Clinical characteristics of membranous nephropathy after allogeneic hematopoietic stem cell transplantation: a real-world multicenter study

Clinical characteristics of membranous nephropathy after allogeneic hematopoietic stem cell transplantation: a real-world multicenter study | 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 Clinical characteristics of membranous nephropathy after allogeneic hematopoietic stem cell transplantation: a real-world multicenter study Yue Jin, Peng Zhao, Yuan-Yuan Zhang, Yi-Shan Ye, Fang Zhou, Ding-Ming Wan, and 25 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4247321/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Membranous nephropathy (MN) is a rare complication that can occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT). MN patients may develop nephrotic syndrome or even kidney failure, which greatly affects their quality of life and prognosis. However, current information regarding MN after allo-HSCT is very limited. Thus, a multicenter nested case‒control study was conducted. Patients who had been diagnosed with MN after allo-HSCT were retrospectively identified at 8 HSCT cent res. A total of 51 patients with MN after allo-HSCT were included. The median age of MN patients after allo-HSCT was 38 years, and the median duration from HSCT to MN was 18 months. The use of HLA-matched donors ( P = 0.0102) and peripheral blood as the graft source ( P = 0.0060) were identified as independent predisposing risk factors for the onset of MN after allo-HSCT. Compared with those in the control group, the incidence of extensive chronic graft-versus-host disease was greater in the MN patients ( P = 0.001). A total of 31 patients developed nephrotic syndrome. Patients receiving combination treatments of corticosteroids and immunosuppressants appeared to have better outcomes. In conclusion, MN is a rare but occasionally severe complication following HSCT and may require active treatment. allogeneic hematopoietic stem cell transplantation membranous nephropathy chronic graft-versus-host disease quality of life Figures Figure 1 Figure 2 Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for a variety of hematologic diseases. 1 Membranous nephropathy (MN) is a rare complication that can occur after allo-HSCT. MN is a type of glomerular disease characterized by a thickening of glomerular capillary walls due to deposits of immune complexes. Proteinuria and edema are the most common clinical manifestations of MN, and in severe cases, MN patients may meet the diagnostic criteria for nephrotic syndrome (NS). Patients who are unable to achieve clinical remission constantly suffer from MN and eventually develop kidney function decline, 2, 3 which greatly affects quality of life and patient prognosis. 4 However, the current information regarding MN after allo-HSCT is very limited, and there is a lack of nested case‒control studies and predisposing risk factor analyses for MN after allo-HSCT. MNs are considered to be associated with chronic graft-versus-host disease (cGVHD) of the kidney, which mainly manifests as NS. 2, 3, 5–7 According to previous studies, the median duration from allo-HSCT to MN was 15-24.4 months, 3,7–10 and patients who received peripheral blood (PB) stem cells might have a greater incidence of MN. 3, 11, 12 Compared with primary MN, MN after allo-HSCT exhibits unique features. In addition to deposits of immune complexes in the subepithelial area of the glomeruli, immune complex deposits in the subendothelial and mesangial areas of the glomeruli and even in the tubular basement membrane have been observed in MNs after allo-HSCT. 13, 14 In patients with MN after allo-HSCT, there was a markedly lower positive rate of anti-PLA2R antibodies than in patients with primary MN. 7, 13, 15–17 It was suggested that patients with MN after allo-HSCT have a better response to corticosteroid (Cs) treatment than patients with primary MN, but Cs treatment alone is mostly insufficient for treating MN after allo-HSCT. 7,12 Calcineurin inhibitors, mycophenolate mofetil (MMF) and rituximab are also common treatments for MN after allo-HSCT. 8, 9, 12, 18–21 In this study, a multicenter analysis was conducted. The purpose of our study was to provide reliable information about MN after allo-HSCT, identify predisposing risk factors for this disease at the early stage posttransplant, and analyze the characteristics, treatment options and response of MN after allo-HSCT to provide suggestions for better prevention and management of its occurrence and relapse. Materials and Methods Study patients Patients who had received allo-HSCT from January 1, 2007, to December 31, 2022, and had been diagnosed with MN were retrospectively identified at 8 HSCT centers. The list of participating hospitals is summarized in Table S1 . For each MN patient, we randomly selected 3 control subjects who had no clinical evidence or diagnosis of MN. In addition, to ensure comparability of two groups and reduce bias, the inclusion criteria of the control subject candidates were based on the transplantation time (± 6 months) and the follow-up time (the whole follow-up period of control subject should be the same as or longer than the duration of corresponding MN patient from transplantation to the onset of MN to ensure that the control group had the same opportunity to develop MN). This study was approved by the Ethics Committee of Peking University People's Hospital and all other hospitals involved and was conducted in accordance with the Helsinki Declaration. Written informed consent for scientific research was signed by all patients involved before transplantation. Definition and diagnostic criteria In this study, we defined membranous nephropathy after allogeneic hematopoietic stem cell transplantation (MN after allo-HSCT) as the new onset of MN after allo-HSCT, excluding other secondary causes. MN was diagnosed only following kidney biopsy. 8, 22–25 At least two pathologists reviewed each biopsy sample. Proteinuria was defined as a 24-hour urine protein ≥ 150 mg/L, and heavy proteinuria was defined as a 24-hour urine protein > 3.5 g/L. The diagnostic criteria for nephrotic syndrome included ( 1 ) 24-hour urine protein > 3.5 g/d and ( 2 ) serum albumin < 30 g/L. 18 Clinical remission of MN was evaluated as follows: ( 1 ) complete remission (CR) was defined as a urine protein concentration < 300 mg/d with stable eGFR (decrease of < 15%); ( 2 ) partial remission (PR) was defined as a urine protein concentration ≥ 300 mg/d and ≤ 3.5 g/d and a decrease in urine protein concentration of at least 50% compared with baseline with stable eGFR; and ( 3 ) failure to meet the criteria of complete remission (CR) or partial remission (PR) was considered no clinical remission (NR). 24, 26 Acute kidney injury (AKI) was defined according to the KDIGO guidelines. 27 Acute graft-versus-host disease (aGVHD) was diagnosed and graded according to Glucksberg guidelines. 28 Chronic GVHD was diagnosed according to the National Institutes of Health (NIH) consensus guideline criteria and was graded as limited or extensive. 29, 30 Conditioning regimens and GVHD prophylaxis Most patients received a busulfan-based conditioning regimen (Bu/Cy). 31, 32 In addition, HLA partially matched recipients received antithymocyte globulin (Bu/Cy + ATG). 32, 33 The specific conditioning regimens were adjusted based on each patient’s condition. Most patients received cyclosporine A (CSA), MMF, and short-term methotrexate (MTX) for GVHD prophylaxis. 31–34 Data collection Blood and urine samples were collected before allo-HSCT and at every follow-up. Blood biochemical parameter examinations were performed before and after allo-HSCT (within 2 months) and at every follow-up. A 24-hour urine protein measurement was performed at the onset of MN and at every follow-up. Kidney biopsy data included ( 1 ) light microscopy, including PASM staining and Masson staining; ( 2 ) immunofluorescence microscopy, including IgG, IgA, IgM, C3, C1q, FRA, and IgG subtypes (IgG1 to 4); and ( 3 ) electron microscopy. Serum autoantibodies were measured in MN patients after diagnosis. Anti-PLA2R antibody levels were determined via an enzyme-linked immunosorbent assay. 