Safety and efficacy of prednisolone, mizoribine and lisinopril combination therapy for severe childhood IgA Nephropathy

Safety and efficacy of prednisolone, mizoribine and lisinopril combination therapy for severe childhood IgA Nephropathy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Safety and efficacy of prednisolone, mizoribine and lisinopril combination therapy for severe childhood IgA Nephropathy Yuko Shima, Hironobu Mukaiyama, Yu Tanaka, Wataru Shimabukuro, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7587733/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Angiotensin-converting enzyme inhibitors such as lisinopril have long been used for childhood IgA Nephropathy (cIgAN). A two-year combined regimen including prednisolone + mizoribine + warfarin + dipyridamole was shown in our previous randomized control trial to be better for severe cIgAN than prednisolone + mizoribine (without warfarin or dipyridamole) in proteinuria remission. However, to avoid warfarin nephropathy and to shorten the duration of prednisolone use, we consider a new two-year combined regimen of prednisolone + mizoribine + lisinopril. Methods Between July 1976 and December 2022, among 567 biopsy-proven cases of cIgAN, there were 93 cases of severe cIgAN treated with prednisolone + mizoribine. We investigated clinicopathological differences between the 77 cases of cIgAN (82.8%) with the previous treatment and the other 16 patients with the new treatment regimen. After 1:1 propensity score matching was performed to account for between-group differences (amount of proteinuria, eGFR, and the percentage of patients with C0, C1, and C2), we analyzed 15 matched pairs. Results Clinicopathological presentations did not significantly differ between the groups. Kaplan-Meier analysis of proteinuria remission showed that the patients with the new treatment achieved significantly higher (90.0 vs. 64.1% at 11 yrs, p = 0.01), and faster (1.0 vs. 4.0 yrs, p = 0.03) proteinuria remission than those with the previous treatment. Proteinuria recurrence was not significantly different between the groups. Conclusions We suggested the superiority of 2-year combined regimen of prednisolone + mizoribine + lisinopril for severe cIgAN in achieving early proteinuria remission and shortening prednisolone use without recurrence of proteinuria. childhood IgA nephropathy angiotensin-converting enzyme inhibitors prednisolone proteinuria remission chronic kidney disease Figures Figure 1 Figure 2 Introduction Immunoglobulin A nephropathy (IgAN) is a notable cause of primary glomerulonephritis. In Japan, since 1974, most cases of childhood IgAN (cIgAN) have been discovered with asymptomatic hematuria and/or proteinuria by the school-based screening program. With normal estimated glomerular filtration rate, cIgAN was once considered to be benign. However, a long-term follow-up study previously revealed that as much as 11% of 241 Japanese cIgAN developed end-stage kidney disease within 15 years [ 1 ]. Factors for poor prognosis of cIgAN include heavy proteinuria and severe pathological changes, such as diffuse mesangial proliferation [ 2 ]. To establish treatment strategies for cIgAN in Japan, there have been various multicenter randomized controlled trials and clinical trials since 1990 [ 3 – 8 ]. Two-year combination treatment comprising prednisolone + azathioprine was shown in a follow-up study to not only ameliorate the activity of the acute phase of nephritis, but also to improve the long-term outcome of severe cIgAN [ 9 ]. Overall, there has been improvement of long-term kidney outcomes in Japanese cases of cIgAN since the beginning of these trials [ 10 ]. In our most recent RCT for severe cIgAN, combination treatment comprising prednisolone + mizoribine + warfarin + dipyridamole was suggested to be an improvement over the combination treatment of prednisolone + mizoribine (without warfarin or dipyridamole) in proteinuria remission [ 7 ]. In warfarin nephropathy, there might be an increase in global glomerulosclerosis due to the vascular calcification of warfarin. Also, there should be consideration of modifying prednisolone administration due to the high cumulative dosage used in previous randomized controlled trials [ 3 – 5 , 7 ]. New combination therapy should therefore be considered, such as prednisolone + mizoribine + lisinopril. Materials and methods Patients This retrospective cohort study included 567 patients aged < 20 years with biopsy-proven IgAN at two university hospitals between July 1976 and December 2022. Diagnosis of IgAN was based on the sole or predominant IgA deposition in the glomerular mesangium in the kidney biopsy tissue without systemic disease. Diagnoses of IgAN were confirmed by a single investigator (NY) using the same criteria throughout the entire study period. Kidney biopsy was performed in those with persistent proteinuria with or without hematuria. Among them, 93 patients had severe cIgAN and were treated with prednisolone and mizoribine. In total, 77 patients received a two-year combined regimen of prednisolone + mizoribine + warfarin + dipyridamole (the previous treatment), and 16 patients received a two-year combined regimen of prednisolone + mizoribine + lisinopril (the new treatment). A 1:1 propensity score-matching method was conducted to select patients who received the previous treatment as the control group, referred as ‘the previous treatment group’. The study flowchart is shown in Fig. 1 . Clinical data We recorded clinical data about sex ratio, onset age, onset mode, episode of gross hematuria, duration from onset to kidney biopsy, urinary protein to creatinine ratio (uP/Cr), eGFR, mean blood pressure, and duration from onset to the latest observation. Data were handled as previously reported [ 11 ]. Pathological data Six pathological variables were selected, those proposed in the Oxford classification (MEST-C) [ 12 – 15 ], and global sclerosis (G). Arterial intimal thickening was not found in cases of this study. Treatments Since the beginning of the 1990s, we have prescribed two-year combined regimen of prednisolone + azathioprine or mizoribine + warfarin + dipyridamole (the previous treatment) for pediatric patients with severe IgAN showing diffuse mesangial proliferation defined on the basis of the World Health Organization criteria and/or heavy proteinuria > 1g/gCr. However, the use of angiotensin converting enzyme inhibitors (ACEi) in pediatric patients with chronic kidney disease has increased and its effectiveness has been confirmed [ 6 , 16 ]. Since around 2008, we have therefore used the new two-year combined regimen of prednisolone + mizoribine + lisinopril (the new treatment) for those with severe cIgAN. In principle, predonisolone was reduced/discontinued after remission of proteinuria was cofirmed in the new treatment. Outcome definitions We determined the end-point of outcome of this study as remission of proteinuria defined as proteinuria qualitative reaction (–) or proteinuria < 0.2 g/gCr. Statistical analyses All statistical analyses were performed using the JMP software package ver. 16.0 (SAS Institute Japan, Tokyo, Japan). Propensity score matching was employed, and the propensity score was based on the amount of proteinuria, eGFR, and the proportion of patients with C0, C1, and C2. A 1:1 matching ratio was adopted. The final sample had 15 matched pairs for analyses. Continuous variables