Novel Cellular Immunotherapy in Refractory Membranous Nephropathy: A First-in-Human Trial of Human Umbilical Cord Blood-Derived Mononuclear Cells

Novel Cellular Immunotherapy in Refractory Membranous Nephropathy: A First-in-Human Trial of Human Umbilical Cord Blood-Derived Mononuclear Cells | 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 Novel Cellular Immunotherapy in Refractory Membranous Nephropathy: A First-in-Human Trial of Human Umbilical Cord Blood-Derived Mononuclear Cells 美君 刘, 边璐 bian, 孙海棚 sun, 刘翠珍 liu, 刘国军 liu, 鹏 张, 王丽雅 wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6824104/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract (Objective) The clinical value of human umbilical cord blood mononuclear cells (hUCBMNCs) in chronic kidney disease and acute renal failure has been confirmed. This study further explores the clinical efficacy and safety of hUCBMNCs in the treatment of refractory membranous nephropathy (MN), and observes the changes in clinical indicators and lymphocyte subsets in patients with refractory MN who have had poor long-term follow-up results with the classic treatment regimen after receiving hUCBMNCs. (Methods) Eight patients with refractory MN diagnosed at Taian Central Hospital in Shandong Province from January 2022 to March 2024 were enrolled. All eight patients had received the classic treatment regimen for MN with poor results. They were then treated with intravenous infusion of hUCBMNCs (a course of treatment consisting of three intravenous infusions of 2.00×10^8 (100 ml) units of hUCB-MNCs, with a 1-week interval between each infusion. Individual patients with BMI > 30 received an additional intravenous infusion of 2.00×10^8 (100 ml) units of hUCB-MNCs). The clinical manifestations and ancillary examination results of the patients were collected. The therapeutic effects and disease outcomes were observed at short-term follow-up (1 week, 2 weeks, and 4 weeks after treatment) and long-term follow-up (12 weeks after treatment). (Results) During the short-term follow-up, 7 patients experienced varying degrees of clinical improvement during the treatment process, while 1 patient showed no response to the treatment. The 24-hour urinary protein excretion and concentration were significantly improved during the treatment (P＜0.05). The maximum reduction in 24-hour urinary protein excretion was 46%-79%. The serum albumin levels increased in 75% of the patients, and the levels of CD3 + 4 + 8 + lymphocytes were elevated (P＜0.05). By the end of the long-term follow-up, 5 patients had significant improvements in 24-hour urinary protein excretion and concentration (P＜0.05), 2 patients showed no response to the treatment, and 1 patient withdrew from the long-term follow-up. The effective rate of treatment was 71%. The reduction in 24-hour urinary protein excretion in the 5 patients ranged from 17% to 76%, with 1 patient achieving complete remission (CR) and 3 patients achieving partial remission (PR). The levels of serum B lymphocytes and NK lymphocytes were increased compared to before the treatment (P＜0.05), and all patients experienced an improvement in fatigue symptoms. (Conclusion) hUCBMNCs can significantly reduce the 24-hour urinary protein excretion and concentration, increase the serum albumin levels, and improve the condition and symptoms of patients with refractory MN through immune regulation and immune system reconstruction. Improvement can be observed immediately after the first treatment, with a rapid onset of action, no need for an accumulation dose, few adverse reactions, and high safety. Umbilical cord blood mononuclear cells membranous nephropathy Figures Figure 1 INTRODUCTION Membranous nephropathy (MN) is a pathological and histological type of glomerular disease caused by various factors, often presenting as asymptomatic proteinuria or nephrotic syndrome. Primary MN is the most common type encountered clinically. The treatment of MN is currently determined based on risk stratification assessment and is mainly divided into immune-related and non-immune treatments. Immune-related treatments primarily focus on the following mechanisms: clearance of B lymphocytes, reduction of antibody production, and inhibition of T-cell activation to indirectly decrease antibody generation. The main treatment regimens include combinations of Glucocorticoids (GCs) with Calcineurin inhibitors (CNIs), Cyclophosphamide (CTX), or Rituximab (RTX). However, we have observed that some MN patients, despite receiving adequate doses and completing a full 6-month course of these classic regimens, still experience a reduction in 24-hour urinary protein excretion (24-hUPE) of less than 50% from baseline, with incomplete remission or poor response. These cases are defined as refractory MN. Common clinical reasons for refractory MN include glucocorticoid resistance, glucocorticoid dependence, and frequent relapses. Despite repeated treatments, the outcomes remain unsatisfactory, and some patients exhibit resistance to monoclonal antibodies. In China, refractory MN is often managed with multi-targeted therapies or long-course, low-dose RTX regimens [ 1 ] . However, regardless of the treatment regimen used, the remission rate remains limited. In recent years, the coordinated development of cell biology and clinical medical technology has opened a new chapter in the biological treatment of MN. The value and safety of umbilical cord blood cell therapy for nephropathy have been confirmed. Human umbilical cord blood mononuclear cells (hUCBMNCs) are a heterogeneous group of cells with a single nucleus, including mesenchymal stem cells, hematopoietic stem cells, and others. As a source of stem cells with multi-directional differentiation potential and immune regulatory functions, hUCBMNCs have been proven in multiple studies to possess immune regulatory, anti-inflammatory, and anti-fibrotic effects. Their clinical benefits in improving chronic kidney disease have also been demonstrated in several studies [ 2 ]−[ 6 ] . This article reports for the first time on the treatment of refractory MN with hUCBMNCs, observing the clinical manifestations and outcomes in patients following treatment. The analysis and summary of therapeutic effects and prognostic changes provide new insights for the cellular-level treatment of refractory MN. METHODS The subjects of our study were eight patients with refractory MN admitted to Taian Central Hospital in Shandong Province from January 2022 to March 2025. The clinical data of all patients, including gender, age, medical history, pathological reports, and treatment regimens, were collected (see Tables 1 and 2 for details).This study was conducted in strict accordance with the ethical principles of the Declaration of Helsinki. All study procedures involving human participants were approved by the Medical Ethics Committee of Taian City Central Hospital (Approval No. 2024-06-22). Written informed consent was obtained from all participants prior to receiving hUCB-MNCs clinical treatment. Inclusion criteria :1.All patients had a confirmed diagnosis of MN through renal biopsy or positive anti-phospholipase A2 receptor (PLA2R) antibody testing. The diagnosis of refractory MN was defined as： Prior treatment with glucocorticoids (GC) combined with cyclophosphamide (CTX), cyclosporine (CsA), or tacrolimus (TAC), or repeated switching of immunosuppressive regimens.Failure to achieve partial remission after ≥6 months of the above immunosuppressive therapy [defined as serum albumin ≥30 g/L and a ≥50% reduction in urinary protein-to-creatinine ratio (UPCR) from baseline], or relapse of proteinuria (reappearance of urinary protein ≥3.5 g/day after complete or partial remission), or a ≥50% increase in serum creatinine from baseline , meeting the criteria for refractory primary MN (PMN) [1] .2.Patients aged between 18 and 65 years.3.Before enrollment in this study, patients understood and signed the informed consent form and agreed to comply with the requirements of the study protocol; they also agreed not to participate in any other clinical studies. Exclusion criteria :1.Patients diagnosed with type 1 or type 2 diabetes according to the WHO criteria (1999) .2.Estimated glomerular filtration rate (eGFR) less than 30 ml·min⁻¹·(1.73 m²)⁻¹.3.Patients with secondary MN.4.Patients with malignancies, severe infections, or dysfunction of vital organs such as the heart, lungs, or liver.5.Patients with mental disorders who could not cooperate with the treatment.6.Pregnant or breastfeeding women.7.Patients with active hepatitis. Table 1 Baseline characteristics of patients with refractory MN characteristics /case 1 2 3 4 5 6 7 8 sex Male Female Male Male Male Male Male Female age（y） 29 56 57 56 34 34 46 40 MN Stage IV II Unknow II II III III Unknow PLA2R Status Negative Positive Positive Positive Negative Negative Positive Positive Duration of disease（month） 91mo 36mo 23mo 30mo 60mo 38mo 36mo 13mo Comorbidities hypertension、 hyperuricemia steroid diabetes、hypertension hypertension 、pulmonary fibrosis hypertension 、Solitary pulmonary nodules、liver cysts、kidney cysts、sParkinson's disease hypertension、 IgA Hypertension、 Hydronephrosis、Renal calculi Hypertension Hypertension complications None None None None None None None None Rituximab Treated Treated Not treated Not treated Not treated Treated Treated Treated Current usage plan (usage time) ARB+Tacrolimus（80mo） Tacrolimus（9mo） Tacrolimus+GCs（10mo） Tacrolimus+GCs（12mo） MMF +Tacrolimus+GCs（12mo） ARB+Finerenone+CSA+GCs （10mo） None None Abbreviations: ARB, angiotensin II receptor blocker; CNI, calcineurin inhibitor; MMF：Mycophenolate mofetil；CSA：Cyclosporine A Table 2 clinical characteristics Demographics Overall Cohort （ n=8 ） PLA2R U/mL 2.96（2.90，26.88） 24-hUPE g/24h 2.55（1.42，3.73） 24-hUCP g/L 0.97(0.80，2.37) Scr μmoI/L 80.4(51.75，90.15) eGFRml/min 101.25(75.28，114.6) BUN mmol/L 6.78(4.50，7.05) Alb g/L 37.7(35.20，44.30) Previous therapy Rituximab, n (%) 5(62.5%) Cumulative rituximab courses Median(g) 2.40（2.15，4.80） Prednisone, n (%) 8(100.0%) Mycophenolate, n (%) 2(25.0%) CNI (tacrolimus or cyclosporine), n (%) 6(75.0%) ARB, n (%) 6(75.0%) Preparation of hUCB-MNCs HUCBMNCs were provided by the Shandong Province Umbilical Cord Blood Hematopoietic Stem Cell Bank. The preparation method was as follows: fresh umbilical cord blood was transferred to a 50ml centrifuge tube, centrifuged at 900g for 15 minutes, the upper plasma was removed, and the lower cells were diluted with physiological saline. After mixing, they were added to Ficoll stratification solution and centrifuged at 800g for 20 minutes. After washing the white membrane layer cells twice with physiological saline (centrifuging at 500 g and 300 g for 10 min at room temperature), resuspended them to obtain a mononuclear cell suspension. After cell counting, viability detection, and flow cytometry phenotype detection, each serving was made into 3 ml containing 2 × 10 8 cells and used in this study（ As shown in Figure 1 ）. HUCBMNCs Infusion Protocol All patients underwent standardized pre-infusion evaluations , including assessments of liver/kidney function , biochemical profiles , tumor markers , cardiopulmonary capacity , and neurological/psychiatric status to confirm eligibility. Based on conventional treatment measures, umbilical cord blood mononuclear cells are intravenously infused once a week, with a single cell count of 2×10 8 . Subjects with BMI30 received four treatments. To prevent possible allergic reactions, 5mg dexamethasone was intravenously injected and 25mg promethazine was intramuscularly injected 5 minutes before infusion, and the patient's vital signs during infusion were monitored by electrocardiogram（ As shown in Figure 1 ）. Follow-up The follow-up was concluded on March 31, 