35 The onset time of MN was based on the presence of clinical manifestations. Clinical manifestations of MN, information on GVHD, treatments and outcomes of each patient were recorded at every follow-up. Statistical analysis The data are presented as medians and ranges; medians, means, standard deviations and ranges; or percentages. Categorical variables were compared using Pearson’s chi-square test or 2-tailed Fisher’s exact test. Continuous variables were compared using the Mann‒Whitney U test. Baseline factors were included in the risk factor Cox analysis. In the univariate Cox analysis, potential risk factors with P < 0.05 were selected for multivariate Cox analysis. In multivariate Cox analysis using the stepwise regression method, factors with P < 0.05 were considered independent risk factors for MN after allo-HSCT. Conditional logistic regression was used to analyze the association between MN and cGVHD. All statistical analyses were performed with SPSS 27.0 (SPSS, Inc., Chicago, IL) and R (R version 4.3.3) software. Results Patient demographic characteristics A total of 51 patients diagnosed with MN after allo-HSCT were included in this study as the case group. A total of 153 patients who were verified to not have MN after HSCT were included in the control group (Table 1 ). The median age at the time of allo-HSCT was 36 years (range, 6 to 54 years) in MN patients. The median age of MN patients after allo-HSCT was 38 years (range, 8 to 55 years), and the median duration from allo-HSCT to MN was 20 months (range, 5 to 94 months). Table 1 Characteristics of the MN patients and the control group MN (N = 51) No MN (N = 153) P Value Age at allo-HSCT, yr, median[range] Follow-up duration*, mo, median[range] Sex, n (%) 36 [6–54] 20 [5–94] 28 [7–64] 44 [5-180] .106 < .001 .622 Male 32 (62.7) 88 (57.5) Female 19 (37.3) 65 (42.5) Underlying disease, n (%) .127 AML ALL CML 20 (39.2) 9 (17.6) 4 (7.8) 59 (38.6) 51 (33.3) 7 (4.6) 1.0 .051 .473 MDS 8 (15.7) 20 (13.1) .814 Others 10 ( 19 , 6 ) 16 (10.5) .146 Donor, n (%) < .001 HLA matched HLA partially matched 36 (70.6) 15 (29.4) 55 (35.9) 98 (64.1) Donor-recipient gender, n (%) 1.0 Matched 27 (52.9) 82 (53.6) Unmatched 24 (47.1) 71 (46.4) Donor-recipient ABO blood type, n (%) 1.0 Matched 32 (62.7) 94 (61.4) Unmatched 19 (37.3) 59 (38.6) SC Source, n (%) < .001 PB + BM 17 (33.3) 103 (67.3) < .001 PB 32 (62.7) 48 (31.4) < .001 Other Graft cell dose infused, median [range] MNC, ×10 8 /kg CD34, ×10 6 /kg 2 (3.9) 8.49 [4.79–30.2] 3.02 [1.33–15.02] 2 (1.3) 8.05 [1.16–22.99] 2.73 [0.62–10.23] .261 .701 .147 Kidney function before allo-HSCT BUN, mmol/L, median[range] Creatinine, umol/L, median [range] eGFR, ml/min, median [range] Uric acid ,umol/L, median [range] Kidney function after allo-HSCT BUN, mmol/L, median[range] Creatinine, umol/L, median[range] eGFR, ml/min, median [range] Uric acid ,umol/L, median [range] Overall aGVHD severity, n (%) 4.64 [1.72–7.9] 57 [27–148] 123.8 [67.6–218.0] 279 [89–508] 4.10 [0.73–12.88] 50 [22–119] 123.9 [48.6-317.7] 260 [98–529] 3.93 [1.02–9.05] 58.5 [24–122] 121.9 [59.6-196.5] 274 [92–586] 4.92 [1.27–17.82] 56 [22–131] 124.3 [42.3-209.5] 223 [68–502] .152 .441 .945 .892 .243 .337 .936 .031 .684 None to aGVHD I 42 (82.4) 122 (79.7) aGVHD II-IV 9 (17.6) 31 (20.3) *Duration from HSCT to the diagnosis of MN for MN patients and from HSCT to the last follow-up for control group. Clinical and laboratory characteristics of MN patients after allo-HSCT The clinical manifestations of MN are summarized in Table S2. The most common clinical manifestations were proteinuria, hypoalbuminemia and edema of the legs. Other types of fluid retention included eyelid edema, whole-body edema, hydrothorax and ascites. Anti-PLA2R antibody assays were performed for 15 MN patients, and all the results were negative. Low-titer anti-nuclear antibodies were detected in 21 MN patients, ranging from 1:20 to 1:320, and anti-Ro-52 antibody positivity was detected in 6 MN patients with positive anti-nuclear antibodies. The detailed laboratory data at the time of MN diagnosis are shown in Table S3. The median peak urine protein level was 5.4 g/d (range, 0.39 to 25.65 g/d), and 30 patients (58.8%) met the diagnostic criteria for NS. Two patients (3.9%) were also diagnosed with thrombotic microangiopathy (TMA) via subsequent kidney biopsy. Edema in the legs was observed as an initial symptom 188 and 235 days after allo-HSCT in these 2 patients. All of these patients developed AKI, proteinuria, hypertension and thrombosis in the legs during the course of disease. However, thrombocytopenia, elevated LDH, elevated bilirubin and schistocytes were observed in only 1 patient. Biopsy characteristics of the MNs All MN patients were diagnosed by kidney biopsy. Detailed kidney biopsy reports, including light microscopy and immunofluorescence microscopy, were available for 36 patients, and detailed electron microscopy data were traceable for 31 patients. The biopsy results were summarized in Table S4. Two patients were also diagnosed with TMA. Based on the results of immunofluorescence staining, all patients were characterized by glomerular IgG deposits, but IgA and/or IgM deposits were also observed. All subtypes of IgG deposits were found in the glomeruli of MN patients after allo-HSCT. According to electron microscopy analysis, the immune complex was deposited mainly in the subepithelial area. Mesangial and subendothelial immune complex deposits were also found in MN patients after allo-HSCT. In addition, a total of 4 patients had immune deposits in the tubular basement membrane. Predisposing risk factors for MN after allo-HSCT Age at allo-HSCT, HLA-matched donor, PB as the graft source, serum uric acid (UA) level after allo-HSCT (within 1 month) and aGVHD were included in the predisposing factor analysis. According to univariate and multivariate analysis, PB as the graft source (HR, 2.365; 95% CI, 1.281 to 4.268; P = 0.0060) and HLA-matched donor (HR, 2.346; 95% CI, 1.224 to 4.495; P = 0.0102) were identified as independent risk factors for MN after allo-HSCT (Table 2 ). Table 2 Predisposing risk factors for MN after allo-HSCT Risk Factor Univariate Cox Analysis Multivariate Cox Analysis P HR 95% CI P HR 95% CI Age at HSCT, yr 0.189 HLA matched donor 0.0001 3.286 1.797–6.009 0.0102 2.346 1.224–4.495 PB as graft source < 0.0001 3.285 1.859–5.805 0.0060 2.365 1.281–4.268 UA after HSCT (within 1 month), umol/L 0.0579 aGVHD II-IV 0.614 Abbreviations: yr, year; PB, peripheral blood; UA, uric acid; aGVHD, acute graft-versus-host disease; HR, hazard ratio; CI, confidence interval. Abbreviations: MN, membranous nephropathy; GI tract, gastrointestinal tract; Cs, corticosteroids; IS, immunosuppressant Abbreviations: CR, complete remission; PR, partial remission; NR, no remission; Cs, corticosteroids; IS, immunosuppressant; AKI, acute kidney injury. Chronic GVHD and MN A total of 34 MN patients developed cGVHD (limited cGVHD in 9 patients and extensive cGVHD in 25 patients). The most commonly involved organ was the skin, followed by the liver, mouth, eyes, lung and gastrointestinal (GI) tract (Table S5). As shown in Fig. 1 , skin, liver and GI tract cGVHD developed mainly within 1 year after allo-HSCT, while the onset time of eyes and lung cGVHD was more discretely distributed. For 20 of 34 patients (58.8%), MN occurred in the context of specific cessation of Cs and/or immunosuppressant (IS) for cGVHD treatment, for a median duration of 3.3 months (range, 0.2 to 37.9 months). At the onset of MN, 15 of 34 patients (44.1%) had active cGVHD manifestations, and 18 of 34 patients (52.9%) achieved remission of prior cGVHD. The median duration from prior cGVHD to MN was 13 months (range, 0 to 87 months). One patient developed skin cGVHD after MN onset. The median onset time of MN was later than that of cGVHD mentioned above. There was a strong correlation between extensive cGVHD and MN after allo-HSCT ( P = 0.0066 for cGVHD and P = 0.0001 for extensive cGVHD, adjusted for PB and HLA-matched donor). Treatment and outcomes of membranous nephropathy The treatments and outcomes of the 20 MN patients at Peking University Institute of Hematology are summarized in Fig. 2 and Table S6. Three of the 20 (15%) patients were diagnosed with AKI and heavy proteinuria at MN onset; of these, 2 patients were also diagnosed with TMA and received combination therapy comprising 1 mg/kg/day Cs and IS; one patient achieved PR, and the other patient suffered from a decrease in GFR at the last follow-up. The other patient with AKI and heavy proteinuria