026rsquo;s HLA genotype influences the immune response. Recent research indicates that the immunogenicity of an HLA mismatch should be viewed in relation to the patient's HLA phenotype, meaning the same donor mismatch may produce varying effects depending on the recipient's HLA types [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe HLA type can influence antigen presentation and T-cell activation. Recipient HLA molecules participate in the indirect allo-recognition pathway, where recipient T cells identify donor-derived peptides presented by self HLA class II molecules on antigen-presenting cells. Reactivity to these donor-derived peptides, especially those in hypervariable regions of class II molecules, has been associated with acute rejection episodes and the development of chronic rejection [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eEvidences that documented the relationship between recipient HLA typing and the development of anti-HLA antibodies in ESRD patients hasn\u0026rsquo;t been systematically reviewed. This scoping review aims to fill that gap by identifying HLA alleles that may increase or decrease the risk of sensitization, providing valuable insights into how immunogenetic factors influence the immunobiology of transplantation in ESRD patients.\u003c/p\u003e\n\u003ch3\u003eRationale for conducting a scoping review\u003c/h3\u003e\n\u003cp\u003eThe relationship between HLA alleles or haplotypes and the development of anti-HLA antibodies in patients with end-stage renal disease (ESRD) or those awaiting kidney transplantation has been extensively studied. However, the existing literature on this subject shows considerable heterogeneity. Research has been carried out across diverse populations, including different ethnic groups and geographical regions, with varying exposures, from specific HLA alleles to broader haplotypes. The outcomes measured also differ, covering several types of anti-HLA antibodies such as panel reactive antibodies (PRA) and donor-specific antibodies (DSA).\u003c/p\u003e\u003cp\u003eThis extensive variability in populations, exposures, outcomes, study designs, and laboratory methods makes it difficult to synthesize the evidence systematically or to conduct a meta-analysis. Therefore, a scoping review were conducted to comprehensively map the existing literature, identify knowledge gaps, and clarify the breadth and nature of the available evidence. The findings of this scoping review will provide a foundation for future systematic reviews, targeted meta-analyses, or primary research aimed at specific subtopics within this complex field.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eObjectives\u003c/h2\u003e\u003cp\u003eTo investigate the reported connections between specific HLA alleles and the production of anti-HLA antibodies in ESRD patients.\u003c/p\u003e\u003c/div\u003e"},{"header":"METHODS","content":"\u003cp\u003eThree databases \u0026mdash; Scopus, PubMed, and ScienceDirect \u0026mdash; were searched to identify relevant articles. The systematic search was conducted from March to June 2025. The studies included end-stage renal disease patients and focused on the relationships between HLA alleles and HLA antibody production in these patients. Synthesis involved grouping based on thematic analysis to provide detailed results. Risk of Bias (RoB) assessment was not performed, as this scoping review aimed to map existing evidence on HLA genotypes and antibody production in ESRD rather than evaluate the quality of individual studies. This approach aligns with current guidance for scoping review methodology, adhering to PRISMA-ScR guidelines.\u003c/p\u003e\n\u003ch3\u003eEligibility criteria\u003c/h3\u003e\n\u003cp\u003eWe include studies examining the relationship between Human Leukocyte Antigen (HLA) alleles and HLA antibody production in patients with end-stage renal disease (ESRD). The inclusion criteria are observational studies\u0026mdash;including cross-sectional, case-control, prospective, and retrospective cohort studies\u0026mdash;that investigate the link between HLA polymorphisms and HLA antibody production in ESRD patients. We exclude systematic reviews and meta-analyses, case reports/series, reviews, editorials, letters, opinion papers, conference abstracts lacking complete data, animal studies, and non-English publications.\u003c/p\u003e\n\u003ch3\u003eIdentification of relevant studies\u003c/h3\u003e\n\u003cp\u003eWe searched the following electronic databases: PubMed, Scopus, ScienceDirect.\u003c/p\u003e\n\u003ch3\u003eStudy selection\u003c/h3\u003e\n\u003cp\u003eTwo authors independently reviewed the titles and abstracts of the identified records. We used the web-based application Rayyan (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://rayyan.qcri.org/welcome\u003c/span\u003e\u003cspan address=\"https://rayyan.qcri.org/welcome\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) for screening. Any disagreements between the authors were discussed, and if disagreements persist, third author were invited to find the resolution. We retrieved the full texts of all potentially eligible studies and assess their eligibility independently based on our predefined criteria. We also documented the reasons if a full text were excluded.