were reported as median (interquartile range). Categorical variables were expressed as counts and percentage. Group comparisons were performed using Mann-Whitney U or ꭕ 2 test. Survival analysis was performed by Kaplan-Meier method. Results were expressed as hazard ratio with 95% confidence intervals. A two-tailed p -value < 0.05 was considered to be statistically significant. Results Baseline characteristics of pediatric patients with IgAN treated with immunosuppressive treatments Among 567 cases of newly biopsy-proven childhood IgAN between 1977 and 2020, there were 93 patients with immunosuppressive treatment including prednisolone and mizoribine. The baseline characteristics of all patients (77 with the previous treatment, 16 with the new treatment) are summarized in Table 1. There were significant differences in uP/Cr (median 1.2 vs. 1.9 g/gCr, p =0.04) and the proportions of patients with C0, C1, and C2 (22 / 42 / 13 vs. 0 / 11 /1 / 5, p =0.04) between the groups. Included in this study were 16 patients with cIgAN who received the new therapy and 15 matched patients who received the previous therapy using propensity score matching (Figure 1). The characteristics of 15 matched pairs are shown in Table 2. There was no significant difference in baseline characteristics. Efficacy outcomes According to Kaplan-Meier analysis, the disappearance rate of proteinuria was significantly higher in the new treatment group than in the previous treatment group during the follow-up period (90.0% at 11 years [95%CI 57.2 – 98.4%] vs. 64.1% at 11 years [95%CI 28.8 – 88.7%], log-rank p = 0.01, Fig.2). Furthermore, in the new trearment group, the percentage of the patients with proteinuria remission at the latest observation was much higher (13 [86.7%] vs. 8 cases [53.3%], p =0.04), the duration from start of treatment to remission was much faster (1.0 [1.0 – 4.0] vs. 4.0 years [2.0 – 10], p =0.03), and the duration of prednisolone use was much shorter (14 [6 – 22] vs. 24 months [24 – 24], p <0.0001) than in the previous treatment group. Despite the shorter observation period in the new therapy group (5 [3 – 8] vs. 8 years [3 – 10], p =0.28), there was no significant difference in proteinuria recurrence rate at the latest observation ( 3 / 13 [23.1%] vs. 3 / 8 [37.5%], p =0.08). Safety outcomes All patients who received the new treatment showed transient moon face and central obesity, but these symptoms disappeared within 2 to 3 months as the steroid dosage was reduced. Five patients (33.3%) had acne, two (13.3%) had glaucoma, and one had transient glucosuria, which were thought to be related to steroid use. One patient showed hyperuricemia due to mizoribine. All of these side effects subsided after treatment. Hypertension, which had been observed in the previous pilot study [5], was not observed in the new treatment group, possibly because lisinopril (an antihypertensive drug) was used. Discussion To establish treatment strategies for severe cIgAN, several Japanese multicenter treatment studies have been conducted since 1990 for cIgAN with diffuse mesangial proliferation, considering a poor kidney outcome [ 3 – 5 , 7 ]. The most effective treatment for severe cIgAN to date based on these clinical trials is likely combined regimen of prednisolone + mizoribine + warfarin + dipyridamole. However, taking into consideration the usefulness of ACEi, which has been widely used in children since the 2000s, and the risk of warfarin nephropathy and side effects due to the use of dipyridamole, it has been reasonable for us to investigate effectiveness of a new combined regimen using prednisolone + mizoribine + ACEi [ 7 ]. Our study showed that the new combination therapy not only led to higher proteinuria remission rates, but it was also demonstrated to have a faster response than the previous regimen. One plausible explanation is the antiproteinuric effect of lisinopril (ACEi), which may have enhanced glomerular hemodynamics and reduced proteinuria by decreasing intraglomerular pressure. Additionally, by avoiding warfarin, the risk of warfarin-associated nephropathy, which is characterized by glomerulosclerosis due to vascular calcification, has been dispelled, further contributing to better kidney outcomes. Long-term use of corticosteroids carries significant risks, including metabolic disturbances, bone demineralization, and growth impairment in pediatric patients. The reduction in prednisolone exposure in the new therapy group (median 14 vs. 24 months, p < 0.0001) is particularly important because it decreases the likelihood of these adverse effects. Moreover, despite shorter prednisolone administration, the new treatment group exhibited superior remission rates, which suggests that the synergistic effects of mizoribine and lisinopril might compensate for reduced steroid dependency. Propensity score matching was used to balance baseline characteristics between the two treatment groups, but certain biases inherent to retrospective studies may still exist. The study population in this study was relatively small (15 matched pairs), and differences in observation periods may impact long-term comparisons. Additionally, we did not evaluate external factors such as dietary changes, genetic predispositions, and adherence to treatment protocols, which could influence disease progression. Further prospective studies with larger cohorts are needed to confirm the efficacy and safety of the new combination therapy in cases of cIgAN. Additional research should explore whether incorporating ACEi into standard treatment regimens could improve long-term kidney outcomes for cases of patients with severe cIgAN. Furthermore, investigations into optimizing prednisolone dosage and duration could help balance efficacy with minimizing side effects. Mizoribine is unique in that its use is largely restricted to Japan [ 17 ], which raises questions about the applicability of this new combination therapy in international settings. Mizoribine has been widely used in Japanese cIgAN treatment protocols due to its immunosuppressive properties and favorable safety profile, but its absence in countries other than Japan means that alternative immunosuppressive agents, such as mycophenolate mofetil (MMF), might need to be considered when adapting this regimen globally. Mizoribine belongs to the class of purine synthesis inhibitors, similar to MMF, but it has a distinct pharmacokinetic profile, including a lower incidence of gastrointestinal side effects and better tolerability in pediatric patients. However, MMF has been more extensively studied in international clinical trials and effectiveness has been shown in IgAN management [ 18 – 24 ]. Future studies should investigate whether MMF or other alternatives can achieve similar efficacy and safety outcomes to mizoribine when used in combination with prednisolone and lisinopril. This may eventually facilitate broader adoption while maintaining the core principles of the treatment strategy: reducing proteinuria, accelerating remission, and minimizing steroid exposure. In recent years, as the pathophysiology of IgAN becomes clearer, new therapeutic candidates based on that pathophysiological mechanism including targeted-release budesonide [ 25 – 28 ], B cell function inhibitors (a proliferation-inducing ligand [APRIL]/ B-cell activation factor [BAFF]/ transmembrane activator and calcium cyclophilin interactor [TACI] antibodies) [ 