Introduction
Immunoglobulin A nephropathy (IgAN) is the most common chronic primary glomerulonephritis worldwide [1]. The estimated point prevalence in Europe is 2.53 per 10000 in patients of all ages and 0.12 per 10000 in pediatric populations. The annual incidence is estimated to be 0.76 per 100000 [2]. The global incidence is consistently higher in Asians than in non-Asians, with males being more commonly affected than females [3]. Although overall disease prognosis is considered variable, progression to end-stage kidney disease represents the most deleterious long-term outcome, affecting 25-30% of patients within 20 years of disease onset [4].
Despite the complex pathophysiological basis of the disease, it has been demonstrated that immune dysregulation, mesangial proliferation, and renin-angiotensin-aldosterone system (RAAS) abnormalities represent cardinal pathological processes [5,6]. On a pathological basis, IgAN is characterized by the deposition of antigen-IgA complexes in the mesangium that trigger a glomerular inflammatory response that can gradually cause loss of functional glomeruli and deterioration of renal function [7]. Additionally, in a clinical context, hypertension and proteinuria are considered the most crucial prognostic factors in predicting disease progression [8]. As a result, pharmacotherapy has primarily focused on reducing daily urinary protein excretion and on blood pressure control.
Many classes of drugs are used in the management of IgAN. Immunosuppressant-based regimens such as corticosteroids and cyclosporine have been shown to improve survival. However, long-term adverse effects such as immunosuppression-related infections, metabolic and hormonal derangements, and tolerability issues seem to hinder its use as standard treatment [9]. Notably, supportive management through antagonism of RAAS function is the backbone of treatment. Prospective trials have proven the efficacy of angiotensin-converting enzyme inhibitors (ACEIs) [10]. However, the probability of discontinuing medication because of bothersome side effects such as a dry cough is higher with ACEIs compared to angiotensin-II receptor blockers (ARBs), making ARBs more tolerable [11].
Angiotensin-II receptor blockers (ARBs) have been one of the most utilized classes of drugs in IgAN management, with losartan being the most extensively studied member [12]. Their mechanism of action depends on decreasing the vasoconstrictive effect of angiotensin-II on the efferent arteriole of renal glomeruli, thereby decreasing intraglomerular pressure and conferring reno-protective and anti-sclerotic properties [13]. Several trials have demonstrated the efficacy of losartan in the treatment of IgAN; for instance, Shimizu et al. demonstrated that low-dose losartan resulted in a significant decrease in proteinuria in a group of normotensive IgAN patients after 12 months of treatment [14]. Other classes of drugs have also been investigated in prospective studies, including calcium channel blockers (CCBs), corticosteroids, and other immunomodulators [15,16,17]. Despite various drug combinations that have been investigated, direct head-to-head comparisons for different drug regimens were sparse and not conclusive, with no single drug or combination regimen emerging as optimal, necessitating the need to integrate available direct and indirect evidence.
Therefore, we have conducted this systematic review and network meta-analysis to fill this knowledge gap and to clarify the long-term effects of various drug choices on IgAN prognosis. We aimed to investigate the effect of losartan, a reference drug, compared with various monotherapy and combination regimens on IgAN management and renoprotective outcomes. These outcomes include change from baseline in daily urinary protein excretion (UPE), office systolic and diastolic blood pressure, mean blood pressure (MBP), serum creatinine, plasma renin activity (PRA), plasma aldosterone activity (PAC), and estimated glomerular filtration rate (eGFR).
Methods
Our systematic review and network meta-analysis were strictly performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) extension statement for network meta-analyses [18] and the Cochrane Handbook of Systematic Reviews and Meta-Analysis, and registered in PROSPERO with registration number CRD42025634499. The protocol was registered on 6 January 2025, prior to data extraction.