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eExtractions\u003c/h2\u003e\u003cp\u003eA data extraction sheet was created based on the review objectives and piloted with a small set of three included studies to ensure clarity and consistency. Two authors independently collected the following information into a pilot-tested data extraction sheet: study characteristics including study design, country where the study was conducted, and the features of the populations targeted by the intervention (age, gender, ethnicity). We also record exposure details (types, examination methods), comparison information (if applicable), follow-up duration (if applicable), outcomes (including outcome measures and time-points of assessment), and disclosure of conflicts of interest (COIs).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eSummary and reporting of the results\u003c/h3\u003e\n\u003cp\u003eWe categorized data based on the identified exposure categories and the targeted population. The exposure classification will be based on the types of Human Leucocyte Antigen (HLA) typing of patients with end-stage renal disease. We specified which outcomes were assessed and proceed with the analysis steps, including descriptive numerical summaries and qualitative thematic analysis. We present the results and generate the outcome related to the overall purpose or research question.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA comprehensive literature review initially identified 469 articles. After removing 7 duplicates and excluding 335 irrelevant records, 127 titles and abstracts were screened for relevance. Of these, 95 were excluded for lacking a clear connection between HLA typing and antibody production. Full-text assessments were then performed on the remaining 34 articles, leading to the inclusion of 8 studies that met the criteria for qualitative synthesis. The remaining 26 articles were excluded because they did not align with the specific objectives of the scoping review. The selection process is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe literature search revealed results on the associations between HLA typing and HLA antibody production in patients with end-stage renal disease, summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The most frequently reported association was between HLA-DR and antibody production (n\u0026thinsp;=\u0026thinsp;7), followed by links involving HLA-A and HLA-B (n\u0026thinsp;=\u0026thinsp;2). Several studies identified antibodies targeting specific HLA antigens, including anti-HLA-A2, A10, A11, A12, A28, BW, B5, B7, B8, B122, B166, and B35.\u003c/p\u003e\u003cp\u003eThese studies were reported from Brazil, the United Kingdom, the USA, Turkey, the Netherlands, and China. All of these studies were observational [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThree studies showed that HLA-DR is a significant risk factor for antibody development, Dankers et al., 2004; Fuller et al., 1999; and Papassavas et al., 2002 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. HLA-DRB1*01:01 and -DRB1*14:01 were notably linked to higher production of antibodies against common epitopes on HLA-A2 (65\u0026ndash;66GK and \u0026minus;\u0026thinsp;62G), while -DRB1*15:01 was associated with antibodies targeting a private epitope (74H) on the same antigen [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSummary Findings\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAuthor (Year)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eStudy site\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSubjects\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExposure\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eOutcome\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eResults\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSaito PK, Yamakawa RH, Aparecida EP, Silva\u003c/p\u003e\u003cp\u003eJunior WV, Borelli SD (2014)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBrazil\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e269 patients with chronic renal failure (CRF), renal transplant candidates.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eThe HLA-A2,-A24,-A01,-B44, -B35,-B15, -DRB1*11, -DRB1*04, -DRB1*03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePanel reactive antibody (PRA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eThe most frequent alleles in CRF patients were the HLA-A02, -A24, -A01,\u003c/p\u003e\u003cp\u003e-B44, -B35, -B15, -DRB1*11, -DRB1*04 and -DRB1*03.\u003c/p\u003e\u003cp\u003eThis study didn't differentiate the frequency of HLA alleles in PRA positive or PRA negative groups.