Abstract
Introduction
Rituximab has become the first-line therapy for patients with membranous nephropathy (MN). However, approximately 30–40% of patients with MN do not respond to rituximab. We presented our single-center experience of treating rituximab-refractory MN with obinutuzumab which is a humanized and glycoengineered type II anti-CD20 monoclonal antibody.
Methods
Seventeen patients with rituximab-refractory phospholipase A2 receptor (PLA2R)-associated MN who received obinutuzumab at the First Affiliated Hospital of Xi’an Jiaotong University were included in this case series study. Clinical and laboratory parameters were evaluated at presentation, before and after obinutuzumab administration.
Results
Of all patients with an average age of 49.7 ± 13.7 years, 11 (64.7%) patients were men. The median disease duration was 12 (12, 42) months. At presentation, the proteinuria and serum albumin levels were 7.51 ± 3.55 g/day and 22.1 ± 3.6 g/L, respectively. The mean estimated glomerular filtration rate level was 103.5 ± 12.9 mL/min/1.73 m2, and the patients had a baseline anti-PLA2R level of 183.2 ± 92.9 RU/mL. At obinutuzumab administration, proteinuria and albumin levels were still consistent with nephrotic syndrome. After a median follow-up of 12.6 ± 5.0 months, complete remission was achieved in 9 (52.9%) and partial remission was achieved in 6 (41.2%) cases. Of the patients who achieved remission, the median remission time was 4.4 (4.0, 6.0) months. At 6 months, 12 (70.6%) patients achieved remission and 11 of 12 patients with available PLA2R measurements reached immunological remission.
Conclusion
Obinutuzumab may represent an attractive alternative therapy in rituximab-refractory patients. Larger prospective studies are needed to validate these findings.
Keywords: Obinutuzumab, Membranous nephropathy, Anti-phospholipase A2 receptor antibody, Rituximab-refractory
Introduction
Primary membranous nephropathy (MN) is one of the most frequent causes of nondiabetic nephrotic syndrome (NS) and is associated with a high risk for life-threatening complications and progression to end-stage kidney disease with persistent proteinuria [1–3]. In the last decades, treatment based on nonspecific immunosuppressive medications has showed promising effects and improved prognosis remarkably, yet accompanied by systemic and renal toxicity [2].
In recent years, the understanding of the pathophysiology of MN has evolved with the discovery of multiple target antigens and their associated circulating antibodies [4]. As a result, it was recognized that B cells played a key role in the pathogenesis of MN and rituximab (RTX) has therefore become the first-line therapy for patients with MN at increased risk of kidney failure [5]. Nevertheless, RTX leads to approximately 60%–70% overall remission rates, and up to 30–40% patients do not respond to RTX [6, 7].
Obinutuzumab is a newer humanized, glycoengineered type II anti-CD20 monoclonal antibody that targets a distinct epitope on CD20, demonstrating a higher affinity for the receptor compared to RTX [8]. De-fucosylation of its Fc region enhances binding to the FcγR III receptor, which increases direct induction of cell death and improves antibody-dependent cellular cytotoxicity [9, 10]. In contrast, obinutuzumab does not induce CD20 translocation into lipid rafts and exhibits relatively lower complement-dependent cytotoxicity activity [11]. Additionally, as a type II antibody, it binds to an overlapping epitope of CD20 in a unique orientation, preventing internalization of the antibody-receptor complex [12]. These characteristics have been demonstrated to induce more profound and long-lasting B-lymphocyte depletion in lymphoid organs and whole blood samples compared with RTX [13]. Therefore, obinutuzumab might provide an attractive option for RTX-refractory MN. To date, there is limited data for obinutuzumab in treatment of patients with RTX-refractory MN. Herein, we presented our single-center experience of treating RTX-refractory MN with obinutuzumab.