29 ], anti-complement drugs [ 30 , 31 ], and endothelin receptor antagonists [ 32 – 34 ] have been developed and clinical trials using these drugs are currently underway, mainly in adult IgAN. If these drugs proven to be safe and effective, they might dramatically change treatments for cIgAN in the future. Conclusions In conclusion, the new combined regimen with prednisolone + mizoribine + lisinopril demonstrated greater efficacy in achieving proteinuria remission with especially lower dose of steroids than the previous therapy, while maintaining comparable safety profiles. Declarations Acknowledgements The authors thank all participants and attending physicians for their contributions. We acknowledge proofreading and editing by Benjamin Phillis, a Board-Certified Editor in the Life Sciences (BELS), at Wakayama Medical University. Author contributions Yuko Shima and Koichi Nakanishi contributed to study conception and design. Material preparation and data collection were performed by all authors. Yuko Shima and Norishige Yoshikawa performed pathological evaluations. Data analysis was performed by Yuko Shima and Koichi Nakanishi. The first draft of the manuscript was written by Yuko Shima and all authors commented on versions of the manuscript. All authors read and approved the final manuscript. Data availability The data that support the findings of this study are available within consent upon reasonable request. Ethics approval The study was conducted according to the principles of the Declaration of Helsinki and the ethical guidelines issued by the Ministry of Health, Labor and Welfare, Japan. The study was also approved by the Wakayama Medical University Ethics Committee (approval number: 798). Consent to participate The necessity for informed consent regarding participation was waived in accordance with the guidelines. Consent for publication The necessity for informed consent regarding publication was waived in accordance with the guidelines. Competing interests None of the authors have potential conflicts of interest to report. References Yoshikawa N, Tanaka R, Iijima K (2001) Pathophysiology and treatment of IgA nephropathy in children. Pediatr Nephrol 16:446–457. https://doi.org/10.1007/s004670100582 Yoshikawa N, Ito H, Nakamura (1992) Prognostic indicators in childhood IgA nephropathy. 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Lancet. 389:2117-2127. https://doi.org/10.1016/S0140-6736(17)30550-0 Barratt J, Lafayette R, Kristensen J, Stone A, Cattran D, Floege J, Tesar V, Trimarchi H, Zhang H, Eren N, Paliege A, Rovin BH; NefIgArd Trial Investigators (2023) Results from part A of the multi-center, double-blind, randomized, placebo-controlled NefIgArd trial, which evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy Kidney Int.103:391-402. https://doi.org/10.1016/j.kint.2022.09.017 Lafayette R, Kristensen J, Stone A, Floege J, Tesař V, Trimarchi H, Zhang H, Eren N, Paliege A, Reich HN, Rovin BH, Barratt J; NefIgArd trial investigators (2023) Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial Lancet. 402:859-870. https://doi.org/10.1016/S0140-6736(23)01554-4 Zhang H, Lafayette R, Wang B, Ying L, Zhu Z, Stone A, Kristensen J, Barratt J (2024) Efficacy and Safety of Nefecon in Patients with IgA Nephropathy from Mainland China: 2-Year NefIgArd Trial Results Kidney360. 5:1881-1892. https://doi.org/10.34067/KID.0000000583 Mathur M, Barratt J, Chacko B, Chan TM, Kooienga L, Oh KH, Sahay M, Suzuki Y, Wong MG, Yarbrough J, Xia J, Pereira BJG; ENVISION Trial Investigators Group (2025) A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy N Engl J Med. 390:20-31. https://doi.org/10.1056/NEJMoa2305635 Zhang H, Rizk DV, Perkovic V, Maes B, Kashihara N, Rovin B, Trimarchi H, Sprangers B, Meier M, Kollins D, Papachristofi O, Milojevic J, Junge G, Nidamarthy PK, Charney A, Barratt J (2024) Results of a randomized double-blind placebo-controlled Phase 2 study propose iptacopan as an alternative complement pathway inhibitor for IgA nephropathy Kidney Int. 105:189-199. https://doi.org/10.1016/j.kint.2023.09.027 Perkovic V, Barratt J, Rovin B, Kashihara N, Maes B, Zhang H, Trimarchi H, Kollins D, Papachristofi O, Jacinto-Sanders S, Merkel T, Guerard N, Renfurm R, Hach T, Rizk DV; APPLAUSE-IgAN Investigators (2025) Alternative Complement Pathway Inhibition with Iptacopan in IgA Nephropathy N Engl J Med. 392:531-543. https://doi.org/10.1056/NEJMoa2410316 Heerspink HJL, Radhakrishnan J, Alpers CE, Barratt J, Bieler S, Diva U, Inrig J, Komers R, Mercer A, Noronha IL, Rheault MN, Rote W, Rovin B, Trachtman H, Trimarchi H, Wong MG, Perkovic V; PROTECT Investigators (2023) Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial Lancet. 401:1584-1594. https://doi.org/10.1016/S0140-6736(23)00569-X Rovin BH, Barratt J, Heerspink HJL, Alpers CE, Bieler S, Chae DW, Diva UA, Floege J, Gesualdo L, Inrig JK, Kohan DE, Komers R, Kooienga LA, Lafayette R, Maes B, Małecki R, Mercer A, Noronha IL, Oh SW, Peh CA, Praga M, Preciado P, Radhakrishnan J, Rheault MN, Rote WE, Tang SCW, Tesar V, Trachtman H, Trimarchi H, Tumlin JA, Wong MG, Perkovic V; DUPRO steering committee and PROTECT Investigators (2023) Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial Lancet. 402:2077-2090. https://doi.org/10.1016/S0140-6736(23)02302-4 Heerspink HJL, Jardine M, Kohan DE, Lafayette RA, Levin A, Liew A, Zhang H, Lodha A, Gray T, Wang Y, Renfurm R, Barratt J; ALIGN Study Investigators (2025) Atrasentan in Patients with IgA Nephropathy. N Engl J Med. 392:544-554. https://doi.org/10.1056/NEJMoa2409415 Tables Table 1: Patient demographics and clinicopathological characteristics at baseline Overall (n=567) The previous treatment (n=77) The new treatment (n=16) p Clinical findings Male (%) 316 (55.2%) 29 (37.7%) 9 (56.4%) 0.17 Onset Age (yrs) 10.8 (8.4 – 12.8) 10.5 (7.5 – 12.5) 9.2 (6.7 – 12.9) 0.45 Onset mode school screening Gross hematuria edema 449 96 22 55 12 10 15 1 0 0.15 Episode of gross hematuria 271 (49.1%) 33 (43.4%) 7 (43.8%) 0.98 Duration from onset to biopsy (m) 7.6 (3.0 – 20.0) 4.5 (1.8 – 15.5) 1.7 (1.3 – 6.0) 0.12 Proteinuria (g / gCr) 0.5 (0.2 – 1.2) 1.2 (0.8 – 2.3) 1.9 (1.2 – 4.5) 0.04 mBp (mmHg) 79.3 (70.7 – 86.7) 80 (70 – 86) 82.8 (79.8 – 89.5) 0.10 eGFR (ml/min/1.73m 2 ) 110 (94.1 – 120) 108.6 (92.5 – 120) 120 (104.5 – 120) 0.09 Follow-up time (yr) 5 (2 – 10) 7 (3 – 10) 5.5 (3.5 – 7.8) 0.32 Pathological findings Oxford Classification of IgA nephropathy Number of Glomeruli 20 (14 – 30) 23 (14 – 38) 16 (12 – 28) 0.08 M1 / M0 (M1; %) 319 / 244 (56.7%) 67 / 8 (89.3%) 12 / 4 (75.0%) 0.12 E1 / E0 (E1; %) 235 / 196 (54.5%) 39 / 16 (70.9%) 13 / 3 (81.3%) 0.41 S1 / S0 (S1; %) 239 / 327 (42.2%) 38 / 39 (49.4%) 6 / 10 (37.5%) 0.39 T2 /T1 / T0 0 / 2 / 539 0 / 1 / 69 0 / 0 / 16 T present / absent (T present; %) 283 / 258 (52.3%) 42 / 28 (60.0%) 10 / 6 (62.5%) 0.85 C2 / C1 / C0 71 / 257 / 238 13 / 42 / 22 5 / 11 / 0 0.04 C2+C1 / C0 (C1+2; %) 328 / 238 (58.0%) 55 / 22 (71.4%) 16 / 0 (100%) 0.01 C2 / C1+C0 (C2;%) 71 / 495 (12.5%) 13 / 64 (16.9%) 5 / 11 (31.3%) 0.19 G present / absent (G present; %) 105 / 461 (18.6%) 16 / 61 (20.8%) 5 / 11 (31.3%) 0.36 The previous treatment (prednisolone + mizoribine + warfarin + dipyridamole) The new treatment (prednisolone + mizoribine + lisinopril) M mesangial hypercellularity, E endocapillary hypercellularity, S segmental glomerulosclerossis or adhesion, T tubular atrophy/interstitial