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKarahan GE, Kekik C, Oguz FS, Onal AE,\u003c/p\u003e\u003cp\u003eBakkaloğlu H, \u0026Ccedil;alişkan H, (2010)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTurkey\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e642 ESRD patients preparing for the first transplantation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHLA-A3,-B18,-B49, -A66,-B49,-DRB1*07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePanel reactive antibody (PRA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHLA-A3 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.018), HLA-A66 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04), HLA-B18 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006), HLA B-49 (p\u0026thinsp;=\u0026thinsp;0,005) were significantly high in PRA-positive group.\u003c/p\u003e\u003cp\u003eHLA-DRB1*07 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02) was significantly high in patients who did not develop any anti-HLA antibodies\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePapassavas AC, Barnardo MC, Bunce M, Welsh KI, (2002)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUK\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e217 renal transplant patients who received an HLA-A2\u0026ndash;mismatched renal graft.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHLA-DRB1*01:01,-DRB1*03:01, -DRB1*04:01, -DRB1*07:01, -DRB1*11:01, -DRB1*13:01, -DRB1*14:01, -DRB1*15:01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eProduction of antibodies against the HLA-A2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eThe HLA-DRB1-*01:01, -DRB1*-14:01 and DRB1-*1501 alleles had positive correlation with the production of HLA class I\u0026ndash;specific antibodies against the HLA-A2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDankers MK, Roelen DL, Nagelkerke NJ, de Lange P, Persijn GG, Doxiadis II, et\u003c/p\u003e\u003cp\u003eal (2004)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNetherlands\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAll HLA-DR homozygous\u003c/p\u003e\u003cp\u003eDutch renal transplants patients, registered\u003c/p\u003e\u003cp\u003eon the Eurotransplant waiting list between 1967\u003c/p\u003e\u003cp\u003eand 2000 (n\u0026thinsp;=\u0026thinsp;1,317 patients).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHLA-DR4,-DR6, -DR52, -DR5, -DR7, -DR52, -DR3, -DR4, -DR53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eHLA Antibodies production\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eRisk factor alleles were HLA-DR4, -DR5, -DR6, -DR52, -DR53\u003c/p\u003e\u003cp\u003eProtective factor alleles were HLA-DR1, -DR3, -DR7, -DR53\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHeise E, Manning C, Thacker L (2001)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e19.440 kidney allograft recipients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHLA-B42, -B53,-A10,-A19, -A36; -DR1,-DR4, -DR7, -B8, -B12, -B40, -A1,-A2,-A11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePanel reactive antibody (PRA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFive allelotypes (HLA-B42,-B53, -A10,-19, -A36) were associated with an increased risk of PRA responses.\u003c/p\u003e\u003cp\u003eNine HLA allelotypes (HLA-DR1,-DR4,-DR7; -B8,-B12,-B40; -A1,-A2,-A11) were associated with a significantly reduced risk of sensitization.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFuller TC, Fuller A (1999)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSera from both solid organ and bone marrow transplant patients were\u003c/p\u003e\u003cp\u003eobtained for purposes of panel-reactive HLA antibody (PRA) screening\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHLA-DRB1*01:01; -DRB1*03:01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAnti HLA BW4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eThere are at least two human Ir genes, HLA-DRB1*01:01, -DRB1*03:01, that\u003c/p\u003e\u003cp\u003econfer a high risk for both humoral allosensitization and renal allograft failure in situations of\u003c/p\u003e\u003cp\u003eHLA-Bw4 incompatibility.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFu Q, Wang C, Zeng W, Liu L (2012)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChina\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eThis study included 383 sensitized patients and 1000 unsensitized patients awaiting kidney transplantation from 2001\u0026ndash;2010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHLA-A2,-A11,-A24, -A33, -A26; -B46,-A60,-A13,-A75,-A58,-DR9,-DR15,-DR12, -DR4, -DR14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePanel reactive antibody (PRA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eThe 5 most frequent HLA alleles in the 2 groups were not different between sensitized and non sensitized groups were HLA-A2,-A11,-A24,-A33,-A26; -B46,-A60,-A13,-A75,-A58; -DR9,-DR15,-DR12,-DR4,-DR14.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLu L, Sun Q (2022)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHunan (China)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e347 ESRD patients awaiting renal transplantation in Hunan Province from 2015 to 2019 and 309 healthy individuals.