Startseite Immunosuppressive treatment for idiopathic membranous nephropathy: An updated network meta-analysis
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Immunosuppressive treatment for idiopathic membranous nephropathy: An updated network meta-analysis

  • Neng Bao , Mingjia Gu , Xiang Yu , Jin Wang , Leiping Gao , Zhiwei Miao EMAIL logo und Wei Kong EMAIL logo
Veröffentlicht/Copyright: 10. Januar 2023
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Open Life Sciences
Aus der Zeitschrift Open Life Sciences Band 18 Heft 1

Abstract

This network meta-analysis (NMA) aims to investigate the efficacy and safety of different pharmacological treatments for idiopathic membranous nephropathy (IMN). Thirty-four relevant studies were extracted from PubMed, Embase, Cochrane database, and MEDLINE. Treatment with tacrolimus (TAC), cyclophosphamide (CTX), mycophenolate mofetil, chlorambucil (CHL), cyclosporin A (CSA), steroids, rituximab (RTX), and conservative therapy were compared. Outcomes were measured using remission rate and incidence of side effects. Summary estimates were expressed as the odds ratio (OR) and 95% confidence intervals (CIs). The quality of findings was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. In the direct meta-analysis for comparison of complete remission (CR) rate, the curative effect of RTX is inferior to CTX (OR 0.37; CI 0.18, 0.75). In the NMA of CR rate, the results showed that the curative effects of CTX, CHL, and TAC were significantly higher than those of the control group. The efficacy of RTX is not inferior to the CTX (OR 0.81; CI 0.32, 2.01), and the level of evidence was moderate; CSA was not as effective as RTX, and the difference was statistically significant with moderate evidence (OR 2.98, CI 1.00, 8.91). In summary, we recommend CTX and RTX as the first-line drug for IMN treatment.

Keywords: idiopathic membranous nephropathy; immunosuppressive treatment; network meta-analysis; GRADE

1 Introduction

In recent years, the incidence rate of idiopathic membranous nephropathy (IMN) was shown to be increasing [1]. IMN is the most prevalent cause of nephrotic syndrome in adults [2]. Although one-third of patients can recover spontaneously [3], nearly 30–40% of patients with nephrotic syndrome do not recover and succumb to end-stage renal disease [4,5]. The pathogenesis of IMN is thought to be caused by the deposition of immune complexes such as IgG and complement protein C3 in the glomerular basement membrane, resulting in the thickening of the glomerular capillary wall and proteinuria [6]. Therefore, immunosuppressive therapy is the mainstay in the treatment of IMN.

The guidelines issued by the Kidney Disease Improving Global Outcomes (KDIGO) in 2021 have been updated in the treatment of membranous nephropathy [7]. Rituximab (RTX) or calcineurin inhibitor (CNI) is recommended as the initial treatment for moderate-risk patients with normal estimated glomerular filtration rate (eGFR) and large proteinuria (greater than 3.5 g/day). For high-risk patients mostly characterized by decreased eGFR, cyclophosphamide (CTX) is recommended as the first-line drug. Compared with the previous version [8], the focus of this guideline update mainly concerns the use of RTX. RTX is a chimeric monoclonal IgG1 antibody, which reduces proteinuria by binding CD20 to consume B cells. In recent years, high-quality randomized controlled trials (RCTs) have shown that RTX is effective in the treatment of IMN, and the incidence of side effects is relatively low [9,10]. Therefore, it has become defined as another effective intervention for the therapy of IMN.

As an emerging intervention parallel to CTX and CNIs recommended by KDIGO guidelines, RTX has attracted extensive attention in academic circles in recent years. However, recently published articles show that it has no advantage in the efficacy and safety of IMN compared with CTX [11,12]. With the advent of RTX, it was necessary to re-evaluate the mainstays of treatment for IMN. Due to the lack of head-to-head RCTs of RTX, CTX, and CNIs, it is difficult for clinicians to comprehensively compare their advantages and disadvantages. A network meta-analysis (NMA) can evaluate multiple interventions simultaneously by calculating the combined effect between various measures. These are mostly based on the Bayesian or frequency methods to calculate and analyze the direct effect quantity (direct comparison of the two treatment interventions) and indirect effect quantity (comparison of the two treatment interventions with one as the reference), respectively. These results are then combined to generate a mixed effect quantity that quantifies the advantages and disadvantages of each treatment.

Therefore, we conducted an NMA to compare the efficacy and safety of common treatments for IMN such as RTX, CTX, and CNIs, and assessed the obtained effect amount according to the Grading of Recommendations Assessment Development, and Evaluation (GRADE) criteria [13,14,15,16,17,18] to provide the corresponding level of evidence for the final results.

2 Methods

The study protocol was registered in the International Prospective Register of Systematic Reviews (CRD42019131825) and was consistent with the statements of Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

2.1 Inclusion criteria

The study in question must be an RCT, and the observation time shall not be less than 6 months. In addition, the following points must be met:

  1. The patients must be adults (over 18 years old) diagnosed with IMN by renal biopsy.

  2. Interventions in the treatment group must be either/or CTX, chlorambucil (CHL), mycophenolate mofetil (MMF), tacrolimus (TAC), cyclosporin A (CSA), RTX, or steroids (STE), of which the first five regimens can be used in combination with steroids or alone.

  3. Measures in the control group included placebo/no treatment, conservative treatment (ACEI/ARB or other supportive treatment), steroids, CTX, CHL, or CSA. The latter three therapies can be used in combination with steroids or alone.

  4. The results must include the rate of remission (including complete or partial remission (PR)) or the incidence of side effects, or both.

2.2 Exclusion criteria

The following criteria were excluded:

  1. Non-randomized trials or observational studies;

  2. Studies of secondary membranous nephropathy (such as hepatitis B related nephropathy);

  3. Studies with patients younger than 18 years;

  4. Studies with observation times less than 6 months;

  5. Alternative treatments such as ACTH and leflunomide;

  6. Studies using herbal or traditional Chinese medicines;

  7. Studies using Azathioprine or mizoribine due to their poor efficacy [19].

2.3 Retrieval strategy

Two researchers (NB and XY) conducted an independent literature search for articles or abstracts. The retrieval databases include PubMed, Embase, Cochrane database, and MEDLINE. The retrieved timeline is set as August 15, 2021 as a reference. Duplicate entries were resolved through negotiation.

2.4 Baseline characteristics and quality assessment

Two researchers (M-JG and XY) extracted the detailed information such as study design, sample size, drug dosing, and specific characteristics of patients in the study. The results were extracted at the end of each study. When multiple points in time were reported, the last point in time was used. We used the Cochrane bias risk assessment tool to assess the quality of single literature. According to the Cochrane risk deviation assessment, the remission rate and the incidence of side effects were objective indicators. Therefore, although most of the included studies were not double-blind, it can be assumed that the above sources of bias are low. Any doubt shall be resolved through direct consultation with the expert group.

2.5 Observation index

Efficacy indicators include complete remission (CR) and total remission (TR). CR refers to urinary protein ≤0.3 g/24 h and stable renal function. PR refers to urinary protein >0.3 g/24 h, but <3.5 g/24 h and <50% baseline value. TR is the sum of CR and PR.

Safety indicators include hepatic and renal injury, infection, bone marrow suppression, gastrointestinal symptoms, nervous system symptoms, cardiovascular symptoms, gonadal suppression, tumor, metabolic disease, psychiatric compromise, and other adverse reactions.

2.6 Statistical methods

We used Stata software (version 15.0, Stata MP, StataCorp, College Station, TX) to conduct NMA for dobby trials (including two or more experimental intervention groups with common control groups, or two control intervention groups, such as the placebo group and the standard treatment group) under the framework of frequency. We calculated the surface under the cumulative ranking area (SUCRA) of each intervention, summarized and ranked the differences in the remission rates of all treatment measures. The greater the ratio of SUCRA, the higher the response rate. We used node splitting methods to evaluate the difference in analysis between direct and indirect comparisons between different studies. When there was no significant statistical difference between the direct comparison and indirect comparison (P > 0.05), we used the consistency model for NMA, otherwise we used the inconsistency effect model. The publication bias of subgroups with more than ten studies was evaluated by observing whether the funnel plot was symmetrical. In subgroups with less than 10 studies, the Egger’s test was used [20].

2.7 Evidence quality assessment

We evaluated the quality of the direct comparison according to the RCT evidence quality evaluation method released by GRADE working group [13,14,15,16,17] (Table S1). At the beginning of the evaluation, all included RCTs were set at a high-quality level. They were then evaluated according to five aspects: risk of bias, inconsistency, indirectness, imprecision, and other considerations. For each criterion that a study failed to meet, the guidance level was reduced by one level. For serious non-compliance, the guidance level can be reduced by two levels. After completing the evaluation of the five projects, the final grade results were summarized.