Sources of data and search strategy
We performed a comprehensive systematic search on the following databases: Scopus, PubMed, Web of Science, and Ovid until 10, January 2025. We have customized and modified the terms and keywords for each database to ensure we reach the most relevant search results for evaluating the effectiveness of losartan in improving the clinical outcomes of patients with IgA nephropathy. The search strategy we used was as follows: ("IgA Glomerulonephritides" OR "IgA Glomerulonephritis" OR "IgA Nephropathy" OR "Berger Disease" OR "Immunoglobulin A Nephropathy" OR IgAN OR "IgA Type Nephritis") AND ("DuP 753" OR "MK 954" OR Losartan OR "Losartan potassium" OR "Angiotensin II Receptor Antagonist" OR "Angiotensin II Receptor blocker" OR ARB). The detailed search strategy of each database is shown in Online Resource 1.
Eligibility criteria
We included studies meeting the following criteria: 1) randomized controlled trials (RCTs); 2) human studies; 3) studies written in English; 4) including IgA nephropathy patients in which the intervention is losartan, either monotherapy or combined, and the comparator is placebo, any other anti-hypertensive drugs, or any other drugs used in IgA nephropathy management. While review articles, case reports, observational studies, animal studies, case series, and comments were excluded.
Study selection process
Four independent authors performed the screening process in Rayyan software in a blinded manner. First, remove duplicates and proceed to title and abstract screening, then to full-text screening, excluding and including studies according to our PICO criteria. Any conflicts between the authors were resolved, and a final decision was reached.
Data extraction
Data extraction was performed by four independent authors using an online Excel sheet to facilitate communication among the authors. Our sheet was divided into study characteristics (sample size, design, population, interventions, comparator, study duration, outcome measures, and key findings), baseline characteristics (sample size, age, year, gender, male, office SBP, office DBP, mean blood pressure, urinary protein excretion, serum creatinine, serum IgA, eGFR, serum uric acid, and creatinine clearance).
The primary outcomes assessed encompassed change from baseline in: - Systolic blood pressure (mmHg), diastolic blood pressure (mmHg), and urinary protein excretion (g/day) at 3, 6, and 12 months.
A decrease of approximately 5–10 mm Hg in systolic blood pressure or about 5 mm Hg in diastolic blood pressure is generally regarded as the minimum clinically meaningful change [19]. Such reductions have been associated with substantial risk reductions in major cardiovascular outcomes, including an estimated 20% decrease in major cardiovascular events, 17% reduction in coronary heart disease, 28% lower risk of heart failure, and 27% reduction in stroke incidence [20].
Secondary outcomes included change from baseline in: - Serum creatinine (mg/dL) at 3 months, eGFR (ml/min/1.73 m2) at 3 months, plasma aldosterone concentration(pg/ml) at 12 months, plasma renin activity (ng/mL/h) at 12 months, and mean blood pressure (mmHg) at 3 and 6 months. Missing outcome data were extracted as reported in the original studies. No imputation was performed at the study or meta-analysis level. When data for specific outcomes or timepoints were unavailable, those studies were excluded from the corresponding analyses.
Bias risk
Using the Cochrane ROB-2 tool for RCTs, four independent authors evaluated the risk of bias [21]. Evaluation of five areas of potential bias (randomization process, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of reported results) was performed using the ROB-2 tool; any conflicts were resolved among the authors, and a final decision was reached.
Statistical analysis
We used RStudio to conduct the network meta-analysis and adopted a frequentist approach with a random-effects model via the "netmeta" package [22]. This approach allowed us to assess various treatments by synthesizing direct and indirect evidence from studies that used a common comparator. For continuous endpoints, effect sizes were reported as mean differences (MD), and for dichotomous outcomes, risk ratios (RR) were reported, accompanied by 95% confidence intervals (CIs). The relative efficacy of the interventions was assessed using the Surface Under the Cumulative Ranking Curve (SUCRA), where higher SUCRA values indicate a greater likelihood that an intervention ranks as the most effective. We created network diagrams to present the relationships among interventions, and we used forest plots to demonstrate effect sizes per comparison. League tables were also used to rank the treatments, thereby enhancing the ease of comparison among them. Transitivity of the network meta-analysis was assessed qualitatively by comparing key clinical and methodological characteristics across treatment comparisons, including age, baseline blood pressure, baseline proteinuria, disease severity, and follow-up duration. No major imbalances suggesting violation of transitivity were identified. Besides, multi-arm trials were included in the network meta-analysis and appropriately accounted for by modeling the correlation between effect estimates to avoid double-counting of shared comparator groups. Regarding inconsistency, global and local inconsistency were planned for assessment; however, due to the sparse network structure and the limited number of studies per comparison, formal inconsistency statistics were not estimable.