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHLA-A2, HLA-B38, HLA-B46, HLA-B60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePanel reactive antibody (PRA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHLA-A2, HLA-B38, and HLA-B46 were significantly higher in the PRA-positive group than in the PRA-negative group (p\u0026thinsp;\u0026lt;\u0026thinsp;0,05), while HLA-B60 was significantly higher in the PRA-negative group (p\u0026thinsp;\u0026lt;\u0026thinsp;0,005).\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThree key studies (Dankers et al., 2004; Fuller et al., 1999; Papassavas et al., 2002) identified HLA-DR as a major risk factor for developing HLA-specific antibodies. Dankers et al. (2004) found specific links between HLA-DR types and antibody responses. They observed that HLA-DR4 was associated with the production of anti-HLA-A3 antibodies (RR\u0026thinsp;=\u0026thinsp;2.78, p\u0026thinsp;\u0026lt;\u0026thinsp;0,05). HLA-DR5 was linked to the production of anti-HLA-A11 (RR\u0026thinsp;=\u0026thinsp;2.78, p\u0026thinsp;\u0026lt;\u0026thinsp;0,05), anti-HLA-B5 (RR\u0026thinsp;=\u0026thinsp;2.28, p\u0026thinsp;\u0026lt;\u0026thinsp;0,05), anti-HLA-B7 (RR\u0026thinsp;=\u0026thinsp;2.90, p\u0026thinsp;\u0026lt;\u0026thinsp;0,001), anti-HLA-B8 (RR\u0026thinsp;=\u0026thinsp;2.76, p\u0026thinsp;\u0026lt;\u0026thinsp;0,01), and anti-HLA-B12 (RR\u0026thinsp;=\u0026thinsp;2.82, p\u0026thinsp;\u0026lt;\u0026thinsp;0,01). HLA-DR6 was associated with the production of anti-HLA-A10 (RR\u0026thinsp;=\u0026thinsp;2.47, p\u0026thinsp;\u0026lt;\u0026thinsp;0,01), anti-HLA-A11 (RR\u0026thinsp;=\u0026thinsp;2.89, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), anti-HLA-A19 (RR\u0026thinsp;=\u0026thinsp;2.43, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and anti-HLA-B35 (RR\u0026thinsp;=\u0026thinsp;2.89, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Finally, HLA-DR52 was linked to the production of anti-HLA-A10 and anti-HLA-A1 (RR\u0026thinsp;=\u0026thinsp;1.76, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05; RR\u0026thinsp;=\u0026thinsp;2.42, p\u0026thinsp;\u0026lt;\u0026thinsp;0.02, respectively) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePapassavas et al. (2002) found that the HLA-DRB1-*01:01 and -*14:01 alleles had a positive correlation with the production of HLA class I\u0026ndash;specific antibodies against the shared HLA-A2 epitopes 65\u0026ndash;66GK and 62G, respectively. Conversely, the HLA-DRB1-*1501 allele was positively correlated with the production of antibodies against the private (74H) HLA-A2 epitope [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eFuller et al. (1999) also found associations between HLA-DRB1*01 and *03 and high levels of humoral sensitization, with 73% of patients with anti-HLA-Bw4 antibodies expressing one of these alleles. Saito et al. (2014) identified HLA-DRB1*11, -DRB1*04, and -DRB1*03 as the most common alleles among ESRD cases; however, they did not stratify by PRA positivity [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAnother HLA allele was identified as a risk factor and showed a positive correlation with HLA antibody production. Karahan et al. (2010) found that HLA-A3, -A66, and -B18 were significantly more common in patients who were PRA-positive. There was also a higher prevalence of HLA-B49 within this group, although it did not reach statistical significance [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Heise \u003cem\u003eet al\u003c/em\u003e. (2001), in a larger group of 19,440 kidney transplant recipients, demonstrated that HLA-A36, -B42, -A10, and a group consisting of HLA-A19, -A29, -A30, -A31, -A32, -A33, and -A74 were linked to an increased risk of PRA. Logistic regression analysis indicated that HLA-A36 was an independent risk factor, while -A10 showed marginal significance; however, group -B53 and -A19 were not statistically significant [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Fu et al. (2012) found no statistically significant difference in the frequency of the most common HLA types between sensitized and non-sensitized subjects in a study of patients from Guangzhou, China [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eFinally, certain HLA alleles may provide protection against sensitization. Karahan et al. (2010) observed that HLA-DRB1*07 was significantly more common in patients who experienced sensitization events without developing anti-HLA antibodies and might have a protective effect [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePapassavas et al. (2002) studied 217 renal transplant patients who received an HLA-A2\u0026ndash;mismatched renal graft. They found that five HLA-DRB1 alleles (-DRB1*01:01, -DRB1*07:01, -DRB1*11:01, -DRB1*13:01, and -DRB1*14:01) showed a tendency toward a negative correlation with the development of HLA class I-specific antibodies against the HLA-A2 group of epitopes [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDankers et al. (2004) also reported that certain HLA alleles might provide a protective effect against developing anti-HLA antibodies. Specifically, the presence of HLA-DR1 and -DR3 was linked to a significantly lower frequency of antibody formation. Individuals with HLA-DR1 showed