fibrosis, C crescent, G global glomerulosclerosis Table 2: Baseline characteristics after propensity matching The previous treatment (n=15) The new treatmen (n=15) p Clinical findings Male (%) 5 (33.3%) 9 (60.0%) 0.27 Age at onset 11.1 (9.4 – 12.4) 11.0 (7.1 – 13.1) 0.48 Episode of gross hematuria 7 (46.7%) 6 (40.0%) 0.71 Duration from onset to biopsy (m) 5.8 (3.6 – 14.7) 1.9 (1.3 – 6.6) 0.09 Proteinuria (g/gCr) 1.9 (1.0 – 2.4) 1.8 (1.2 – 3.2) 0.78 mBp (mmHg) 83 (69 – 87) 83 (80 – 90) 0.30 eGFR (ml/min/1.73m 2 ) 117 (90 – 120) 120 (103 – 120) 0.67 Pathological findings Oxford Classification of IgA nephropathy Number of glomeruli 19 (10 – 23) 14 (11 – 23) 0.64 M1/M0 (M1 %) 14 / 1 (93.3%) 11 / 4 (73.3%) 0.33 E1 / E0 (E1 %) 7 / 5 (58.3%) 13 / 2 (86.7%) 0.18 S1 / S0 (S1 %) 10 / 5 (66.7%) 6 / 9 (40.0%) 0.27 T present / absent (T present %) 9 / 3 (75.0%) 10 / 5 (66.7%) 0.70 C2 /C1 /C0 5 / 10 / 0 5 / 10 / 0 1.00 G present/absent (G present %) 3 / 12 (20.0%) 5 / 10 (33.3%) 0.68 The previous treatment (prednisolone + mizoribine + warfarin + dipyridamole) The new treatment (prednisolone + mizoribine + lisinopril) M mesangial hypercellularity, E endocapillary hypercellularity, S segmental glomerulosclerossis or adhesion, T tubular atrophy/interstitial fibrosis, C crescent, G global glomerulosclerosis Table 3: Comparison of efficacy of treatments after propensity matching The previous treatment (n=15) The new treatment (n=15) p Remission of proteinuria [P (-) or P/Cr<0.2] 8 (53.3%) 13 (86.7%) 0.04 Duration from start of treatment to remission (years) 4.0 (2.0 – 10) 1.0 (1.0 – 4.0) 0.03 Duration of prednisolone use (months) 24 (24 – 24) 14 (6 – 22) <0.0001 Observation period (years) 8 (3 – 10) 5 (3 – 8) 0.28 Recurrence of proteinuria at the latest observation 3/8 (37.5%) 3/13 (23.1%) 0.08 The previous treatment (prednisolone + mizoribine + warfarin + dipyridamole) The new treatment (prednisolone + mizoribine + lisinopril) Supplementary Files Graphicalabstructnewcombinationsubmission.pptx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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1","display":"","copyAsset":false,"role":"figure","size":35210,"visible":true,"origin":"","legend":"\u003cp\u003ePatient profiles.\u003c/p\u003e","description":"","filename":"Figuresnewcombinationsubmission1.png","url":"https://assets-eu.researchsquare.com/files/rs-7587733/v1/5dfc6f7c43b86ad657fbc212.png"},{"id":91953647,"identity":"eded97ac-3f66-4806-a6fc-8dd13bb78f38","added_by":"auto","created_at":"2025-09-23 06:59:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":31737,"visible":true,"origin":"","legend":"\u003cp\u003eDisappearance of proteinuria.\u003c/p\u003e","description":"","filename":"Figuresnewcombinationsubmission2.png","url":"https://assets-eu.researchsquare.com/files/rs-7587733/v1/eefc918f07027a45903c04f6.png"},{"id":92658730,"identity":"90e02422-2410-4217-8b88-e67ef5bc3cd4","added_by":"auto","created_at":"2025-10-02 14:17:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1001764,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7587733/v1/ac2782a5-1618-4a29-aa7a-60160945539b.pdf"},{"id":91953648,"identity":"541fd6b4-70d1-4abd-8b6c-986ce55106ee","added_by":"auto","created_at":"2025-09-23 06:59:54","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":183077,"visible":true,"origin":"","legend":"","description":"","filename":"Graphicalabstructnewcombinationsubmission.pptx","url":"https://assets-eu.researchsquare.com/files/rs-7587733/v1/55ab20e7c94f3acb714ad0af.pptx"}],"financialInterests":"","formattedTitle":"Safety and efficacy of prednisolone, mizoribine and lisinopril combination therapy for severe childhood IgA Nephropathy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eImmunoglobulin A nephropathy (IgAN) is a notable cause of primary glomerulonephritis. In Japan, since 1974, most cases of childhood IgAN (cIgAN) have been discovered with asymptomatic hematuria and/or proteinuria by the school-based screening program. With normal estimated glomerular filtration rate, cIgAN was once considered to be benign. However, a long-term follow-up study previously revealed that as much as 11% of 241 Japanese cIgAN developed end-stage kidney disease within 15 years [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Factors for poor prognosis of cIgAN include heavy proteinuria and severe pathological changes, such as diffuse mesangial proliferation [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. To establish treatment strategies for cIgAN in Japan, there have been various multicenter randomized controlled trials and clinical trials since 1990 [\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Two-year combination treatment comprising prednisolone\u0026thinsp;+\u0026thinsp;azathioprine was shown in a follow-up study to not only ameliorate the activity of the acute phase of nephritis, but also to improve the long-term outcome of severe cIgAN [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Overall, there has been improvement of long-term kidney outcomes in Japanese cases of cIgAN since the beginning of these trials [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn our most recent RCT for severe cIgAN, combination treatment comprising prednisolone\u0026thinsp;+\u0026thinsp;mizoribine\u0026thinsp;+\u0026thinsp;warfarin\u0026thinsp;+\u0026thinsp;dipyridamole was suggested to be an improvement over the combination treatment of prednisolone\u0026thinsp;+\u0026thinsp;mizoribine (without warfarin or dipyridamole) in proteinuria remission [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In warfarin nephropathy, there might be an increase in global glomerulosclerosis due to the vascular calcification of warfarin. Also, there should be consideration of modifying prednisolone administration due to the high cumulative dosage used in previous randomized controlled trials [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. New combination therapy should therefore be considered, such as prednisolone\u0026thinsp;+\u0026thinsp;mizoribine\u0026thinsp;+\u0026thinsp;lisinopril.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePatients\u003c/h2\u003e\u003cp\u003eThis retrospective cohort study included 567 patients aged\u0026thinsp;\u0026lt;\u0026thinsp;20 years with biopsy-proven IgAN at two university hospitals between July 1976 and December 2022. Diagnosis of IgAN was based on the sole or predominant IgA deposition in the glomerular mesangium in the kidney biopsy tissue without systemic disease. Diagnoses of IgAN were confirmed by a single investigator (NY) using the same criteria throughout the entire study period. Kidney biopsy was performed in those with persistent proteinuria with or without hematuria. Among them, 93 patients had severe cIgAN and were treated with prednisolone and mizoribine. In total, 77 patients received a two-year combined regimen of prednisolone\u0026thinsp;+\u0026thinsp;mizoribine\u0026thinsp;+\u0026thinsp;warfarin\u0026thinsp;+\u0026thinsp;dipyridamole (the previous treatment), and 16 patients received a two-year combined regimen of prednisolone\u0026thinsp;+\u0026thinsp;mizoribine\u0026thinsp;+\u0026thinsp;lisinopril (the new treatment). A 1:1 propensity score-matching method was conducted to select patients who received the previous treatment as the control group, referred as \u0026lsquo;the previous treatment group\u0026rsquo;. The study flowchart is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eClinical data\u003c/h3\u003e\n\u003cp\u003eWe recorded clinical data about sex ratio, onset age, onset mode, episode of gross hematuria, duration from onset to kidney biopsy, urinary protein to creatinine ratio (uP/Cr), eGFR, mean blood pressure, and duration from onset to the latest observation. Data were handled as previously reported [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003ePathological data\u003c/h3\u003e\n\u003cp\u003eSix pathological variables were selected, those proposed in the Oxford classification (MEST-C) [\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], and global sclerosis (G). Arterial intimal thickening was not found in cases of this study.