Article Text
PDF
Abstract
Background Immune checkpoint inhibitor (ICPi) combined with anti-vascular endothelial growth factor (VEGF) therapy has increasingly become a promising strategy in various malignancies. However, the combination might be associated with increased risk of nephrotoxicity.
Methods We retrospectively recruited patients who suffered kidney injury and received renal biopsy after anti-VEGF/ICPi mono- or combination therapy and divided them into three groups: anti-VEGF monotherapy, ICPi monotherapy and combination therapy. Clinical and histopathological features of three groups were analysed. All patients were followed-up for 3 months after biopsy, with or without glucocorticoid treatment, and renal outcome were compared.
Results A total of 46 patients were enrolled. Eighteen patients received anti-VEGF monotherapy, 12 received ICPi monotherapy and 16 received combined treatment of anti-VEGF and ICPi. Proteinuria level of anti-VEGF group, ICPi group and combination group were 4.07±3.17 g/day, 0.60±0.61 g/day and 2.05±2.50 g/day, respectively (p=0.002). The peak serum creatinine level of combination group (1.75±0.77 mg/dL) was also in between ICPi group (2.79±0.90 mg/dL) and anti-VEGF group (1.34±0.60 mg/dL) (p<0.001). Multiple histopathological patterns involving glomerulus, tubulointerstitium and vessel existed in the majority of cases in combination group (68.8%). Renal complete and partial recovery rate of combination therapy were also in between monotherapy (57.1% vs 40.0% in anti-VEGF group, 100.0% in ICPi group, respectively).
Conclusions Kidney injury in patients treated with combination therapy of ICPi and anti-VEGF shows hybrid pathological patterns and intermediate clinical features compared with monotherapy. Cohorts with larger sample and better design, as well as basic research, are needed to elucidate the mechanism of ‘protection’ effect of combination anti-cancer therapy to renal function.
- NEPHROLOGY
- GLOMERULONEPHRITIS
- Medical Oncology
Data availability statement
Data are available upon reasonable request. The data presented in this study are available on request from the corresponding author.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
WHAT IS ALREADY KNOWN ON THIS TOPIC
Anti-vascular endothelial growth factor (anti-VEGF) and immune checkpoint inhibitor (ICPi) medications both have renal nephrotoxicity.
WHAT THIS STUDY ADDS
Kidney injury in patients treated with combination therapy of ICPi and anti-VEGF shows hybrid pathological patterns and intermediate clinical features and renal outcome compared with monotherapy. This study showed that VEGF blockage might relieve ICPi-associated acute tubulointerstitial nephritis and ICPi might protect podocyte towards anti-VEGF regimen.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
It is necessary to perform kidney biopsy for any forms of kidney injury in patients using combination therapies of anti-VEGF and ICPi. Additional research based on preclinical studies and large size clinical trials were needed to figure out the ‘mutual protection’ cross influence of anti-VEGF and ICPi.
Introduction
Novel anti-cancer therapy, including anti-vascular endothelial growth factor (VEGF) and immune checkpoint inhibitors (ICPi), has demonstrated significant clinical benefits due to tumour suppression and increased survival in recent years. However, ICPi and anti-VEGF therapies are accompanied with renal toxicity. Renal impacts of VEGF blockage include proteinuria, hypertension and renal insufficiency. Incidence of proteinuria after bevacizumab therapy ranged from 21% to 62%,1 while the total incidence of all-grade and high-grade proteinuria in patients receiving TKIs was 18.7% and 2.4%, respectively.2 Adverse kidney effects of ICPi include acute kidney injury (AKI), proteinuria and electrolyte abnormalities, with a reported incidence of 2% to 5% in clinical trial.3 4 In a phase Ib trial of 55 patients treated with PD-L1 inhibitor (avelumab) and VEGF receptor inhibitor (axitinib) for advanced renal cell carcinoma, proteinuria and hypertension has been reported in 10.9% and 47% of patients, respectively.5
With the extensive use of anti-VEGF and ICPi in various types of malignancies, combination of ICPis and VEGF inhibitors is increasing recently, especially for hepatocellular carcinoma and renal cell carcinoma.6 7 Most of the previous reports of kidney injury by anti-VEGF or ICPi therapy were single-case reports or case series reports of monotherapy. Whether the combination therapy of ICPi and anti-VEGF increases the severity of renal toxicity and reduces renal recovery rates as a result of potential synergistic interactions remains unclear. Therefore, we conducted a single-centre retrospective study to evaluate clinical and histopathological patterns of kidney injury after the combination therapy of anti-VEGF and ICPi, and followed-up for 3 months to assess renal outcome after biopsy and appropriate medical measures.