2025. Follow-up assessments were conducted through outpatient visits and hospital evaluations at 1 week, 2 weeks, 4 weeks, and 12 weeks after the initial infusion. General information, including name, gender, and age, was collected. Clinical data, such as pathological results, initial treatment or relapse retreatment, and previous treatment regimens, were also gathered. Laboratory data were tested before each treatment and during the follow-up period. All indicators were derived from the laboratory tests performed during the patients' hospital stays or outpatient follow-ups at our hospital. This study was approved by the Ethics Committee of Taian Central Hospital (approval number 2024-06-22), and all patients or their guardians signed the informed consent form for hUCBMNCs clinical therapy. Outcomes The primary evaluation indicators included the efficacy rate of treatment, remission rate, complete remission (CR), and partial remission (PR). Specifically:CR was defined as a urinary protein excretion of <0.5 g/d , accompanied by a normal serum albumin level and a normal serum creatinine level. PR was defined as a urinary protein excretion of ≥ 0.3 g/d and < 3.5 g/d, or uPCR ≥ 0.3 g/g and < 3.5 g/g, with a 50% or greater reduction from peak values accompanied by an improvement or normalization of the serum albumin level and a stable serum creatinine. Relapse was defined as a recurrence of proteinuria with urinary protein excretion ≥ 3.5 g/d or urinary protein-to-creatinine ratio (uPCR) ≥ 3.5 g/g after remission had been achieved. Efficacy rate of treatment = (Number of patients with remission) / (Total number of patients) × 100%. Remission rate = (Number of patients with complete remission + Number of patients with partial remission) / (Total number of patients) × 100%. Secondary evaluation indicators included changes in uPCR, serum albumin（Bun）, serum creatinine（Scr）, anti-PLA2R antibodies, and lymphocyte subsets in all patients after the administration of hUCBMNCs . Statistical Analysis Continuous variables were tested for normality. Normally distributed continuous variables were presented as mean ± standard deviation, and comparisons among three groups were performed using one-way analysis of variance (ANOVA). Non-normally distributed continuous variables were expressed as medians, and comparisons among three groups were conducted using the Friedman test for K related samples. Categorical variables were described using frequencies and percentages (%), and comparisons between groups were made using the chi-square test or Fisher's exact test. All statistical analyses were performed using SPSS version 26.0. All figures were generated using GraphPad Prism version 9. A p-value of less than 0.05 was considered statistically significant. Short-term follow up During the short-term follow-up, the 24-hUPE significantly decreased (P＜0.05), and the 24-hour urinary total protein (24-hUTP) was alleviated (P＜0.05) during the infusion process. The serum albumin levels increased in 75.0% of the patients. One patient achieved complete remission (CR) 2 weeks after the first infusion, two patients achieved PR, and two patients had a reduction in 24-hUPE but did not reach the level of PR. Flow cytometry was used to analyze the proportions of lymphocyte subsets. The infusion of hUCB-MNCs significantly increased the levels of CD3 + 4 + 8 + cells (P＜0.05), while the levels of other lymphocytes remained unchanged. There were no significant changes in Scr、BUN、or eGFR(see Tables 3 and 4 for details). Long-term follow up During the long-term follow-up, one patient withdrew from the study due to relocation. The 24-hUPE significantly decreased (P＜0.05) in 71.4% of the patients during the infusion process, with a reduction range of 31% to 75%. The 24-hUTP also significantly decreased (P＜0.05). One patient achieved CR, two patients achieved PR, two patients had a reduction in 24-hUPE but did not reach the level of PR, and two patients showed no significant improvement. An upward trend in serum albumin levels was observed in some patients, while Scr、BUN and other indicators remained unchanged. The total levels of lymphocytes, CD3 + 4 + 8 + , CD19 + , and NK cells significantly increased (P＜0.05). However, there were no significant changes in the absolute values of helper/inducer T lymphocytes and suppressor/cytotoxic T lymphocytes(see Tables 3 and 5 for details). Table 3 Primary Outcomes of Patients after hUCBMNCs Demographics Overall Cohort Mean time to treatment effect(W) 1 Short-term follow up （ n=8 ） Remission（n，%） 7（87.5%） Mean time to first partial remission （w） 1.7 Mean time to first complete remission （w） 1 Long-term follow up （ n=7 ） Remission （n，%） 6（75.0%） PR（n，%） 2（25.0%） CR（n，%） 1（12.5%） First relapse-free survival time during follow-up（w） 12（10.0，12.0） Treatment failure （n，%） 1（12.5%） Relapse （n，%） 0（0%） Table 4 Changes in Clinical Indicators After Treatment （ Short-term follow up ） Clinical Indicators Pre-treatment （ n=8 ） 1 week post-treatment （ n=8 ） 4 weeks post-treatment （ n=8 ） P PLA2R U/mL 2.96（2.90，26.88） 2.97（2.91，27.69） 2.90（2.90，2.90） 0.129 24-hUPE g/24h 2.55（1.42，3.73） * 1.40（0.90，2.89） * 2.14（1.20，2.59） 0.021 24-hUCP g/L 0.97(0.80，2.37) * 0.60（0.41，1.05） * 0.84（0.64，1.22） 0.044 Scr μmoI/L 80.4(51.75，90.15) 81.75（49.78，90.43） 92.00（44.45，110.43） 0.657 eGFRml/min 101.25(75.28，114.6) 94.07（86.68，115.88） 79.92（69.26，117.60） 0.882 BUN mmol/L 6.78(4.50，7.05) 7.42（4.25，7.93） 7.73（4.50，8.60） 0.786 Alb g/L 37.7(35.2，44.3) 35.95（34.78，44.20） 41.10（36.13，44.10） 0.497 lymphocyte count （ UL ） 1509（1080.25，2010.25） 1674.00（1109.00，1917.50） 1862.00（1297.25，2917.50） 0.197 helper/inducer T lymphocytes （ UL ） 578.00（140.00，915.75） 596.00（128.84，724.75） 641.50（167.25，1173.25） 0.882 suppressor/cytotoxic T lymphocytes （ UL ） 417.00（95.25，515.00） 275.00（63.25，570.75） 380.00（87.25，23.50） 0.508 CD3 + 4 + 8 + cells （ UL ） 7.50（2.50，23.00） # 8.50（5.25，14.50） * 9.50（8.25，23.50） *# 0.034 CD3 + cells （ UL ） 1309.50（1160.75，1511.50） 1206.50（826.25，1546.00） 1436.00（1087.50，2194.75） 0.607 CD19 + cells （ UL ） 73.50（0，341.75） 80.00（1.25，210.25） 121.50（11.00，313.00） 0.241 NK cells （ UL ） 126.50（77.75，247.75） 139.00（77.25，349.25） 292.00（156.75，328.00） 0.197 Groups marked with *# indicate a statistically significant difference between the two groups (P＜0.05). Table 5 Changes in Clinical Indicators After Treatment （ Long-term follow up ） Clinical Indicators Pre-treatment （ n=7 ） 1 week post-treatment （ n=7 ） 4 weeks post-treatment （ n=7 ） 12 weeks post-treatment （ n=7 ） P PLA2R U/mL 2.95（2.90，2.98） 2.96（2.90，2.98） 2.90（2.90，2.98） 2.90（2.90，2.91） 0.066 24-hUPE g/24h 2.10（1.40，3.65） # * 1.12（0.87，2.40）* 2.04（1.04，2.70） 1.25(0.88，1.50) # 0.033 24-hUCP g/L 0.94（0.78，1.96）* & 0.54（0.40，0.70） & 0.82（0.62，1.19） # 0.56(0.35，0.65)* # 0.004 Scr μmoI/L 87.00（57.00，91.00） 85.00（58.10，91.90） 99.00（51.50，110.90） 97.00(54.00，105.00) 0.856 eGFRml/min 98.22（70.00，104.00） 92.37（86.28，106.52） 73.84（68.00，110.38） 74.00(70.00，114.55) 0.692 BUN mmol/L 7.00（6.00，7.06） 7.83（5.00，7.96） 7.84（6.00，8.80） 7.00(5.00，8.72) 0.850 Alb g/L 38.40（35.80，45.70） 36.90（34.70，44.60） 41.20（39.50，45.00） 42.00(36.00，44.00) 0.366 lymphocyte count （ UL ） 1448（967.00，2060.00）* 1605.00（1091.00，1929.00） # 1470.00(1249.00，3127.00) 2408.00(1532.00，3588.00)* # 0.029 helper/inducer T lymphocytes （ UL ） 635.00（371.00，958.00） 694.00（334.00，727.00） 685.00(516.00，1330.00) 737.00(54.00，866.00) 0.934 suppressor/cytotoxic T lymphocytes （ UL ） 421.00（318.00，533.00） 308.00（190.00，583.00） 421.00(289.00，819.00) 431.00(39.00，552.00) 0.615 CD3 + 4 + 8 + cells （ UL ） 8.00（4.00，26.00） 8.00（5.00，16.00）* # 10.00(9.00，28.00) # 11.00(10.00，18.00)* 0.01 CD3 + cells （ UL ） 1291.00（1150.00，1541.00） 1080.00（826.00，1567.00） 1257(1076.00，2348.00) 1795.00(1307.00，2508.00) 0.094 CD19 + cells （ UL ） 112.00（0，378.00）* 132.00（5.00，226.00） 202.00(35.00，321.00) 226.00(61.00，384.00)* 0.041 NK cells （ UL ） 125.00（74.00，199.00）* 85.00（76.00，242.00）* 267.00(127.00，325.00) 332.00(119.00，358.00)* # 0.02 Groups marked with *# indicate a statistically significant difference between the two groups (P＜0.05). Safety During the follow-up period, no severe treatment-related adverse events were observed during or shortly after treatments.One patient (12.5%) experienced diarrhea 5 weeks after the treatment due to improper diet. The patient recovered after symptomatic antidiarrheal and anti-infective treatments.Another patient (12.5%) had elevated uric acid levels 6 weeks after the treatment following the consumption of seafood, which led to an increase in serum creatinine and 24-hUPE. Symptomatic treatments for renal protection and uric acid reduction were administered. After the serum uric acid levels normalized, the serum creatinine and 24-hUPE levels improved again. DISCUSSION The therapeutic value of hUCBMNCs in chronic kidney disease has piqued our interest in exploring their potential role in MN. In this study, 7 out of 8 patients (87.5%) with refractory MN achieved PR or CR (12.5%). Even among the 5 patients (62.5%) who had previously shown poor response to rituximab treatment, significant efficacy was observed. During the treatment, all patients experienced varying degrees of reduction in 24-hUPE (P＜0.05). In the short-term follow-up, a relatively rapid onset of action was observed, with 7 patients (87.5%) showing improvement within 1 week after the initial treatment. One patient (12.5%) achieved complete remission 2 weeks after the initial treatment, and three patients (37.5%) achieved partial remission. In previous studies, the median time to remission with rituximab and obinutuzumab treatments was reported to be 2.7-7.1 months [2]-[3] . In contrast, we found that hUCBMNCs had a faster onset of action, without the need for an accumulation dose, with most patients showing improvement after the first treatment. However, after the completion of the three-infusion course, we observed an upward trend in 24-hUPE in five patients at 4 weeks post-treatment. Among them, four patients experienced a temporary increase followed by a decrease, and they remained in remission at the end of the follow-up. We believe that this fluctuation in 24-hUPE warrants further attention in future studies, as it may suggest that some patients may require additional treatment. By the end of the long-term follow-up, we observed significant reductions in 24-hUPE and 24-hUPC (P＜0.05), with two patients achieving PR and one achieving CR. Compared to the improvement in 24-hUPE, only some patients with improved conditions showed an increase in serum albumin, which is consistent with the phenomenon that urinary parameters improve first during the remission process of membranous nephropathy. Moreover, all patients experienced significant improvement in clinical symptoms such as fatigue and insomnia. One patient with a history of Parkinson's disease reported a marked improvement in resting tremors after stem cell infusion, which may be related to the neurotrophic factor secretion and neuronal differentiation of hUCB-MNCs, contributing to protective and reparative effects [9]-[10] . Oxidative stress and fibrotic reactions are key pathological processes in membranous nephropathy. The anti-inflammatory and anti-fibrotic effects of hUCB-MNCs have been demonstrated in studies on myocardial injury [6] . In a study by Li Xuwei et al., hUCBMNCs were found to prevent and improve renal tubulointerstitial fibrosis by inhibiting oxidative stress and inflammation in renal tissues [7] . Therefore, we believe that the improvement in proteinuria observed in this study is related to the regulation of inflammatory responses and renal fibrosis by hUCBMNCs.No significant changes in serum creatinine or eGFR were observed in this study. We hypothesize that this may be related to transient increases in serum creatinine