The quality assessment of the indirect comparison was carried out according to the method described by Puhan et al. [18] and relative references [21,22,23]. First, the best comparable path was selected. The fewer the interventions present in the indirect comparison path, the higher the credibility of the results. After determining the best indirect comparison path, the evidence quality of a single direct comparison in the path was evaluated according to the method. The lowest level of evidence was selected to reflect the final evidence quality of this group of indirect comparisons. If there are both direct and indirect effects in a set of comparisons, the two comparisons are evaluated separately, and a higher level of evidence was selected to reflect the result. The final step was to assess the inconsistency of results, including baseline characteristics, common references, and differences in outcome measurements between different groups. If the difference is significant, the final quality level will be further reduced by one level. This work was carried out on GRADE profile.

2.8 Patient and public involvement

Our study was a meta-analysis, so we did not involve any patients in this study. Since our data come from previously published clinical data, we were unable to disseminate the results to participants.

3 Results

Using the above retrieval strategy, a total of 1,108 articles were retrieved (Table S2 for the complete retrieval strategies). After excluding duplicate and other irrelevant articles, 115 articles were suitable for analysis. After carefully reviewing each article according to the above inclusion and exclusion criteria, a total of 34 articles [9,10,11,12,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53] were included. Of the 81 excluded articles, the following issues were found: 6 articles included other types of nephritis; 2 papers were on traditional Chinese medicine; 41 papers were not RCTs; 11 papers used uncommon drugs; the results of 7 papers did not meet the standard; 3 papers used the preliminary results; 10 papers compared different dosages of the same drug; and the outcome indicators of 1 paper did not meet the inclusion criteria. The details are shown in Figure 1.

Figure 1 Flow chart depicting the process of identification of studies.
Figure 1

Flow chart depicting the process of identification of studies.

3.1 Characteristics and quality of included studies

Tables S3 and S4 summarize the basic characteristics of the study, including 34 RCTs, with a total sample size of 2,064 and a follow-up period of 6–120 months. All studies reported remission rates, except that by Kosmadakis et al. [49]. All other studies reported the incidence of various side effects in detail. Of the 34 studies included, 32 [9,10,11,12,24,25,26,27,28,29,30,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,50,51,52,53] were two-arm studies and the remaining two were three-arm studies.

The literature quality assessment is based on the Cochrane bias risk assessment tool. The overall quality is the risk of medium and low bias. Since remission rates and side effects are objective indicators, single-blind or non-blind studies have little impact on these results. Details of the literature quality assessment are shown in Figures 2 and 3 and Table S5.

Figure 2 Risk of bias assessment: overall risk of bias for all included trials.
Figure 2

Risk of bias assessment: overall risk of bias for all included trials.

Figure 3 Risk of bias summary: overall risk of bias for all included trials.
Figure 3

Risk of bias summary: overall risk of bias for all included trials.

3.2 Direct meta-analysis

3.2.1 CR rate

The meta-analysis of the direct comparison showed that the curative effect of RTX was significantly inferior to that of CTX (OR 0.37, CI 0.18, 0.75) with moderate evidence. CTX was significantly better than that of conservative treatment (OR 6.26, CI 1.02, 38.45) with low evidence. CHL was significantly better than that of conservative treatment (OR 8.43, CI 3.49, 20.38), with high evidence (Figure S1).

3.2.2 TR rate

A meta-analysis of the direct comparison showed that in terms of TR rate, CTX (OR 4.06, CI 2.01, 18.19) and CHL (OR 4.65, CI 2.49, 8.68) were significantly better than conservative treatment with high evidence. RTX was also significantly better than CSA (OR 6.00, CI 2.74, 13.15) with moderate evidence. STE was inferior to CHL (OR 0.38, CI 0.16, 0.87) with low evidence (Figure S2).

3.3 NMA

3.3.1 CR rate

A total of 31 articles reported the CR rate. Among them, 18 articles reported CTX, 11 mentioned conservative treatment, 8 papers used CHL, 4 articles reported STE, 5 papers reported CSA, 8 articles mentioned TAC, 7 studies reported MMF, and 4 was RTX. The network diagram of each treatment for CR is shown in Figure 4.

Figure 4 Network diagram for CR: The network of all treatments used for the evaluation of CR. The node size was found to be proportional to the number of patients who were randomized for each modality and the line thickness was corresponded to the number of direct comparisons. For example, the size of the CTX circle was the largest, while the line between CTX and CON was the thickest. This indicates that CTX had the greatest number of studies, and direct comparisons between CTX and CON were commonly found in the literature.
Figure 4

Network diagram for CR: The network of all treatments used for the evaluation of CR. The node size was found to be proportional to the number of patients who were randomized for each modality and the line thickness was corresponded to the number of direct comparisons. For example, the size of the CTX circle was the largest, while the line between CTX and CON was the thickest. This indicates that CTX had the greatest number of studies, and direct comparisons between CTX and CON were commonly found in the literature.

3.3.1.1 Publication bias

A general funnel plot generated by Stata is included (Figure 5). The results showed that the included studies had no publication bias. Egger’s test was used to detect the publication bias for each direct comparison with more than two studies. If P > 0.1, there was no publication bias, otherwise it means publication bias (Table S6).

Figure 5 Funnel plot for CR, with a complex evidence network including 16 sets of head-to-head randomized trials as shown above. Single markers represented the individual primary studies, while the orange vertical line showed the summary effect estimate, and the dashed oblique lines showed the 95% CIs at varying degrees of precision.
Figure 5

Funnel plot for CR, with a complex evidence network including 16 sets of head-to-head randomized trials as shown above. Single markers represented the individual primary studies, while the orange vertical line showed the summary effect estimate, and the dashed oblique lines showed the 95% CIs at varying degrees of precision.

3.3.1.2 Contribution chart

The direct comparison weights of the top three were STE vs conservative therapy (CON) (54.0%), MMF vs CTX (42.9%), and CTX vs RTX (42.0%). This means that the reliability of the above results is relatively high (Figure S3).

3.3.1.3 Inconsistency test

The node splitting method was used to perform the inconsistency test. If P > 0.05, there was no inconsistency between these studies, otherwise there was local comparison inconsistency. The results showed that, as shown in Table S7, there was no inconsistency in all comparisons between these groups except CSA vs CTX and RTX vs CTX. First, the inconsistency model was used for NMA to evaluate the global comparison inconsistency. The results of the inconsistency model suggest that there was no inconsistency among the design effects, so it can be simplified as the consistency effect model for calculation.

3.3.1.4 Results

The results of NMA using the consistency model suggest that for the CR rate, the ranking of SUCRA is CTX (82.5) > CHL (75.8) > RTX (71.2) > TAC (69.8) > MMF (41.9) > STE (23.7) > CSA (18.1) > CON (16.9) (Figure 6). CTX was significantly better than conservative treatment (OR 3.85; CI 1.39, 11.11) with moderate evidence. CHL was also significantly better than conservative treatment (OR 3.51; CI 1.34, 9.21), and the evidence was high. CSA was not as effective as CTX (OR 0.26, CI 0.07, 0.91) with low evidence (Table 1 and Table S8).

Figure 6 CR ranking among different interventions. A simple numerical summary to present the graphical display of cumulative ranking was used to estimate the SUCRA line for each treatment. SUCRA would be 100% when a treatment was certain to be the best and 0 when a treatment was certain to be the worst. If a treatment always ranks first, then it will have 100% SUCRA, and if it always ranks last, it will have 0 SUCRA. This enabled us to rank the treatments overall. For example, treatment CTX emerged as the best, followed by CHL, and last came CON.
Figure 6

CR ranking among different interventions. A simple numerical summary to present the graphical display of cumulative ranking was used to estimate the SUCRA line for each treatment. SUCRA would be 100% when a treatment was certain to be the best and 0 when a treatment was certain to be the worst. If a treatment always ranks first, then it will have 100% SUCRA, and if it always ranks last, it will have 0 SUCRA. This enabled us to rank the treatments overall. For example, treatment CTX emerged as the best, followed by CHL, and last came CON.