received combination therapy comprising Cs < 1 mg/kg/day and CSA. After treatment, a reduction in the serum creatinine concentration was observed, but there was still heavy proteinuria. Thirteen of the 20 patients (65%) were diagnosed with heavy proteinuria and 4 of the 20 patients (20%) were diagnosed with proteinuria. CR to initial therapy could only be achieved in patients who received the combination therapy comprising Cs and IS. Six patients who achieved a PR or NR at the initial therapy received subsequent therapy with the addition of Cs or IS. Two of the 6 patients achieved CR after subsequent therapy, and 2 of the 6 patients lacked a response to subsequent therapy. A decrease in the eGFR was observed in 3 patients at follow-up, including 1 patient with AKI at the onset of MN. Seven and seven of the 20 patients (35% and 35%) achieved CR and PR, respectively, at the last follow-up. One patient with heavy proteinuria relapsed at 18.2g/24h 3 months after PR because of cessation of Cs (1mg/kg/day) and MMF; subsequently, the patient was treated with Cs>1mg/kg/day and MMF and achieved PR 1 month later. Notably, only 2 MN patients who were diagnosed with TMA developed thrombosis in the lower legs during the course of disease. At the last follow-up, 1 of the 20 patients died from cerebral hemorrhage 7 years after MN onset and 1 of the 20 patients died from relapse of blood disease 6 months after MN onset. Discussion Glomerular diseases after allo-HSCT are very rare, and membranous nephropathy (MN) is the most common pathological type. 2, 3, 7 To our knowledge, this is the first multicenter study reporting the largest series of MN after allo-HSCT. We recorded and analyzed the clinical and kidney biopsy characteristics, predisposing risk factors, treatments and outcomes of MN patients after allo-HSCT. In 2009, Beck et al. 36 found that approximately 70% of patients with primary MN exhibited a high percentage of positive anti-PLA2R antibodies. However, in this study, all traceable anti-PLA2R antibody tests (n = 15) in MN patients after allo-HSCT were negative. In previous research, the percentage of patients with MN positive for anti-PLA2R antibodies after HSCT was also low, ranging from 0–20%. 7, 13, 15–17 In 2022, Sethi et al. 15 reported that the protocadherin FAT1, was detected in the glomeruli of 14 patients with newly developed MN after allo-HSCT, indicating that MN after allo-HSCT has a different pathogenesis than primary MN. In previous studies, the average occurrence duration from HSCT to MN occurrence was between 15 and 24.4 months 3, 7–10 , and in our study, it was 18 months. Therefore, MN might be a late-onset complication of allo-HSCT. The initial manifestation of increased urine protein in MN patients is inconspicuous, which might be one reason why the time at which symptoms were discovered lagged behind the time at which kidney lesions began. MNs after allo-HSCT are considered to be associated with cGVHD. 2, 3, 7, 14, 37–41 The occurrence of MN might be related to prior cGVHD and cessation of Cs and/or IS. Additionally, extensive cGVHD generally occurred prior to MN, and active cGVHD might overlap with MN. Therefore, MN is not excluded as one of the manifestations of cGVHD. HLA-matched donor and the use of PB as the graft sources were significant risk factors according to both univariate and multivariate analyses in this study. In previous studies, Byrne-Dugan et al. 7 revealed that compared with MN related to other organ transplantation, MN patients after HSCT were mostly HLA-matched. Hu et al. 3 and Beyar-Katz et al. 12 also found that in glomerular diseases, patients who received PB stem cells presented a higher probability of developing MN. However, because of the small sample size, previous studies were lack of risk factor analysis. Therefore, we conducted this nested case-control study including comparable control group to investigate the risk factors of MN after allo-HSCT. The clinical manifestations of MN after allo-HSCT were mostly legs edema and proteinuria. More than half of the MN patients were diagnosed with NS when they sought for treatment. In the present study, the deposits in the glomeruli were composed mainly of IgG. Previous studies have shown the same results. 8, 13–15, 17 Electron microscopy analysis has indicated that, unlike in primary MN, immune deposits in MNs after allo-HSCT are deposited not only in the subepithelial area of the glomeruli but also deposited in subendothelial, mesangial, and even the tubular basement membrane. 14, 42 TMA is an early complication occurring mostly between 20 to 100 day after allo-HSCT 15, 43–45 . However, in our study, 2 patients diagnosed with MN and TMA by kidney biopsy developed kidney manifestations more than 100 days after allo-HSCT. Previous, one case of late-onset HSCT-associated TMA overlapped with MN was reported. 46 The association between TMA and MN needs further study. In previous studies, corticosteroids demonstrated a good response in MN patients after allo-HSCT. 7–9, 12, 17 MMF and calcineurin inhibitors have also been widely applied. 7, 9, 12 Previous studies have shown that rituximab effetely treats MN after HSCT alone or when corticosteroids, MMF or calcineurin inhibitors are ineffective. 7, 8, 12, 19, 21 In this study, treatment with a combination of Cs and IS tended to yield better outcomes; however, patients who experienced a poor response to initial treatment with Cs and IS still tended to experience no remission after subsequent therapy with the addition of Cs or IS. The most direct cause of death in MN patients was not kidney diseases in our study. This study has several limitations. First, this was a retrospective study; thus, missing data and confounding factors were unavoidable. Second, since the diagnosis of MN mostly requires kidney biopsy results and some patients with mild symptoms do not need to undergo kidney biopsy, the number of MN patients after allo-HSCT is underestimated. Third, this study was a nested case‒control study and MN is a rare complication after allo-HSCT. Although we randomly selected 3 control subjects for each MN patients to analyze predisposing risk factors, the control group could not represent the whole cohort because of the difference in population size. In conclusion, MN is a rare late-onset complication following allo-HSCT. The main manifestations included various levels of proteinuria and edema. Patients who received combination treatments of Cs and IS appeared to have better outcomes; however, those who lacked a response to treatments might suffer from continuous proteinuria or a decrease in kidney function. Therefore, active treatments are essential for MN patients after allo-HSCT. However, further research is needed. Abbreviations yr year mo month AML acute myeloid leukemia ALL acute lymphoblastic leukemia CML chronic myeloid leukemia MDS myelodysplastic syndrome HLA human leukocyte antigen SC stem cell PB peripheral blood BM bone marrow MNCs mononuclear cells BUN blood urea nitrogen eGFR estimated glomerular filtration rate. Declarations Acknowledgements: The authors thank the patients and medical staff who participated in this study, and the department of medical record libraries for providing medical records. Authorship: YJ, PZ, and YYZ analyzed the data and wrote the manuscript; YJ and PZ performed statistical analysis; YJ and PZ designed the study, analyzed the data, and edited the manuscript; the remaining authors contributed to the data collection and helped write and edit the manuscript. Declaration of interest: The authors declare that they have no competing interests. Competing Interests : The authors declare that they have no competing interests. Funding: This work was supported by the National Key Research and Development Program of China (No. 2021YFC2500304), Key Program of National Natural Science Foundation of China (No. 82230004), National Natural Science of Foundation of China (No. 81970113) and Capital Health Research and Development of Special (No. 2022-1-4082). Data Availability Statement : The data that support the findings of this study are available on request from the corresponding author, Xiao-Hui Zhang, PhD, MD. The data are not publicly available due to their containing information that could compromise the privacy of research participants. References Zhang, X. H.; Chen, J.; Han, M. Z.; Huang, H.; Jiang, E. L.; Jiang, M.; Lai, Y. R.; Liu, D. H.; Liu, Q. F.; Liu, T.; Ren, H. Y.; Song, Y. P.; Sun, Z. M.; Tang, X. W.; Wang, J. M.; Wu, D. P.; Xu, L. P.; Zhang, X.; Zhou, D. B.; Huang, X. 