Optimal drug treatment for children with IgA vasculitis nephritis: a systematic review and network meta-analysis

Introduction

Henoch-Schönlein purpura (HSP), a small-vessel autoimmune vasculitis, features palpable purpura and involves multiple organ systems. Renal involvement resulting from HSP is Henoch-Schönlein purpura nephritis (HSPN) (1). HSPN refers to the occurrence of hematuria and/or proteinuria within 6 months of onset in the anaphylactoid purpura population, excluding other causes of glomerulonephritis (GN). At the 2012 Revised International Chapel Hill Consensus Conference on the Nomenclature of Vasculitides, HSP was officially replaced by immunoglobulin A vasculitis (IgAV) (2). Accordingly, HSPN has been renamed IgA vasculitis nephritis (IgAVN) in international contexts. However, since “IgAVN” has not been encompassed in the International Classification of Diseases (ICD) coding system, the term HSPN continues to be used in some literature.

Corticosteroids remain the most effective therapeutic approach for childhood IgAVN; however, their long-term safety profile warrants further investigation. IgAV has an estimated annual incidence of 3–27 cases per 100,000 children, making it the most common vasculitis of childhood (3,4). A 20-year epidemiological study conducted in northwestern Spain reported a higher incidence of IgAV during autumn and winter, with an annual rate of 10.45 cases per 100,000 children under 14 years (4). Renal involvement occurs in approximately 40–85% of patients, with clinical manifestations ranging from isolated microscopic hematuria to nephrotic syndrome or renal failure (5,6). IgAVN is a prevalent secondary glomerular illness in the pediatric population, with 20–80% exhibiting hematuria and/or proteinuria four to six weeks after first diagnosis. Among them, approximately 1–7% possibly develop renal failure or end-stage renal disease (ESRD) (7,8). Those showing ≥50% glomerular crescents on renal biopsy have a 5–20% likelihood of progressing to chronic kidney disease (CKD) (7). The incidence of IgAVN is highest among East Asian populations and lowest in individuals of African descent residing in Europe (9,10). A nationwide, multicenter retrospective study conducted across 40 tertiary hospitals in China analyzed 4,863 pediatric IgAVN cases diagnosed between 2008 and 2011. The incidence rate showed a gradual rise over time, with a higher prevalence in males (male-to-female ratio of 1.52:1). The average age at diagnosis was 8.9. The most frequent presentation was coexisting hematuria and proteinuria (58.2%; n=2,830), followed by nephrotic syndrome (13.8%; n=672) and isolated hematuria (13.2%; n=642) (11). The International Study of Kidney Disease in Children (ISKDC) classification system is widely employed for pathological pediatric IgAVN diagnosis in China (12). The dominant histological subtypes are Type II (31.0%) and Type III (53.5%) (11). Overall, the severity of proteinuria and kidney impairment in Chinese pediatric IgAVN patients is similar to that reported in Americans and Japanese (13,14). However, the prevalence of crescent formation is markedly higher in the Chinese pediatric population (60–80%) in comparison to Japanese patients (1.9%) (13). IgAVN is generally considered to have a favorable prognosis. In a study on 104 Chinese pediatric patients with IgAVN, 58.7% achieved complete remission, 77.9% achieved remission of albuminuria, and 36.5% experienced recurrence of nephritis (15). During a median 40-month follow-up (range: 12–145 months), 7.7% of patients exhibited deteriorated kidney function.