Table 1

Final results and GRADE assessment for CR

Direct estimates Indirect estimates Network meta-analysis
Pharmacological intervention OR（95% CI） Quality of evidence OR（95% CI） Quality of evidence OR(95% CI) Quality of evidence
Compared with TAC
CTX 1.07 (0.73, 1.57) Very low 1.08 (0.48, 2.42) Low 1.24 (0.60, 2.57) Low
CON 2.04 (0.43, 9.70) Low 0.24 (0.08, 0.70) Low 0.32 (0.10, 1.00) Low
MMF 0.22 (0.07, 0.69) Moderate 0.62 (0.20, 1.97) Very low 0.58 (0.19, 1.72) Moderate
CHL N/A 0.80 (0.29, 2.24) Very low 1.13 (0.35, 3.72) Very low
CSA 0.64 (0.15, 2.76) Low 0.35 (0.09, 1.30) Very low 0.32 (0.09, 1.18) Low
STE N/A 0.22 (0.07, 0.74) Low 0.35 (0.08, 1.51) Low
RTX N/A 1.55(0.17, 13.70) Low 1.12 (0.28, 4.45) Low
Compared with CTX
CON 0.16 (0.03, 0.98) Low 0.22(0.09, 0.55) Moderate 0.26 (0.09, 0.72) Moderate
MMF 0.87 (0.40, 1.90) Moderate 0.58(0.24, 1.38) Low 0.46 (0.18, 1.21) Moderate
CHL 0.47 (0.21, 1.03) Moderate 0.75(0.37, 1.54) Low 0.91 (0.32, 2.58) Moderate
CSA 0.11 (0.01, 1.34) Low 0.32(0.10, 1.02) Low 0.26 (0.07, 0.91) Low
STE N/A 0.21 (0.07, 0.60) Low 0.29 (0.07, 1.11) Low
RTX 0.37 (0.18, 0.75) Moderate 1.44(0.19, 10.86) Low 0.90 (0.27, 3.03) Moderate
Compared with CON
MMF 0.42 (0.03, 5.06) Low 2.69 (0.80, 9.02) Low 1.78 (0.52, 6.08) Low
CHL 8.43 (3.49, 20.38) High 3.53 (1.27, 9.80) Low 3.51 (1.34, 9.21) High
CSA 3.32 (0.12, 91.60) Low 1.63 (0.55, 4.83) Low 0.99 (0.24, 4.12) Low
STE 0.82 (0.42, 1.60) Low 0.94 (0.47, 1.88) Low 1.10 (0.36, 3.38) Low
RTX 8.63 ( 1.01, 74.11) Low 4.03 (0.54, 30.15) Low 3.46 (0.82, 14.56) Low
Compared with MMF
CHL 2.25 (0.29, 17.76) Low 1.30(0.46, 3.65) Moderate 1.97 (0.57, 6.84) Moderate
CSA 0.85 (0.16, 4.43) Low 0.56 (0.16, 1.94) Low 0.56 (0.14, 2.19) Low
STE N/A 0.36 (0.10, 1.26) Low 0.62 (0.14, 2.80) Low
RTX N/A 2.49 (0.30, 20.91) Moderate 1.94 (0.43, 8.71) Moderate
Compared with CHL
CSA N/A 0.43 (0.12, 1.50) Low 0.28 (0.06, 1.24) Low
STE 0.60 (0.23, 1.53) Low 0.27(0.09, 0.82) Low 0.31 (0.09, 1.08) Low
RTX N/A 1.92 (0.23, 15.68) Moderate 0.99 (0.22, 4.47) Moderate
Compared with CSA
STE 0.59 (0.05, 6.96) Low 0.64 (0.19, 2.13) Low 1.11 (0.22, 5.48) Low
RTX 72.44 (4.28, 1224.53) Moderate 4.47 (0.63, 31.93) Low 3.50 (0.70, 17.51) Moderate
Compared with STE
RTX N/A 4.29 (0.56, 32.91) Low 3.15 (0.57, 17.51) Low

3.3.2 TR rate

A total of 33 articles reported the overall remission rate of proteinuria. Among them, 18 articles reported CTX, 13 mentioned conservative treatment, 8 papers used CHL, 4 articles reported STE, 6 papers reported CSA, 8 articles mentioned TAC, 7 researchers reported MMF, and 4 was RTX. Figure 7 shows the network diagram and consistency test results of various treatment interventions for TR.

Figure 7 Network diagram for TR: The network of all treatments used for the evaluation of TR. The node size was found to be proportional to the number of patients who were randomized for each modality and the line thickness was corresponded to the number of direct comparisons. For example, the size of the CTX circle was the largest, while the line between CTX and CON was the thickest. This indicates that that CTX had the greatest number of studies, and direct comparisons between CTX and CON were commonly found in the literature.
Figure 7

Network diagram for TR: The network of all treatments used for the evaluation of TR. The node size was found to be proportional to the number of patients who were randomized for each modality and the line thickness was corresponded to the number of direct comparisons. For example, the size of the CTX circle was the largest, while the line between CTX and CON was the thickest. This indicates that that CTX had the greatest number of studies, and direct comparisons between CTX and CON were commonly found in the literature.

3.3.2.1 Publication bias

A general funnel plot performed by Stata is included (Figure 8). The results showed that the included studies had no publication bias. The Beggar’s and Egger’s tests were used to detect the publication bias for each direct comparison with more than two studies. If P > 0.1, there was no publication bias, otherwise, it means publication bias (Table S9).

Figure 8 Funnel plot for TR with a complex evidence network including 16 sets of head-to-head randomized trials as shown above. Single markers represented the individual primary studies, while the orange vertical line showed the summary effect estimate, and the dashed oblique lines showed the 95% CIs at varying degrees of precision.
Figure 8

Funnel plot for TR with a complex evidence network including 16 sets of head-to-head randomized trials as shown above. Single markers represented the individual primary studies, while the orange vertical line showed the summary effect estimate, and the dashed oblique lines showed the 95% CIs at varying degrees of precision.

3.3.2.2 Contribution chart

The direct comparison weights of the top three were CHL vs CON (44.6%), CSA vs RTX (43.2%), and CTX vs CON (36.2%). This means that the reliability of the above results is relatively high (Figure S4).

3.3.2.3 Inconsistency tests

Stata was used to perform the inconsistency test. If P > 0.05, there was no inconsistency between these studies, otherwise there is inconsistency. The results shown in Table S10 indicate no inconsistency in all comparisons between these groups, and the consistency effect model can be used.

3.3.2.4 Results

The results of NMA using the consistency model suggest that for the TR rate, the ranking for SUCRA is CTX (86.7) > RTX (74.6) > TAC (73.6) > CHL (62.2) > MMF (46.0) > STE (31.8) > CSA (18.3) > CON (6.7) (Figure 9). Compared with conservative treatment, CTX (OR 4.76; CI 2.33, 9.09), CHL (OR 3.12; CI 1.45, 6.71), and RTX (OR 3.78; CI 1.41, 10.09) were associated with significantly higher probabilities of TR, with high and moderate evidence, respectively. There was no significant difference between RTX and CTX (OR 0.81, CI 0.32, 2.01) with moderate evidence; CSA was not as effective as RTX in the TR rate, the difference was statistically significant (OR 0.34, CI 0.11, 1.00), and the evidence was moderate (Table 2 and Table S11).

Figure 9 TR ranking among different interventions. A simple numerical summary to present the graphical display of cumulative ranking was used to estimate the SUCRA line for each treatment. SUCRA would be 100% when a treatment was certain to be the best and 0 when a treatment was certain to be the worst. If a treatment always ranks first, then it will have 100% SUCRA, and if it always ranks last, it will have 0 SUCRA. This enabled us to rank the treatments overall. For example, treatment CTX emerged as the best, followed by RTX, and last came CON.
Figure 9

TR ranking among different interventions. A simple numerical summary to present the graphical display of cumulative ranking was used to estimate the SUCRA line for each treatment. SUCRA would be 100% when a treatment was certain to be the best and 0 when a treatment was certain to be the worst. If a treatment always ranks first, then it will have 100% SUCRA, and if it always ranks last, it will have 0 SUCRA. This enabled us to rank the treatments overall. For example, treatment CTX emerged as the best, followed by RTX, and last came CON.