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Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterial.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 16 May, 2024 Reviews received at journal 10 May, 2024 Reviews received at journal 01 May, 2024 Reviewers agreed at journal 23 Apr, 2024 Reviewers agreed at journal 22 Apr, 2024 Reviewers invited by journal 22 Apr, 2024 Editor assigned by journal 18 Apr, 2024 Submission checks completed at journal 18 Apr, 2024 First submitted to journal 10 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4247321","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":294165491,"identity":"daf01ef7-4664-4b54-9bd9-c0a9d4b93eca","order_by":0,"name":"Yue Jin","email":"","orcid":"","institution":"Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease","correspondingAuthor":false,"prefix":"","firstName":"Yue","middleName":"","lastName":"Jin","suffix":""},{"id":294165493,"identity":"a80f877f-3d72-48c7-af43-942eb24bca58","order_by":1,"name":"Peng 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12:20:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4247321/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4247321/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55514299,"identity":"37fa9107-627e-4fd8-8aa8-c574257fc53f","added_by":"auto","created_at":"2024-04-29 13:01:27","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":267817,"visible":true,"origin":"","legend":"\u003cp\u003eDuration from allo-HSCT to MN; cGVHD in the skin, mouth, liver, GI tract and eyes; and cessation of Cs and/or IS in MN patients (n=51).\u003c/p\u003e\n\u003cp\u003eAbbreviations: MN, membranous nephropathy; GI tract, gastrointestinal tract; Cs, corticosteroids; IS, immunosuppressant\u003c/p\u003e","description":"","filename":"Fig.1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4247321/v1/2463aa318dcf3295a9853354.jpg"},{"id":55515329,"identity":"0cd5f3c5-8fdd-4b4b-8e07-1482294d802f","added_by":"auto","created_at":"2024-04-29 13:09:27","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":91419,"visible":true,"origin":"","legend":"\u003cp\u003eTreatments and outcomes of 20 MN patients.\u003c/p\u003e\n\u003cp\u003eAbbreviations: CR, complete remission; PR, partial remission; NR, no remission; Cs, corticosteroids; IS, immunosuppressant; AKI, acute kidney injury.\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-4247321/v1/c0cb0c0706f6160320feaa7a.png"},{"id":55516589,"identity":"2ad7089e-fd75-4d72-bd50-9c3892db8686","added_by":"auto","created_at":"2024-04-29 13:17:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":662616,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4247321/v1/dfc2fa2d-a525-4b1a-a24b-eba71e039aac.pdf"},{"id":55514297,"identity":"63595962-e32d-418f-aacb-68019138edde","added_by":"auto","created_at":"2024-04-29 13:01:27","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":278089,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-4247321/v1/5a626a406e2460f02d67550b.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical characteristics of membranous nephropathy after allogeneic hematopoietic stem cell transplantation: a real-world multicenter study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for a variety of hematologic diseases. \u003csup\u003e1\u003c/sup\u003e Membranous nephropathy (MN) is a rare complication that can occur after allo-HSCT.\u003c/p\u003e \u003cp\u003eMN is a type of glomerular disease characterized by a thickening of glomerular capillary walls due to deposits of immune complexes. Proteinuria and edema are the most common clinical manifestations of MN, and in severe cases, MN patients may meet the diagnostic criteria for nephrotic syndrome (NS). Patients who are unable to achieve clinical remission constantly suffer from MN and eventually develop kidney function decline, \u003csup\u003e2, 3\u003c/sup\u003e which greatly affects quality of life and patient prognosis.\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHowever, the current information regarding MN after allo-HSCT is very limited, and there is a lack of nested case‒control studies and predisposing risk factor analyses for MN after allo-HSCT. MNs are considered to be associated with chronic graft-versus-host disease (cGVHD) of the kidney, which mainly manifests as NS.\u003csup\u003e2, 3, 5\u0026ndash;7\u003c/sup\u003e According to previous studies, the median duration from allo-HSCT to MN was 15-24.4 months,\u003csup\u003e3,7\u0026ndash;10\u003c/sup\u003e and patients who received peripheral blood (PB) stem cells might have a greater incidence of MN.\u003csup\u003e3, 11, 12\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eCompared with primary MN, MN after allo-HSCT exhibits unique features. In addition to deposits of immune complexes in the subepithelial area of the glomeruli, immune complex deposits in the subendothelial and mesangial areas of the glomeruli and even in the tubular basement membrane have been observed in MNs after allo-HSCT. \u003csup\u003e13, 14\u003c/sup\u003e In patients with MN after allo-HSCT, there was a markedly lower positive rate of anti-PLA2R antibodies than in patients with primary MN.\u003csup\u003e7, 13, 15\u0026ndash;17\u003c/sup\u003e It was suggested that patients with MN after allo-HSCT have a better response to corticosteroid (Cs) treatment than patients with primary MN, but Cs treatment alone is mostly insufficient for treating MN after allo-HSCT.\u003csup\u003e7,12\u003c/sup\u003e Calcineurin inhibitors, mycophenolate mofetil (MMF) and rituximab are also common treatments for MN after allo-HSCT.\u003csup\u003e8, 9, 12, 18\u0026ndash;21\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn this study, a multicenter analysis was conducted. The purpose of our study was to provide reliable information about MN after allo-HSCT, identify predisposing risk factors for this disease at the early stage posttransplant, and analyze the characteristics, treatment options and response of MN after allo-HSCT to provide suggestions for better prevention and management of its occurrence and relapse.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy patients\u003c/h2\u003e \u003cp\u003ePatients who had received allo-HSCT from January 1, 2007, to December 31, 2022, and had been diagnosed with MN were retrospectively identified at 8 HSCT centers. The list of participating hospitals is summarized in Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e. For each MN patient, we randomly selected 3 control subjects who had no clinical evidence or diagnosis of MN. In addition, to ensure comparability of two groups and reduce bias, the inclusion criteria of the control subject candidates were based on the transplantation time (\u0026plusmn;\u0026thinsp;6 months) and the follow-up time (the whole follow-up period of control subject should be the same as or longer than the duration of corresponding MN patient from transplantation to the onset of MN to ensure that the control group had the same opportunity to develop MN). This study was approved by the Ethics Committee of Peking University People's Hospital and all other hospitals involved and was conducted in accordance with the Helsinki Declaration. Written informed consent for scientific research was signed by all patients involved before transplantation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDefinition and diagnostic criteria\u003c/h2\u003e \u003cp\u003eIn this study, we defined membranous nephropathy after allogeneic hematopoietic stem cell transplantation (MN after allo-HSCT) as the new onset of MN after allo-HSCT, excluding other secondary causes. MN was diagnosed only following kidney biopsy.\u003csup\u003e8, 22\u0026ndash;25\u003c/sup\u003e At least two pathologists reviewed each biopsy sample.\u003c/p\u003e \u003cp\u003eProteinuria was defined as a 24-hour urine protein\u0026thinsp;\u0026ge;\u0026thinsp;150 mg/L, and heavy proteinuria was defined as a 24-hour urine protein\u0026thinsp;\u0026gt;\u0026thinsp;3.5 g/L. The diagnostic criteria for nephrotic syndrome included (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) 24-hour urine protein\u0026thinsp;\u0026gt;\u0026thinsp;3.5 g/d and (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) serum albumin\u0026thinsp;\u0026lt;\u0026thinsp;30 g/L.