\u003c/p\u003e\n\u003ch3\u003eTreatments\u003c/h3\u003e\n\u003cp\u003eSince the beginning of the 1990s, we have prescribed two-year combined regimen of prednisolone\u0026thinsp;+\u0026thinsp;azathioprine or mizoribine\u0026thinsp;+\u0026thinsp;warfarin\u0026thinsp;+\u0026thinsp;dipyridamole (the previous treatment) for pediatric patients with severe IgAN showing diffuse mesangial proliferation defined on the basis of the World Health Organization criteria and/or heavy proteinuria\u0026thinsp;\u0026gt;\u0026thinsp;1g/gCr. However, the use of angiotensin converting enzyme inhibitors (ACEi) in pediatric patients with chronic kidney disease has increased and its effectiveness has been confirmed [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Since around 2008, we have therefore used the new two-year combined regimen of prednisolone\u0026thinsp;+\u0026thinsp;mizoribine\u0026thinsp;+\u0026thinsp;lisinopril (the new treatment) for those with severe cIgAN. In principle, predonisolone was reduced/discontinued after remission of proteinuria was cofirmed in the new treatment.\u003c/p\u003e\n\u003ch3\u003eOutcome definitions\u003c/h3\u003e\n\u003cp\u003eWe determined the end-point of outcome of this study as remission of proteinuria defined as proteinuria qualitative reaction (\u0026ndash;) or proteinuria\u0026thinsp;\u0026lt;\u0026thinsp;0.2 g/gCr.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analyses\u003c/h2\u003e\u003cp\u003eAll statistical analyses were performed using the JMP software package ver. 16.0 (SAS Institute Japan, Tokyo, Japan). Propensity score matching was employed, and the propensity score was based on the amount of proteinuria, eGFR, and the proportion of patients with C0, C1, and C2. A 1:1 matching ratio was adopted. The final sample had 15 matched pairs for analyses. Continuous variables were reported as median (interquartile range). Categorical variables were expressed as counts and percentage. Group comparisons were performed using Mann-Whitney U or ꭕ\u003csup\u003e2\u003c/sup\u003e test. Survival analysis was performed by Kaplan-Meier method. Results were expressed as hazard ratio with 95% confidence intervals. A two-tailed \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered to be statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eBaseline characteristics of pediatric patients with IgAN treated with immunosuppressive treatments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong 567 cases of newly biopsy-proven childhood IgAN between 1977 and 2020, there were 93 patients with immunosuppressive treatment including prednisolone and mizoribine.\u003c/p\u003e\n\u003cp\u003eThe baseline characteristics of all patients (77 with the previous treatment, 16 with the new treatment) are summarized in Table 1. There were significant differences in uP/Cr (median 1.2 vs. 1.9 g/gCr, \u003cem\u003ep\u003c/em\u003e=0.04) and the proportions of patients with C0, C1, and C2 (22 / 42 / 13 vs. 0 / 11 /1 / 5, \u003cem\u003ep\u003c/em\u003e=0.04) between the groups.\u003c/p\u003e\n\u003cp\u003eIncluded in this study were 16 patients with cIgAN who received the new therapy and 15 matched patients who received the previous therapy using propensity score matching (Figure 1). The characteristics of 15 matched pairs are shown in Table 2. There was no significant difference in baseline characteristics.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEfficacy outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to Kaplan-Meier analysis, the disappearance rate of proteinuria was significantly higher in the new treatment group than in the previous treatment group during the follow-up period (90.0% at 11 years [95%CI 57.2 – 98.4%] vs. 64.1% at 11 years [95%CI 28.8 – 88.7%], log-rank \u003cem\u003ep\u003c/em\u003e= 0.01, Fig.2). Furthermore, in the new trearment group, the percentage of the patients with proteinuria remission at the latest observation was much higher (13 [86.7%] vs. 8 cases [53.3%], \u003cem\u003ep\u003c/em\u003e=0.04), the duration from start of treatment to remission was much faster (1.0 [1.0 – 4.0] vs. 4.0 years [2.0 – 10], \u003cem\u003ep\u003c/em\u003e=0.03), and the duration of prednisolone use was much shorter (14 [6 – 22] vs. 24 months [24 – 24], \u003cem\u003ep\u003c/em\u003e \u0026lt;0.0001) than in the previous treatment group. Despite the shorter observation period in the new therapy group (5 [3 – 8] vs. 8 years [3 – 10], \u003cem\u003ep\u003c/em\u003e=0.28), there was no significant difference in proteinuria recurrence rate at the latest observation ( 3 / 13 [23.1%] vs. 3 / 8 [37.5%], \u003cem\u003ep\u003c/em\u003e=0.08).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients who received the new treatment showed transient moon face and central obesity, but these symptoms disappeared within 2 to 3 months as the steroid dosage was reduced. Five patients (33.3%) had acne, two (13.3%) had glaucoma, and one had transient glucosuria, which were thought to be related to steroid use. One patient showed hyperuricemia due to mizoribine. All of these side effects subsided after treatment.\u003c/p\u003e\n\u003cp\u003eHypertension, which had been observed in the previous pilot study [5], was not observed in the new treatment group, possibly because lisinopril (an antihypertensive drug) was used.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo establish treatment strategies for severe cIgAN, several Japanese multicenter treatment studies have been conducted since 1990 for cIgAN with diffuse mesangial proliferation, considering a poor kidney outcome [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The most effective treatment for severe cIgAN to date based on these clinical trials is likely combined regimen of prednisolone\u0026thinsp;+\u0026thinsp;mizoribine\u0026thinsp;+\u0026thinsp;warfarin\u0026thinsp;+\u0026thinsp;dipyridamole. However, taking into consideration the usefulness of ACEi, which has been widely used in children since the 2000s, and the risk of warfarin nephropathy and side effects due to the use of dipyridamole, it has been reasonable for us to investigate effectiveness of a new combined regimen using prednisolone\u0026thinsp;+\u0026thinsp;mizoribine\u0026thinsp;+\u0026thinsp;ACEi [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOur study showed that the new combination therapy not only led to higher proteinuria remission rates, but it was also demonstrated to have a faster response than the previous regimen. One plausible explanation is the antiproteinuric effect of lisinopril (ACEi), which may have enhanced glomerular hemodynamics and reduced proteinuria by decreasing intraglomerular pressure. Additionally, by avoiding warfarin, the risk of warfarin-associated nephropathy, which is characterized by glomerulosclerosis due to vascular calcification, has been dispelled, further contributing to better kidney outcomes.