levels due to elevated uric acid levels in two patients. However, based on previous research, we believe that increasing the sample size and extending the follow-up period would yield better results. This is because hUCB-MNCs have been shown to differentiate into new renal cells or vascular endothelial cells to reconstruct sclerotic or ischemic renal tissues, as demonstrated in an in vitro experiment by Paker et al. in 2011 [8] . hUCB-MNCs can home to the kidneys and differentiate into the required cells to repair and restore renal function. Additionally, in animal experiments, Zhang Chi et al. observed that hUCBMNCs can improve renal injury by enhancing local organ blood supply [9]. The specific mechanisms may involve the regulation of humoral effects and the promotion of vascular endothelial growth factor (VEGF) secretion by hUCBMNCs, with these regulatory effects being significantly enhanced under hypoxic conditions. This function can effectively and promptly alleviate early renal injury following ischemia-reperfusion [10] . An interesting observation was made in the five patients with a history of rituximab treatment. After hUCBMNCs therapy, there was a significant increase in the previously depleted B lymphocytes (P＜0.05). We propose that hUCB-MNCs may regulate the balance of B cell subsets, particularly promoting the redistribution and maturation of naive B cells within the B cell population that does not express CD20 [11] . Moreover, hUCBMNCs can secrete cytokines to modulate immune responses and promote the proliferation of regulatory B cells (Bregs), thereby improving immune reactions [12] . This redistribution of B cells may help reduce the production of autoantibodies, thereby alleviating glomerular basement membrane damage and synergistically assisting patients in rebuilding their immune system alongside rituximab. In this study, the levels of NK cells and CD3 + 4 + 8 + lymphocytes all increased. The rise in NK cells following hUCBMNCs treatment can enhance the immune system's surveillance function, aiding in the clearance of damaged cells and abnormal immune cells, thereby alleviating inflammatory responses [13] . Simultaneously, hUCBMNCs regulate the immune microenvironment, optimize the distribution of cell subsets, and improve inflammatory states, collectively contributing to the alleviation of patients' conditions and the reduction of urinary protein excretion. In vitro studies have shown that hUCBMNCs can inhibit T cell proliferation and activation, induce apoptosis, and alter the balance of cytokines TH1 and TH2 [14] . However, no significant changes in T lymphocytes were observed in this study, which may be related to the small sample size. Among the five patients who were on tacrolimus treatment during the study, four patients showed initial improvement in the short-term follow-up, with two achieving CR. By the end of the long-term follow-up, the treatment efficacy rate reached 60%, with one patient achieving CR and another achieving PR. We believe that tacrolimus, by inhibiting T cell activation and reducing cell-mediated immune responses, may work synergistically with hUCBMNCs, which can regulate B cell function and further optimize the immune microenvironment. This combined effect may more effectively suppress abnormal immune reactions, promote B cell recovery, and contribute to the alleviation of patients' conditions and the reduction of urinary protein excretion [11] . In analyzing patients who experienced disease flare-ups during treatment, we identified the following factors: hyperuricemia and overweight status. Among the three overweight patients (BMI＞30), all showed initial improvement in 24-hUPE after the three treatments, but experienced a relapse trend within one month during follow-up. Two of these patients were given an additional fourth treatment, and three months later, their 24-hUPE levels, after a temporary increase, continued to decline. This suggests that we should tailor individualized hUCBMNCs infusion treatment plans based on BMI. Additionally, as the number of treatments increased, the majority of patients experienced gradual improvement in their conditions. This is consistent with another study on umbilical cord blood, which proposed that improvement is related to the degree of renal tubular fibrosis, the duration of treatment, and the frequency of infusions. The more infusions, the better the improvement. Therefore, multiple treatments with human umbilical cord blood mononuclear cells are necessary. Based on this study, we suggest that the number of treatments should be more than four, and we also recommend increasing the cell dosage per infusion. In this study, one patient showed no response throughout the treatment course. We found that a pulmonary CT scan performed at the beginning of the treatment indicated pulmonary fibrosis, which we believe may have been the primary factor affecting the treatment outcome. A 2015 study on neonates confirmed that hUCBMNCs first home to the lungs upon entering the human body, and the health status of the lungs can influence the long-term engraftment of hUCBMNCs and the treatment efficacy [15] . Several limitations exist in our study. First, the relatively small sample size means that our conclusions need to be further verified through multicenter, large-sample, long-term follow-up clinical trials. However, as the first exploratory clinical trial in this area, our study still reached promising conclusions with significant clinical implications. Second, this study focused on the use of hUCBMNCs for refractory MN, and its findings cannot be generalized to all patients with membranous nephropathy. The long-term adverse effects and the correlation between renal pathology and therapeutic efficacy could be explored in future studies. Third, cellular therapy for membranous nephropathy is still in its infancy, with few studies currently available. The treatment dosage used in this study was based on empirical evidence. Based on our findings, we suggest increasing the number of treatments and the cell dosage per treatment to achieve better therapeutic outcomes. Conclusion In conclusion, our study demonstrated that hUCBMNCs have a favorable therapeutic effect on patients with refractory MN who have shown poor response to first-line treatments such as tacrolimus, rituximab, and cyclophosphamide. hUCBMNCs can significantly improve 24-hUPE and 24-hUCP. Through immune regulation and immune system reconstruction, hUCBMNCs can modulate the immune microenvironment to treat refractory MN. They also appear to have synergistic therapeutic effects with rituximab and tacrolimus, with high safety and few adverse reactions. hUCBMNCs hold great potential for future applications in the field of nephrology. It is essential to establish standards for the control and clinical application of hUCBMNCs and to conduct multicenter, large-sample, randomized controlled clinical trials in the future, in order to provide a safer and more effective new treatment option for refractory MN. Declarations Disclosure Statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This work is original and has not been published elsewhere, nor is it currently under consideration for another journal. Ethical Statement This study was conducted in strict accordance with the ethical principles of the Declaration of Helsinki. All study procedures involving human participants were approved by the Medical Ethics Committee of Taian City Central Hospital (Approval No. 2024-06-22). Written informed consent was obtained from all participants prior to receiving hUCB-MNCs clinical treatment. Funding Declaration The authors declare that this study received no external funding. Author Contribution *L.B.: Investigation, Writing - Original Draft.L.: Formal analysis (Figure 1).S.Z.: Data collection, Validation (Tables).L.G.J.: Resources (Stem cells).W.: Supervision, Writing - Review & Editing.*All authors agree to take responsibility for their contributions and ensure that any issues related to the accuracy or completeness of all parts of this article are appropriately investigated and resolved. The corresponding author of this article guarantees that all listed authors have approved the manuscript before submission, including the author's name and order, and ensure that all authors have received the submitted manuscript and all substantive communications with the editor, as well as complete review and verification of all data and charts. Acknowledgement This study was supported by Tai'an Central Hospital of Qingdao University Affiliated Hospital in Shandong Province, China. The author thanks Shandong Umbilical Cord Blood Bank Engineering Co., Ltd. for providing technical support, as well as Mr. Z for his assistance in writing the paper. We also appreciate the constructive feedback provided by the anonymous reviewer. Data Availability The datasets generated and analyzed during the current study are not publicly available due to they are part of an ongoing study, but anonymized data may be shared upon approval by the research team. They are available from the corresponding author on reasonable request.Requests should be directed to [email protected] . References 《KDIGO 2021 Clinical practice guideline for the management of glomerular diseases. Kidney Int. 2021;100(4s):S1-s276.》. 《Ruggenenti P, Cravedi P, Chianca A, et al. Rituximab in idiopathic membranous nephropathy. J Am Soc Nephrol.2012;23(8):1416-1425. doi:10.1681/asn.2012020181》. 《Lin Y, Han Q, Chen L, Wang Y, Ren P, Liu G, Lan L, Lei X, Chen J, Han F. Obinutuzumab in Refractory Membranous Nephropathy: A Case Series. Kidney Med. 2024 Jun 18;6(8):100853. doi: 10.1016/j.xkme.2024.100853. PMID: 39100869; PMCID: PMC11295861.》. 《Ramli Y, Alwahdy AS, Kurniawan M, Juliandi B, Wuyung PE. Intra-arterial transplantation of human umbilical cord blood mononuclear cells in sub- acute ischemic stroke increases VEGF expression in rats. J Stem Cells Regen Med 2018;14:P69e79.》. 《Mukhamedshina Y, Gilazieva Z, Arkhipova S, Galieva L, Garanina E, Shulman A, et al. Electrophysiological, morphological, and ultrastructural features of the injured spinal cord tissue after transplantation of human umbilical cord blood mononuclear cells genetically modified with the VEGF and GDNF genes. Neural Plast 2017;2017:9857918.》. 《Jun Y, Chunju Y, Qi A, Liuxia D, Guolong Y. The effects of compound danshen dripping pills and human umbilical cord blood mononuclear cell transplant after acute myocardial infarction. Exp Clin Transplant. 2014 Apr;12(2):123-8. PMID: 24702144IF: 0.7 Q4 .》. X.-W. Liet al. 《Human umbilical cord blood mononuclear cells protect against renal tubulointerstitial fibrosis in cisplatin-treated rats》, Biomedicine & Pharmacotherapy , 2020, doi: 10.1016/j.biopha.2019.109310. 《J. Parker Can stem cell transplant treat diabetes and kidney disease?Stem Cells J., 29 (2011), pp. 38-42》. Zhang Chi, Xiao Rijun, Zhang Na, Li Huazhu, Yang Xiaochun, Zhou Guilian, Wang Min, Xiong Pu, Chen Jing, Wang Xia, Liu Ying. Experimental study of umbilical cord blood stem cell transplantation in the treatment of lower limb ischemia in diabetes rats [J]. Chinese Journal of Injury and Repair (Electronic Edition), 2012, (1): 12-16 H. R. Jang et al.《Effect of preemptive treatment with human umbilical cord blood-derived mesenchymal stem cells on the development of renal ischemia-reperfusion injury in mice》, American Journal of Physiology-Renal Physiology , F1149–F1161, 112014, doi: 10.1152/ajprenal.00555.2013. 《Xi Y, Yue G, Gao S, Ju R, Wang Y. Human umbilical cord blood mononuclear cells transplantation for perinatal brain injury. Stem Cell Res Ther. 2022 Sep 5;13(1):458. doi: 10.1186/s13287-022-03153-y. PMID: 36064459; PMCID: PMC9446746.》. 《Hoffman W, Lakkis FG, Chalasani G. B Cells, Antibodies, and More. Clin J Am Soc Nephrol. 