Materials and methods
Patients
We retrospectively recruited patients who suffered kidney injury and received renal biopsy after anti-VEGF/ICPi monotherapy or combination therapy from 2018.1 to 2022.9 in Zhongshan Hospital, Fudan University. Exclusion criteria were as follows: age<18 years old, biopsy-proved kidney disease secondary to other systemic disease.
Clinical characteristics and definitions
The following clinical and laboratory features were obtained from electronic medical record: age; sex; type of malignancy; anticancer regimen; comorbidities; 24-hour urine protein quantitation or urine protein to creatinine ratio; presence of haematuria; serum creatinine (sCr) levels before anti-cancer therapies and at biopsy. Estimated glomerular filtration rate (eGFR) was calculated with CKD-EPI equation.
Clinical definitions used include: (1) nephrotic-range proteinuria, 24-hour urine protein excretion >3.5 g/day or urine protein/creatinine ratio of >3.5 g/g; (2) subnephrotic range proteinuria, 24-hour urine protein excretion ≥0.3 g/day and ≤3.5 g/day or urine protein/creatinine ratio of ≥0.3 g/g and ≤3.5 g/g; (3) AKI, emerging development of sCr >1.2 mg/dL or >0.3 mg/dL increase from baseline over a period of <3 months; (4) chronic kidney disease (CKD), sCr>1.2 mg/dL for at least 3 months in the absence of AKI, CKD stage was defined according to KDIGO guideline 2012.
Renal biopsy and examination
All renal biopsies were evaluated by light microscopic (LM), immunofluorescence (IF) and electron microscopy (EM) studies as routine procedures. All evaluations were examined and reviewed independently by at least two well-trained specialists with rich experience in renal pathology. Due to the complexity of biopsy interpretation in our cohort, kidney biopsy diagnoses were tabulated according to the major tissue compartment involved and the dominant pathologic findings. Because of the high frequency of multiple diagnoses, each biopsy was assigned its major clinical-pathologic diagnosis for purposes of descriptive statistics and analysis.
Treatment
Following medical measures were taken under the joint guidance of nephrologists and oncologists: (1) anti-cancer therapy discontinuation; (2) glucocorticoid or other immunosuppressant therapy, such as Rituximab; (3) supportive treatment, including renin angiotensin aldosterone inhibitors and anticoagulation medications.
Follow-up visits
Patients were followed up for at least 3 months by medical visits. For every follow-up visit, patient’s survival status as well as sCr and 24-hour urinary protein was documented.
Renal prognosis
The renal outcome was defined as: (1) complete recovery (CR): for patients presenting AKI, CR referred to a reduction in sCr to less than 0.5 mg/dL above the baseline, for patients presenting proteinuria, CR referred to a decrease in proteinuria by 50%, and urine protein less than 0.5 g/day with improved or stable renal function; (2) partial recovery (PR): for patients presenting AKI, PR referred to a reduction in sCr to a level between 0.5 mg/dL above the baseline and below the peak sCr, and dialysis independence; for patients presenting proteinuria, PR referred to decrease in proteinuria by 50%, and urine protein less than 3 g/day but greater than 0.5 g/day with improved or stable renal function; (3) no recovery (NR): for patients presenting AKI, NR was defined by the sCr without decrease or dependence on kidney replacement therapy; for patients presenting proteinuria, NR was defined as decrease in proteinuria less than 50% or reduction of renal function.
Statistical analysis
Analysis was performed using SPSS, V.24.0, statistical software package (SPSS Inc). Data are demonstrated as mean±SD or median with IQR for continuous variables and number with percentage for categorical variables. Continuous and categorical data were compared using the Wilcoxon rank-sum and Fisher exact tests, respectively. Two-sided p<0.05 was considered statistically significant.