\u003c/p\u003e\u003cp\u003eLong-term use of corticosteroids carries significant risks, including metabolic disturbances, bone demineralization, and growth impairment in pediatric patients. The reduction in prednisolone exposure in the new therapy group (median 14 vs. 24 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) is particularly important because it decreases the likelihood of these adverse effects. Moreover, despite shorter prednisolone administration, the new treatment group exhibited superior remission rates, which suggests that the synergistic effects of mizoribine and lisinopril might compensate for reduced steroid dependency.\u003c/p\u003e\u003cp\u003ePropensity score matching was used to balance baseline characteristics between the two treatment groups, but certain biases inherent to retrospective studies may still exist. The study population in this study was relatively small (15 matched pairs), and differences in observation periods may impact long-term comparisons. Additionally, we did not evaluate external factors such as dietary changes, genetic predispositions, and adherence to treatment protocols, which could influence disease progression.\u003c/p\u003e\u003cp\u003eFurther prospective studies with larger cohorts are needed to confirm the efficacy and safety of the new combination therapy in cases of cIgAN. Additional research should explore whether incorporating ACEi into standard treatment regimens could improve long-term kidney outcomes for cases of patients with severe cIgAN. Furthermore, investigations into optimizing prednisolone dosage and duration could help balance efficacy with minimizing side effects.\u003c/p\u003e\u003cp\u003eMizoribine is unique in that its use is largely restricted to Japan [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], which raises questions about the applicability of this new combination therapy in international settings. Mizoribine has been widely used in Japanese cIgAN treatment protocols due to its immunosuppressive properties and favorable safety profile, but its absence in countries other than Japan means that alternative immunosuppressive agents, such as mycophenolate mofetil (MMF), might need to be considered when adapting this regimen globally. Mizoribine belongs to the class of purine synthesis inhibitors, similar to MMF, but it has a distinct pharmacokinetic profile, including a lower incidence of gastrointestinal side effects and better tolerability in pediatric patients. However, MMF has been more extensively studied in international clinical trials and effectiveness has been shown in IgAN management [\u003cspan additionalcitationids=\"CR19 CR20 CR21 CR22 CR23\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Future studies should investigate whether MMF or other alternatives can achieve similar efficacy and safety outcomes to mizoribine when used in combination with prednisolone and lisinopril. This may eventually facilitate broader adoption while maintaining the core principles of the treatment strategy: reducing proteinuria, accelerating remission, and minimizing steroid exposure.\u003c/p\u003e\u003cp\u003eIn recent years, as the pathophysiology of IgAN becomes clearer, new therapeutic candidates based on that pathophysiological mechanism including targeted-release budesonide [\u003cspan additionalcitationids=\"CR26 CR27\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], B cell function inhibitors (a proliferation-inducing ligand [APRIL]/ B-cell activation factor [BAFF]/ transmembrane activator and calcium cyclophilin interactor [TACI] antibodies) [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], anti-complement drugs [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], and endothelin receptor antagonists [\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] have been developed and clinical trials using these drugs are currently underway, mainly in adult IgAN. If these drugs proven to be safe and effective, they might dramatically change treatments for cIgAN in the future.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, the new combined regimen with prednisolone\u0026thinsp;+\u0026thinsp;mizoribine\u0026thinsp;+\u0026thinsp;lisinopril demonstrated greater efficacy in achieving proteinuria remission with especially lower dose of steroids than the previous therapy, while maintaining comparable safety profiles.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank all participants and attending physicians for their contributions. We acknowledge proofreading and editing by Benjamin Phillis, a Board-Certified Editor in the Life Sciences (BELS), at Wakayama Medical University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYuko Shima and Koichi Nakanishi contributed to study conception and design. Material preparation and data collection were performed by all authors. Yuko Shima and Norishige Yoshikawa performed pathological evaluations. Data analysis was performed by Yuko Shima and Koichi Nakanishi. The first draft of the manuscript was written by Yuko Shima and all authors commented on versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available within consent upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted according to the principles of the Declaration of Helsinki and the ethical guidelines issued by the Ministry of Health, Labor and Welfare, Japan. The study was also approved by the Wakayama Medical University Ethics Committee (approval number: 798).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe necessity for informed consent regarding participation was waived in accordance with the guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe necessity for informed consent regarding publication was waived in accordance with the guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone of the authors have potential conflicts of interest to report.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eYoshikawa N, Tanaka R, Iijima K (2001) Pathophysiology and treatment of IgA nephropathy in children. Pediatr Nephrol 16:446\u0026ndash;457. https://doi.org/10.1007/s004670100582\u003c/li\u003e\n\u003cli\u003eYoshikawa N, Ito H, Nakamura (1992) Prognostic indicators in childhood IgA nephropathy. Nephron 60:60\u0026ndash;67. https://doi.org/10.1159/000186706\u003c/li\u003e\n\u003cli\u003eYoshikawa N, Ito H, Sakai T, Takekoshi Y, Honda M, Awazu M, Ito K, Iitaka K, Koitabashi Y, Yamaoka K, Nakagawa K, Nakamura H, Matsuyama S, Seino Y, Takeda N, Hattori S, Ninomiya M, The Japanese Pediatric IgA Nephropathy Treatment Study Group (1999) A controlled trial of combined therapy for newly diagnosed severe childhood IgA nephropathy. J Am Soc Nephrol 10:101\u0026ndash;109. https://doi.org/10.1681/ASN.V101101\u003c/li\u003e\n\u003cli\u003eYoshikawa N, Honda M, Iijima K, Awazu M, Hattori S, Nakanishi K, Ito H, Japanese Pediatric IgA Nephropathy Treatment Study Group (2006) Steroid treatment for severe childhood IgA nephropathy: a randomized, controlled trial. Clin J Am Soc Nephrol 1:511\u0026ndash;517. https://doi.org/10.2215/CJN.01120905\u003c/li\u003e\n\u003cli\u003eYoshikawa N, Nakanishi K, Ishikura K, Hataya H, Iijima K, Honda M, Japanese Pediatric IgA Nephropathy Treatment Study Group (2008) Combination therapy with mizoribine for severe childhood IgA nephropathy: a pilot study. Pediatr Nephrol 23:757\u0026ndash;763. https://doi.org/10.1007/s00467-007-0731-8\u003c/li\u003e\n\u003cli\u003eNakanishi K, Iijima K, Ishikura K, Hataya H, Awazu M, Sako M, Honda M, Yoshikawa N; Japanese Pediatric IgA Nephropathy Treatment Study Group (2009) Efficacy and safety of lisinopril for mild childhood IgA nephropathy: a pilot study. Pediatr Nephrol. 