\u003csup\u003e18\u003c/sup\u003e Clinical remission of MN was evaluated as follows: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) complete remission (CR) was defined as a urine protein concentration\u0026thinsp;\u0026lt;\u0026thinsp;300 mg/d with stable eGFR (decrease of \u0026lt;\u0026thinsp;15%); (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) partial remission (PR) was defined as a urine protein concentration\u0026thinsp;\u0026ge;\u0026thinsp;300 mg/d and \u0026le;\u0026thinsp;3.5 g/d and a decrease in urine protein concentration of at least 50% compared with baseline with stable eGFR; and (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) failure to meet the criteria of complete remission (CR) or partial remission (PR) was considered no clinical remission (NR).\u003csup\u003e24, 26\u003c/sup\u003e Acute kidney injury (AKI) was defined according to the KDIGO guidelines.\u003csup\u003e27\u003c/sup\u003e Acute graft-versus-host disease (aGVHD) was diagnosed and graded according to Glucksberg guidelines.\u003csup\u003e28\u003c/sup\u003e Chronic GVHD was diagnosed according to the National Institutes of Health (NIH) consensus guideline criteria and was graded as limited or extensive.\u003csup\u003e29, 30\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eConditioning regimens and GVHD prophylaxis\u003c/h2\u003e \u003cp\u003eMost patients received a busulfan-based conditioning regimen (Bu/Cy).\u003csup\u003e31, 32\u003c/sup\u003e In addition, HLA partially matched recipients received antithymocyte globulin (Bu/Cy\u0026thinsp;+\u0026thinsp;ATG).\u003csup\u003e32, 33\u003c/sup\u003e The specific conditioning regimens were adjusted based on each patient\u0026rsquo;s condition. Most patients received cyclosporine A (CSA), MMF, and short-term methotrexate (MTX) for GVHD prophylaxis.\u003csup\u003e31\u0026ndash;34\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003eBlood and urine samples were collected before allo-HSCT and at every follow-up. Blood biochemical parameter examinations were performed before and after allo-HSCT (within 2 months) and at every follow-up. A 24-hour urine protein measurement was performed at the onset of MN and at every follow-up. Kidney biopsy data included (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) light microscopy, including PASM staining and Masson staining; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) immunofluorescence microscopy, including IgG, IgA, IgM, C3, C1q, FRA, and IgG subtypes (IgG1 to 4); and (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) electron microscopy. Serum autoantibodies were measured in MN patients after diagnosis. Anti-PLA2R antibody levels were determined via an enzyme-linked immunosorbent assay.\u003csup\u003e35\u003c/sup\u003e The onset time of MN was based on the presence of clinical manifestations. Clinical manifestations of MN, information on GVHD, treatments and outcomes of each patient were recorded at every follow-up.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe data are presented as medians and ranges; medians, means, standard deviations and ranges; or percentages. Categorical variables were compared using Pearson\u0026rsquo;s chi-square test or 2-tailed Fisher\u0026rsquo;s exact test. Continuous variables were compared using the Mann‒Whitney U test. Baseline factors were included in the risk factor Cox analysis. In the univariate Cox analysis, potential risk factors with \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were selected for multivariate Cox analysis. In multivariate Cox analysis using the stepwise regression method, factors with \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered independent risk factors for MN after allo-HSCT. Conditional logistic regression was used to analyze the association between MN and cGVHD. All statistical analyses were performed with SPSS 27.0 (SPSS, Inc., Chicago, IL) and R (R version 4.3.3) software.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatient demographic characteristics\u003c/h2\u003e \u003cp\u003eA total of 51 patients diagnosed with MN after allo-HSCT were included in this study as the case group. A total of 153 patients who were verified to not have MN after HSCT were included in the control group (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The median age at the time of allo-HSCT was 36 years (range, 6 to 54 years) in MN patients. The median age of MN patients after allo-HSCT was 38 years (range, 8 to 55 years), and the median duration from allo-HSCT to MN was 20 months (range, 5 to 94 months).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the MN patients and the control group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMN (N\u0026thinsp;=\u0026thinsp;51)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo MN (N\u0026thinsp;=\u0026thinsp;153)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at allo-HSCT, yr, median[range]\u003c/p\u003e \u003cp\u003eFollow-up duration*, mo, median[range]\u003c/p\u003e \u003cp\u003eSex, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 [6\u0026ndash;54]\u003c/p\u003e \u003cp\u003e20 [5\u0026ndash;94]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 [7\u0026ndash;64]\u003c/p\u003e \u003cp\u003e44 [5-180]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.106\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003cp\u003e.622\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (62.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88 (57.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (37.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65 (42.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnderlying disease, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.127\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAML\u003c/p\u003e \u003cp\u003eALL\u003c/p\u003e \u003cp\u003eCML\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (39.2)\u003c/p\u003e \u003cp\u003e9 (17.6)\u003c/p\u003e \u003cp\u003e4 (7.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59 (38.6)\u003c/p\u003e \u003cp\u003e51 (33.3)\u003c/p\u003e \u003cp\u003e7 (4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003cp\u003e.051\u003c/p\u003e \u003cp\u003e.473\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (15.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (13.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.814\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (10.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.146\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDonor, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHLA matched\u003c/p\u003e \u003cp\u003eHLA partially matched\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (70.6)\u003c/p\u003e \u003cp\u003e15 (29.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55 (35.9)\u003c/p\u003e \u003cp\u003e98 (64.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDonor-recipient gender, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMatched\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (52.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e82 (53.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnmatched\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (47.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71 (46.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDonor-recipient ABO blood type, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMatched\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (62.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e94 (61.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnmatched\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (37.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59 (38.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSC Source, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePB\u0026thinsp;+\u0026thinsp;BM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e103 (67.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (62.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (31.