Currently, therapeutic options for IgAVN primarily encompass steroids, immunosuppressive agents, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ARBs), as well as patented traditional Chinese medicines. These treatments are pivotal in disease management. Although many case reports, systematic reviews, and randomized controlled trials (RCTs) have examined their effects, the optimal treatment in terms of efficacy and safety remains unclear. Quality evidence to guide treatment decisions in pediatric IgAVN is still limited. Existing guidelines, like Kidney Disease: Improving Global Outcomes (KDIGO) (16) and Chinese evidence-based guidelines (17,18), differ significantly regarding the use of steroids and immunosuppressants, leading to substantial regional variability in treatment approaches. Therefore, the prevalence and prognosis of IgAVN also vary across different regions, underscoring the urgent need for more robust evidence to inform therapeutic strategies. Network meta-analysis (NMA) involves the integration of direct and indirect evidence, facilitating a thorough comparison of the relative efficacy and safety of interventions. Therefore, this study aims to identify the optimal pharmacological treatment strategy for children with IgAVN through a systematic review and NMA. We present this article in accordance with the PRISMA-NMA reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-605/rc) (19).

Methods

Registration

This meta-analysis has been registered in the PROSPERO database under Registration (No. CRD42024602385).

Literature search

PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang, VIP, as well as Sinomed were comprehensively retrieved until October 29, 2024, for Chinese and English research. Both subject headings and free-text terms were utilized, with the Medical Subject Headings (MeSH) including “IgA Vasculitis”, “Nephritis”, and “Drug Therapy”. Moreover, the references of pertinent articles and grey literature were manually checked for eligible studies. The strategy is detailed in https://cdn.amegroups.cn/static/public/tp-2025-605-1.pdf.

Eligibility criteria

Inclusion criteria were: (I) subjects: children aged below 18 with steroids; (II) intervention: drug therapy; (III) the control group was treated using conventional methods and/or a different drug treatment approach from that of the experimental group; (IV) type of study: RCT; (V) outcome measures: curative effect, urinary protein (UP) quantification, urinary red blood cell (RBC), and blood urea nitrogen (BUN).

Exclusion criteria were: (I) animal or cell experiments, case reports, scientific experiment plans, reviews, letters, editorials, and conference papers; (II) lacking data or serious errors; (III) repeated publication of literature; (IV) inaccessible full texts; (V) Chinese medicine compound, Chinese patent medicine injection; (VI) and literature that does not meet the inclusion criteria.

Data extraction

The retrieved literature was uploaded to EndNote. J.G., Ya Wang, Ying He, and F.C. independently checked titles and abstracts and reviewed the full texts as per eligibility criteria. Conflicting literature was reassessed via team discussion or consultation with an independent researcher (F.Y.). Four investigators independently gathered the following data via a pre-developed spreadsheet: first author, publication year, country, study design (randomization and blinding), experimental and control protocols, treatment duration, participant demographics, and outcome measures as outlined in the baseline signature table.

Quality assessment

J.G. and Ya Wang independently rated the methodological quality of incorporated studies utilizing the Cochrane Risk of Bias (ROB 2.0) (20), which assessed random sequence generation, allocation concealment, blind method implementation, data missing, and selective reporting. Each item is rated as high, some, or low risk based on the degree of possible bias. If all five items are rated as low risk, or if only one item is rated as moderate risk while the others are low risk, the article is classified as a low-risk study. If four or more of the five items are rated as moderate risk, or if any one item is rated as high risk, the article is classified as a high-risk study. All other cases are classified as moderate-risk studies. The quality assessment of the encompassed literature was performed independently by two authors, and dissents were addressed through a third author (F.Y.).