Methods
In this case series study, patients with rituximab-refractory phospholipase A2 receptor (PLA2R) antibody-associated MN who received obinutuzumab at the First Affiliated Hospital of Xi’an Jiaotong University between January 2021 and June 2023 were retrospectively enrolled. MN was diagnosed through kidney biopsy and/or serum anti-PLA2R antibodies ≥14 relative units (RU)/mL. RTX-refractory MN was defined as the continued presence of high or unchanged levels of anti-PLA2R antibodies or experiencing persistent NS with low serum albumin levels during a follow-up period exceeding 6 months after two doses of 1 g RTX administration. Complete remission (CR) was defined as urinary protein excretion <0.3 g/day along with normal serum albumin concentration and stable renal function. Partial remission (PR) was defined as urinary protein excretion <3.5 g/day and with ≥50% reduction from baseline, accompanied by improvement or normalization of serum albumin concentration and stable GFR. Prior immunosuppressive therapy referred to any administration of immunosuppressants (including following drugs, namely, glucocorticoid, calcineurin inhibitors, RTX, cyclophosphamide, and mycophenolate mofetil) before the initiation of obinutuzumab infusion. Patients who received concomitant immunosuppressive therapy after the initial infusion of obinutuzumab and who were followed up for <6 months were excluded.
Generally, RTX was administered intravenously at a dose of 1 g for two doses with a 2-week interval. Premedication with 5 mg of intravenous dexamethasone and 20 mg of intramuscular diphenhydramine was given 30 min before RTX infusion. For obinutuzumab administration, patients received two doses of 1,000 mg obinutuzumab 2 weeks apart with diphenhydramine 25 mg and dexamethasone 20 mg as premedications routinely. In a few cases, one single infusion of obinutuzumab was administered according to professional consultation by the clinician and preference of patients. After the initial course of obinutuzumab, patients were followed up for at least 6 months to assess the clinical indicators and their response to treatment. The decision to administer additional infusions of obinutuzumab is based on the patient’s clinical indicators, including PLA2R antibody levels, B-cell counts, serum albumin levels, and urinary protein quantification. Generally, if the PLA2R antibody remains positive after approximately 6 months of the initial obinutuzumab course, additional treatment may be recommended. Similarly, if the serum PLA2R antibody has become negative but B-cell reconstitution occurs or CR has not been achieved, further medication may also be suggested. Clinical and laboratory parameters were evaluated at baseline (within 7 days before the initial obinutuzumab infusion) with bimonthly monitoring of proteinuria, serum albumin, and kidney function, as well as quarterly evaluation of PLA2R antibody levels and CD19+ B-cell counts. For patients who have received RTX without combination of other immunosuppressants and sequential obinutuzumab treatment, clinical and laboratory parameters before and after RTX were documented. Clinical information was retrospectively collected from the medical records. Estimated glomerular filtration rate (eGFR) was calculated according to the chronic kidney disease-epidemiology collaboration creatinine equation.
The follow-up time for all patients was defined as starting from the initiation of obinutuzumab therapy (date of the first dose) and continuing until the last visit during the study period. The primary outcome was the incidence of remission of proteinuria. Remission time was calculated from the day of first obinutuzumab infusion to the medical records-proven PR or CR. Secondary outcomes included change in serum PLA2R antibody, serum albumin, and serum creatinine after obinutuzumab compared to baseline. Immunological remission was defined as reduction of serum anti-PLA2R levels to <2.7 RU/mL measured on a clinical-grade assay (anti-PLA2R IgG ELISA kit; Euroimmun AG). Adverse events were monitored for 1 year after obinutuzumab infusions.
Baseline characteristics were analyzed with descriptive statistics and are presented as numbers and percentages, mean ± standard deviation, or median (IQR) as appropriate. A comparative analysis was performed on clinical indicators (eGFR, proteinuria, serum albumin levels, PLA2R-Ab levels) before and after the administration of RTX and obinutuzumab. Kaplan-Meier product limit method was used to estimate time to CR or PR. A two-sided p < 0.05 was considered statistically significant. Data analyses were performed using Prism (version 9.4.1; GraphPad Software) and SPSS Statistics (version 27.0, IBM).
Results
In total, 17 eligible patients with rituximab-refractory PLA2R-associated MN were included in this study. Baseline characteristics of these patients are shown in Table 1. Eleven (64.7%) patients were men, and the mean age was 49.7 ± 13.7 years. Twelve (70.6%) patients underwent kidney biopsy. All patients tested positive for anti-PLA2R antibodies and presented with NS with a mean urine protein quantification of 7.51 ± 3.55 g/24 h and a mean serum albumin level of 22.1 ± 3.6 g/L. Their renal function was normal and had a median baseline anti-PLA2R level of 183.2 ± 92.9 RU/mL. Ten patients had received RTX, and remaining 7 patients had been previously exposed to RTX and other immunosuppressants including steroids, alkylating agents, and/or calcineurin inhibitors (online suppl. Table S1; for all online suppl. material, see https://doi.org/10.1159/000545995).