Results
Clinical and laboratory findings
A total of 46 patients were enrolled in this study and were divided into three groups as anti-VEGF group, ICPi group and the combination group (figure 1). Demographic details and baseline clinical features are summarised in table 1. The distributions of age and sex were similar among three groups. There were no significant differences of baseline renal functions between three groups.
Cohort profile. CR, complete recovery; ICPi, immune checkpoint inhibitor; NR, no recovery; PR, partial recovery; VEGF, vascular endothelial growth factor.
Baseline clinical characteristics before mono or combination therapy of anti-VEGF and ICPi
The time from anti-cancer therapy to kidney injury and clinical manifestation are demonstrated in table 2. The interval between anti-cancer therapy and clinical onset of kidney injury of combination group (26.52±25.44 weeks) was intermediate between anti-VEGF group (58.37±60.65 weeks) and ICPi group (13.51±7.01 weeks) (p=0.012). The peak sCr level of the combination group (1.75±0.77 mg/dL) also intermediate between anti-VEGF group (1.34±0.60 mg/dL) and ICPi group (2.79±0.90 mg/dL) (p<0.001). Similarly, proteinuria level of the combination group was also intermediate (2.05±2.50 g/day) between anti-VEGF group (4.07±3.17 g/day) and ICPi group (0.60±0.61 g/day) (p=0.002).
Clinical and laboratory features of renal toxicity after mono- or combination therapy of anti-VEGF and ICPi
Renal pathological features
The spectrum of kidney biopsy patterns is presented in table 3. Pathological patterns were significantly different between three groups. Glomerular-dominant pattern was most common in anti-VEGF group (61.1%), followed by combination group (31.2%) and ICPi group (25.0%). Tubulointerstitial-dominant pattern was most common in ICPi group (75.0%), followed by combination group (31.2%) and anti-VEGF group (11.1%). Vascular-dominant pattern, which referred to thrombotic microangiopathy (TMA), was most common in combination group (37.5%), followed by anti-VEGF group (27.8%), while none of ICPi group showed TMA-predominant pattern.
The spectrum of kidney biopsy findings of patients receiving mono or combination therapy of anti-VEGF and ICPi
Multiple diagnoses were most common in Combination group (68.8%) compared with anti-VEGF group (22.2%) and ICPi group (8.3%) (p=0.001) (table 3). The most common diagnosis was TMA (37.5%), followed by tubulointerstitial nephritis (25.0%) and focal segmental glomerulosclerosis (FSGS) (16.7%) (figure 2). The detailed clinical and pathological findings of combination group are shown in table 4 and online supplemental table 3. Only 5/16 had single diagnosis, the rest 11 cases had two or even three diagnoses, illustrating the complexity of biopsy interpretation in patients receiving combination therapies. In those with multiple pathological features, TMA was the most common presentation (10/11), followed by tubulointerstitial nephritis (4/11), FSGS (3/11) and IgA nephropathy (3/11). It is noteworthy that two cases were too intricate to be classified into conventional pathological types. Case C6 showed membranoproliferative-like glomerulonephritis with capillary wall IgA deposits (online supplemental figure 1), and Case C10 showed TMA with capillary wall IgA deposits.
Supplemental material
Representative renal pathology images of kidney injury associated with the combination therapy of anti-VEGF and ICPi (A–C) from case showed acute TMA and IgA nephropathy; (D–F) from case showed FSGS accompanied by segmental TMA; (G–I) from cases showed ATIN. (A) Silver stain shows massive thrombus in glomerular capillary lumens, small artery is not affected (×400). (B) Electronic microscopy shows marked endothelial swelling and subendothelial expansion by lucent material (bar=10 µm). (C) Electronic microscopy shows mesangial and subendothelial deposits (bar=10 µm). (D) Periodic acid-Schiff stain shows segmental sclerotic glomeruli (×400). (E) Silver stain shows segmental endothelial swelling (×200). (F) Electronic microscopy shows endothelial swelling and segmental foot process effacement (bar=5 µm). (G) H&E stain shows diffuse interstitial infiltrates predominantly composed of lymphocytes, with several eosinophils (arrows, ×400). (H) H&E stain shows diffuse interstitial inflammation surrounding a mildly ischaemic glomerulus (×200). (I) Electronic microscopy shows shrinking glomerular tufts without deposits (bar=5 µm). ATIN, acute tubulointerstitial nephritis; ICPi, immune checkpoint inhibitor; FSGS, focal segmental glomerulosclerosis; TMA, thrombotic microangiopathy; VEGF, vascular endothelial growth factor.