Statistical analysis

The outcome indicators included both continuous and dichotomous variables. For continuous outcomes, the weighted mean difference (WMD) was used as the effect size. Regarding dichotomous ones, the risk ratio (RR) served as the effect measure. A Bayesian NMA (BNMA) model was constructed via the Markov Chain Monte Carlo (MCMC) method to estimate the relative efficacy of varied treatment regimens. Model parameters included a chain number of 4, a burn-in (annealing) value of 10,000, an iteration number of 50,000, a thinning interval of 10, and an initial value of 2.5, all aimed at generating the posterior distribution. The validity of the NMA rests on three fundamental assumptions: transitivity, homogeneity, and consistency. Heterogeneity was detected via the mtc.anohe function in the GeMTC package. Overall I² value below 50% was considered indicative of acceptable heterogeneity within each comparison, thereby satisfying the assumption of homogeneity. The mtc.nodesplit function in GeMTC was utilized to examine inconsistency across direct and indirect comparisons via node-splitting analysis. P>0.05 denoted insignificant inconsistency, supporting the consistency assumption. Convergence of patient baseline characteristics and study results was assessed through arithmetic quality testing. A network diagram was constructed with standardized mean differences represented by edges (lines) and intervention strategies represented by nodes. The relative efficacy of treatments was evaluated using a cumulative ranking probability curve, with the surface under the cumulative ranking curve (SUCRA) reported for every intervention. In the network plot, nodes and edges represented different interventions and direct head-to-head comparisons, respectively. The size of every node and the thickness of each edge corresponded to the number of trials and comparisons involved, respectively. Publication bias was examined through funnel plots. Our statistical analyses were enabled by R 4.4.2 and STATA 15.1.

Results

Literature screening process and results

There were 7,661 initially retrieved records. After the removal of 3,335 duplicates, 1,794 records were excluded based on title and abstract screening. The full texts of the rest were checked, and studies were included or excluded strictly as per the predefined eligibility criteria. At last, 73 studies were encompassed. The process is detailed in Figure 1.

Figure 1 Flow chart of included studies. TCM, Traditional Chinese Medicine.

Baseline characteristics and quality assessment

The encompassed 73 studies in Table S1 were carried out in China, America, and Finland and involved 5,384 patients: 2,591 males and 1,983 females aged 2.8–16 years.

The risk of bias assessment results revealed that most studies demonstrated low risk, though 13 were deemed to have moderate risk largely owing to the possible lack of blinding measures.

NMA

Network relationship diagram

In the network diagram, each node represents an intervention. Node size reflects the volume of studies for each intervention. Larger nodes represent more studies. Connecting lines show direct comparisons across interventions, and thicker lines reflect more available comparative studies. The network structure is presented in Figure 2.

Figure 2 Network relationship diagram. ACEI, angiotensin-converting enzyme inhibitor; CPM, cyclophosphamide; IG, immunoglobulin; IM, immunomodulator; ims, immunosuppressor; LRA, lipid-regulating agent; PV, plasma volume; Soc, standard of care.

Curative effect

There were 61 studies reporting curative effects. According to the NMA, steroids demonstrated the most favorable treatment outcome for pediatric steroids when compared with standard of care (Soc) [steroids vs. Soc: RR =1.17, 95% confidence interval (CI): 1.02–1.34; Table S2].

SUCRA rankings showed the following probabilities of efficacy: steroids (94.64%) > steroids + peripheral vasodilators (89.54%) > immunomodulators + steroids + immunoglobulin (85.35%) > statins (83.44%). Steroids were identified as the most effective treatment (Figure 3A).

Figure 3 Cumulative probability graph. ACEI, angiotensin-converting enzyme inhibitor; CPM, cyclophosphamide; IG, immunoglobulin; IM, immunomodulator; ims, immunosuppressor; LRA, lipid-regulating agent; PV, plasma volume; Soc, standard of care.

UP quantitation

UP levels were reported in 54 studies. The NMA indicated that leukotriene (LT) receptor antagonists were the most effective in reducing UP in children with steroids in comparison to Soc [odds ratio (OR) =13.28, 95% CI: 9.12–17.45] (Table S3).

SUCRA probabilities ranked the interventions as follows: LT receptor antagonists (99.97%) > immunosuppressants + anticoagulants (77.16%) > immunosuppressants + steroids + Chinese patent medicine (72.33%) > Chinese patent medicine + immunosuppressants (70.78%) (Figure 3B).

Urinary RBC

Urinary RBC counts were reported in 27 studies. All CIs for comparisons with Soc included 0, indicating statistically insignificant disparities (P>0.05). However, regarding effect size, immunosuppressants combined with immunoglobulin are possibly the most promising for reducing hematuria (OR =17.42, 95% CI: −0.69, 36.52) (Table S4).