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003cp\u003eGraft cell dose infused, median [range]\u003c/p\u003e \u003cp\u003eMNC, \u0026times;10\u003csup\u003e8\u003c/sup\u003e/kg\u003c/p\u003e \u003cp\u003eCD34, \u0026times;10\u003csup\u003e6\u003c/sup\u003e/kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (3.9)\u003c/p\u003e \u003cp\u003e8.49 [4.79\u0026ndash;30.2]\u003c/p\u003e \u003cp\u003e3.02 [1.33\u0026ndash;15.02]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1.3)\u003c/p\u003e \u003cp\u003e8.05 [1.16\u0026ndash;22.99]\u003c/p\u003e \u003cp\u003e2.73 [0.62\u0026ndash;10.23]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.261\u003c/p\u003e \u003cp\u003e.701\u003c/p\u003e \u003cp\u003e.147\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKidney function before allo-HSCT\u003c/p\u003e \u003cp\u003eBUN, mmol/L, median[range]\u003c/p\u003e \u003cp\u003eCreatinine, umol/L, median [range]\u003c/p\u003e \u003cp\u003eeGFR, ml/min, median [range]\u003c/p\u003e \u003cp\u003eUric acid ,umol/L, median [range]\u003c/p\u003e \u003cp\u003eKidney function after allo-HSCT\u003c/p\u003e \u003cp\u003eBUN, mmol/L, median[range]\u003c/p\u003e \u003cp\u003eCreatinine, umol/L, median[range]\u003c/p\u003e \u003cp\u003eeGFR, ml/min, median [range]\u003c/p\u003e \u003cp\u003eUric acid ,umol/L, median [range]\u003c/p\u003e \u003cp\u003eOverall aGVHD severity, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.64 [1.72\u0026ndash;7.9]\u003c/p\u003e \u003cp\u003e57 [27\u0026ndash;148]\u003c/p\u003e \u003cp\u003e123.8 [67.6\u0026ndash;218.0]\u003c/p\u003e \u003cp\u003e279 [89\u0026ndash;508]\u003c/p\u003e \u003cp\u003e4.10 [0.73\u0026ndash;12.88]\u003c/p\u003e \u003cp\u003e50 [22\u0026ndash;119]\u003c/p\u003e \u003cp\u003e123.9 [48.6-317.7]\u003c/p\u003e \u003cp\u003e260 [98\u0026ndash;529]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.93 [1.02\u0026ndash;9.05]\u003c/p\u003e \u003cp\u003e58.5 [24\u0026ndash;122]\u003c/p\u003e \u003cp\u003e121.9 [59.6-196.5]\u003c/p\u003e \u003cp\u003e274 [92\u0026ndash;586]\u003c/p\u003e \u003cp\u003e4.92 [1.27\u0026ndash;17.82]\u003c/p\u003e \u003cp\u003e56 [22\u0026ndash;131]\u003c/p\u003e \u003cp\u003e124.3 [42.3-209.5]\u003c/p\u003e \u003cp\u003e223 [68\u0026ndash;502]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.152\u003c/p\u003e \u003cp\u003e.441\u003c/p\u003e \u003cp\u003e.945\u003c/p\u003e \u003cp\u003e.892\u003c/p\u003e \u003cp\u003e.243\u003c/p\u003e \u003cp\u003e.337\u003c/p\u003e \u003cp\u003e.936\u003c/p\u003e \u003cp\u003e.031\u003c/p\u003e \u003cp\u003e.684\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNone to aGVHD I\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 (82.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e122 (79.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eaGVHD II-IV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (17.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (20.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e*Duration from HSCT to the diagnosis of MN for MN patients and from HSCT to the last follow-up for control group.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eClinical and laboratory characteristics of MN patients after allo-HSCT\u003c/h2\u003e \u003cp\u003eThe clinical manifestations of MN are summarized in Table S2. The most common clinical manifestations were proteinuria, hypoalbuminemia and edema of the legs. Other types of fluid retention included eyelid edema, whole-body edema, hydrothorax and ascites.\u003c/p\u003e \u003cp\u003eAnti-PLA2R antibody assays were performed for 15 MN patients, and all the results were negative. Low-titer anti-nuclear antibodies were detected in 21 MN patients, ranging from 1:20 to 1:320, and anti-Ro-52 antibody positivity was detected in 6 MN patients with positive anti-nuclear antibodies. The detailed laboratory data at the time of MN diagnosis are shown in Table S3. The median peak urine protein level was 5.4 g/d (range, 0.39 to 25.65 g/d), and 30 patients (58.8%) met the diagnostic criteria for NS.\u003c/p\u003e \u003cp\u003eTwo patients (3.9%) were also diagnosed with thrombotic microangiopathy (TMA) via subsequent kidney biopsy. Edema in the legs was observed as an initial symptom 188 and 235 days after allo-HSCT in these 2 patients. All of these patients developed AKI, proteinuria, hypertension and thrombosis in the legs during the course of disease. However, thrombocytopenia, elevated LDH, elevated bilirubin and schistocytes were observed in only 1 patient.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eBiopsy characteristics of the MNs\u003c/h2\u003e \u003cp\u003eAll MN patients were diagnosed by kidney biopsy. Detailed kidney biopsy reports, including light microscopy and immunofluorescence microscopy, were available for 36 patients, and detailed electron microscopy data were traceable for 31 patients. The biopsy results were summarized in Table S4. Two patients were also diagnosed with TMA. Based on the results of immunofluorescence staining, all patients were characterized by glomerular IgG deposits, but IgA and/or IgM deposits were also observed. All subtypes of IgG deposits were found in the glomeruli of MN patients after allo-HSCT. According to electron microscopy analysis, the immune complex was deposited mainly in the subepithelial area. Mesangial and subendothelial immune complex deposits were also found in MN patients after allo-HSCT. In addition, a total of 4 patients had immune deposits in the tubular basement membrane.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePredisposing risk factors for MN after allo-HSCT\u003c/h2\u003e \u003cp\u003eAge at allo-HSCT, HLA-matched donor, PB as the graft source, serum uric acid (UA) level after allo-HSCT (within 1 month) and aGVHD were included in the predisposing factor analysis. According to univariate and multivariate analysis, PB as the graft source (HR, 2.365; 95% CI, 1.281 to 4.268; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0060) and HLA-matched donor (HR, 2.346; 95% CI, 1.224 to 4.495; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0102) were identified as independent risk factors for MN after allo-HSCT (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePredisposing risk factors for MN after allo-HSCT\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRisk Factor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eUnivariate Cox Analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eMultivariate Cox Analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at HSCT, yr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.189\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHLA matched donor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.286\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.797\u0026ndash;6.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.0102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.346\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.224\u0026ndash;4.495\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePB as graft source\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.285\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.859\u0026ndash;5.805\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.0060\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.365\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.281\u0026ndash;4.268\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUA after HSCT (within 1 month), umol/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0579\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eaGVHD II-IV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.614\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eAbbreviations: yr, year; PB, peripheral blood; UA, uric acid; aGVHD, acute graft-versus-host disease; HR, hazard ratio; CI, confidence interval.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eAbbreviations: MN, membranous nephropathy; GI tract, gastrointestinal tract; Cs, corticosteroids; IS, immunosuppressant\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eAbbreviations: CR, complete remission; PR, partial remission; NR, no remission; Cs, corticosteroids; IS, immunosuppressant; AKI, acute kidney injury.