Clinicopathological features of the combination therapy group (n=16) of anti-VEGF and ICPi and renal outcome
In anti-VEGF group, the most common diagnosis was FSGS (33.3%), followed by immune-complex mediated glomerulonephritis (27.8%) and TMA (27.8%). Tubulointerstitial nephritis accounted for only 11.1% in anti-VEGF group. Four out of 18 patients were observed to have multiple pathological features. Case V5 showed TMA with capillary wall IgA deposits. Case V6 was a very intricate case, which greatly mimic membranous nephropathy (MN) under IF and LM but showed only subendothelial and mesangial deposits under EM, thus was considered a ‘pseudo-MN’ with TMA (online supplemental figure 2). Case V7 showed FSGS with TMA. Case V12 showed FSGS with diabetic nephropathy. The detailed clinical and pathological findings of anti-VEGF group are shown in online supplemental table 1.
In ICPi group, the most common diagnosis was tubulointerstitial nephritis (75.0%), followed by FSGS (16.7%) and pauci-immune necrotising glomerulonephritis (8.3%). Only one case presented multiple pathological features, which showed FSGS and acute tubulointerstitial nephritis (ATIN). The detailed clinical and pathological findings of ICPi group are shown in online supplemental table 2.
Treatment and outcomes
Medical treatment after renal biopsy and renal outcomes are shown in table 5. Anti-cancer therapy discontinuation, corticosteroid administration and supportive treatment were prescribed. The average and total follow-up time were 4.1 months and 165.5 months.
Medical treatment and renal outcomes of the kidney injury after mono or combination therapy of anti-VEGF and ICPi
In combination group, 14 patients discontinued their combination therapies and 8 patients achieved CR or PR. Six patients received corticosteroids and two achieved CR. There was no obvious correlation between pathological patterns with outcomes.
In anti-VEGF group, nine patients discontinued anti-VEGF medication, but only three reached CR or PR. While in the rest nine patients who continued current anti-VEGF medication and refused immunosuppression, three achieved PR.
In ICPi group, 10 patients discontinued ICPi medication. Among them, immunosuppression with intravenous pulse steroids followed by oral prednisone at a starting dosage of 0.5 to 1.0 mg/kg were prescribed for nine patients, while three achieved CR, and six achieved PR. One patient discontinued ICPi medication but did not received corticosteroids achieved CR.
Discussion
Nephrotoxicity of targeted anti-cancer therapy is an emerging issue with expanding clinical application and trials in oncology. However, beyond case series and case reports, rare data revealed the renal pathologic characterisation and renal prognosis in patients treated with the combination therapy of ICPi and anti-VEGF. Our study reported for the first time in the world with 46 cases that renal pathological patterns induced by the combination therapy of anti-VEGF and ICPi showed hybrid characteristics with those of monotherapy. The impact of the combination therapy to renal function and prognosis was intermediate between monotherapy, with moderate proteinuria, milder than anti-VEGF group and moderate sCr increase, milder than ICPi group. Anti-VEGF group mostly showed glomerular-dominant pattern, and ICPi group mostly showed tubulointerstitial-dominant pattern, while combination group showed quite similar proportions of glomerular-dominant, tubulointerstitial-dominant and vascular-dominant patterns.