SUCRA rankings: immunosuppressants + immunoglobulin (94.73%) > immunosuppressants + anticoagulants (65.86%) > Chinese patent medicine + immunosuppressants (60.36%) > steroids + immunoglobulin (56.80%). The top-performing intervention is shown in Figure 3C.

BUN

BUN levels were reported in 16 studies. All CIs for comparisons with Soc included 0, implying no statistically significant disparities (P>0.05). Nevertheless, based on the magnitude of the effect size, Chinese patent medicine showed the greatest potential (OR =1.59, 95% CI: −1.72, 4.87; Table S5).

SUCRA probability sorting results show: Chinese patent medicine (86.85%) > steroids + anticoagulants (80.94%) > calcium ion antagonist (73.19%) > Soc (60.30%). Chinese patent medicine has the best effect on regulating BUN in children with steroids (Figure 3D).

Publication bias

The publication bias test was conducted by drawing corrected-comparison funnel plots. The results showed that all funnel plots presented symmetry, indicating no publication bias (Figure S1).

Meta-regression analysis for heterogeneity exploration

Bayesian meta-regression was performed to assess potential sources of heterogeneity across all outcomes (curative effect, UP, urinary RBC, and BUN). Unfortunately, the source of heterogeneity could not be identified.

Discussion

Our study results demonstrated that in comparison to Soc, steroid therapy provides the most favorable overall outcomes for children with IgAVN. LT receptor antagonists are the most effective in lowering UP levels. Immunosuppressants combined with immunoglobulin possibly offer the best effect in reducing urinary RBC counts. Furthermore, Chinese patent medicine is possibly the most effective in regulating BUN levels in affected children.

IgA1 is the main constituent of immune deposits in IgAV. IgAVN involves abnormal O-glycosylation patterns in the hinge region of IgA1 (21), leading to the exposure of N-acetylgalactosamine residues that act as novel antigenic epitopes. Autoantibodies recognizing these neoepitopes bind to galactose-deficient IgA1 (Gd-IgA1), forming pathogenic immune complexes (IgG-Gd-IgA1) (22). IgA binds to plenty of receptors like the transferrin receptor (CD71). CD71 overexpression in mesangial cells promotes IgG-Gd-IgA1 immune complex deposition in the mesangium (23). Such accumulation in the renal tissue stimulates mesangial cells, promotes extracellular matrix synthesis, induces inflammatory cytokine release, and attracts immune cells to the glomerular capillaries. These pathological processes collectively contribute to the development of glomerular sclerosis (24). Therefore, IgAVN is a recognized inflammatory illness, which lays a theoretical basis for corticosteroid treatment. Steroids suppress the secretion of Gd-IgA1 from B cells via the NF-κB signaling pathway inhibition, thereby mitigating the mesangial deposition of pathogenic immune complexes. In addition, steroids facilitate circulating immune complex clearance by upregulating the expression of macroglobulin receptors in hepatocytes. During the vascular repair phase, steroids inhibit the TLR4/MyD88 signaling pathway in mesangial cells, lowering MCP-1 and collagen IV expression, thus slowing the progression of glomerulosclerosis.