2016 Jan 7;11(1):137-54. doi: 10.2215/CJN.09430915. Epub 2015 Dec 23. PMID: 26700440; PMCID: PMC4702236.》. 《Rosenzwajg M, Languille E, Debiec H, Hygino J, Dahan K, Simon T, Klatzmann D, Ronco P. B- and T-cell subpopulations in patients with severe idiopathic membranous nephropathy may predict an early response to rituximab. Kidney Int. 2017 Jul;92(1):227-237. doi: 10.1016/j.kint.2017.01.012. Epub 2017 Mar 15. PMID: 28318628.》. D. G. Phinney and M. F. Pittenger, 《Concise Review: MSC-Derived Exosomes for Cell-Free Therapy》, Stem Cells , doi: 10.1002/stem.2575. M. O’Reilly and B. Thébaud, 《Stem Cells for the Prevention of Neonatal Lung Disease》, Neonatology , doi: 10.1159/000381135. 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Primary MN is the most common type encountered clinically. The treatment of MN is currently determined based on risk stratification assessment and is mainly divided into immune-related and non-immune treatments. Immune-related treatments primarily focus on the following mechanisms: clearance of B lymphocytes, reduction of antibody production, and inhibition of T-cell activation to indirectly decrease antibody generation. The main treatment regimens include combinations of Glucocorticoids (GCs) with Calcineurin inhibitors (CNIs), Cyclophosphamide (CTX), or Rituximab (RTX). However, we have observed that some MN patients, despite receiving adequate doses and completing a full 6-month course of these classic regimens, still experience a reduction in 24-hour urinary protein excretion (24-hUPE) of less than 50% from baseline, with incomplete remission or poor response. These cases are defined as refractory MN. Common clinical reasons for refractory MN include glucocorticoid resistance, glucocorticoid dependence, and frequent relapses. Despite repeated treatments, the outcomes remain unsatisfactory, and some patients exhibit resistance to monoclonal antibodies. In China, refractory MN is often managed with multi-targeted therapies or long-course, low-dose RTX regimens \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. However, regardless of the treatment regimen used, the remission rate remains limited.\u003c/p\u003e \u003cp\u003eIn recent years, the coordinated development of cell biology and clinical medical technology has opened a new chapter in the biological treatment of MN. The value and safety of umbilical cord blood cell therapy for nephropathy have been confirmed. Human umbilical cord blood mononuclear cells (hUCBMNCs) are a heterogeneous group of cells with a single nucleus, including mesenchymal stem cells, hematopoietic stem cells, and others. As a source of stem cells with multi-directional differentiation potential and immune regulatory functions, hUCBMNCs have been proven in multiple studies to possess immune regulatory, anti-inflammatory, and anti-fibrotic effects. Their clinical benefits in improving chronic kidney disease have also been demonstrated in several studies \u003csup\u003e[\u003cspan additionalcitationids=\"CR3 CR4 CR5\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u0026minus;[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. This article reports for the first time on the treatment of refractory MN with hUCBMNCs, observing the clinical manifestations and outcomes in patients following treatment. The analysis and summary of therapeutic effects and prognostic changes provide new insights for the cellular-level treatment of refractory MN.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eThe subjects of our study were eight patients with refractory MN admitted to Taian Central Hospital in Shandong Province from January 2022 to March 2025. The clinical data of all patients, including gender, age, medical history, pathological reports, and treatment regimens, were collected (see Tables 1 and 2 for details).This study was conducted in strict accordance with the ethical principles of the Declaration of Helsinki. All study procedures involving human participants were approved by the Medical Ethics Committee of Taian City Central Hospital (Approval No. 2024-06-22). Written informed consent was obtained from all participants prior to receiving hUCB-MNCs clinical treatment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e:1.All patients had a confirmed diagnosis of MN through renal biopsy or positive anti-phospholipase A2 receptor (PLA2R) antibody testing. The diagnosis of refractory MN was defined as：\u003cstrong\u003ePrior treatment with glucocorticoids (GC) combined with cyclophosphamide (CTX), cyclosporine (CsA), or tacrolimus (TAC), or repeated switching of immunosuppressive regimens.Failure to achieve partial remission after \u0026ge;6 months of the above immunosuppressive therapy\u003c/strong\u003e [defined as serum albumin \u0026ge;30 g/L \u003cstrong\u003eand\u003c/strong\u003e a \u0026ge;50% reduction in urinary protein-to-creatinine ratio (UPCR) from baseline], \u003cstrong\u003eor relapse of proteinuria\u003c/strong\u003e (reappearance of urinary protein \u0026ge;3.5 g/day after complete or partial remission), \u003cstrong\u003eor a \u0026ge;50% increase in serum creatinine from baseline\u003c/strong\u003e, meeting the criteria for refractory primary MN (PMN)\u003csup\u003e\u0026nbsp;[1]\u003c/sup\u003e.2.Patients aged between 18 and 65 years.3.Before enrollment in this study, patients understood and signed the informed consent form and agreed to comply with the requirements of the study protocol; they also agreed not to participate in any other clinical studies.\u003cstrong\u003eExclusion criteria\u003c/strong\u003e:1.Patients diagnosed with type 1 or type 2 diabetes according to the WHO criteria (1999) .2.Estimated glomerular filtration rate (eGFR) less than 30 ml\u0026middot;min⁻\u0026sup1;\u0026middot;(1.73 m\u0026sup2;)⁻\u0026sup1;.3.Patients with secondary MN.4.Patients with malignancies, severe infections, or dysfunction of vital organs such as the heart, lungs, or liver.5.Patients with mental disorders who could not cooperate with the treatment.6.Pregnant or breastfeeding women.7.Patients with active hepatitis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e \u003cstrong\u003eBaseline characteristics of patients with refractory MN\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"756\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003echaracteristics\u003c/strong\u003e\u003cstrong\u003e/case\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003esex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eage（y）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMN Stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eUnknow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eUnknow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003ePLA2R Status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eDuration of disease（month）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e91mo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e36mo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e23mo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e30mo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e60mo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e38mo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e36mo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e13mo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eComorbidities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003ehypertension、\u003c/p\u003e\n \u003cp\u003ehyperuricemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003esteroid diabetes、hypertension\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003ehypertension\u003c/p\u003e\n \u003cp\u003e、pulmonary fibrosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003ehypertension\u003c/p\u003e\n \u003cp\u003e、Solitary pulmonary nodules、liver cysts、kidney cysts、sParkinson\u0026apos;s disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003ehypertension、\u003c/p\u003e\n \u003cp\u003eIgA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eHypertension、\u003c/p\u003e\n \u003cp\u003eHydronephrosis、Renal calculi\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003ecomplications\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNone\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNone\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNone\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNone\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNone\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNone\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNone\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNone\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eRituximab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eTreated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eTreated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eNot treated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eNot treated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eNot treated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eTreated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eTreated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eTreated\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eCurrent usage plan (usage time)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eARB+Tacrolimus（80mo）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eTacrolimus（9mo）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eTacrolimus+GCs（10mo）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eTacrolimus+GCs（12mo）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eMMF\u003c/p\u003e\n \u003cp\u003e+Tacrolimus+GCs（12mo）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003eARB+Finerenone+CSA+GCs\u003c/p\u003e\n \u003cp\u003e（10mo）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNone\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.1111%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNone\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: ARB, angiotensin II receptor blocker; CNI, calcineurin inhibitor; MMF：Mycophenolate mofetil；CSA：Cyclosporine A\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2 clinical characteristics\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"43%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDemographics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall Cohort\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003en=8\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003ePLA2R\u0026nbsp;U/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e2.96（2.90，26.88）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e24-hUPE\u0026nbsp;\u003c/strong\u003eg/24h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e2.55（1.42，3.73）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e24-hUCP g/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e0.97(0.80，2.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003eScr \u0026mu;moI/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e80.4(51.75，90.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003eeGFRml/min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e101.25(75.28，114.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003eBUN mmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e6.78(4.50，7.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003eAlb g/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e37.7(35.20，44.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003ePrevious therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003eRituximab, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e5(62.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003eCumulative rituximab courses\u003c/p\u003e\n \u003cp\u003eMedian(g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e2.40（2.15，4.80）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003ePrednisone, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e8(100.