Table 2

Final results and GRADE assessment for TR

Direct estimates Indirect estimates Network meta-analysis
Pharmacological intervention OR（95% CI） Quality of evidence OR（95% CI） Quality of evidence OR(95% (C) Quality of evidence
Compared with TAC
CTX 0.99 (0.35, 2.77) Low 1.14 (0.47, 2.73) Low 1.26 (0.64, 2.48) Low
CON 0.66 (0.20, 2.17) Low 0.23 (0.08, 0.67) Low 0.27 (0.11, 0.65) Low
MMF 0.47 (0.14, 1.61) Low 0.63 (0.24, 1.71) Low 0.52 (0.19, 1.41) Low
CHL N/A 0.90 (0.30, 2.76) Low 0.84 (0.31, 2.30) Low
CSA 0.39 (0.06, 2.55) Low 0.47 (0.14, 1.63) Very low 0.34 (0.11, 1.04) Very low
STE N/A 0.38 (0.12, 1.26) Low 0.32 (0.09, 1.08) Low
RTX N/A 0.81 (0.24, 2.71) Low 1.02 (0.34, 3.02) Low
Compared with CTX
CON 0.25 (0.12, 0.50) High 0.20 (0.10, 0.41) Low 0.21 (0.11, 0.43) High
MMF 0.59 (0.19, 1.83) Low 0.56 (0.21, 1.45) Low 0.41 (0.17, 0.97) Low
CHL 0.35 (0.08, 1.59) Low 0.79 (0.36, 1.74) High 0.67 (0.29, 1.53) High
CSA 0.08 (0.00, 1.88) Low 0.42 (0.12, 1.41) Very low 0.27 (0.10, 0.75) Very low
STE N/A 0.34 (0.14, 0.84) Moderate 0.25 (0.08, 0.76) Moderate
RTX 0.56 (0.14, 2.24) Moderate 0.72 (0.30, 1.70) Low 0.81 (0.32, 2.01) Moderate
Compared with CON
MMF 0.83 (0.22, 3.19) Low 2.79 (0.90, 8.70) Low 1.92 (0.75, 4.94) Low
CHL 4.65 (2.49, 8.68) High 3.98 (2.25, 7.03) Low 3.12 (1.45, 6.71) High
CSA 0.97 (0.01, 177.01) Very low 2.09 (0.59, 7.42) Low 1.27 (0.45, 3.56) Low
STE 2.15 (0.94, 4.94) Moderate 1.69 (0.86, 3.32) Very low 1.18 (0.45, 3.12) Moderate
RTX 3.55 (1.37, 9.19) Low 3.58 (1.57, 8.17) Moderate 3.78 (1.41, 10.09) Moderate
Compared with MMF
CHL 1.50 (0.26, 8.82) Low 1.42 (0.46, 4.39) Low 1.62 (0.58, 4.57) Low
CSA 0.63 (0.15, 2.54) Low 0.75 (0.22, 2.49) Very low 0.66 (0.21, 2.05) Very low
STE N/A 0.60 (0.18, 2.04) Low 0.61 (0.18, 2.15) Low
RTX N/A 1.28 (0.37, 4.44) Low 1.96 (0.61, 6.29) Low
Compared with CHL
CSA N/A 0.53 (0.14, 1.96) Low 0.41 (0.13, 1.29) Low
STE 0.38 (0.16, 0.87) Low 0.42 (0.22, 0.84) Moderate 0.38 (0.13, 1.08) Moderate
RTX N/A 0.90 (0.35, 2.32) Low 1.21 (0.39, 3.74) Low
Compared with CSA
STE 0.23 (0.06, 0.97) Low 0.81 (0.21, 3.12） Very Low 0.93 (0.28, 3.15) Very Low
RTX 6.00 (2.74, 13.15) Moderate 1.72 (0.44, 6.74） Low 2.98 (1.00, 8.91) Moderate
Compared with STE
RTX N/A 2.12 (0.75, 6.03） Low 0.31 (0.09, 1.13) Low

3.4 Side effect profiles

The use of immunosuppressants can reduce the immune function of patients, and the drug itself has many toxic and side effects. The adverse drug reactions analyzed in this study mainly include infection, bone marrow suppression, hepatic and renal function injury, cardiovascular events, adverse reactions of the nervous system and gastrointestinal tract, metabolic diseases, gonadal toxicity, etc. The statistics of adverse reactions of different treatments are shown in Table 3. Among the schemes, the three interventions with the highest incidence of infection were CTX (23.34%), followed by RTX (20.33%) and MMF (19.82%). The three immunosuppressive agents associated with a higher frequency of bone marrow suppression were CHL (12.9%), CTX (12.2%), and RTX (6.1%). In addition, it should be noticed that TAC was related to the highest incidence rate of glucose intolerance (17.1%) and RTX was related to the highest incidence rate of transfusion reaction (15.9%).

Table 3

Side effects

Side effect Drugs
CTX TAC CSA CHL MMF STE RTX CON
Infection Cases 109 43 25 21 22 0 37 18
Percentage 23.34% 17.13% 17.24% 9.68% 19.82% 0.00% 20.33% 4.16%
Leukopenia Cases 37 1 0 25 0 0 2 0
Percentage 7.92% 0.40% 0.00% 11.52% 0.00% 0.00% 1.10% 0.00%
Anemia Cases 20 1 1 3 4 0 9 1
Percentage 4.28% 0.40% 0.69% 1.38% 3.60% 0.00% 4.95% 0.23%
Hepatotoxicity Cases 28 16 3 3 2 0 0 0
Percentage 6.00% 6.37% 2.07% 1.38% 1.80% 0.00% 0.00% 0.00%
Hyperglycemia Cases 35 43 3 5 2 5 3 2
Percentage 7.49% 17.13% 2.07% 2.30% 1.80% 2.11% 1.65% 0.46%
Gastrointestinal symptoms Cases 32 20 31 17 13 10 20 2
Percentage 6.85% 7.97% 21.38% 7.83% 11.71% 4.22% 10.99% 0.46%
Neuropathy Cases 29 20 36 9 4 3 52 8
Percentage 6.21% 7.97% 24.83% 4.15% 3.60% 1.27% 28.57% 1.85%
Renal toxicity Cases 8 10 16 0 0 0 18 2
Percentage 1.71% 3.98% 11.03% 0.00% 0.00% 0.00% 9.89% 0.46%
Hypertension/hypotension Cases 13 8 23 0 1 6 6 4
Percentage 2.78% 3.19% 15.86% 0.00% 0.90% 2.53% 3.30% 0.92%
Cancer Cases 4 0 1 2 2 1 4 1
Percentage 0.86% 0.00% 0.69% 0.92% 1.80% 0.42% 2.20% 0.23%
Psychosis Cases 20 0 8 2 0 5 10 1
Percentage 4.28% 0.00% 5.52% 0.92% 0.00% 2.11% 5.49% 0.23%
Cardiovascular disease Cases 11 3 0 0 0 6 9 6
Percentage 2.36% 1.20% 0.00% 0.00% 0.00% 2.53% 4.95% 1.39%
Amenorrhea Cases 5 0 0 3 0 0 0 0
Percentage 1.07% 0.00% 0.00% 1.38% 0.00% 0.00% 0.00% 0.00%
Transfusion reaction Cases 2 0 0 0 0 0 29 0
Percentage 0.43% 0.00% 0.00% 0.00% 0.00% 0.00% 15.93% 0.00%

4 Discussion

By comparing the direct effect and mixed effect of various interventions in the treatment of IMN, this NMA draws the following conclusions. First, in the SUCRA ranking of TR and CR, CTX, TAC, RTX, and CHL were in the top four. The efficacy of these treatments was found to be significantly better than that of conservative treatment. About single interventions, the TR of RTX in the treatment of IMN was not inferior to CTX, although it is at a certain disadvantage compared to CR. Third, as one of the representative drugs of CNIs, the therapeutic effect of CSA is disappointing, so we no longer recommend it as the first-line drug for IMN treatment.

In recent years, immunosuppressive therapy of IMN has been a difficult point in the clinical practice of nephrology, which has been summarized by many studies. Ren et al. [54] completed an NMA in 2017, which included a total of 2,018 patients from 36 RCTs, and mainly observed the mortality, incidence of end-stage renal disease, and CR rate. The results showed that CTX and CHL could reduce the risk of death or deterioration of renal function, and TAC and CSA cannot protect renal function but can significantly reduce proteinuria. Zheng et al. [55] also conducted a, NMA in 2019. They included 48 RCTs, a total of 2,736 patients, including 13 immunosuppressive treatment regimens. The results showed that TAC and CTX were better than other interventions in curative effect, and the effect of the former was more significant after adding Tripterygium wilfordii glycosides. However, the side effects caused by the two should be noted, such as hyperglycemia, infection, and bone marrow suppression. Liu et al. [56] performed an NMA on the incidence of infection after immunosuppressive therapy for IMN. A total of 38 RCTs were included in the study. Statistical analysis was conducted on the infection caused by major immunosuppressive therapies. The results showed that the infection rate caused by CTX and CSA was lower than that caused by other drugs. Dai et al. [57] included a total of 4,806 patients in 75 reports (including Chinese papers) and compared the cost effect of each regimen in the treatment of IMN. The results showed that CTX was effective and cheap, TAC, although expensive, had a high remission rate. The above studies in different periods have made objective and pertinent evaluations on the selection of appropriate immunosuppressive interventions, which has certain guiding significance for the clinical treatment of IMN. However, with the continuous attention to the treatment of IMN in the past 2 years, we urgently need to reassess the above issues.