Discussion
The present network meta-analysis compares different IgAN monotherapies and combination therapies, including various drugs from several classes (e.g., losartan, temocapril, enalapril, mizoribine, amlodipine, and antiplatelet agents). Regarding urinary protein excretion, although none of the interventions showed a statistically significant difference compared with losartan at 3 months, mizoribine and mizoribine + losartan showed significantly greater reductions than losartan at 12 months. Mizoribine is an imidazole nucleoside extracted from the fungus Eupenicillium brefeldianum [26]. It reduces urinary protein excretion by inhibiting nonhemodynamic activities, including lymphocyte proliferation, mesangial cell activity, and inflammatory markers. [27,28,29] Therefore, whether as monotherapy or in combination, mizoribine requires a sufficiently long treatment period to exert its effects and achieve maximal reduction in protein excretion. Similarly, Yoshikawa et al. [30] demonstrated that children with severe IgAN treated with mizoribine combined with standard therapy for 2 years showed a substantial reduction in protein excretion.
Our analysis revealed that amlodipine resulted in a statistically significant reduction in UPE compared with other interventions at 3 months. This finding aligns with the Praga et al. trial [31], which found that amlodipine resulted in no significant reduction in proteinuria in non-diabetic proteinuric renal diseases. Several reasons might contribute to the interpretation of this finding. Studies showed that dihydropyridine calcium channel blockers (CCBs) such as amlodipine reduced proximal tubular protein reabsorption, evidenced by increased excretion of urinary \documentclass[12pt]{minimal}
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\begin{document}$\beta_2$\end{document}β2-microglobulin, a marker of proximal tubular protein reabsorption [32,33,34]. Furthermore, dihydropyridine CCBs dilate afferent and efferent arterioles, which may increase proteinuria [35]. Therefore, despite the considerable reduction in blood pressure, dihydropyridine CCBs provide no additional benefit in reducing proteinuria. However, the observed difference in proteinuria reflects a comparative advantage of other regimens over amlodipine, which is generally considered proteinuria-neutral or, in some cases, proteinuria-worsening.
The comparison between losartan, temocapril, and the combination therapy (losartan + temocapril) revealed no statistically significant differences in urinary protein excretion at 3, 6, and 12 months. However, the combination therapy demonstrated greater antiproteinuric activity and ranked first at 3 and 6 months, with SUCRAS of 73% and 86%, respectively. Similarly, Huo et al. [36] showed that the combination therapy of ACEIs and ARBs best reduced proteinuria compared to ACEIs or ARBs monotherapies. The enhanced effects of dual therapy may be explained by the fact that ACEI or ARB monotherapy results in a partial blockage of the renin-angiotensin-aldosterone system (RAAS), a phenomenon known as ‘‘ACE escape. Consequently, combined therapy may cause more hindrance of angiotensin II’s actions on the kidney by reducing glomerular capillary pressure and hyperfiltration, resulting in better response in terms of proteinuria and blood pressure reduction [37,36]. Moreover, dual therapy seems effective in improving glomerular permselectivity [38,39]. Interestingly, losartan monotherapy resulted in the best decrease in SBP at 3 months. However, combination therapy resulted in higher reductions than monotherapies in SBP at 6 and 12 months. Likewise, losartan and temocapril showed greater reductions in DBP at 3 and 6 months, but at 12 months, losartan + temocapril showed the greatest reduction. Therefore, we can deduce that the combination therapy of losartan + temocapril may require a sufficiently long treatment course to achieve optimal blood pressure reduction. However, due to the sparsity and potential small-study effects, certainty needs to be supported by further RCTs. Additionally, given the limited safety data in our included studies, the safety of dual ACEI + ARB therapy remains unclear and should be investigated further.