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003eMycophenolate, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e2(25.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003eCNI (tacrolimus or cyclosporine), n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e6(75.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003eARB, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e6(75.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003ePreparation of hUCB-MNCs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHUCBMNCs\u003c/strong\u003e were provided by the Shandong Province Umbilical Cord Blood Hematopoietic Stem Cell Bank. The preparation method was as follows: fresh umbilical cord blood was transferred to a 50ml centrifuge tube, centrifuged at 900g for 15 minutes, the upper plasma was removed, and the lower cells were diluted with physiological saline. After mixing, they were added to Ficoll stratification solution and centrifuged at 800g for 20 minutes. After washing the white membrane layer cells twice with physiological saline (centrifuging at 500 g and 300 g for 10 min at room temperature), resuspended them to obtain a mononuclear cell suspension. After cell counting, viability detection, and flow cytometry phenotype detection, each serving was made into 3 ml containing 2 \u0026times; 10\u003csup\u003e8\u003c/sup\u003e cells and used in this study（\u003cstrong\u003eAs shown in Figure 1\u003c/strong\u003e）.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eHUCBMNCs\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Infusion Protocol\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eAll patients underwent \u003cstrong\u003estandardized pre-infusion evaluations\u003c/strong\u003e, including assessments of \u003cstrong\u003eliver/kidney function\u003c/strong\u003e, \u003cstrong\u003ebiochemical profiles\u003c/strong\u003e, \u003cstrong\u003etumor markers\u003c/strong\u003e, \u003cstrong\u003ecardiopulmonary capacity\u003c/strong\u003e, and \u003cstrong\u003eneurological/psychiatric status\u003c/strong\u003e to confirm eligibility.\u003c/p\u003e\n\u003cp\u003eBased on conventional treatment measures, umbilical cord blood mononuclear cells are intravenously infused once a week, with a single cell count of 2\u0026times;10\u003csup\u003e8\u003c/sup\u003e. Subjects with BMI\u0026lt;30 received three treatments, while those with BMI\u0026gt;30 received four treatments. To prevent possible allergic reactions, 5mg dexamethasone was intravenously injected and 25mg promethazine was intramuscularly injected 5 minutes before infusion, and the patient\u0026apos;s vital signs during infusion were monitored by electrocardiogram（\u003cstrong\u003eAs shown in Figure 1\u003c/strong\u003e）.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThe follow-up was concluded on March 31, 2025. Follow-up assessments were conducted through outpatient visits and hospital evaluations at 1 week, 2 weeks, 4 weeks, and 12 weeks after the initial infusion. General information, including name, gender, and age, was collected. Clinical data, such as pathological results, initial treatment or relapse retreatment, and previous treatment regimens, were also gathered. Laboratory data were tested before each treatment and during the follow-up period. All indicators were derived from the laboratory tests performed during the patients\u0026apos; hospital stays or outpatient follow-ups at our hospital. This study was approved by the Ethics Committee of Taian Central Hospital (approval number 2024-06-22), and all patients or their guardians signed the informed consent form for\u0026nbsp;\u003cstrong\u003ehUCBMNCs\u003c/strong\u003e clinical therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary evaluation indicators included the efficacy rate of treatment, remission rate, complete remission (CR), and partial remission (PR). Specifically:CR was defined as a urinary protein excretion of \u0026lt;0.5 g/d , accompanied by a normal serum albumin level and a normal serum creatinine level. \u0026nbsp;PR was defined as a urinary protein excretion of \u0026ge; 0.3 g/d and \u0026lt; 3.5 g/d, or uPCR \u0026ge; 0.3 g/g and \u0026lt; 3.5 g/g, with a 50% or greater reduction from peak values accompanied by an improvement or normalization of the serum albumin level and a stable serum creatinine.\u003cstrong\u003eRelapse\u003c/strong\u003e was defined as a recurrence of proteinuria with urinary protein excretion \u0026ge; 3.5 g/d or urinary protein-to-creatinine ratio (uPCR) \u0026ge; 3.5 g/g after remission had been achieved. \u003cstrong\u003eEfficacy rate of treatment\u003c/strong\u003e = (Number of patients with remission) / (Total number of patients) \u0026times; 100%. \u003cstrong\u003eRemission rate\u003c/strong\u003e = (Number of patients with complete remission + Number of patients with partial remission) / (Total number of patients) \u0026times; 100%. Secondary evaluation indicators included changes in uPCR, serum albumin（Bun）, serum creatinine（Scr）, anti-PLA2R antibodies, and lymphocyte subsets in all patients after the administration of\u0026nbsp;\u003cstrong\u003ehUCBMNCs\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eContinuous variables were tested for normality. Normally distributed continuous variables were presented as mean \u0026plusmn; standard deviation, and comparisons among three groups were performed using one-way analysis of variance (ANOVA). Non-normally distributed continuous variables were expressed as medians, and comparisons among three groups were conducted using the Friedman test for K related samples. Categorical variables were described using frequencies and percentages (%), and comparisons between groups were made using the chi-square test or Fisher\u0026apos;s exact test. All statistical analyses were performed using SPSS version 26.0. All figures were generated using GraphPad Prism version 9. A p-value of less than 0.05 was considered statistically significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eShort-term follow\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eup\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the short-term follow-up, the\u0026nbsp;\u003cstrong\u003e24-hUPE\u003c/strong\u003e significantly decreased (P＜0.05), and the 24-hour urinary total protein (24-hUTP) was alleviated (P＜0.05) during the infusion process. The serum albumin levels increased in 75.0% of the patients. One patient achieved complete remission (CR) 2 weeks after the first infusion, two patients achieved\u0026nbsp;PR, and two patients had a reduction in\u0026nbsp;\u003cstrong\u003e24-hUPE\u003c/strong\u003e but did not reach the level of PR. Flow cytometry was used to analyze the proportions of lymphocyte subsets. The infusion of hUCB-MNCs significantly increased the levels of CD3\u003csup\u003e+\u003c/sup\u003e4\u003csup\u003e+\u003c/sup\u003e8\u003csup\u003e+\u003c/sup\u003e cells (P＜0.05), while the levels of other lymphocytes remained unchanged. There were no significant changes in Scr、BUN、or\u0026nbsp;eGFR(see Tables 3 and 4 for details).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLong-term follow\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eup\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the long-term follow-up, one patient withdrew from the study due to relocation. The\u0026nbsp;\u003cstrong\u003e24-hUPE\u003c/strong\u003e significantly decreased (P＜0.05) in 71.4% of the patients during the infusion process, with a reduction range of 31% to 75%. The 24-hUTP also significantly decreased (P＜0.05). One patient achieved CR, two patients achieved\u0026nbsp;PR, two patients had a reduction in\u0026nbsp;\u003cstrong\u003e24-hUPE\u0026nbsp;\u003c/strong\u003ebut did not reach the level of PR, and two patients showed no significant improvement. An upward trend in serum albumin levels was observed in some patients, while Scr、BUN\u0026nbsp;and other indicators remained unchanged. The total levels of lymphocytes, CD3\u003csup\u003e+\u003c/sup\u003e4\u003csup\u003e+\u003c/sup\u003e8\u003csup\u003e+\u003c/sup\u003e, CD19\u003csup\u003e+\u003c/sup\u003e, and NK cells significantly increased (P＜0.05). However, there were no significant changes in the absolute values of helper/inducer T lymphocytes and suppressor/cytotoxic T lymphocytes(see Tables 3 and 5 for details).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;3\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ePrimary Outcomes of Patients after\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ehUCBMNCs\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDemographics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall Cohort\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u0026nbsp;\u003c/strong\u003etime to treatment effect(W)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eShort-term follow\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eup\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003en=8\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003eRemission（n，%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e7（87.5%）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean time to\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003efirst partial remission\u003c/strong\u003e（w）\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e1.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMean time to first complete remission\u003c/strong\u003e（w）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLong-term follow\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eup\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003en=7\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRemission\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e（n，%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e6（75.0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003ePR（n，%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e2（25.0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003eCR（n，%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e1（12.5%）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003eFirst relapse-free survival time during\u003c/p\u003e\n \u003cp\u003efollow-up（w）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e12（10.0，12.0）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment failure\u003c/strong\u003e（n，%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e1（12.5%）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRelapse\u003c/strong\u003e（n，%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 50%;\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eChanges in Clinical Indicators After Treatment\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eShort-term follow\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eup\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"99%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical Indicators\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePre-treatment\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003en=8\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1 week post-treatment\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003en=8\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4 weeks post-treatment\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003en=8\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8333%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePLA2R U/mL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e2.96（2.90，26.88）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e2.97（2.91，27.69）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e2.90（2.90，2.90）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.8333%;\"\u003e\n \u003cp\u003e0.129\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e24-hUPE\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eg/24h\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e2.55（1.42，3.73）\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e1.40（0.90，2.89）\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e2.14（1.20，2.59）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.8333%;\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e24-hUCP g/L\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e0.97(0.80，2.37)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e0.60（0.41，1.05）\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e0.84（0.64，1.22）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.8333%;\"\u003e\n \u003cp\u003e0.044\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eScr \u0026mu;moI/L\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e80.4(51.75，90.