Alkylating agents, including CTX and CHL, have long been the first-line drugs for the treatment of IMN. In 2012, KDIGO guidelines took CTX as the first choice for the treatment of IMN [8], and in 2021, it was adjusted to the treatment of high-risk patients [7]. Our results suggest that CTX ranks first and CHL ranks fourth in the SUCRA ranking of TR. More importantly, in comparison with the mixed effect of conservative treatment, the TR mediated by CTX and CHL were significantly higher than that of conservative treatment, and the level of evidence was high. In addition, Howman et al. confirmed through an RCT involving 108 patients that CHL has an effect on protecting renal function [58], which is not possessed by other types of immunosuppression. In sharp contrast to the good curative effect, alkylating agents have relatively serious side effects. Our study suggests that in terms of the incidence of bone marrow suppression, CHL ranks first, CTX ranks second, and the incidence of both for infections are high. In addition, the infection combined with bone marrow suppression is more serious than the normal infection. It is worth noting that previous studies [59] have confirmed that patients who use CTX for a long time have a 3-fold increase in the risk of malignant tumor compared with normal. Infertility is another terrible side effect of CTX, especially when the cumulative dose of CTX exceeds 10 g, the incidence will increase significantly [60]. Comprehensive efficacy and side effects, we believe that CTX should be the first choice when IMN patients have severe nephrotic syndrome or renal function injury. For the above patients, if the use of CTX is contraindicated or ineffective, CHL can be used as an alternative.

RTX is an emerging drug for the treatment of IMN. It is recommended by KDIGO guidelines in 2021 for patients with moderate-risk IMN, whose main feature is a normal eGFR. As such, RTX should be the first choice [7]. RTX was first used to treat Hodgkin’s disease and is a monoclonal antibody that acts on the surface antigen CD20 of B cells. It reduces proteinuria in patients with IMN by consuming B cells [61]. Our results of NMA showed that RTX was inferior to CTX in the comparison of CR direct effect, and the difference was statistically significant. However, in the comparison of the mixed effects of CR and TR, there was no significant difference between the two drugs, and the level of evidence was moderate. In addition, compared with the conservative treatment of TR, the mixed effect of RTX was significantly higher than the former, and the difference was statistically significant with a moderate level of evidence. The efficacy of RTX was not inferior to CTX but was significantly better than conservative treatment. In terms of side effects, our study found that the incidence of complications caused by RTX, such as infusion reaction, infection, gastrointestinal syndrome, neurological symptoms, and acute renal injury, was not low. However, unlike alkylating agents, RTX rarely causes serious side effects, such as bone marrow suppression, gonadal destruction, and malignant tumors. It should be noted that we attributed the sequential treatment (TAC + RTX) used in the Starmen trial [11] to the RTX regimen. The study [33] confirmed that the relapse rate of IMN in the 24th month after treatment with CINs (TAC/CSA) was very high. The main purpose of adding RTX in this trial is to reduce the relapse rate of IMN. The final number of recurrences of IMN is only three, which confirms that RTX played a major role in this therapeutic regimen. At present, there is still a lack of RCT for RTX in the treatment of IMN. In addition, the mechanism of its efficacy has not been fully clarified and an optimal dosage has not been determined [62]. In conclusion, RTX is suitable for IMN patients who should not use CTX, such as moderate-risk patients mentioned in KDIGO guidelines in 2021.

CNIs are traditional immunosuppressive drugs for the treatment of IMN, mainly including TAC and CSA. Its effective mechanism is to reduce the production of T cell-derived lymphocytes by directly acting on renal podocytes, to eliminate proteinuria [63]. In 2021, KDIGO guidelines recommended that CNIs, like RTX, be used as the first choice for patients with moderate-risk IMN [7]. Our results show that TAC ranks second in SUCRA in TR. In the comparison of mixed effects of TR, there was no significant difference between TAC and CTX, but TAC had an obvious curative effect compared with the conservative treatment. The common side effects of TAC are hyperglycemia and infection. Properly managed, neither will cause serious harm to the patient. However, the above results of TAC need to be interpreted with caution. First, most studies regarding TAC [25,29,30,35] have a follow-up time that is less than 12 months, with absent follow-up data. This makes it impossible to objectively evaluate the relapse rate after TAC treatment. Second, the evidence level of all mixed effect results of TAC compared with other interventions is low or very low, which is not convincing enough. Therefore, the current evidence is insufficient to prove that TAC can be used as the initial treatment regimen for patients with moderate-risk IMN. CSA is another representative drug of CNIs. Our results show that in the comparison of mixed effects of TR, the efficacy of CSA is significantly worse than that of RTX. This result is due to that the included studies on CSA have been followed up for more than 2 years, and a significant increase in patients with relapse is observed at the end point of follow-up. This also confirms the view of some researchers that CNIs has a high relapse rate [33,64,65]. In view of the unsatisfactory clinical efficacy of CSA, we do not recommend it as a first-line drug for immunosuppressive therapy of IMN.

Our study also found that there were no significant differences between MMF/STE and conservative treatment in TR. As such, they should not be used as the first choice for the treatment of IMN, which was consistent with the opinions of KDIGO guidelines in 2021.

There are several limitations to this study. First, the protective effect of renal function is also an important index to measure the curative effect, which is mainly aimed at patients with renal failure. However, most of the studies included are aimed at patients with normal renal function, which makes us unable to comprehensively extract and analyze this information, so that the curative effect evaluation is not comprehensive. Second, the intervention measures included in the study were not completely unified. For example, immunosuppressive steroids delivered at different doses and routes may lead to differences in the baseline level of the included literature.

5 Conclusion

With regard to TR rate, CTX, TAC, RTX, and CHL were significantly better than conservative treatment. In the comparison of single regimens, the TR rate of RTX was not inferior to CTX, and the therapeutic effect of CSA was poor. Therefore, we recommend CTX and RTX as the first-line drug for IMN treatment.

  1. Funding information: This work was supported by Suzhou science and technology development plan (SKJYD2021203).

  2. Author contributions: N.B. and M.J.G. contributed equally to this work and should be considered co-first authors. N.B. performed the review. N.B. and X.Y. analyzed the data, N.B. and X.Y. wrote the article and W.J. revised it. L.P.G. was responsible for quality control of the study. W.K. and Z.W.M. conceived and designed the project, and approved the final version of the manuscript.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2022-06-06
Revised: 2022-08-23
Accepted: 2022-11-02
Published Online: 2023-01-10