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eChronic GVHD and MN\u003c/h2\u003e \u003cp\u003eA total of 34 MN patients developed cGVHD (limited cGVHD in 9 patients and extensive cGVHD in 25 patients). The most commonly involved organ was the skin, followed by the liver, mouth, eyes, lung and gastrointestinal (GI) tract (Table S5). As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, skin, liver and GI tract cGVHD developed mainly within 1 year after allo-HSCT, while the onset time of eyes and lung cGVHD was more discretely distributed. For 20 of 34 patients (58.8%), MN occurred in the context of specific cessation of Cs and/or immunosuppressant (IS) for cGVHD treatment, for a median duration of 3.3 months (range, 0.2 to 37.9 months). At the onset of MN, 15 of 34 patients (44.1%) had active cGVHD manifestations, and 18 of 34 patients (52.9%) achieved remission of prior cGVHD. The median duration from prior cGVHD to MN was 13 months (range, 0 to 87 months). One patient developed skin cGVHD after MN onset. The median onset time of MN was later than that of cGVHD mentioned above. There was a strong correlation between extensive cGVHD and MN after allo-HSCT (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0066 for cGVHD and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0001 for extensive cGVHD, adjusted for PB and HLA-matched donor).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eTreatment and outcomes of membranous nephropathy\u003c/h2\u003e \u003cp\u003eThe treatments and outcomes of the 20 MN patients at Peking University Institute of Hematology are summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Table S6. Three of the 20 (15%) patients were diagnosed with AKI and heavy proteinuria at MN onset; of these, 2 patients were also diagnosed with TMA and received combination therapy comprising 1 mg/kg/day Cs and IS; one patient achieved PR, and the other patient suffered from a decrease in GFR at the last follow-up. The other patient with AKI and heavy proteinuria received combination therapy comprising Cs\u0026thinsp;\u0026lt;\u0026thinsp;1 mg/kg/day and CSA. After treatment, a reduction in the serum creatinine concentration was observed, but there was still heavy proteinuria. Thirteen of the 20 patients (65%) were diagnosed with heavy proteinuria and 4 of the 20 patients (20%) were diagnosed with proteinuria. CR to initial therapy could only be achieved in patients who received the combination therapy comprising Cs and IS. Six patients who achieved a PR or NR at the initial therapy received subsequent therapy with the addition of Cs or IS. Two of the 6 patients achieved CR after subsequent therapy, and 2 of the 6 patients lacked a response to subsequent therapy. A decrease in the eGFR was observed in 3 patients at follow-up, including 1 patient with AKI at the onset of MN. Seven and seven of the 20 patients (35% and 35%) achieved CR and PR, respectively, at the last follow-up. One patient with heavy proteinuria relapsed at 18.2g/24h 3 months after PR because of cessation of Cs (1mg/kg/day) and MMF; subsequently, the patient was treated with Cs\u0026gt;1mg/kg/day and MMF and achieved PR 1 month later. Notably, only 2 MN patients who were diagnosed with TMA developed thrombosis in the lower legs during the course of disease. At the last follow-up, 1 of the 20 patients died from cerebral hemorrhage 7 years after MN onset and 1 of the 20 patients died from relapse of blood disease 6 months after MN onset.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eGlomerular diseases after allo-HSCT are very rare, and membranous nephropathy (MN) is the most common pathological type.\u003csup\u003e2, 3, 7\u003c/sup\u003e To our knowledge, this is the first multicenter study reporting the largest series of MN after allo-HSCT. We recorded and analyzed the clinical and kidney biopsy characteristics, predisposing risk factors, treatments and outcomes of MN patients after allo-HSCT.\u003c/p\u003e \u003cp\u003eIn 2009, Beck et al.\u003csup\u003e36\u003c/sup\u003e found that approximately 70% of patients with primary MN exhibited a high percentage of positive anti-PLA2R antibodies. However, in this study, all traceable anti-PLA2R antibody tests (n\u0026thinsp;=\u0026thinsp;15) in MN patients after allo-HSCT were negative. In previous research, the percentage of patients with MN positive for anti-PLA2R antibodies after HSCT was also low, ranging from 0\u0026ndash;20%.\u003csup\u003e7, 13, 15\u0026ndash;17\u003c/sup\u003e In 2022, Sethi et al.\u003csup\u003e15\u003c/sup\u003e reported that the protocadherin FAT1, was detected in the glomeruli of 14 patients with newly developed MN after allo-HSCT, indicating that MN after allo-HSCT has a different pathogenesis than primary MN.\u003c/p\u003e \u003cp\u003eIn previous studies, the average occurrence duration from HSCT to MN occurrence was between 15 and 24.4 months\u003csup\u003e3, 7\u0026ndash;10\u003c/sup\u003e, and in our study, it was 18 months. Therefore, MN might be a late-onset complication of allo-HSCT. The initial manifestation of increased urine protein in MN patients is inconspicuous, which might be one reason why the time at which symptoms were discovered lagged behind the time at which kidney lesions began. MNs after allo-HSCT are considered to be associated with cGVHD.\u003csup\u003e2, 3, 7, 14, 37\u0026ndash;41\u003c/sup\u003e The occurrence of MN might be related to prior cGVHD and cessation of Cs and/or IS. Additionally, extensive cGVHD generally occurred prior to MN, and active cGVHD might overlap with MN. Therefore, MN is not excluded as one of the manifestations of cGVHD.\u003c/p\u003e \u003cp\u003eHLA-matched donor and the use of PB as the graft sources were significant risk factors according to both univariate and multivariate analyses in this study. In previous studies, Byrne-Dugan et al.\u003csup\u003e7\u003c/sup\u003e revealed that compared with MN related to other organ transplantation, MN patients after HSCT were mostly HLA-matched. Hu et al.\u003csup\u003e3\u003c/sup\u003e and Beyar-Katz et al.\u003csup\u003e12\u003c/sup\u003e also found that in glomerular diseases, patients who received PB stem cells presented a higher probability of developing MN. However, because of the small sample size, previous studies were lack of risk factor analysis. Therefore, we conducted this nested case-control study including comparable control group to investigate the risk factors of MN after allo-HSCT.\u003c/p\u003e \u003cp\u003eThe clinical manifestations of MN after allo-HSCT were mostly legs edema and proteinuria. More than half of the MN patients were diagnosed with NS when they sought for treatment. In the present study, the deposits in the glomeruli were composed mainly of IgG. Previous studies have shown the same results.\u003csup\u003e8, 13\u0026ndash;15, 17\u003c/sup\u003e Electron microscopy analysis has indicated that, unlike in primary MN, immune deposits in MNs after allo-HSCT are deposited not only in the subepithelial area of the glomeruli but also deposited in subendothelial, mesangial, and even the tubular basement membrane.\u003csup\u003e14, 42\u003c/sup\u003e TMA is an early complication occurring mostly between 20 to 100 day after allo-HSCT \u003csup\u003e15, 43\u0026ndash;45\u003c/sup\u003e. However, in our study, 2 patients diagnosed with MN and TMA by kidney biopsy developed kidney manifestations more than 100 days after allo-HSCT. Previous, one case of late-onset HSCT-associated TMA overlapped with MN was reported.\u003csup\u003e46\u003c/sup\u003e The association between TMA and MN needs further study.\u003c/p\u003e \u003cp\u003eIn previous studies, corticosteroids demonstrated a good response in MN patients after allo-HSCT.\u003csup\u003e7\u0026ndash;9, 12, 17\u003c/sup\u003e MMF and calcineurin inhibitors have also been widely applied.\u003csup\u003e7, 9, 12\u003c/sup\u003e Previous studies have shown that rituximab effetely treats MN after HSCT alone or when corticosteroids, MMF or calcineurin inhibitors are ineffective.\u003csup\u003e7, 8, 12, 19, 21\u003c/sup\u003e In this study, treatment with a combination of Cs and IS tended to yield better outcomes; however, patients who experienced a poor response to initial treatment with Cs and IS still tended to experience no remission after subsequent therapy with the addition of Cs or IS. The most direct cause of death in MN patients was not kidney diseases in our study.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, this was a retrospective study; thus, missing data and confounding factors were unavoidable. Second, since the diagnosis of MN mostly requires kidney biopsy results and some patients with mild symptoms do not need to undergo kidney biopsy, the number of MN patients after allo-HSCT is underestimated. Third, this study was a nested case‒control study and MN is a rare complication after allo-HSCT. Although we randomly selected 3 control subjects for each MN patients to analyze predisposing risk factors, the control group could not represent the whole cohort because of the difference in population size.