Steroids are widely utilized by clinicians in treating IgAVN, with methylprednisolone pulse therapy combined with oral steroids being commonly administered, particularly in severe cases. A national survey conducted in 2013 across 40 centers in China reviewed 4,863 pediatric cases of IgAVN and found that 75.6% of children received steroid monotherapy or a combination of steroids and immunosuppressants. Notably, about 50% of individuals with isolated hematuria underwent treatment involving steroids or immunosuppressants. Moreover, steroids alone were administered to 35.9% of patients exhibiting both hematuria and proteinuria (11). In China, evidence-based guidelines for diagnosing and treating IgAVN were published in 2017 (18). These guidelines recommend corticosteroid therapy, either alone or in combination with immunosuppressants, for children presenting with albuminuria exceeding 1 g/day/1.73 m² or exhibiting mesangial hyperplasia. In cases of nephrotic-range proteinuria, hematuria with proteinuria, or crescent formation, methylprednisolone pulse therapy possibly be considered, particularly when diffuse mesangial hyperplasia or crescentic lesions involve more than 50% of glomeruli. A pediatric study demonstrated that glucocorticoid therapy significantly accelerated the resolution of hematuria and proteinuria compared with placebo, achieving remission in 61% and 34% of patients, respectively, at six months. This benefit was most pronounced in children older than 6 years with mild renal involvement at baseline, suggesting that glucocorticoids may alter the disease trajectory in early-stage IgAVN (25). Consistently, a prospective, non-controlled study by Niaudet et al. reported complete resolution of renal impairment and/or nephrotic syndrome in 27 of 38 children (mean follow-up: 5.6 years) after treatment with three pulses of methylprednisolone followed by oral prednisone for more than 3 months (26). However, the optimal use of steroids in children with steroids in China remains to be determined and necessitates further investigation through prospective studies or multi-center RCTs. Moreover, the long-term utilization of steroids is limited owing to adverse effects, so it is imperative to develop new therapeutic strategies.

In recent years, domestic and foreign literature has reported that LTs are involved in the pathogenesis of IgAV. LTs are a series of products metabolized by arachidonic acid through the 5-lipoxygenase pathway, including LTB4 and Cysteinyl LTs (CysLTs), namely LTC4, LTD4 as well as LTE4 (27). CysLTs are abnormally expressed in various kidney diseases and promote the development of many kidney diseases (28). LT receptor antagonists are the most potent specific CysLTs receptor antagonists. They can not only block the binding of CysLTs to LT receptors, preventing them from exerting their biological characteristics, but also reduce the infiltration of eosinophils and basophils and alleviate the inflammatory response of small blood vessels. Cystatin C (CysC), also referred to as a cysteine protease inhibitor, is a low-molecular-weight protein that shows a strong correlation with glomerular filtration rate (GFR) (29). LT receptor antagonists can markedly alleviate renal tubulointerstitial damage and reduce inflammatory cell infiltration in the pediatric IgAV population (30). A study conducted by Tuğtepe and colleagues demonstrated that blocking LTCysLT1 receptors with montelukast attenuates oxidative renal injury and ameliorates kidney function. This protective effect is achieved by inhibiting neutrophil infiltration, suppressing reactive oxygen species release, and downregulating pro-inflammatory cytokine activity (31). Reinhold et al.’s study indicates that LTs are candidate mediators for controlling renal function (28).