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e81.75（49.78，90.43）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e92.00（44.45，110.43）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.8333%;\"\u003e\n \u003cp\u003e0.657\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eeGFRml/min\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e101.25(75.28，114.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e94.07（86.68，115.88）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e79.92（69.26，117.60）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.8333%;\"\u003e\n \u003cp\u003e0.882\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBUN mmol/L\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e6.78(4.50，7.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e7.42（4.25，7.93）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e7.73（4.50，8.60）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.8333%;\"\u003e\n \u003cp\u003e0.786\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAlb g/L\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e37.7(35.2，44.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e35.95（34.78，44.20）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e41.10（36.13，44.10）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.8333%;\"\u003e\n \u003cp\u003e0.497\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e\u003cstrong\u003elymphocyte count\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eUL\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e1509（1080.25，2010.25）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e1674.00（1109.00，1917.50）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e1862.00（1297.25，2917.50）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.8333%;\"\u003e\n \u003cp\u003e0.197\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ehelper/inducer T lymphocytes\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eUL\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e578.00（140.00，915.75）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e596.00（128.84，724.75）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e641.50（167.25，1173.25）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.8333%;\"\u003e\n \u003cp\u003e0.882\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e\u003cstrong\u003esuppressor/cytotoxic T lymphocytes\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eUL\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e417.00（95.25，515.00）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e275.00（63.25，570.75）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e380.00（87.25，23.50）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.8333%;\"\u003e\n \u003cp\u003e0.508\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCD3\u003csup\u003e+\u003c/sup\u003e4\u003csup\u003e+\u003c/sup\u003e8\u003csup\u003e+\u0026nbsp;\u003c/sup\u003ecells\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eUL\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e7.50（2.50，23.00）\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e8.50（5.25，14.50）\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e9.50（8.25，23.50）\u003csup\u003e*#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.8333%;\"\u003e\n \u003cp\u003e0.034\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCD3\u003csup\u003e+\u003c/sup\u003e cells\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eUL\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e1309.50（1160.75，1511.50）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e1206.50（826.25，1546.00）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e1436.00（1087.50，2194.75）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.8333%;\"\u003e\n \u003cp\u003e0.607\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCD19\u003csup\u003e+\u0026nbsp;\u003c/sup\u003ecells\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eUL\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e73.50（0，341.75）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e80.00（1.25，210.25）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e121.50（11.00，313.00）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.8333%;\"\u003e\n \u003cp\u003e0.241\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNK cells\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eUL\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e126.50（77.75，247.75）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e139.00（77.25，349.25）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.7917%;\"\u003e\n \u003cp\u003e292.00（156.75，328.00）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.8333%;\"\u003e\n \u003cp\u003e0.197\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eGroups marked with *# indicate a statistically significant difference between the two groups (P＜0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e5\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eChanges in Clinical Indicators After Treatment\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eLong-term follow\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eup\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"928\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical Indicators\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePre-treatment\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003en=7\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1 week post-treatment\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003en=7\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4 weeks post-treatment\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003en=7\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e12 weeks post-treatment\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003en=7\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePLA2R U/mL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e2.95（2.90，2.98）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e2.96（2.90，2.98）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e2.90（2.90，2.98）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e2.90（2.90，2.91）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e0.066\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e24-hUPE\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eg/24h\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e2.10（1.40，3.65）\u003csup\u003e#\u003c/sup\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e1.12（0.87，2.40）*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e2.04（1.04，2.70）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e1.25(0.88，1.50)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e24-hUCP g/L\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e0.94（0.78，1.96）*\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e0.54（0.40，0.70）\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e0.82（0.62，1.19）\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e0.56(0.35，0.65)*\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eScr \u0026mu;moI/L\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e87.00（57.00，91.00）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e85.00（58.10，91.90）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e99.00（51.50，110.90）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e97.00(54.00，105.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e0.856\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eeGFRml/min\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e98.22（70.00，104.00）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e92.37（86.28，106.52）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e73.84（68.00，110.38）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e74.00(70.00，114.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e0.692\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBUN mmol/L\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e7.00（6.00，7.06）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e7.83（5.00，7.96）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e7.84（6.00，8.80）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e7.00(5.00，8.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e0.850\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAlb g/L\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e38.40（35.80，45.70）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e36.90（34.70，44.60）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e41.20（39.50，45.00）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e42.00(36.00，44.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e0.366\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e\u003cstrong\u003elymphocyte count\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eUL\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e1448（967.00，2060.00）*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e1605.00（1091.00，1929.00）\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e1470.00(1249.00，3127.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e2408.00(1532.00，3588.00)*\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e0.029\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ehelper/inducer T lymphocytes\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eUL\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e635.00（371.00，958.00）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e694.00（334.00，727.00）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e685.00(516.00，1330.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e737.00(54.00，866.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e0.934\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e\u003cstrong\u003esuppressor/cytotoxic T lymphocytes\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eUL\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e421.00（318.00，533.00）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e308.00（190.00，583.00）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e421.00(289.00，819.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e431.00(39.00，552.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e0.615\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCD3\u003csup\u003e+\u003c/sup\u003e4\u003csup\u003e+\u003c/sup\u003e8\u003csup\u003e+\u003c/sup\u003e cells\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eUL\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e8.00（4.00，26.00）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e8.00（5.00，16.00）*\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e10.00(9.00，28.00)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e11.00(10.00，18.00)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCD3\u003csup\u003e+\u003c/sup\u003e cells\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eUL\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e1291.00（1150.00，1541.00）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e1080.00（826.00，1567.00）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e1257(1076.00，2348.