Table 1.
Baseline patient characteristics
| Parameter | N = 17 |
|---|---|
| Age, years | 49.7±13.7 |
| Male (%) | 11 (64.7) |
| Time from diagnosis of MN to obinutuzumab, months | 12 (12, 42) |
| Kidney biopsy (%) | 12 (70.6) |
| Time from biopsy to obinutuzumab, months | 22.5 (6.5–75.0) |
| Pathological features of MN (n = 12) | |
| Glomerular sclerosis, n (%) | |
| 0% | 4 (33.3) |
| −25% | 8 (66.7) |
| >25% | 0 (0) |
| Renal tubular atrophy, n (%) | 6 (50) |
| Renal interstitial fibrosis, n (%) | 2 (16.7) |
| Hypertension (%) | 7 (41.2) |
| Diabetes (%) | 5 (29.4) |
| Laboratory tests at presentation | |
| Serum albumin, g/L | 22.1±3.6 |
| Urinary protein excretion, g/24 h | 7.51±3.55 |
| Creatinine, µmol/L | 65.8±12.7 |
| eGFR, mL/min/1.73 m2 | 103.5±12.9 |
| PLA2R-Ab, RU/mL | 183.2±92.9 |
| PLA2R-Ab at RTX administration, RU/mL | 131.4±96.1 |
| Prior immunosuppressive therapy, n (%) | |
| RTX | 10 (58.8) |
| RTX and other immunosuppressants | 7 (41.2) |
| Laboratory tests at obinutuzumab administration | |
| Serum albumin, g/L | 22.6±3.6 |
| Urinary protein excretion, g/24 h | 8.7±3.1 |
| Creatinine, µmol/L | 77.5±30.9 |
| eGFR, mL/min/1.73 m2 | 94.0±27.8 |
| PLA2R-Ab, RU/mL | 28.3 (5.9, 135.7) |
| Obinutuzumab, doses, n | |
| One | 1 (5.9) |
| Two | 7 (41.2) |
| Three | 6 (35.3) |
| Four | 3 (17.6) |
| Follow-up time, months | 12.6±5.0 |
Of all patients, 11 (64.7%) patients received two doses of 1 g of RTX without combination of other immunosuppressants with all RTX-free intervals exceeding 6 months. After RTX treatment, the clinical data of these patients are presented in Figure 1 and online supplementary Table S2. The results indicated no statistically significant changes in these indicators during the 6-month follow-up period after RTX treatment compared to baseline values. The patients showed persistent nonresponse during the 6-month follow-up. Of note, the anti-PLA2R levels had decreased slightly, whereas no one achieved immunological response within 6 months. Circulating CD19+ B-cell count decreased to <5 cells/μL in all patients within 2 weeks after RTX treatment. Nevertheless, circulating CD19 B-cell reconstitution (increased to >5 cells/μL) was observed in 9 of 11 (81.8%) patients within 6 months.
Fig. 1.
Changes in clinical parameters within 6 months after RTX administration. a Twenty-four-hour urinary protein excretion did not decrease (blue), and serum albumin did not increase (red) after RTX administration. b Scr and eGFR remained stable compared to baseline after RTX administration. c Changes in anti-PLA2R antibody levels at 0, 4, and 6 months after RTX administration. d Circulating CD19+ B cells at 0, 0.5, and 6 months after RTX infusion. Data represent means ± SD. eGFR, estimated glomerular filtration rate; Scr, serum creatinine; PLA2R, phospholipase A2 receptor.
At obinutuzumab administration, proteinuria and albumin levels of these patients were still consistent with NS. The mean albumin levels were 22.6 ± 3.6 g/L, and urine protein quantification was 8.7 ± 3.1 g/24 h. Three patients presented with impaired renal function (eGFR <60 mL/min/1.73 m2). Sixteen patients had detectable serum PLA2R antibodies with a median level of 28.3 (5.9, 135.7) RU/mL. Circulating CD19+ B-cell depletion (i.e., cell count reduction to <5/μL) was observed in 2 patients.