Given the multi-hit hypothesis underlying IgAVN (32), the utilization of immunosuppressive agents in affected patients is well justified. Commonly employed immunosuppressants include cyclophosphamide (CYC), mycophenolate mofetil (MMF), leflunomide (LF), tacrolimus, cyclosporine, etc. CYC inhibits T and B cell activity, thereby mitigating the generation and accumulation of pathogenic immune complexes within the glomeruli (33). The 2021 KDIGO guidelines recommend the use of CYC in cases of IgAVN presenting with nephrotic syndrome or rapidly progressive renal impairment (16). MMF, a prodrug of mycophenolic acid (MPA), inhibits lymphocyte proliferation, promotes the death of activated T cells, reduces antibody production, and possibly limits the recruitment of inflammatory cells to glomeruli following immune complex deposition (34). A recent meta-analysis by Wang et al. demonstrated superior efficacy and safety of MMF combined with glucocorticoids compared with CYC plus glucocorticoids in pediatric IgAVN. Across 675 patients from ten studies, MMF-steroid therapy achieved significantly higher complete remission rates at both 6 and 12 months, with fewer adverse events (35). LF was initially recognized for its anti-inflammatory properties (36,37), believed to act by modulating innate immune responses. Pediatric IgAVN was successfully treated via LF in combination with steroids (38). Tacrolimus is a more potent new immunosuppressant that has been applied in clinical practice after cyclosporine A (39). By competitively binding to cytoplasmic immunophilins and inhibiting calcineurin activity, tacrolimus disrupts the transcription of cytokines, thereby modulating T-cell function and exerting immunosuppressive effects (40). It has increasingly been applied in autoimmune illnesses like refractory nephrotic syndrome and lupus nephritis (41). Short-term studies have also indicated that tacrolimus markedly reduces proteinuria in children with IgAV (42). In a retrospective study by Gan et al., 37.5% and 31.2% of patients achieved complete and partial remission of proteinuria, respectively, while 31.2% showed no response (43). These findings position tacrolimus as a potentially effective therapeutic option for refractory pediatric IgAVN, particularly for inducing proteinuria remission. Nonetheless, further studies are required to confirm its long-term efficacy and safety. Cyclosporine A, also a calcineurin inhibitor, has extensive clinical use in immune-mediated conditions and organ transplantation. Current evidence supports the use of calcineurin inhibitors, particularly in mild-to-moderate IgAVN (44). Cyclosporine A, in particular, has demonstrated high efficacy and safety in patients with nephrotic-range proteinuria, although CyA dependence may develop in some cases (45,46). Early initiation of immunosuppressive therapy in pediatric IgAVN is associated with favorable renal outcomes and may arrest or even reverse disease progression (47). However, a large retrospective study identified key factors influencing outcomes in IgAVN and found no evidence that any specific immunosuppressive therapy was superior to others (48). Therefore, when selecting an immunosuppressive treatment regimen, clinicians should base their decision on patient-specific factors, including age, disease severity, side effect profiles, economic considerations, patient preferences, and drug availability.

The Chinese patented medicines included in this article are: Tripterygium wilfordii polyglycosides (TWP), Huaiqihuang (HQH) granules, Huangkui capsules (HKC), Bailing capsules, and Shenyankangfu tablets (SYKFT). TWP is a preparation derived from the xylem of Tripterygium wilfordii roots, composed of multiple natural bioactive compounds. Its effectiveness in proteinuria reduction in GN was first reported in 1977. Besides low cost, TWP exerts anti-inflammation, immunomodulatory, as well as podocyte-protective effects (49-51). It shows promise as an adjunct therapy for managing IgAVN, with studies indicating that its addition significantly improves short-term remission rates compared to glucocorticoid monotherapy (52). HQH granule, a patented herbal formula composed of Huaier (Trametes robiniophila), Lycium barbarum (Gouqizi), and Polygonatum sibiricum (Huangjing), has been widely used in treating various CKDs like primary nephrotic syndrome, IgA nephropathy, IgAVN, as well as other primary or secondary kidney disorders (53-55). Animal studies and in vitro experiments suggest HQH’s therapeutic effects by modulating immune responses, attenuating inflammation, protecting podocytes, inhibiting mesangial cell proliferation, and ameliorating renal fibrosis (56-59). A systematic review of RCTs demonstrated that HQH, when combined with conventional pharmacotherapy, significantly improves outcomes in children with IgAVN without increasing the incidence of adverse events (60). Bailing Capsule, derived from low-temperature Cordyceps strain fermentation, frequently serves as a supplementary therapy for chronic renal insufficiency due to various etiologies, including GN, diabetic nephropathy, nephrotic syndrome, and lupus nephritis. Bailing Capsules, in conjunction with conventional Western therapies, can better reduce proteinuria and preserve kidney function than Western medicine alone (61-63). The primary bioactive constituent of HKC is total flavonoids of Abelmoschus manihot L. (TFA). HKC can protect renal function by regulating the immune response, controlling inflammation, as well as ameliorating vascular endothelial injury (64). In recent years, multiple prospective, multicenter RCTs have confirmed its safety and effectiveness in proteinuria reduction among the CKD population, including primary glomerular diseases and IgA nephropathy (65,66). SYKFT, composed of 13 traditional Chinese herbs, is among the most frequently used Chinese patent medicines in the treatment of GN and CKD. SYKFT exerts therapeutic effects through a multi-component, multi-target, and multi-pathway approach (67).