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
https://doi.org/10.1515/biol-2022-0527
Schlagwörter für diesen Artikel
idiopathic membranous nephropathy; immunosuppressive treatment; network meta-analysis; GRADE
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Biomedical Sciences
  2. Systemic investigation of inetetamab in combination with small molecules to treat HER2-overexpressing breast and gastric cancers
  3. Immunosuppressive treatment for idiopathic membranous nephropathy: An updated network meta-analysis
  4. Identifying two pathogenic variants in a patient with pigmented paravenous retinochoroidal atrophy
  5. Effects of phytoestrogens combined with cold stress on sperm parameters and testicular proteomics in rats
  6. A case of pulmonary embolism with bad warfarin anticoagulant effects caused by E. coli infection
  7. Neutrophilia with subclinical Cushing’s disease: A case report and literature review
  8. Isoimperatorin alleviates lipopolysaccharide-induced periodontitis by downregulating ERK1/2 and NF-κB pathways
  9. Immunoregulation of synovial macrophages for the treatment of osteoarthritis
  10. Novel CPLANE1 c.8948dupT (p.P2984Tfs*7) variant in a child patient with Joubert syndrome
  11. Antiphospholipid antibodies and the risk of thrombosis in myeloproliferative neoplasms
  12. Immunological responses of septic rats to combination therapy with thymosin α1 and vitamin C
  13. High glucose and high lipid induced mitochondrial dysfunction in JEG-3 cells through oxidative stress
  14. Pharmacological inhibition of the ubiquitin-specific protease 8 effectively suppresses glioblastoma cell growth
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  16. Age-related changes in peripheral T-cell subpopulations in elderly individuals: An observational study
  17. Single-cell transcription analysis reveals the tumor origin and heterogeneity of human bilateral renal clear cell carcinoma
  18. Identification of iron metabolism-related genes as diagnostic signatures in sepsis by blood transcriptomic analysis
  19. Long noncoding RNA ACART knockdown decreases 3T3-L1 preadipocyte proliferation and differentiation
  20. Surgery, adjuvant immunotherapy plus chemotherapy and radiotherapy for primary malignant melanoma of the parotid gland (PGMM): A case report
  21. Dosimetry comparison with helical tomotherapy, volumetric modulated arc therapy, and intensity-modulated radiotherapy for grade II gliomas: A single‑institution case series
  22. Soy isoflavone reduces LPS-induced acute lung injury via increasing aquaporin 1 and aquaporin 5 in rats
  23. Refractory hypokalemia with sexual dysplasia and infertility caused by 17α-hydroxylase deficiency and triple X syndrome: A case report
  24. Meta-analysis of cancer risk among end stage renal disease undergoing maintenance dialysis
  25. 6-Phosphogluconate dehydrogenase inhibition arrests growth and induces apoptosis in gastric cancer via AMPK activation and oxidative stress
  26. Experimental study on the optimization of ANM33 release in foam cells
  27. Primary retroperitoneal angiosarcoma: A case report
  28. Metabolomic analysis-identified 2-hydroxybutyric acid might be a key metabolite of severe preeclampsia
  29. Malignant pleural effusion diagnosis and therapy
  30. Effect of spaceflight on the phenotype and proteome of Escherichia coli
  31. Comparison of immunotherapy combined with stereotactic radiotherapy and targeted therapy for patients with brain metastases: A systemic review and meta-analysis
  32. Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation
  33. Association between the VEGFR-2 -604T/C polymorphism (rs2071559) and type 2 diabetic retinopathy
  34. The role of IL-31 and IL-34 in the diagnosis and treatment of chronic periodontitis
  35. Triple-negative mouse breast cancer initiating cells show high expression of beta1 integrin and increased malignant features
  36. mNGS facilitates the accurate diagnosis and antibiotic treatment of suspicious critical CNS infection in real practice: A retrospective study
  37. The apatinib and pemetrexed combination has antitumor and antiangiogenic effects against NSCLC
  38. Radiotherapy for primary thyroid adenoid cystic carcinoma
  39. Design and functional preliminary investigation of recombinant antigen EgG1Y162–EgG1Y162 against Echinococcus granulosus
  40. Effects of losartan in patients with NAFLD: A meta-analysis of randomized controlled trial
  41. Bibliometric analysis of METTL3: Current perspectives, highlights, and trending topics
  42. Performance comparison of three scaling algorithms in NMR-based metabolomics analysis
  43. PI3K/AKT/mTOR pathway and its related molecules participate in PROK1 silence-induced anti-tumor effects on pancreatic cancer
  44. The altered expression of cytoskeletal and synaptic remodeling proteins during epilepsy
  45. Effects of pegylated recombinant human granulocyte colony-stimulating factor on lymphocytes and white blood cells of patients with malignant tumor
  46. Prostatitis as initial manifestation of Chlamydia psittaci pneumonia diagnosed by metagenome next-generation sequencing: A case report
  47. NUDT21 relieves sevoflurane-induced neurological damage in rats by down-regulating LIMK2
  48. Association of interleukin-10 rs1800896, rs1800872, and interleukin-6 rs1800795 polymorphisms with squamous cell carcinoma risk: A meta-analysis
  49. Exosomal HBV-DNA for diagnosis and treatment monitoring of chronic hepatitis B
  50. Shear stress leads to the dysfunction of endothelial cells through the Cav-1-mediated KLF2/eNOS/ERK signaling pathway under physiological conditions
  51. Interaction between the PI3K/AKT pathway and mitochondrial autophagy in macrophages and the leukocyte count in rats with LPS-induced pulmonary infection
  52. Meta-analysis of the rs231775 locus polymorphism in the CTLA-4 gene and the susceptibility to Graves’ disease in children
  53. Cloning, subcellular localization and expression of phosphate transporter gene HvPT6 of hulless barley
  54. Coptisine mitigates diabetic nephropathy via repressing the NRLP3 inflammasome
  55. Significant elevated CXCL14 and decreased IL-39 levels in patients with tuberculosis
  56. Whole-exome sequencing applications in prenatal diagnosis of fetal bowel dilatation
  57. Gemella morbillorum infective endocarditis: A case report and literature review
  58. An unusual ectopic thymoma clonal evolution analysis: A case report
  59. Severe cumulative skin toxicity during toripalimab combined with vemurafenib following toripalimab alone
  60. Detection of V. vulnificus septic shock with ARDS using mNGS
  61. Novel rare genetic variants of familial and sporadic pulmonary atresia identified by whole-exome sequencing
  62. The influence and mechanistic action of sperm DNA fragmentation index on the outcomes of assisted reproduction technology
  63. Novel compound heterozygous mutations in TELO2 in an infant with You-Hoover-Fong syndrome: A case report and literature review
  64. ctDNA as a prognostic biomarker in resectable CLM: Systematic review and meta-analysis
  65. Diagnosis of primary amoebic meningoencephalitis by metagenomic next-generation sequencing: A case report
  66. Phylogenetic analysis of promoter regions of human Dolichol kinase (DOLK) and orthologous genes using bioinformatics tools
  67. Collagen changes in rabbit conjunctiva after conjunctival crosslinking
  68. Effects of NM23 transfection of human gastric carcinoma cells in mice
  69. Oral nifedipine and phytosterol, intravenous nicardipine, and oral nifedipine only: Three-arm, retrospective, cohort study for management of severe preeclampsia
  70. Case report of hepatic retiform hemangioendothelioma: A rare tumor treated with ultrasound-guided microwave ablation
  71. Curcumin induces apoptosis in human hepatocellular carcinoma cells by decreasing the expression of STAT3/VEGF/HIF-1α signaling
  72. Rare presentation of double-clonal Waldenström macroglobulinemia with pulmonary embolism: A case report
  73. Giant duplication of the transverse colon in an adult: A case report and literature review
  74. Ectopic thyroid tissue in the breast: A case report
  75. SDR16C5 promotes proliferation and migration and inhibits apoptosis in pancreatic cancer
  76. Vaginal metastasis from breast cancer: A case report
  77. Screening of the best time window for MSC transplantation to treat acute myocardial infarction with SDF-1α antibody-loaded targeted ultrasonic microbubbles: An in vivo study in miniswine
  78. Inhibition of TAZ impairs the migration ability of melanoma cells
  79. Molecular complexity analysis of the diagnosis of Gitelman syndrome in China
  80. Effects of maternal calcium and protein intake on the development and bone metabolism of offspring mice
  81. Identification of winter wheat pests and diseases based on improved convolutional neural network
  82. Ultra-multiplex PCR technique to guide treatment of Aspergillus-infected aortic valve prostheses
  83. Virtual high-throughput screening: Potential inhibitors targeting aminopeptidase N (CD13) and PIKfyve for SARS-CoV-2
  84. Immune checkpoint inhibitors in cancer patients with COVID-19
  85. Utility of methylene blue mixed with autologous blood in preoperative localization of pulmonary nodules and masses
  86. Integrated analysis of the microbiome and transcriptome in stomach adenocarcinoma
  87. Berberine suppressed sarcopenia insulin resistance through SIRT1-mediated mitophagy
  88. DUSP2 inhibits the progression of lupus nephritis in mice by regulating the STAT3 pathway
  89. Lung abscess by Fusobacterium nucleatum and Streptococcus spp. co-infection by mNGS: A case series
  90. Genetic alterations of KRAS and TP53 in intrahepatic cholangiocarcinoma associated with poor prognosis