Initially, 16 (94.1%) patients received 2 infusions and 1 patient received 1 infusion of obinutuzumab with the dosage of 1 g. During the follow-up, additional infusions were administered to 9 patients. Among them, 1 case failed to achieve clinical remission and had a high anti-PLA2R antibody level of 2.94 RU/mL, prompting the administration of a third obinutuzumab infusion. The remaining 8 patients developed PR at the third infusion of obinutuzumab. Nevertheless, 3 of them still exhibited low titers of anti-PLA2R antibodies (3.94–8.63 RU/mL), necessitating an additional infusion of obinutuzumab due to inadequate dosing. In contrast, the PLA2R antibodies in the other 5 patients were undetectable, but B cells were reconstituted. To prevent the risk of relapse, additional obinutuzumab was administered to these patients as well. The median interval between the second and third administration was 6.5 (IQR: 5.6–8.4) months.
In the study group as a whole, after obinutuzumab treatment, significant decreases in PLA2R antibodies and urinary protein were observed along with an increase in serum albumin levels compared with baseline (online suppl. Table S3). At 6 months, the mean urine protein reduction percentage was 75.1% from 8.7 ± 3.1 g/24 h to 2.4 ± 2.1 g/24 h and serum albumin level had increased by 62.1% from 22.6 ± 3.6 g/L to 35.4 ± 5.2 g/L compared with the onset of obinutuzumab. eGFR improved or stabilized in all patients. The anti-PLA2R titers progressively decreased by medians of 94.6%. Within 4 months, immunological remission was achieved in 13 of 17 patients. At 6 months, 11 of 12 patients with available PLA2R measurements reached immunological remission. Regarding B cells, complete circulating CD19 B-cell depletion was observed in all available measurements within 4 months and in 6 of 10 available measurements within 6 months (60.0%). The trends of parameters after obinutuzumab therapy are shown in Figure 2. As for measurements of other lymphocyte subsets following obinutuzumab treatment, no significant changes were observed, except for CD19+ B cells. Detailed information is presented in online supplementary Table S4.
Fig. 2.
Changes in clinical parameters within 9 months after obinutuzumab administration. a Twenty-four-hour urinary protein excretion significantly decreased (blue) and serum albumin levels significantly increased (red) after obinutuzumab administration. b Scr and eGFR remained stable compared to baseline after obinutuzumab administration. c Changes in anti-PLA2R antibody levels at 0, 4, 6 and 9 months after obinutuzumab administration. d Circulating CD19+ B cells at 0, 4, 6 and 9 months after obinutuzumab infusion. Data represent means ± SD. eGFR, estimated glomerular filtration rate; Scr, serum creatinine; PLA2R, phospholipase A2 receptor.
After a median follow-up of 12.6 ± 5.0 months, CR was achieved in 9 (52.9%) and PR was achieved in 6 (41.2%) patients. The median remission time was 4.4 (4.0, 6.0) months in those who achieved remission. At 6 months, 12 (70.6%) patients achieved PR or CR. Figure 3 shows the proportion of patients who achieved CR or PR over time. Of the 8 patients who had been followed up more than 12 months, 4 patients maintained CR without additional obinutuzumab infusion. There were no proteinuria relapses.
Fig. 3.
Kaplan-Meier curves for the probability of reaching the combined end point of CR or PR of NS after obinutuzumab administration in the study group considered as a whole.
Of the 2 patients who did not reach CR or PR, one had a 6-month follow-up, showing a 40.0% reduction in proteinuria. Additionally, the titer of the PLA2R antibody decreased from 6.54 to 2.94 RU/mL, while B-cell depletion was maintained. The second patient demonstrated a 75.9% reduction in proteinuria, from 17.1 g to 4.12 g, after 11.2 months of follow-up. Furthermore, serum albumin level increased from 22.2 g/L at the time of obinutuzumab infusion to 37.7 g/L, and immunological remission was achieved. The characteristics of 2 patients with no response were summarized in online supplementary Table S5.
With regard to safety, 4 patients were considered to experience the treatment-related infusion reactions including oropharyngeal discomfort or rash and itching. These events were not severe and patients recovered completely after transient infusion interruption. Only one patient developed infection of COVID-19 which required hospitalization. No other obinutuzumab-related severe adverse events were observed during the follow-up period.