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e1795.00(1307.00，2508.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e0.094\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCD19\u003csup\u003e+\u0026nbsp;\u003c/sup\u003ecells\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eUL\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e112.00（0，378.00）*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e132.00（5.00，226.00）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e202.00(35.00，321.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e226.00(61.00，384.00)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNK cells\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eUL\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e125.00（74.00，199.00）*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e85.00（76.00，242.00）*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e267.00(127.00，325.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e332.00(119.00，358.00)*\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.6667%;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eGroups marked with *# indicate a statistically significant difference between the two groups (P＜0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the follow-up period, no severe treatment-related adverse events were observed during or shortly after treatments.One patient (12.5%) experienced diarrhea 5 weeks after the treatment due to improper diet. The patient recovered after symptomatic antidiarrheal and anti-infective treatments.Another patient (12.5%) had elevated uric acid levels 6 weeks after the treatment following the consumption of seafood, which led to an increase in serum creatinine and 24-hUPE. Symptomatic treatments for renal protection and uric acid reduction were administered. After the serum uric acid levels normalized, the serum creatinine and 24-hUPE levels improved again.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe therapeutic value of hUCBMNCs in chronic kidney disease has piqued our interest in exploring their potential role in MN. In this study, 7 out of 8 patients (87.5%) with refractory MN achieved PR or CR (12.5%). Even among the 5 patients (62.5%) who had previously shown poor response to rituximab treatment, significant efficacy was observed. During the treatment, all patients experienced varying degrees of reduction in 24-hUPE (P＜0.05). In the short-term follow-up, a relatively rapid onset of action was observed, with 7 patients (87.5%) showing improvement within 1 week after the initial treatment. One patient (12.5%) achieved complete remission 2 weeks after the initial treatment, and three patients (37.5%) achieved partial remission. In previous studies, the median time to remission with rituximab and obinutuzumab treatments was reported to be 2.7-7.1 months\u003csup\u003e\u0026nbsp;[2]-[3]\u003c/sup\u003e. In contrast, we found that hUCBMNCs had a faster onset of action, without the need for an accumulation dose, with most patients showing improvement after the first treatment. However, after the completion of the three-infusion course, we observed an upward trend in 24-hUPE in five patients at 4 weeks post-treatment. Among them, four patients experienced a temporary increase followed by a decrease, and they remained in remission at the end of the follow-up. We believe that this fluctuation in 24-hUPE warrants further attention in future studies, as it may suggest that some patients may require additional treatment.\u003c/p\u003e\n\u003cp\u003eBy the end of the long-term follow-up, we observed significant reductions in 24-hUPE and 24-hUPC (P＜0.05), with two patients achieving PR and one achieving CR. Compared to the improvement in 24-hUPE, only some patients with improved conditions showed an increase in serum albumin, which is consistent with the phenomenon that urinary parameters improve first during the remission process of membranous nephropathy. Moreover, all patients experienced significant improvement in clinical symptoms such as fatigue and insomnia. One patient with a history of Parkinson\u0026apos;s disease reported a marked improvement in resting tremors after stem cell infusion, which may be related to the neurotrophic factor secretion and neuronal differentiation of hUCB-MNCs, contributing to protective and reparative effects\u003csup\u003e\u0026nbsp;[9]-[10]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eOxidative stress and fibrotic reactions are key pathological processes in membranous nephropathy. The anti-inflammatory and anti-fibrotic effects of hUCB-MNCs have been demonstrated in studies on myocardial injury\u003csup\u003e\u0026nbsp;[6]\u003c/sup\u003e. In a study by Li Xuwei et al., hUCBMNCs were found to prevent and improve renal tubulointerstitial fibrosis by inhibiting oxidative stress and inflammation in renal tissues\u003csup\u003e\u0026nbsp;[7]\u003c/sup\u003e. Therefore, we believe that the improvement in proteinuria observed in this study is related to the regulation of inflammatory responses and renal fibrosis by hUCBMNCs.No significant changes in serum creatinine or eGFR were observed in this study. We hypothesize that this may be related to transient increases in serum creatinine levels due to elevated uric acid levels in two patients. However, based on previous research, we believe that increasing the sample size and extending the follow-up period would yield better results. This is because hUCB-MNCs have been shown to differentiate into new renal cells or vascular endothelial cells to reconstruct sclerotic or ischemic renal tissues, as demonstrated in an in vitro experiment by Paker et al. in 2011\u003csup\u003e\u0026nbsp;[8]\u003c/sup\u003e. hUCB-MNCs can home to the kidneys and differentiate into the required cells to repair and restore renal function. Additionally, in animal experiments, Zhang Chi et al. observed that hUCBMNCs can improve renal injury by enhancing local organ blood supply [9]. The specific mechanisms may involve the regulation of humoral effects and the promotion of vascular endothelial growth factor (VEGF) secretion by hUCBMNCs, with these regulatory effects being significantly enhanced under hypoxic conditions. This function can effectively and promptly alleviate early renal injury following ischemia-reperfusion\u003csup\u003e\u0026nbsp;[10]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eAn interesting observation was made in the five patients with a history of rituximab treatment. After hUCBMNCs therapy, there was a significant increase in the previously depleted B lymphocytes (P＜0.05). We propose that hUCB-MNCs may regulate the balance of B cell subsets, particularly promoting the redistribution and maturation of naive B cells within the B cell population that does not express CD20\u003csup\u003e[11]\u003c/sup\u003e. Moreover, hUCBMNCs can secrete cytokines to modulate immune responses and promote the proliferation of regulatory B cells (Bregs), thereby improving immune reactions\u003csup\u003e[12]\u003c/sup\u003e. This redistribution of B cells may help reduce the production of autoantibodies, thereby alleviating glomerular basement membrane damage and synergistically assisting patients in rebuilding their immune system alongside rituximab.\u003c/p\u003e\n\u003cp\u003eIn this study, the levels of NK cells and CD3\u003csup\u003e+\u003c/sup\u003e4\u003csup\u003e+\u003c/sup\u003e8\u003csup\u003e+\u003c/sup\u003e lymphocytes all increased. The rise in NK cells following hUCBMNCs treatment can enhance the immune system\u0026apos;s surveillance function, aiding in the clearance of damaged cells and abnormal immune cells, thereby alleviating inflammatory responses\u003csup\u003e\u0026nbsp;[13]\u003c/sup\u003e. Simultaneously, hUCBMNCs regulate the immune microenvironment, optimize the distribution of cell subsets, and improve inflammatory states, collectively contributing to the alleviation of patients\u0026apos; conditions and the reduction of urinary protein excretion. In vitro studies have shown that hUCBMNCs can inhibit T cell proliferation and activation, induce apoptosis, and alter the balance of cytokines TH1 and TH2\u003csup\u003e\u0026nbsp;[14]\u003c/sup\u003e. However, no significant changes in T lymphocytes were observed in this study, which may be related to the small sample size.\u003c/p\u003e\n\u003cp\u003eAmong the five patients who were on tacrolimus treatment during the study, four patients showed initial improvement in the short-term follow-up, with two achieving CR. By the end of the long-term follow-up, the treatment efficacy rate reached 60%, with one patient achieving CR and another achieving \u0026nbsp;PR. We believe that tacrolimus, by inhibiting T cell activation and reducing cell-mediated immune responses, may work synergistically with hUCBMNCs, which can regulate B cell function and further optimize the immune microenvironment. This combined effect may more effectively suppress abnormal immune reactions, promote B cell recovery, and contribute to the alleviation of patients\u0026apos; conditions and the reduction of urinary protein excretion\u003csup\u003e\u0026nbsp;[11]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn analyzing patients who experienced disease flare-ups during treatment, we identified the following factors: hyperuricemia and overweight status. Among the three overweight patients (BMI＞30), all showed initial improvement in 24-hUPE after the three treatments, but experienced a relapse trend within one month during follow-up. Two of these patients were given an additional fourth treatment, and three months later, their 24-hUPE levels, after a temporary increase, continued to decline. This suggests that we should tailor individualized hUCBMNCs infusion treatment plans based on BMI. Additionally, as the number of treatments increased, the majority of patients experienced gradual improvement in their conditions. This is consistent with another study on umbilical cord blood, which proposed that improvement is related to the degree of renal tubular fibrosis, the duration of treatment, and the frequency of infusions. The more infusions, the better the improvement. Therefore, multiple treatments with human umbilical cord blood mononuclear cells are necessary. Based on this study, we suggest that the number of treatments should be more than four, and we also recommend increasing the cell dosage per infusion.\u003c/p\u003e\n\u003cp\u003eIn this study, one patient showed no response throughout the treatment course. We found that a pulmonary CT scan performed at the beginning of the treatment indicated pulmonary fibrosis, which we believe may have been the primary factor affecting the treatment outcome. A 2015 study on neonates confirmed that hUCBMNCs first home to the lungs upon entering the human body, and the health status of the lungs can influence the long-term engraftment of hUCBMNCs and the treatment efficacy \u003csup\u003e[15]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eSeveral limitations exist in our study. First, the relatively small sample size means that our conclusions need to be further verified through multicenter, large-sample, long-term follow-up clinical trials. However, as the first exploratory clinical trial in this area, our study still reached promising conclusions with significant clinical implications. Second, this study focused on the use of hUCBMNCs for refractory MN, and its findings cannot be generalized to all patients with membranous nephropathy. The long-term adverse effects and the correlation between renal pathology and therapeutic efficacy could be explored in future studies. Third, cellular therapy for membranous nephropathy is still in its infancy, with few studies currently available. The treatment dosage used in this study was based on empirical evidence. Based on our findings, we suggest increasing the number of treatments and the cell dosage per treatment to achieve better therapeutic outcomes.