  91. Granulomatous polyangiitis involving the fourth ventricle: Report of a rare case and a literature review
  92. Studying infant mortality: A demographic analysis based on data mining models
  93. Metaplastic breast carcinoma with osseous differentiation: A report of a rare case and literature review
  94. Protein Z modulates the metastasis of lung adenocarcinoma cells
  95. Inhibition of pyroptosis and apoptosis by capsaicin protects against LPS-induced acute kidney injury through TRPV1/UCP2 axis in vitro
  96. TAK-242, a toll-like receptor 4 antagonist, against brain injury by alleviates autophagy and inflammation in rats
  97. Primary mediastinum Ewing’s sarcoma with pleural effusion: A case report and literature review
  98. Association of ADRB2 gene polymorphisms and intestinal microbiota in Chinese Han adolescents
  99. Tanshinone IIA alleviates chondrocyte apoptosis and extracellular matrix degeneration by inhibiting ferroptosis
  100. Study on the cytokines related to SARS-Cov-2 in testicular cells and the interaction network between cells based on scRNA-seq data
  101. Effect of periostin on bone metabolic and autophagy factors during tooth eruption in mice
  102. HP1 induces ferroptosis of renal tubular epithelial cells through NRF2 pathway in diabetic nephropathy
  103. Intravaginal estrogen management in postmenopausal patients with vaginal squamous intraepithelial lesions along with CO2 laser ablation: A retrospective study
  104. Hepatocellular carcinoma cell differentiation trajectory predicts immunotherapy, potential therapeutic drugs, and prognosis of patients
  105. Effects of physical exercise on biomarkers of oxidative stress in healthy subjects: A meta-analysis of randomized controlled trials
  106. Identification of lysosome-related genes in connection with prognosis and immune cell infiltration for drug candidates in head and neck cancer
  107. Development of an instrument-free and low-cost ELISA dot-blot test to detect antibodies against SARS-CoV-2
  108. Research progress on gas signal molecular therapy for Parkinson’s disease
  109. Adiponectin inhibits TGF-β1-induced skin fibroblast proliferation and phenotype transformation via the p38 MAPK signaling pathway
  110. The G protein-coupled receptor-related gene signatures for predicting prognosis and immunotherapy response in bladder urothelial carcinoma
  111. α-Fetoprotein contributes to the malignant biological properties of AFP-producing gastric cancer
  112. CXCL12/CXCR4/CXCR7 axis in placenta tissues of patients with placenta previa
  113. Association between thyroid stimulating hormone levels and papillary thyroid cancer risk: A meta-analysis
  114. Significance of sTREM-1 and sST2 combined diagnosis for sepsis detection and prognosis prediction
  115. Diagnostic value of serum neuroactive substances in the acute exacerbation of chronic obstructive pulmonary disease complicated with depression
  116. Research progress of AMP-activated protein kinase and cardiac aging
  117. TRIM29 knockdown prevented the colon cancer progression through decreasing the ubiquitination levels of KRT5
  118. Cross-talk between gut microbiota and liver steatosis: Complications and therapeutic target
  119. Metastasis from small cell lung cancer to ovary: A case report
  120. The early diagnosis and pathogenic mechanisms of sepsis-related acute kidney injury
  121. The effect of NK cell therapy on sepsis secondary to lung cancer: A case report
  122. Erianin alleviates collagen-induced arthritis in mice by inhibiting Th17 cell differentiation
  123. Loss of ACOX1 in clear cell renal cell carcinoma and its correlation with clinical features
  124. Signalling pathways in the osteogenic differentiation of periodontal ligament stem cells
  125. Crosstalk between lactic acid and immune regulation and its value in the diagnosis and treatment of liver failure
  126. Clinicopathological features and differential diagnosis of gastric pleomorphic giant cell carcinoma
  127. Traumatic brain injury and rTMS-ERPs: Case report and literature review
  128. Extracellular fibrin promotes non-small cell lung cancer progression through integrin β1/PTEN/AKT signaling
  129. Knockdown of DLK4 inhibits non-small cell lung cancer tumor growth by downregulating CKS2
  130. The co-expression pattern of VEGFR-2 with indicators related to proliferation, apoptosis, and differentiation of anagen hair follicles
  131. Inflammation-related signaling pathways in tendinopathy
  132. CD4+ T cell count in HIV/TB co-infection and co-occurrence with HL: Case report and literature review
  133. Clinical analysis of severe Chlamydia psittaci pneumonia: Case series study
  134. Bioinformatics analysis to identify potential biomarkers for the pulmonary artery hypertension associated with the basement membrane
  135. Influence of MTHFR polymorphism, alone or in combination with smoking and alcohol consumption, on cancer susceptibility
  136. Catharanthus roseus (L.) G. Don counteracts the ampicillin resistance in multiple antibiotic-resistant Staphylococcus aureus by downregulation of PBP2a synthesis
  137. Combination of a bronchogenic cyst in the thoracic spinal canal with chronic myelocytic leukemia
  138. Bacterial lipoprotein plays an important role in the macrophage autophagy and apoptosis induced by Salmonella typhimurium and Staphylococcus aureus
  139. TCL1A+ B cells predict prognosis in triple-negative breast cancer through integrative analysis of single-cell and bulk transcriptomic data
  140. Ezrin promotes esophageal squamous cell carcinoma progression via the Hippo signaling pathway
  141. Ferroptosis: A potential target of macrophages in plaque vulnerability
  142. Predicting pediatric Crohn's disease based on six mRNA-constructed risk signature using comprehensive bioinformatic approaches
  143. Applications of genetic code expansion and photosensitive UAAs in studying membrane proteins
  144. HK2 contributes to the proliferation, migration, and invasion of diffuse large B-cell lymphoma cells by enhancing the ERK1/2 signaling pathway
  145. IL-17 in osteoarthritis: A narrative review
  146. Circadian cycle and neuroinflammation
  147. Probiotic management and inflammatory factors as a novel treatment in cirrhosis: A systematic review and meta-analysis
  148. Hemorrhagic meningioma with pulmonary metastasis: Case report and literature review
  149. SPOP regulates the expression profiles and alternative splicing events in human hepatocytes
  150. Knockdown of SETD5 inhibited glycolysis and tumor growth in gastric cancer cells by down-regulating Akt signaling pathway
  151. PTX3 promotes IVIG resistance-induced endothelial injury in Kawasaki disease by regulating the NF-κB pathway
  152. Pancreatic ectopic thyroid tissue: A case report and analysis of literature
  153. The prognostic impact of body mass index on female breast cancer patients in underdeveloped regions of northern China differs by menopause status and tumor molecular subtype
  154. Report on a case of liver-originating malignant melanoma of unknown primary
  155. Case report: Herbal treatment of neutropenic enterocolitis after chemotherapy for breast cancer
  156. The fibroblast growth factor–Klotho axis at molecular level
  157. Characterization of amiodarone action on currents in hERG-T618 gain-of-function mutations
  158. A case report of diagnosis and dynamic monitoring of Listeria monocytogenes meningitis with NGS
  159. Effect of autologous platelet-rich plasma on new bone formation and viability of a Marburg bone graft
  160. Small breast epithelial mucin as a useful prognostic marker for breast cancer patients
  161. Continuous non-adherent culture promotes transdifferentiation of human adipose-derived stem cells into retinal lineage
  162. Nrf3 alleviates oxidative stress and promotes the survival of colon cancer cells by activating AKT/BCL-2 signal pathway
  163. Favorable response to surufatinib in a patient with necrolytic migratory erythema: A case report
  164. Case report of atypical undernutrition of hypoproteinemia type
  165. Down-regulation of COL1A1 inhibits tumor-associated fibroblast activation and mediates matrix remodeling in the tumor microenvironment of breast cancer
  166. Sarcoma protein kinase inhibition alleviates liver fibrosis by promoting hepatic stellate cells ferroptosis
  167. Research progress of serum eosinophil in chronic obstructive pulmonary disease and asthma
  168. Clinicopathological characteristics of co-existing or mixed colorectal cancer and neuroendocrine tumor: Report of five cases
  169. Role of menopausal hormone therapy in the prevention of postmenopausal osteoporosis
  170. Precisional detection of lymph node metastasis using tFCM in colorectal cancer
  171. Advances in diagnosis and treatment of perimenopausal syndrome
  172. A study of forensic genetics: ITO index distribution and kinship judgment between two individuals
  173. Acute lupus pneumonitis resembling miliary tuberculosis: A case-based review
  174. Plasma levels of CD36 and glutathione as biomarkers for ruptured intracranial aneurysm
  175. Fractalkine modulates pulmonary angiogenesis and tube formation by modulating CX3CR1 and growth factors in PVECs
  176. Novel risk prediction models for deep vein thrombosis after thoracotomy and thoracoscopic lung cancer resections, involving coagulation and immune function
  177. Exploring the diagnostic markers of essential tremor: A study based on machine learning algorithms
  178. Evaluation of effects of small-incision approach treatment on proximal tibia fracture by deep learning algorithm-based magnetic resonance imaging
  179. An online diagnosis method for cancer lesions based on intelligent imaging analysis
  180. Medical imaging in rheumatoid arthritis: A review on deep learning approach
  181. Predictive analytics in smart healthcare for child mortality prediction using a machine learning approach