\u003c/p\u003e \u003cp\u003eIn conclusion, MN is a rare late-onset complication following allo-HSCT. The main manifestations included various levels of proteinuria and edema. Patients who received combination treatments of Cs and IS appeared to have better outcomes; however, those who lacked a response to treatments might suffer from continuous proteinuria or a decrease in kidney function. Therefore, active treatments are essential for MN patients after allo-HSCT. However, further research is needed.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eyr\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eyear\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003emo\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emonth\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAML\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eacute myeloid leukemia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eALL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eacute lymphoblastic leukemia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCML\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003echronic myeloid leukemia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMDS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emyelodysplastic syndrome\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHLA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehuman leukocyte antigen\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estem cell\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eperipheral blood\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebone marrow\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMNCs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emononuclear cells\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBUN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eblood urea nitrogen\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\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eThe authors thank the patients and medical staff who participated in this study, and the department of medical record libraries for providing medical records.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthorship:\u0026nbsp;\u003c/strong\u003eYJ, PZ, and YYZ analyzed the data and wrote the manuscript; YJ and PZ performed statistical analysis; YJ and PZ designed the study, analyzed the data, and edited the manuscript; the remaining authors contributed to the data collection and helped write and edit the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of interest:\u003c/strong\u003e The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e: The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis work was supported by the National Key Research and Development Program of China (No. 2021YFC2500304), Key Program of National Natural Science Foundation of China (No. 82230004), National Natural Science of Foundation of China (No. 81970113) and Capital Health Research and Development of Special (No. 2022-1-4082).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e: The data that support the findings of this study are available on request from the corresponding author, Xiao-Hui Zhang, PhD, MD. The data are not publicly available due to their containing information that could compromise the privacy of research participants.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eZhang, X. H.; Chen, J.; Han, M. Z.; Huang, H.; Jiang, E. L.; Jiang, M.; Lai, Y. R.; Liu, D. H.; Liu, Q. F.; Liu, T.; Ren, H. Y.; Song, Y. P.; Sun, Z. M.; Tang, X. W.; Wang, J. M.; Wu, D. P.; Xu, L. P.; Zhang, X.; Zhou, D. B.; Huang, X. J., The consensus from The Chinese Society of Hematology on indications, conditioning regimens and donor selection for allogeneic hematopoietic stem cell transplantation: 2021 update. \u003cem\u003eJ Hematol Oncol \u003c/em\u003e\u003cstrong\u003e2021,\u003c/strong\u003e \u003cem\u003e14\u003c/em\u003e (1), 145.\u003c/li\u003e\n\u003cli\u003eTroxell, M. L.; Pilapil, M.; Miklos, D. B.; Higgins, J. 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X.; Sun, X. W.; Huang, Q. S.; Liu, X.; Zhu, X. L.; Wang, F. R.; Zhang, Y. Y.; Mo, X. D.; Han, W.; Wang, J. Z.; Wang, Y.; Chen, H.; Chen, Y. H.; Zhao, X. Y.; Chang, Y. J.; Xu, L. P.; Liu, K. Y.; Huang, X. J.; Zhang, X. H., A prognostic model (BATAP) with external validation for patients with transplant-associated thrombotic microangiopathy. \u003cem\u003eBlood Adv \u003c/em\u003e\u003cstrong\u003e2021,\u003c/strong\u003e \u003cem\u003e5\u003c/em\u003e (24), 5479-5489.\u003c/li\u003e\n\u003cli\u003eMasuzawa, N.; Nishimura, A.; Kitani, T.; Tamagaki, K.; Sugitani, M.; Nagoshi, H.; Kuroda, J.; Konishi, E., A Case of the nephrotic syndrome in bone marrow transplantation recipient, histologically showing overlapped glomerular lesions of thrombotic microangiopathy and membranous nephropathy. \u003cem\u003ePathol Int \u003c/em\u003e\u003cstrong\u003e2017,\u003c/strong\u003e \u003cem\u003e67\u003c/em\u003e (12), 620-625.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"allogeneic hematopoietic stem cell transplantation, membranous nephropathy, chronic graft-versus-host disease, quality of life","lastPublishedDoi":"10.21203/rs.3.rs-4247321/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4247321/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMembranous nephropathy (MN) is a rare complication that can occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT). MN patients may develop nephrotic syndrome or even kidney failure, which greatly affects their quality of life and prognosis. However, current information regarding MN after allo-HSCT is very limited. Thus, a multicenter nested case‒control study was conducted. Patients who had been diagnosed with MN after allo-HSCT were retrospectively identified at 8 HSCT cent res. A total of 51 patients with MN after allo-HSCT were included. The median age of MN patients after allo-HSCT was 38 years, and the median duration from HSCT to MN was 18 months. The use of HLA-matched donors (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0102) and peripheral blood as the graft source (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0060) were identified as independent predisposing risk factors for the onset of MN after allo-HSCT. Compared with those in the control group, the incidence of extensive chronic graft-versus-host disease was greater in the MN patients (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). A total of 31 patients developed nephrotic syndrome. Patients receiving combination treatments of corticosteroids and immunosuppressants appeared to have better outcomes. In conclusion, MN is a rare but occasionally severe complication following HSCT and may require active treatment.\u003c/p\u003e","manuscriptTitle":"Clinical characteristics of membranous nephropathy after allogeneic hematopoietic stem cell transplantation: a real-world multicenter study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-29 13:01:22","doi":"10.21203/rs.3.rs-4247321/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-05-16T13:06:44+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-10T19:34:41+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-01T15:33:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"73e601c6-3280-4dcb-9acd-5cc974260018","date":"2024-04-23T06:41:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"47801d45-1329-41c6-9e89-e4dcb6384a39","date":"2024-04-22T15:15:16+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-22T11:46:41+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-19T01:38:45+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-19T01:38:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2024-04-10T12:17:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e3c3660d-863d-48d7-b7e8-22e42d67f741","owner":[],"postedDate":"April 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-07-01T17:12:15+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-29 13:01:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4247321","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4247321","identity":"rs-4247321","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}