notably lower rates of antibodies against HLA-A3 (RR\u0026thinsp;=\u0026thinsp;0.001, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and HLA-A11 (RR\u0026thinsp;=\u0026thinsp;0.001, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.02) compared to those with other HLA-DR alleles. Similarly, the presence of HLA-DR3 was associated with reduced antibody responses to HLA-A1 (RR\u0026thinsp;=\u0026thinsp;0.003, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), HLA-A3 (RR\u0026thinsp;=\u0026thinsp;0.28, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), HLA-B5 (RR\u0026thinsp;=\u0026thinsp;0.30, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.02), and HLA-B35 (RR\u0026thinsp;=\u0026thinsp;0.18, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) ) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eA study by Heise et al. (2001) reported findings consistent with those of Papassavas et al. (2002), showing that HLA-DR1 and -DR7 are linked to a decreased risk of sensitization and subsequent production of anti-HLA antibodies [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Other HLA alleles identified as potentially protective included HLA-DR4, -A1, -A2, -A11, -B8, -B12, and -B40. Among these, HLA-DR1, -DR4, -DR7, -B12, -A1, and -A2 were independently associated with protection against sensitization. Additionally, a specific HLA allele\u0026mdash;HLA-B60\u0026mdash;was identified by Lu, Long et al. as significantly protective against HLA antibody production (RR\u0026thinsp;=\u0026thinsp;0.475, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0036) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eHeise et al. (2001) also examined combinations of HLA-DR, -B, and -A alleles to identify haplotypes or genotypes that might be linked to an increased or decreased risk of sensitization. Using stepwise logistic regression analysis, five genotype combinations were identified as providing a protective effect: DR1-B35-A3, DR1-B35-A2, DR1-B44-A2, DR4-B44-A2, and DR7-B57-A1, each with a relative risk (RR) ranging from 0.63 to 0.83, which indicates an average risk reduction of 27%. Conversely, six allele combinations were associated with a higher risk of sensitization: DR2-B44-A2, DR2-B53-A2, DR3-B8-A1, DR3-B42-A30, DR6-B42-A30, and DR11-B53-A30, with RRs between 1.48 and 2.76, reflecting an average 70% increase in risk. These results provide strong evidence that genes within the HLA region, especially at the DR locus, greatly influence the anti-HLA panel reactive antibody (PRA) response. Significantly, the effect of DR-B-A allele combinations on PRA risk was about twice as large as that of individual alleles alone, highlighting the critical role of HLA-DR in affecting sensitization [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIt\u0026rsquo;s important to note that not all studies found statistically significant links. For example, Fu et al. (2012) reported no meaningful difference in HLA allele distribution between sensitized and non-sensitized groups in a Chinese cohort. This indicates that population-specific factors and other non-HLA immune or environmental factors may influence the results [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThis scoping review emphasizes the important role of specific HLA alleles and haplotypes in affecting the production of anti-HLA antibodies among patients with end-stage renal disease (ESRD). Most of the included studies showed strong links between HLA-DR alleles and increased sensitization, with additional contributions from HLA-A and HLA-B loci. Notably, the most frequently reported associations involved HLA-DRB1 alleles, highlighting the importance of HLA class II molecules in the immune response.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eThis scoping review highlights the crucial role of recipient HLA typing in influencing the risk of developing anti-HLA antibodies in patients with end-stage renal disease (ESRD). Most of the included studies demonstrated a strong association between specific HLA-DR alleles, such as DRB1*01:01, DRB1*14:01, DRB1*15:01, HLA-DRB1*01:01, -DRB1*03:01, HLA-DR4, -DR5, -DR6, -DR52, -DR53, and increased sensitization. Conversely, several HLA alleles were repeatedly and consistently associated with reduced sensitization risk in some studies, such as HLA-DRB1*07 and HLA-DR1.\u003c/p\u003e\u003cp\u003eThese findings collectively indicate that individual and combined HLA genotypes significantly influence alloimmune responses in ESRD patients. Recognizing these genetic factors can improve sensitization risk assessment and enable more personalized immunological monitoring in kidney transplants. However, additional research\u0026mdash;including prospective, multi-ethnic cohort studies\u0026mdash;is necessary to confirm these links and evaluate their impact on clinical practice and transplant outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cp\u003eNot applicable, as this study is a scoping review of previously published literature and did not involve human participants or animals.