Discussion
In this study, we evaluated the efficacy of obinutuzumab treatment in patients with rituximab-refractory PLA2R-associated MN and the results demonstrated that 15 of 17 (88.2%) patients achieved either PR or CR during the mean 12.6-month follow-up period. Furthermore, at 6 months 12 (70.6%) patients achieved remission and 11 of 12 patients with available PLA2R measurements reached immunological remission. It is remarkable that anti-PLA2R antibody levels progressively decreased and accompanied by a decrease in urinary protein paralleled by a significant increase in serum albumin. Generally, obinutuzumab was well tolerated, and the infusion reactions related to treatment were not severe.
In recent decades, with several important advances in the understanding of the pathogenesis and landscape trials underlying MN, RTX that targets autoantibody-producing B cells has been recommended to be first-line therapy in the guidelines [14]. However, it is important to underline that a non-negligible proportion of patients with MN do not respond to RTX [15]. To address this issue, several factors should be considered. First, in patients with severe NS loss of RTX in the urine might lead to lower serum RTX levels along with lower response rates [16, 17]. Second, the presence of neutralizing antibodies directed toward RTX itself might be responsible for RTX resistance [18]. Third, apart from short-lived plasma cells which derived from memory B cells that express CD20 on their surface and are therefore targeted by RTX, long-lived plasma cells instead may be driving anti-PLA2R autoantibody production [19]. In addition, insufficient B-cell depletion in immunological niches, such as the bone marrow, lymph nodes, and tissues, may contribute to resistance to RTX as well. The patients enrolled in this study had already received one or more courses of RTX treatment in the past, whereas all patients continued to test positive for anti-PLA2R antibodies and experience with severe NS during the 6-month follow-up. According to the Mentor trial, these patients were considered to have treatment failure and no further RTX was administered [15]. These findings suggested that RTX failed to eliminate the autoreactive B-cell clones responsible for the production of MN-associated autoantibodies. Meanwhile, circulating CD19 B-cell reconstitution occurred in the majority of these patients within 6 months.
In these settings, obinutuzumab which is a fully humanized type II monoclonal antibody against CD20 was primarily designed to overcome several postulated mechanisms of RTX resistance [20]. Previously, obinutuzumab has been reported to be effective in refractory MN patients in small case series and podocytopathies [21–26]. These studies included MN patients who were unresponsive to multiple immunosuppressive therapies, including CTX, CNI, or RTX, with a relatively low incidence of resistance to RTX. The results from the study by Su et al. [25] demonstrated that CR or PR was achieved by 84.7% of patients (50 of 59), including 64.3% (9/14) of patients with resistance to RTX. Sethi et al. [22] found that 85.7% of 11 refractory patients including 7 patients previously treated with RTX achieved remission after two doses of obinutuzumab. The study by Xu et al. [26] reported a remission rate of 80% (8/10) among patients who were also resistant to RTX. Another study revealed that of 12 patients who received RTX previously, all achieved remission successfully, including 8 patients (66.7%) achieving PR and 4 patients (33.3%) achieving CR [24]. The present study focused on a specific cohort of patients who were PLA2R-Ab positive and did not respond to RTX therapy. These cases were more challenging, and the historical data during the course of RTX were presented as self-controls. Finally, the results demonstrated that 15 of 17 (88.2%) patients achieved either PR or CR during the mean 12.6-month follow-up period, closely aligning with previous findings. Variability in remission rates across studies may be due to differences in patient population, obinutuzumab doses, and follow-up durations. It was noteworthy that the response to obinutuzumab was rapid as the median remission time was 4.4 months and 70.6% of patients achieved remission at 6 months higher than that reported in the Membranous Nephropathy Trial of Rituximab study [15]. Moreover, the effect of obinutuzumab was long lasting and complete depletion of B cells was maintained within 6 months in 60% patients. All these results could be attributed to its molecular structure and mechanism. Due to the humanized nature and lower immunogenicity of obinutuzumab, patients are less likely to develop hypersensitivity and produce antidrug antibodies. Compared with RTX, obinutuzumab recognizes an overlapping epitope of CD20 in a different orientation and has been glycoengineered to produce greater cytotoxicity and B-cell apoptosis through mechanisms such as direct cell death, antibody-dependent phagocytosis, and antibody-dependent cellular cytotoxicity [9]. Consequently, obinutuzumab has demonstrated superiority in the B-lymphocyte depletion in whole blood samples and also induces a deeper depletion of B cells in spleen and lymph nodes, resulting in superior clinical response in patients in certain hematological malignancies and kidney disease [13, 23, 27, 28].