In our study, it was interesting to discover that, in combination group, although TMA and FSGS-dominant pattern accounted for half, their proteinuria level was much lower than anti-VEGF group. Was this ‘proteinuria protection’ phenomenon the result of the combined ICPi? As previously reported, the most common manifestation of kidney damage of VEGF blockage is proteinuria and hypertension, due to the disruption of transmembrane communication between podocyte and endothelium via VEGF signalling, which cause structural and functional changes of glomerular filtration barrier.8 Inducible podocyte-specific Vegfa deletion in adult mice generates renal-specific TMA,9 which recapitulates kidney pathologic findings in individuals treated with VEGF inhibitors. While TKIs tend to develop podocytopathies, including minimal change disease and collapsing FSGS, probably mediated by tyrosine phosphorylation of nephrin. A very recent study reported a critical role of PD-1 signalling in podocyte ageing and podocytopathy.10 Injection with anti-PD-1 antibody in aged mice extended the life span of podocytes but not that of parietal epithelial, mesangial or endothelial cells. Administering the same anti-PD-1 antibody to young mice with experimental FSGS lowered proteinuria and improved podocyte number. However, it still takes risk to administrate ICPi to relieve podocytopathy as the underlying renal toxicity of ICPi—tubulointerstitial nephritis.11 12 Our findings give some clues to the possible protective effect of ICPi for nephrotoxicity of anti-VEGF therapy.
In combination group, we also noticed that the incidence and severity of AKI were lower than that in ICPi monotherapy. Renal pathology also showed less tubulointerstitial nephritis. This interesting phenomenon to some extent mimics the mutually enhancing anti-cancer effect of anti-VEGF and ICPi combination in non-tumour tissues.13 In tumour tissues, anti-VEGF blocks the negative immune signals by increasing ratio of anti−/pro-tumour immune cell and decreasing the expression of multiple immune checkpoints, while ICPi therapy could restore immune-supportive microenvironment and promote vessel normalisation.14 One of the potential mechanisms of ICPi-induced AKI is the production of autoantibodies against self-antigens presented by tubule epithelial cells, mesangial cells or podocytes. This hypothesis is supported by the finding that ICPi treatment is associated with the activation of self-reactive T cells and increased serum levels of several cytokines, including CXCL10, TNF, IL-6 and IL-10.15 In patients with non-small cell lung cancer (NSCLC) receiving ICPi treatment, baseline and post-treatment plasma IL-10 levels were found independently associated with risk of immune-related adverse events.16 Anti-VEGF drugs could suppress the generation of regulatory T cells (Tregs), tumour-associated macrophages and myeloid-derived suppressor cells and to negatively regulate the expression of immunosuppressive cytokines such as TGF-β and IL-1017–19 to relieve AKI severity.
The renal pathology of patients receiving combination therapy of anti-VEGF and ICPi was seldomly reported. Only one case of TMA and mesangial proliferative glomerulonephritis was reported in a Japanese patient receiving atezolizumab and bevacizumab.20 Our study showed multiple pathological diagnoses in more than two-thirds patients from combination group. The predominant pathological phenotypes in combination group were mostly similar to those in monotherapy, including FSGS and TMA similar to the majorities in anti-VEGF group, and ATIN similar to the majorities in ICPi group. The hybrid pathological patterns were also consistent with intermediate clinical features compared with monotherapy. These phenomena suggest that anti-VEGF and ICPi might simultaneously cause structural injury in different compartment of the kidney with unequal severity, therefore leading to almost equal percentage of glomerular, tubulointerstitial and vascular injury in our cohort. The heterogeneity of renal pathological patterns in patients receiving combination therapies calls for further investigation. Cohorts with larger sample size and basic research are needed to establish relationship between unbalanced injury degree and anticancer regimens.
Notably, in our study, a series of distinct pathological patterns which cannot fit any conventional pathological phenotypes were observed in anti-VEGF group and combination group. Three cases (case V5, C6 and C10) shared capillary wall IgA deposits with endothelial injury in common, which might be confused with IgA nephropathy. Previous case reports have observed similar pathological features in a few patients on anti-VEGF-associated TMA.9 21 This finding is not generally observed in other causes of TMA, therefore probably indicating a predisposition to deposit glomerular IgA caused by anti-VEGF therapy. It remains ambiguous whether these findings represent a true immunological reaction due to anti-VEGF therapy, or a coincidental glomerulonephritis independent of anti-VEGF. Based on the current findings, we suggest to suspect drug association when capillary wall IgA deposition is seen in cases with a history of anti-VEGF therapy, after ruling out infection-related glomerulonephritis. One case from anti-VEGF group (case V8) greatly mimics MN under LM and IF but showed no subepithelial deposits under EM. This pathological feature cannot fall into any reported glomerulonephritis types, so we term it as ‘pseudo-MN’ for reference. This interesting case raised our alert that, for the MN-mimic cases by IF and LM in patients receiving anti-cancer therapies, EM should never be neglected.