  182. Utility of neutrophil–lymphocyte ratio and platelet–lymphocyte ratio in predicting acute-on-chronic liver failure survival
  183. A biomedical decision support system for meta-analysis of bilateral upper-limb training in stroke patients with hemiplegia
  184. TNF-α and IL-8 levels are positively correlated with hypobaric hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats
  185. Stochastic gradient descent optimisation for convolutional neural network for medical image segmentation
  186. Comparison of the prognostic value of four different critical illness scores in patients with sepsis-induced coagulopathy
  187. Application and teaching of computer molecular simulation embedded technology and artificial intelligence in drug research and development
  188. Hepatobiliary surgery based on intelligent image segmentation technology
  189. Value of brain injury-related indicators based on neural network in the diagnosis of neonatal hypoxic-ischemic encephalopathy
  190. Analysis of early diagnosis methods for asymmetric dementia in brain MR images based on genetic medical technology
  191. Early diagnosis for the onset of peri-implantitis based on artificial neural network
  192. Clinical significance of the detection of serum IgG4 and IgG4/IgG ratio in patients with thyroid-associated ophthalmopathy
  193. Forecast of pain degree of lumbar disc herniation based on back propagation neural network
  194. SPA-UNet: A liver tumor segmentation network based on fused multi-scale features
  195. Systematic evaluation of clinical efficacy of CYP1B1 gene polymorphism in EGFR mutant non-small cell lung cancer observed by medical image
  196. Rehabilitation effect of intelligent rehabilitation training system on hemiplegic limb spasms after stroke
  197. A novel approach for minimising anti-aliasing effects in EEG data acquisition
  198. ErbB4 promotes M2 activation of macrophages in idiopathic pulmonary fibrosis
  199. Clinical role of CYP1B1 gene polymorphism in prediction of postoperative chemotherapy efficacy in NSCLC based on individualized health model
  200. Lung nodule segmentation via semi-residual multi-resolution neural networks
  201. Evaluation of brain nerve function in ICU patients with Delirium by deep learning algorithm-based resting state MRI
  202. A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis
  203. Markov model combined with MR diffusion tensor imaging for predicting the onset of Alzheimer’s disease
  204. Effectiveness of the treatment of depression associated with cancer and neuroimaging changes in depression-related brain regions in patients treated with the mediator-deuterium acupuncture method
  205. Molecular mechanism of colorectal cancer and screening of molecular markers based on bioinformatics analysis
  206. Monitoring and evaluation of anesthesia depth status data based on neuroscience
  207. Exploring the conformational dynamics and thermodynamics of EGFR S768I and G719X + S768I mutations in non-small cell lung cancer: An in silico approaches
  208. Optimised feature selection-driven convolutional neural network using gray level co-occurrence matrix for detection of cervical cancer
  209. Incidence of different pressure patterns of spinal cerebellar ataxia and analysis of imaging and genetic diagnosis
  210. Pathogenic bacteria and treatment resistance in older cardiovascular disease patients with lung infection and risk prediction model
  211. Adoption value of support vector machine algorithm-based computed tomography imaging in the diagnosis of secondary pulmonary fungal infections in patients with malignant hematological disorders
  212. From slides to insights: Harnessing deep learning for prognostic survival prediction in human colorectal cancer histology
  213. Ecology and Environmental Science
  214. Monitoring of hourly carbon dioxide concentration under different land use types in arid ecosystem
  215. Comparing the differences of prokaryotic microbial community between pit walls and bottom from Chinese liquor revealed by 16S rRNA gene sequencing
  216. Effects of cadmium stress on fruits germination and growth of two herbage species
  217. Bamboo charcoal affects soil properties and bacterial community in tea plantations
  218. Optimization of biogas potential using kinetic models, response surface methodology, and instrumental evidence for biodegradation of tannery fleshings during anaerobic digestion
  219. Understory vegetation diversity patterns of Platycladus orientalis and Pinus elliottii communities in Central and Southern China
  220. Studies on macrofungi diversity and discovery of new species of Abortiporus from Baotianman World Biosphere Reserve
  221. Food Science
  222. Effect of berrycactus fruit (Myrtillocactus geometrizans) on glutamate, glutamine, and GABA levels in the frontal cortex of rats fed with a high-fat diet
  223. Guesstimate of thymoquinone diversity in Nigella sativa L. genotypes and elite varieties collected from Indian states using HPTLC technique
  224. Analysis of bacterial community structure of Fuzhuan tea with different processing techniques
  225. Untargeted metabolomics reveals sour jujube kernel benefiting the nutritional value and flavor of Morchella esculenta
  226. Mycobiota in Slovak wine grapes: A case study from the small Carpathians wine region
  227. Elemental analysis of Fadogia ancylantha leaves used as a nutraceutical in Mashonaland West Province, Zimbabwe
  228. Microbiological transglutaminase: Biotechnological application in the food industry
  229. Influence of solvent-free extraction of fish oil from catfish (Clarias magur) heads using a Taguchi orthogonal array design: A qualitative and quantitative approach
  230. Chromatographic analysis of the chemical composition and anticancer activities of Curcuma longa extract cultivated in Palestine
  231. The potential for the use of leghemoglobin and plant ferritin as sources of iron
  232. Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM
  233. Bioengineering and Biotechnology
  234. Biocompatibility and osteointegration capability of β-TCP manufactured by stereolithography 3D printing: In vitro study
  235. Clinical characteristics and the prognosis of diabetic foot in Tibet: A single center, retrospective study
  236. Agriculture
  237. Biofertilizer and NPSB fertilizer application effects on nodulation and productivity of common bean (Phaseolus vulgaris L.) at Sodo Zuria, Southern Ethiopia
  238. On correlation between canopy vegetation and growth indexes of maize varieties with different nitrogen efficiencies
  239. Exopolysaccharides from Pseudomonas tolaasii inhibit the growth of Pleurotus ostreatus mycelia
  240. A transcriptomic evaluation of the mechanism of programmed cell death of the replaceable bud in Chinese chestnut
  241. Melatonin enhances salt tolerance in sorghum by modulating photosynthetic performance, osmoregulation, antioxidant defense, and ion homeostasis
  242. Effects of plant density on alfalfa (Medicago sativa L.) seed yield in western Heilongjiang areas
  243. Identification of rice leaf diseases and deficiency disorders using a novel DeepBatch technique
  244. Artificial intelligence and internet of things oriented sustainable precision farming: Towards modern agriculture
  245. Animal Sciences
  246. Effect of ketogenic diet on exercise tolerance and transcriptome of gastrocnemius in mice
  247. Combined analysis of mRNA–miRNA from testis tissue in Tibetan sheep with different FecB genotypes
  248. Isolation, identification, and drug resistance of a partially isolated bacterium from the gill of Siniperca chuatsi
  249. Tracking behavioral changes of confined sows from the first mating to the third parity
  250. The sequencing of the key genes and end products in the TLR4 signaling pathway from the kidney of Rana dybowskii exposed to Aeromonas hydrophila
  251. Development of a new candidate vaccine against piglet diarrhea caused by Escherichia coli
  252. Plant Sciences
  253. Crown and diameter structure of pure Pinus massoniana Lamb. forest in Hunan province, China
  254. Genetic evaluation and germplasm identification analysis on ITS2, trnL-F, and psbA-trnH of alfalfa varieties germplasm resources
  255. Tissue culture and rapid propagation technology for Gentiana rhodantha
  256. Effects of cadmium on the synthesis of active ingredients in Salvia miltiorrhiza
  257. Cloning and expression analysis of VrNAC13 gene in mung bean
  258. Chlorate-induced molecular floral transition revealed by transcriptomes
  259. Effects of warming and drought on growth and development of soybean in Hailun region
  260. Effects of different light conditions on transient expression and biomass in Nicotiana benthamiana leaves
  261. Comparative analysis of the rhizosphere microbiome and medicinally active ingredients of Atractylodes lancea from different geographical origins
  262. Distinguish Dianthus species or varieties based on chloroplast genomes
  263. Comparative transcriptomes reveal molecular mechanisms of apple blossoms of different tolerance genotypes to chilling injury
  264. Study on fresh processing key technology and quality influence of Cut Ophiopogonis Radix based on multi-index evaluation
  265. An advanced approach for fig leaf disease detection and classification: Leveraging image processing and enhanced support vector machine methodology
  266. Erratum
  267. Erratum to “Protein Z modulates the metastasis of lung adenocarcinoma cells”
  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
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© 2025 De Gruyter Brill
Heruntergeladen am 6.9.2025 von https://www.degruyterbrill.com/document/doi/10.1515/biol-2022-0527/html
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