The current network meta-analysis stands out in some points. It is the first network meta-analysis to focus on losartan-anchored regimens across several predefined timepoints, aiming to provide evidence on the best regimen for IgAN management. Moreover, we investigated the primary outcomes at multiple time points to evaluate the long-term sustainability of the drugs’ efficacy. Consequently, our study provided valuable clinical implications for the optimal use of the investigated drugs in the management of IgAN. However, the study had several limitations. The study involved a relatively small number of trials and patients, which might affect the generalizability of our findings. The limited number of studies and small sample sizes reduced statistical power and led to wide confidence intervals for several comparisons, limiting the precision of effect estimates and increasing uncertainty around clinically meaningful differences. The sparse nature of the evidence network limits the precision of heterogeneity estimates and reduces the stability of treatment rankings. Consequently, SUCRA values should not be interpreted as definitive evidence of superiority. Instead, clinical decision-making should rely primarily on the magnitude and precision of treatment effects. Besides, the different doses of the interventions included in our study might affect the comparison of interventions. The included trials predominantly evaluated fixed-dose regimens, often at submaximal doses, whereas routine clinical practice involves titration to the maximum tolerated dose. Therefore, the observed treatment effects may differ under dose-optimized regimens, potentially underestimating the effectiveness achieved in real-world practice. Variability in the eligibility criteria of the included studies regarding blood pressure, proteinuria levels, and renal function parameters represented another constraint. For instance, Park et al.2003 included hypertensive patients, while other included studies included patients with normal blood pressure. However, we couldn’t perform meta-regression due to the small sample size and the limited number of included studies. The lack of a comprehensive safety assessment and certainty evaluation represents another limitation of our study and may influence the strength and clinical applicability of the investigated regimens. Subgroup analyses based on key characteristics such as age (pediatric vs. adult), baseline blood pressure (normotensive vs. hypertensive), or proteinuria levels were not feasible due to limited reporting and small numbers of studies. Consequently, potential sources of heterogeneity could not be formally explored, and results should be interpreted with caution. Assessment of publication bias was planned; however, due to the small number of studies per comparison (\documentclass[12pt]{minimal}
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\begin{document}$<10$\end{document}<10), formal statistical tests and reliable funnel plot interpretation were not feasible. Moreover, all studies included in this network meta-analysis were conducted in East Asian populations, predominantly from Japan, Korea, and China. Ethnic and geographic differences in the epidemiology and clinical course of IgA nephropathy, background standards of care, and pharmacogenomic responses—particularly to renin–angiotensin system blockade and immunomodulatory therapies—may limit the generalizability of these findings to non-Asian populations. Consequently, the observed comparative effectiveness and safety profiles may not be directly extrapolated to Western or other ethnically diverse cohorts. Future randomized trials, including broader geographic representation, are needed to validate these findings across different populations. Besides, this analysis focused on surrogate outcomes, including blood pressure and proteinuria, which may not fully capture patient-important endpoints such as progression to end-stage kidney disease, mortality, or quality of life. Although reductions in proteinuria are commonly used as treatment targets in IgA nephropathy, their relationship with long-term kidney survival remains uncertain, particularly over short follow-up periods. Moreover, none of the included studies reported adherence or dropout rates, precluding assessment of real-world effectiveness.
Given the limitations of our study, we recommend that future research focus on conducting more RCTs comparing losartan with different classes of drugs, involving larger numbers of IgAN patients. Besides, since we could not evaluate the safety of the various interventions used in IgAN due to the lack of safety data in our included trials, long-term RCTs investigating the safety of IgAN commonly prescribed drugs are highly recommended. In addition, RCTs comparing losartan’s efficacy and safety with those of other ARBs may yield valuable clinical insights into the optimal regimen for IgAN management. We did not assess economic outcomes. Given that dual RAAS blockade is more costly than monotherapy, formal cost-effectiveness analyses would be valuable to guide clinical decision-making, particularly when efficacy differences are modest. Moreover, trials investigating the effectiveness of these interventions in IgAN patients with different comorbidities would be of great value.