24:845-849. https://doi.org/10.1007/s00467-008-1006-8\u003c/li\u003e\n\u003cli\u003eShima Y, Nakanishi K, Kaku Y, Ishikura K, Hataya H, Matsuyama T, Honda M, Sako M, Nozu K, Tanaka R, Iijima K, Yoshikawa N; Japanese Pediatric IgA Nephropathy Treatment Study Group (2018) Combination therapy with or without warfarin and dipyridamole for severe childhood IgA nephropathy: an RCT. Pediatr Nephrol. 33:2103-2112. https://doi.org/10.1007/s00467-018-4011-6\u003c/li\u003e\n\u003cli\u003eShima Y, Nakanishi K, Sako M, Saito-Oba M, Hamasaki Y, Hataya H, Honda M, Kamei K, Ishikura K, Ito S, Kaito H, Tanaka R, Nozu K, Nakamura H, Ohashi Y, Iijima K, Yoshikawa N; Japanese Study Group of Kidney Disease in Children (JSKDC) (2019) Lisinopril versus lisinopril and losartan for mild childhood IgA nephropathy: a randomized controlled trial (JSKDC01 study) Pediatr Nephrol. 34:837-846. https://doi.org/10.1007/s00467-018-4099-8\u003c/li\u003e\n\u003cli\u003eKamei K, Nakanishi K, Ito S, Saito M, Sako M, Ishikura K, Hataya H, Honda M, Iijima K, Yoshikawa N, Japanese Pediatric IgA Nephropathy Treatment Study Group (2011) Long-term results of a randomized controlled trial in childhood IgA nephropathy. Clin J Am Soc Nephrol 6:1301\u0026ndash;1307. https://doi.org/10.2215/CJN.08630910\u003c/li\u003e\n\u003cli\u003eYata N, Nakanishi K, Shima Y, Togawa H, Obana M, Sako M, Nozu K, Tanaka R, Iijima K, Yoshikawa N (2008) Improved renal survival in Japanese children with IgA nephropathy Pediatr Nephrol. 23:905-912. https://doi.org/10.1007/s00467-007-0726-5\u003c/li\u003e\n\u003cli\u003eShima Y, Nakanishi K, Mukaiyama H, Tanaka Y, Wada T, Tanaka R, Kaito H, Nozu K, Sako M, Iijima K, Yoshikawa N (2021) Clinicopathological significance of glomerular capillary IgA deposition in childhood IgA nephropathy. Pediatr Nephrol 36:899\u0026ndash;908. https://doi.org/10.1007/s00467-020-04772-4.\u003c/li\u003e\n\u003cli\u003eWorking Group of the International IgA Nephropathy Network and the Renal Pathology Society, Cattran DC, Coppo R, Cook HT, Feehally J, Roberts IS, Troyanov S, Alpers CE, Amore A, Barratt J, Berthoux F, Bonsib S, Bruijn JA, D\u0026rsquo;Agati V, D\u0026rsquo;Amico G, Emancipator S, Emma F, Ferrario F, Fervenza FC, Florquin S, Fogo A, Geddes CC, Groene HJ, Haas M, Herzenberg AM, Hill PA, Hogg RJ, Hsu SI, Jennette JC, Joh K, Julian BA, Kawa-mura T, Lai FM, Leung CB, Li LS, Li PK, Liu ZH, Mackinnon B, Mezzano S, Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H (2009) The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int 76:534\u0026ndash;545. https://doi.org/10.1038/ki.2009.243\u003c/li\u003e\n\u003cli\u003eWorking Group of the International IgA Nephropathy Network and the Renal Pathology Society, Roberts IS, Cook HT, Troyanov S, Alpers CE, Amore A, Barratt J, Berthoux F, Bonsib S, Bruijn JA, Cattran DC, Coppo R, D\u0026rsquo;Agati V, D\u0026rsquo;Amico G, Emancipator S, Emma F, Feehally J, Ferrario F, Fervenza FC, Florquin S, Fogo A, Geddes CC, Groene HJ, Haas M, Herzen-berg AM, Hill PA, Hogg RJ, Hsu SI, Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Li LS, Li PK, Liu ZH, Mackinnon B, Mezzano S, Schena FP, Tomino Y, Walker PD, Wang H, Ween-ing JJ, Yoshikawa N, Zhang H (2009) The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility. Kidney Int 76:546\u0026ndash;556. https://doi.org/10.1038/ki.2009.168\u003c/li\u003e\n\u003cli\u003eWorking Group of the International IgA Nephropathy Network and the Renal Pathology Society, Coppo R, Troyanov S, Camilla R, Hogg RJ, Cattran DC, Cook HT, Feehally J, Roberts IS, Amore A, Alpers CE, Barratt J, Berthoux F, Bonsib S, Bruijn JA, D\u0026rsquo;Agati V, D\u0026rsquo;Amico G, Emancipator SN, Emma F, Ferrario F, Fervenza FC, Florquin S, Fogo AB, Geddes CC, Groene HJ, Haas M, Herzenberg AM, Hill PA, Hsu SI, Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Li LS, Li PK, Liu ZH, Mezzano S, Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H (2010) The Oxford IgA nephropathy clinicopathological classification is valid for children as well as adults. Kidney Int 77:921\u0026ndash;927. https://doi.org/10.1038/ki.2010.43\u003c/li\u003e\n\u003cli\u003eTrimarchi H, Barratt J, Cattran DC, Cook HT, Coppo R, Haas M, Liu ZH, Roberts IS, Yuzawa Y, Zhang H, Feehally J; IgAN Classification Working Group of the International IgA Nephropathy Network and the Renal Pathology Society; Conference Participants (2017) Oxford classification of IgA nephropathy 2016: an update from the IgA nephropathy classification working group. Kidney Int 91:1014\u0026ndash;1021. https://doi.org/10.1016/j.kint.2017.02.003\u003c/li\u003e\n\u003cli\u003eCoppo R, Peruzzi L, Amore A, Piccoli A, Cochat P, StoneR, Kirschstein M, Linn\u0026eacute; T (2007) IgACE: a placebo-controlled, randomized trial of angiotensin-converting en-zyme inhibitors in children and young people with IgAnephropathy and moderate proteinuria. J Am Soc Nephrol18:1880\u0026ndash;1888 https:// doi: 10.1681/ASN.2006040347.\u003c/li\u003e\n\u003cli\u003eAlladin A, Hahn D, Hodson EM, Ravani P, Pfister K, Quinn RR, Samuel SM (2024) Immunosuppressive therapy for IgA nephropathy in children. Cochrane Database Syst Rev. 6:CD015060. https://doi.org/10.1002/14651858.CD015060.pub2\u003c/li\u003e\n\u003cli\u003eHogg RJ, Wyatt RJ; Scientific Planning Committee of the North American IgA Nephropathy Study (2004) A randomized controlled trial of mycophenolate mofetil in patients with IgA nephropathy [ISRCTN62574616] BMC Nephrol 5:3. https://doi.org/10.1186/1471-2369-5-3\u003c/li\u003e\n\u003cli\u003eMaes BD, Oyen R, Claes K, Evenepoel P, Kuypers D, Vanwalleghem J, Van Damme B, Vanrenterghem YF (2004) Mycophenolate mofetil in IgA nephropathy: results of a 3-year prospective placebo-controlled randomized study Kidney Int. 65:1842-9. https://doi.org/10.1111/j.1523-1755.2004.00588.x\u003c/li\u003e\n\u003cli\u003eTang S, Leung JC, Chan LY, Lui YH, Tang CS, Kan CH, Ho YW, Lai KN (2005) Mycophenolate mofetil alleviates persistent proteinuria in IgA nephropathy. Kidney Int. 68:802-12. https://doi.org/10.1111/j.1523-1755.2005.00460.x\u003c/li\u003e\n\u003cli\u003eFrisch G, Lin J, Rosenstock J, Markowitz G, D\u0026apos;Agati V, Radhakrishnan J, Preddie D, Crew J, Valeri A, Appel G (2005) Mycophenolate mofetil (MMF) vs placebo in patients with moderately advanced IgA nephropathy: a double-blind randomized controlled trial. Nephrol Dial Transplant. 