Furthermore, although not explicitly addressed in the included literature, the renin–renin-angiotensin-aldosterone system (RAAS) also plays a crucial role in IgAVN management. RAAS regulates blood pressure, electrolyte balance, and intravascular volume via cardiovascular and renal pathways. Angiotensin II promotes aldosterone secretion from the adrenal zona glomerulosa and induces post-glomerular arteriolar constriction, thereby modulating protein ultrafiltration and further aldosterone release. The long-term renoprotective benefits of angiotensin-converting enzyme inhibitors (ACE inhibitors, ACE-i) are well established. Current consensus guidelines recommend ACE-i or ARBs for patients with persistent proteinuria (>3 months) to mitigate secondary glomerular damage (8). Although IgAN and IgAVN share histopathological features, their pathogenesis and clinical course differ. In pediatric IgAN, ACE-i therapy significantly increased proteinuria remission compared with placebo (partial remission: 40.6% vs. 8.8%; complete remission: 12.5% vs. 0%) (68). These findings have been extrapolated to IgAVN management; however, dedicated RCTs in pediatric IgAVN remain lacking, underscoring the need for further evaluation of RAAS inhibition in this population. Immunoglobulin therapy may also offer therapeutic benefit in select IgAV cases due to its broad immunomodulatory effects (69). In a prospective study by Rostoker et al. (70), patients with severe IgA nephropathy (including primary IgAN and IgAVN) and poor prognostic indicators received high-dose immunoglobulin therapy consisting of 2 g/kg/month intravenously for 3 months, followed by intramuscular maintenance every two weeks for 6 months. This regimen yielded favorable clinical outcomes. However, due to high costs and limited availability, immunoglobulin therapy has not been widely adopted, though it may be particularly beneficial in patients with active disease complicated by infection. Rituximab (RTX), a monoclonal antibody targeting CD20⁺ B lymphocytes, induces profound B-cell depletion via complement-dependent and antibody-dependent cytotoxic mechanisms (71). At present, RTX use is primarily limited to refractory IgAVN due to limited evidence regarding its efficacy in improving renal outcomes or modulating galactose-deficient IgA1 (Gd-IgA1) levels. The current evidence base consists primarily of isolated case reports and small case series in both pediatric and adult populations (72-74).

This study has several important limitations. First, considerable heterogeneity was observed among the included studies. Although potential moderating effects of sample size and publication year were examined using Bayesian meta-regression analysis, no significant moderators were identified. This suggests that the observed variability likely reflects unmeasured confounders, such as differences in pathological subtype distribution and regional variations in the use of traditional Chinese medicine. Second, the predominance of Chinese-language studies introduces potential interpretation bias and limits generalizability. Finally, insufficient data precluded meta-analysis of estimated GFR as an outcome measure. Accordingly, the present work should be regarded as an exploratory synthesis of existing evidence. Future research should focus on prospective, large-scale RCTs employing standardized therapeutic protocols and well-defined patient subgroups.

Conclusions

Steroids exhibit the most effective therapeutic effect on childhood IgAVN. In clinical practice, the optimal treatment can be selected based on the patient’s predominant symptoms. For example, LT receptor antagonists may be considered for patients whose steroids are mainly characterized by proteinuria. For those with primarily increased urinary RBCs, the preferred treatment is immunosuppressants combined with immunoglobulin. Traditional Chinese medicine should be the first choice for improving BUN levels. Due to certain limitations of this study, the foregoing conclusions require validation via further clinical trials.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA-NMA reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-605/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-605/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-605/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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