In this study, 9 patients received additional obinutuzumab infusions during the follow-up. The decision to administer additional infusions of obinutuzumab is based on a thorough assessment of PLA2R antibody levels, B-cell counts, serum albumin levels, and urinary protein quantification. According to the Mentor trial, additional medication may be considered in patients who achieved PR [15]. However, it is remarkable that 4 patients have remained CR 13–21 months after one course of obinutuzumab. In this respect, obinutuzumab would be cost-effective and avoid the inconvenience of repeated infusions. In this study, one patient received 1 g of obinutuzumab and it took longer to achieve remission which occurred at 8.9 months. The optimal strategy for obinutuzumab therapy including the initial and additional doses required further investigation. Based on these findings, it is proposed that obinutuzumab treatment may be beneficial for patients with PLA2R-associated MN who do not achieve immunological remission with RTX. Notably, for the two patients who did not achieve remission, varying degrees of serum albumin elevation and urine protein reduction were observed. One patient achieved immunological remission during an 11.2-month follow-up period, with improvements in clinical indicators. However, the patient declined further obinutuzumab infusions due to financial constraints. Despite this, clinical remission may still be possible with extended follow-up. The other patient exhibited persistently low levels of serum anti-PLA2R autoantibodies, despite undetectable CD19+ B cells. In this case, the use of anti-CD38 agents could be a promising option, as long-lived plasma cells were likely responsible for the sustained antibody production.
This study had several limitations. First, this is a non-comparative retrospective study with a small sample size and short-term follow-up, which led to limited statistical power to evaluate the clinical efficacy. Due to the nature of retrospective study, the data during the follow-up were incomplete in some patients especially B cell and anti-PLA2R antibodies with high costs. Obinutuzumab in patients with MN who were treatment-naive and RTX-resistant is currently being evaluated by ongoing clinical trials (NCT04629248 and NCT05050214) which might provide valuable insights and further evidence in managing MN. Second, RTX-refractory MN was defined as the continued presence of high or unchanged levels of anti-PLA2R antibodies or experiencing persistent NS with low serum albumin levels during a follow-up period exceeding 6 months after only two doses of 1 g RTX administration without receiving additional infusions. Third, serum IgG levels were not collected in the follow-up. Fourth, anti-RTX antibodies and serum RTX levels were not available, and their role in mediating RTX resistance remained unclear.
In conclusion, despite dramatic improvements in the therapeutic management of MN, a number of patients may confront refractory MN in clinical practice, which are candidates for alternative therapeutic approaches. The current study highlights obinutuzumab as a promising strategy in RTX-refractory phospholipase A2 receptor-related MN. Future prospective randomized clinical trials are warranted to evaluate whether obinutuzumab could potentially be the first-line agent in the treatment of MN or alternative therapy in patients with a limited response or frequent relapses after initial immunosuppressive therapy.
Statement of Ethics
This study protocol was reviewed and approved by the Ethics Committee of The First Affiliated Hospital of Xi’an Jiaotong University, Approval No. KYLISL-2022-289. All participants provided written informed consent to obinutuzumab infusion and retrospective analyses of outcome data in compliance with the Declaration of Helsinki.
Conflict of Interest Statement
All the authors declared no competing interests.
Funding Sources
Xinfang Xie was supported by the National Natural Science Foundation of China Grant (No. 82270747). Huixian Li was supported by the Natural Science Basic Research Program of Shaanxi (2023-JC-QN-1001). Wanhong Lu was supported by Clinical Research Award of The First Affiliated Hospital of Xi’an Jiaotong University (XJTU1AF-CRF-2022-029).
Author Contributions
H.L. and W.L. conceived of the presented idea, designed the study, drafted the manuscript, and assembled the figure. H.L., L.J., X.X., G.X., and A.K. assisted the data collection. H.L. performed the analysis. J.S., D.N., J.F., and X.Z. revised the manuscript. All authors discussed the results and commented on the manuscript.
Funding Statement
Xinfang Xie was supported by the National Natural Science Foundation of China Grant (No. 82270747). Huixian Li was supported by the Natural Science Basic Research Program of Shaanxi (2023-JC-QN-1001). Wanhong Lu was supported by Clinical Research Award of The First Affiliated Hospital of Xi’an Jiaotong University (XJTU1AF-CRF-2022-029).
Data Availability Statement
The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon reasonable request.
Supplementary Material.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon reasonable request.