Although National Comprehensive Cancer Network22 and the American Society of Clinical Oncology guidelines23 both do not advocate for kidney biopsy in the evaluation of patients with ICPi-associated kidney injury, our findings appealed the necessity of renal biopsy in patients with kidney injury during anti-VEGF and ICPi combination therapy, since clinical findings and laboratory tests are often not parallel with the kidney lesions. The precise pathological diagnosis would be helpful to guide the most effective and appropriate strategy. Kidney biopsy is especially recommended for patients with dominant proteinuria or kidney failure irresponsive to therapy cessation. Moreover, we strongly recommend baseline urinalysis, with quantification of proteinuria or microalbuminuria if present, before targeted therapies. With this information, oncologists would be more cautious of patients’ renal injury during therapy.
Corticosteroid is considered as the first-line immuno-suppressive treatment for ICPi-related acute tubulointerstitial nephritis (ATIN).24 25 However, no guidelines are available on the treatment of proteinuria secondary to anti-VEGF agents. Therapeutic options besides cessation or dose adjustment of anti-VEGF agents are mostly non-specific, including renin-angiotensin system inhibitors. Although previous reports showed certain efficacy of additional immunosuppressant agents for ICPi-associated glomerulonephritis,26 the risk of counteracting the therapeutic effects of ICPi and interfering with overall cancer outcomes should be taken into consideration. Most of the studies have not shown worsening of outcomes with systemic immuno-suppression,27 28 but some studies have indicated that higher doses of corticosteroids may reduce survival, with prednisone doses ≥10 mg/day (or equivalent) have been associated with poorer outcome in patients with NSCLC treated with PD-L1 inhibitors.29 30 Therefore, cautious use of corticosteroids based on definite pathological diagnosis of interstitial nephritis might be more appropriate in clinical practice.
Our study has several limitations. This is a real-world study related to the single-centre clinical experience, which may be subjected to certain biases. First, the category and grade of primary cancer were within a wide range, and the dosage of anti-VEGF and ICPi was not analysed. Second, in some cases, we cannot completely exclude the presence of underlying kidney diseases prior to targeted therapies. Finally, since combination therapy was mostly offered in very recent clinical trials, the time of follow-up was relatively short. Given the novelty of ICPi and anti-VEGF combination therapy, much remains unknown.
Additional research based on preclinical studies and large size clinical trials were needed to figure out the ‘mutual protection’ cross influence of anti-VEGF and ICPi, which is first clinically observed and reported in our study that VEGF blockage might relieve ICPi-associated ATIN, and ICPi might protect podocyte towards anti-VEGF regimen. Prompt and close collaboration between oncologists and nephrologists is encouraged to establish a treatment strategy for kidney injury associated with ICPi combining anti-VEGF therapy.
Data availability statement
Data are available upon reasonable request. The data presented in this study are available on request from the corresponding author.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by Ethics Committee of Zhongshan Hospital, Fudan University (Approval Number B2021-346R). Participants gave informed consent to participate in the study before taking part.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Handling editor Vikram Deshpande.
SJ and ZS contributed equally.
Contributors SJ and ZS conceived and designed the study. SJ wrote the manuscript. ZS revised the manuscript. HL is responsible for the overall content as guarantor, accepts full responsibility for the finished work, had access to the data, and controlled the decision to publish. HL and XD supervised the project. JL, XL, QZ, FL collected pathological data. YS, XX, PL, XC. XG collected clinical data and performed data analysis and statistical analysis. All the authors read and approved the final version of the manuscript.
Funding This research was funded by the National Natural Science Foundation of China [Grant Numbers 81803880, 82002018, 81870476]; Shanghai Clinical Research Center for Kidney Disease (22MC1940100); Shanghai Federation of Nephrology Project supported by Shanghai ShenKang Hospital Development Center (SHDC2202230); Shanghai Key Laboratory of Kidney and Blood Purification (Number 20DZ2271600); Shanghai Municipal Key Clinical Specialty (shslczdzk02501).
Disclaimer The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer-reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.