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cp\u003eNot applicable, as this study is a scoping review based on previously published literature and did not include individual patient data.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eI.P., T.T. developed the study concept, designed the review protocol, and provided overall supervision. I.P., A.E.H. constructed and implemented the search strategy across databases. I.P., T.T and K.H. independently screened titles/abstracts, assessed full texts, and piloted the data extraction sheet. I.P., A.E.H. performed data charting, summarized evidence, and prepared figures/tables. I.P., TT., and N.K. critically interpreted the findings and revised the manuscript for its important intellectual content. All authors read, contributed, and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAll data generated or analysed during this study are included in this published article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKissmeyer-Nielsen F, Olsen S, Petersen VP, Fjeldborg O. Hyperacute rejection of kidney allografts, associated with pre-existing humoral antibodies against donor cells. 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Clin Transpl. 2022;36(3):e24251. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/ctr.14251\u003c/span\u003e\u003cspan address=\"10.1111/ctr.14251\" 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":false,"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":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"HLA typing, HLA antibodies, End-stage renal disease, Kidney transplantation, Panel reactive antibodies","lastPublishedDoi":"10.21203/rs.3.rs-7621059/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7621059/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eKidney transplantation is the primary choice of renal replacement therapy for patients with end-stage renal disease (ESRD). However, the development of anti-human leukocyte antigen (HLA) antibodies remains a significant immunological barrier to successful transplantation. While sensitization is often linked to previous exposure to alloantigens through pregnancy, transfusion, or prior transplants, the impact of the recipient\u0026rsquo;s HLA alleles on antibody formation has not been systematically reviewed.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA scoping review was conducted in accordance with PRISMA-ScR guidelines. A thorough search of major databases identified 469 studies. After removing duplicates and irrelevant records, 8 observational studies met the inclusion criteria and were included in the qualitative synthesis. The review examined the links between specific HLA alleles and the development of anti-HLA antibodies in ESRD patients.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe HLA-DR alleles are believed to predict the strength of the alloimmune response, especially HLA-DRB1*01:01, -DRB1*14:01, -DRB1*15:01, -DR4, -DR5, -DR6, -DR52, and -DR53. Additional risk alleles include HLA-A3, -A36, -A66, -B18, and -B42. Conversely, DRB1*07:01, DRB1*11:01, -DRB1*13:01, and -B60 are identified as potentially protective against sensitization. Some studies also report that multi-locus haplotypes (e.g., DR1-B35-A2, DR7-B57-A1) have a stronger predictive value for sensitization risk than individual alleles. One study conducted in China found no significant differences in HLA allele distribution between sensitized and non-sensitized patients, suggesting potential population-based variation.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eThis review provides initial evidence that certain HLA alleles, especially at the HLA-DR locus, may influence the risk of anti-HLA antibody development in ESRD patients. Identifying both immunogenic and protective HLA alleles or haplotypes could enable more personalized immunological risk assessments for transplant candidates. Larger, prospective studies across diverse ethnic populations are required to validate these results and enhance transplant outcomes.\u003c/p\u003e","manuscriptTitle":"Do recipient HLA alleles influence HLA Antibody Production in End- stage renal disease (ESRD)? A Scoping Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-30 11:54:21","doi":"10.21203/rs.3.rs-7621059/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"239752966384866175243163434726721239440","date":"2025-10-16T11:43:46+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-16T10:12:19+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-19T08:05:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-17T11:32:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-17T11:31:29+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2025-09-15T13:13:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4a29ecda-e6f4-4439-bf41-ea0d011157ad","owner":[],"postedDate":"October 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-10-30T11:54:21+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-30 11:54:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7621059","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7621059","identity":"rs-7621059","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}