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our study demonstrated that hUCBMNCs have a favorable therapeutic effect on patients with refractory MN who have shown poor response to first-line treatments such as tacrolimus, rituximab, and cyclophosphamide. hUCBMNCs can significantly improve 24-hUPE and 24-hUCP. Through immune regulation and immune system reconstruction, hUCBMNCs can modulate the immune microenvironment to treat refractory MN. They also appear to have synergistic therapeutic effects with rituximab and tacrolimus, with high safety and few adverse reactions. hUCBMNCs hold great potential for future applications in the field of nephrology. It is essential to establish standards for the control and clinical application of hUCBMNCs and to conduct multicenter, large-sample, randomized controlled clinical trials in the future, in order to provide a safer and more effective new treatment option for refractory MN.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDisclosure Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003cem\u003eThis work is original and has not been published elsewhere, nor is it currently under consideration for another journal.\u003c/em\u003e\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eEthical Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in strict accordance with the ethical principles of the Declaration of Helsinki. All study procedures involving human participants were approved by the Medical Ethics Committee of Taian City Central Hospital (Approval No. 2024-06-22). Written informed consent was obtained from all participants prior to receiving hUCB-MNCs clinical treatment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that this study received no external funding.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003e*L.B.: Investigation, Writing - Original Draft.L.: Formal analysis (Figure 1).S.Z.: Data collection, Validation (Tables).L.G.J.: Resources (Stem cells).W.: Supervision, Writing - Review \u0026amp; Editing.*All authors agree to take responsibility for their contributions and ensure that any issues related to the accuracy or completeness of all parts of this article are appropriately investigated and resolved. The corresponding author of this article guarantees that all listed authors have approved the manuscript before submission, including the author's name and order, and ensure that all authors have received the submitted manuscript and all substantive communications with the editor, as well as complete review and verification of all data and charts.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThis study was supported by Tai'an Central Hospital of Qingdao University Affiliated Hospital in Shandong Province, China. The author thanks Shandong Umbilical Cord Blood Bank Engineering Co., Ltd. for providing technical support, as well as Mr. Z for his assistance in writing the paper. We also appreciate the constructive feedback provided by the anonymous reviewer.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and analyzed during the current study are not publicly available due to they are part of an ongoing study, but anonymized data may be shared upon approval by the research team. They are available from the corresponding author on reasonable request.Requests should be directed to [email protected].\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003e《KDIGO 2021 Clinical practice guideline for the management of glomerular diseases. Kidney Int. 2021;100(4s):S1-s276.》.\u003c/li\u003e\n\u003cli\u003e《Ruggenenti P, Cravedi P, Chianca A, et al. Rituximab in idiopathic membranous nephropathy. J Am Soc Nephrol.2012;23(8):1416-1425. doi:10.1681/asn.2012020181》.\u003c/li\u003e\n\u003cli\u003e《Lin Y, Han Q, Chen L, Wang Y, Ren P, Liu G, Lan L, Lei X, Chen J, Han F. Obinutuzumab in Refractory Membranous Nephropathy: A Case Series. Kidney Med. 2024 Jun 18;6(8):100853. doi: 10.1016/j.xkme.2024.100853. PMID: 39100869; PMCID: PMC11295861.》.\u003c/li\u003e\n\u003cli\u003e《Ramli Y, Alwahdy AS, Kurniawan M, Juliandi B, Wuyung PE. Intra-arterial transplantation of human umbilical cord blood mononuclear cells in sub- acute ischemic stroke increases VEGF expression in rats. J Stem Cells Regen Med 2018;14:P69e79.》.\u003c/li\u003e\n\u003cli\u003e《Mukhamedshina Y, Gilazieva Z, Arkhipova S, Galieva L, Garanina E, Shulman A, et al. Electrophysiological, morphological, and ultrastructural features of the injured spinal cord tissue after transplantation of human umbilical cord blood mononuclear cells genetically modified with the VEGF and GDNF genes. Neural Plast 2017;2017:9857918.》.\u003c/li\u003e\n\u003cli\u003e《Jun Y, Chunju Y, Qi A, Liuxia D, Guolong Y. The effects of compound danshen dripping pills and human umbilical cord blood mononuclear cell transplant after acute myocardial infarction. Exp Clin Transplant. 2014 Apr;12(2):123-8. PMID: 24702144IF: 0.7 Q4 .》.\u003c/li\u003e\n\u003cli\u003eX.-W. Liet al. 《Human umbilical cord blood mononuclear cells protect against renal tubulointerstitial fibrosis in cisplatin-treated rats》, \u003cem\u003eBiomedicine \u0026amp; Pharmacotherapy\u003c/em\u003e, 2020, doi: 10.1016/j.biopha.2019.109310.\u003c/li\u003e\n\u003cli\u003e《J. Parker Can stem cell transplant treat diabetes and kidney disease?Stem Cells J., 29 (2011), pp. 38-42》.\u003c/li\u003e\n\u003cli\u003eZhang Chi, Xiao Rijun, Zhang Na, Li Huazhu, Yang Xiaochun, Zhou Guilian, Wang Min, Xiong Pu, Chen Jing, Wang Xia, Liu Ying. Experimental study of umbilical cord blood stem cell transplantation in the treatment of lower limb ischemia in diabetes rats [J]. Chinese Journal of Injury and Repair (Electronic Edition), 2012, (1): 12-16\u003c/li\u003e\n\u003cli\u003eH. R. Jang et al.《Effect of preemptive treatment with human umbilical cord blood-derived mesenchymal stem cells on the development of renal ischemia-reperfusion injury in mice》, \u003cem\u003eAmerican Journal of Physiology-Renal Physiology\u003c/em\u003e, F1149\u0026ndash;F1161, 112014, doi: 10.1152/ajprenal.00555.2013.\u003c/li\u003e\n\u003cli\u003e《Xi Y, Yue G, Gao S, Ju R, Wang Y. Human umbilical cord blood mononuclear cells transplantation for perinatal brain injury. Stem Cell Res Ther. 2022 Sep 5;13(1):458. doi: 10.1186/s13287-022-03153-y. PMID: 36064459; PMCID: PMC9446746.》.\u003c/li\u003e\n\u003cli\u003e《Hoffman W, Lakkis FG, Chalasani G. B Cells, Antibodies, and More. Clin J Am Soc Nephrol. 2016 Jan 7;11(1):137-54. doi: 10.2215/CJN.09430915. Epub 2015 Dec 23. PMID: 26700440; PMCID: PMC4702236.》.\u003c/li\u003e\n\u003cli\u003e《Rosenzwajg M, Languille E, Debiec H, Hygino J, Dahan K, Simon T, Klatzmann D, Ronco P. B- and T-cell subpopulations in patients with severe idiopathic membranous nephropathy may predict an early response to rituximab. Kidney Int. 2017 Jul;92(1):227-237. doi: 10.1016/j.kint.2017.01.012. Epub 2017 Mar 15. PMID: 28318628.》.\u003c/li\u003e\n\u003cli\u003eD. G. Phinney and M. F. Pittenger, 《Concise Review: MSC-Derived Exosomes for Cell-Free Therapy》, \u003cem\u003eStem Cells\u003c/em\u003e, doi: 10.1002/stem.2575.\u003c/li\u003e\n\u003cli\u003eM. O\u0026rsquo;Reilly and B. Th\u0026eacute;baud, 《Stem Cells for the Prevention of Neonatal Lung Disease》, \u003cem\u003eNeonatology\u003c/em\u003e, doi: 10.1159/000381135.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Umbilical cord blood, mononuclear cells, membranous nephropathy","lastPublishedDoi":"10.21203/rs.3.rs-6824104/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6824104/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003e(Objective)\u003c/strong\u003e The clinical value of human umbilical cord blood mononuclear cells (hUCBMNCs) in chronic kidney disease and acute renal failure has been confirmed. This study further explores the clinical efficacy and safety of hUCBMNCs in the treatment of refractory membranous nephropathy (MN), and observes the changes in clinical indicators and lymphocyte subsets in patients with refractory MN who have had poor long-term follow-up results with the classic treatment regimen after receiving hUCBMNCs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(Methods)\u003c/strong\u003e Eight patients with refractory MN diagnosed at Taian Central Hospital in Shandong Province from January 2022 to March 2024 were enrolled. All eight patients had received the classic treatment regimen for MN with poor results. They were then treated with intravenous infusion of hUCBMNCs (a course of treatment consisting of three intravenous infusions of 2.00×10^8 (100 ml) units of hUCB-MNCs, with a 1-week interval between each infusion. Individual patients with BMI \u0026gt; 30 received an additional intravenous infusion of 2.00×10^8 (100 ml) units of hUCB-MNCs). The clinical manifestations and ancillary examination results of the patients were collected. The therapeutic effects and disease outcomes were observed at short-term follow-up (1 week, 2 weeks, and 4 weeks after treatment) and long-term follow-up (12 weeks after treatment).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(Results)\u003c/strong\u003e During the short-term follow-up, 7 patients experienced varying degrees of clinical improvement during the treatment process, while 1 patient showed no response to the treatment. The 24-hour urinary protein excretion and concentration were significantly improved during the treatment (P＜0.05). The maximum reduction in 24-hour urinary protein excretion was 46%-79%. The serum albumin levels increased in 75% of the patients, and the levels of CD3\u003csup\u003e+\u003c/sup\u003e4\u003csup\u003e+\u003c/sup\u003e8\u003csup\u003e+\u003c/sup\u003e lymphocytes were elevated (P＜0.05). By the end of the long-term follow-up, 5 patients had significant improvements in 24-hour urinary protein excretion and concentration (P＜0.05), 2 patients showed no response to the treatment, and 1 patient withdrew from the long-term follow-up. The effective rate of treatment was 71%. The reduction in 24-hour urinary protein excretion in the 5 patients ranged from 17% to 76%, with 1 patient achieving complete remission (CR) and 3 patients achieving partial remission (PR). The levels of serum B lymphocytes and NK lymphocytes were increased compared to before the treatment (P＜0.05), and all patients experienced an improvement in fatigue symptoms.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(Conclusion) \u003c/strong\u003ehUCBMNCs can significantly reduce the 24-hour urinary protein excretion and concentration, increase the serum albumin levels, and improve the condition and symptoms of patients with refractory MN through immune regulation and immune system reconstruction. Improvement can be observed immediately after the first treatment, with a rapid onset of action, no need for an accumulation dose, few adverse reactions, and high safety.\u003c/p\u003e","manuscriptTitle":"Novel Cellular Immunotherapy in Refractory Membranous Nephropathy: A First-in-Human Trial of Human Umbilical Cord Blood-Derived Mononuclear Cells","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-24 12:34:32","doi":"10.21203/rs.3.rs-6824104/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7bd5993b-5e4e-4104-9a70-679574e2d69f","owner":[],"postedDate":"June 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-09T08:54:52+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-24 12:34:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6824104","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6824104","identity":"rs-6824104","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}