20:2139-45. https://doi.org/10.1093/ndt/gfh974\u003c/li\u003e\n\u003cli\u003eHogg RJ, Bay RC, Jennette JC, Sibley R, Kumar S, Fervenza FC, Appel G, Cattran D, Fischer D, Hurley RM, Cerda J, Carter B, Jung B, Hernandez G, Gipson D, Wyatt RJ (2015) Randomized controlled trial of mycophenolate mofetil in children, adolescents, and adults with IgA nephropathy. Am J Kidney Dis. 66:783-91. https://doi.org/10.1053/j.ajkd.2015.06.013\u003c/li\u003e\n\u003cli\u003eHou JH, Le WB, Chen N, Wang WM, Liu ZS, Liu D, Chen JH, Tian J, Fu P, Hu ZX, Zeng CH, Liang SS, Zhou ML, Zhang HT, Liu ZH (2017) Mycophenolate Mofetil Combined With Prednisone Versus Full-Dose Prednisone in IgA Nephropathy With Active Proliferative Lesions: A Randomized Controlled Trial Am J Kidney Dis. 69:788-795. https://doi.org/10.1053/j.ajkd.2016.11.027\u003c/li\u003e\n\u003cli\u003eHou FF, Xie D, Wang J, Xu X, Yang X, Ai J, Nie S, Liang M, Wang G, Jia N; MAIN Trial Investigators (2023) Effectiveness of Mycophenolate Mofetil Among Patients With Progressive IgA Nephropathy: A Randomized Clinical Trial JAMA Netw Open. 6:e2254054. https://doi.org/10.1001/jamanetworkopen.2022.54054\u003c/li\u003e\n\u003cli\u003eFellstr\u0026ouml;m BC, Barratt J, Cook H, Coppo R, Feehally J, de Fijter JW, Floege J, Hetzel G, Jardine AG, Locatelli F, Maes BD, Mercer A, Ortiz F, Praga M, S\u0026oslash;rensen SS, Tesar V, Del Vecchio L; NEFIGAN Trial Investigators (2017) Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial. Lancet. 389:2117-2127. https://doi.org/10.1016/S0140-6736(17)30550-0\u003c/li\u003e\n\u003cli\u003eBarratt J, Lafayette R, Kristensen J, Stone A, Cattran D, Floege J, Tesar V, Trimarchi H, Zhang H, Eren N, Paliege A, Rovin BH; NefIgArd Trial Investigators (2023) Results from part A of the multi-center, double-blind, randomized, placebo-controlled NefIgArd trial, which evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy Kidney Int.103:391-402. https://doi.org/10.1016/j.kint.2022.09.017\u003c/li\u003e\n\u003cli\u003eLafayette R, Kristensen J, Stone A, Floege J, Tesař V, Trimarchi H, Zhang H, Eren N, Paliege A, Reich HN, Rovin BH, Barratt J; NefIgArd trial investigators (2023) Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial Lancet. 402:859-870. https://doi.org/10.1016/S0140-6736(23)01554-4\u003c/li\u003e\n\u003cli\u003eZhang H, Lafayette R, Wang B, Ying L, Zhu Z, Stone A, Kristensen J, Barratt J (2024) Efficacy and Safety of Nefecon in Patients with IgA Nephropathy from Mainland China: 2-Year NefIgArd Trial Results Kidney360. 5:1881-1892. https://doi.org/10.34067/KID.0000000583\u003c/li\u003e\n\u003cli\u003eMathur M, Barratt J, Chacko B, Chan TM, Kooienga L, Oh KH, Sahay M, Suzuki Y, Wong MG, Yarbrough J, Xia J, Pereira BJG; ENVISION Trial Investigators Group (2025) A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy N Engl J Med. 390:20-31. https://doi.org/10.1056/NEJMoa2305635\u003c/li\u003e\n\u003cli\u003eZhang H, Rizk DV, Perkovic V, Maes B, Kashihara N, Rovin B, Trimarchi H, Sprangers B, Meier M, Kollins D, Papachristofi O, Milojevic J, Junge G, Nidamarthy PK, Charney A, Barratt J (2024) Results of a randomized double-blind placebo-controlled Phase 2 study propose iptacopan as an alternative complement pathway inhibitor for IgA nephropathy Kidney Int. 105:189-199. https://doi.org/10.1016/j.kint.2023.09.027\u003c/li\u003e\n\u003cli\u003ePerkovic V, Barratt J, Rovin B, Kashihara N, Maes B, Zhang H, Trimarchi H, Kollins D, Papachristofi O, Jacinto-Sanders S, Merkel T, Guerard N, Renfurm R, Hach T, Rizk DV; APPLAUSE-IgAN Investigators (2025) Alternative Complement Pathway Inhibition with Iptacopan in IgA Nephropathy N Engl J Med. 392:531-543. https://doi.org/10.1056/NEJMoa2410316\u003c/li\u003e\n\u003cli\u003eHeerspink HJL, Radhakrishnan J, Alpers CE, Barratt J, Bieler S, Diva U, Inrig J, Komers R, Mercer A, Noronha IL, Rheault MN, Rote W, Rovin B, Trachtman H, Trimarchi H, Wong MG, Perkovic V; PROTECT Investigators (2023) Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial Lancet. 401:1584-1594. https://doi.org/10.1016/S0140-6736(23)00569-X\u003c/li\u003e\n\u003cli\u003eRovin BH, Barratt J, Heerspink HJL, Alpers CE, Bieler S, Chae DW, Diva UA, Floege J, Gesualdo L, Inrig JK, Kohan DE, Komers R, Kooienga LA, Lafayette R, Maes B, Małecki R, Mercer A, Noronha IL, Oh SW, Peh CA, Praga M, Preciado P, Radhakrishnan J, Rheault MN, Rote WE, Tang SCW, Tesar V, Trachtman H, Trimarchi H, Tumlin JA, Wong MG, Perkovic V; DUPRO steering committee and PROTECT Investigators (2023) Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial Lancet. 402:2077-2090. https://doi.org/10.1016/S0140-6736(23)02302-4\u003c/li\u003e\n\u003cli\u003eHeerspink HJL, Jardine M, Kohan DE, Lafayette RA, Levin A, Liew A, Zhang H, Lodha A, Gray T, Wang Y, Renfurm R, Barratt J; ALIGN Study Investigators (2025) Atrasentan in Patients with IgA Nephropathy. N Engl J Med. 392:544-554. https://doi.org/10.1056/NEJMoa2409415\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Patient demographics and clinicopathological characteristics at baseline\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"680\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(n=567)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eThe previous treatment\u0026nbsp;\u003c/strong\u003e(n=77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eThe new treatment\u003c/strong\u003e (n=16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical findings\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003eMale (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e316 (55.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e29 (37.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e9 (56.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003eOnset Age (yrs)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e10.8 (8.4 \u0026ndash; 12.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e10.5 (7.5 \u0026ndash; 12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e9.2 (6.7 \u0026ndash; 12.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003eOnset mode\u003c/p\u003e\n \u003cp\u003eschool screening\u003c/p\u003e\n \u003cp\u003eGross hematuria\u003c/p\u003e\n \u003cp\u003eedema\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e449\u003c/p\u003e\n \u003cp\u003e96\u003c/p\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003eEpisode of gross hematuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e271 (49.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e33 (43.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e7 (43.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e0.98\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003eDuration from onset to biopsy (m)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e7.6 (3.0 \u0026ndash; 20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e4.5 (1.8 \u0026ndash; 15.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e1.7 (1.3 \u0026ndash; 6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003eProteinuria (g / gCr)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e0.5 (0.2 \u0026ndash; 1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e1.2 (0.8 \u0026ndash; 2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e1.9 (1.2 \u0026ndash; 4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003emBp (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e79.3 (70.7 \u0026ndash; 86.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e80 (70 \u0026ndash; 86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e82.8 (79.8 \u0026ndash; 89.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003eeGFR (ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e110 (94.1 \u0026ndash; 120)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e108.6 (92.5 \u0026ndash; 120)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e120 (104.5 \u0026ndash; 120)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003eFollow-up time (yr)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e5 (2 \u0026ndash; 10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e7 (3 \u0026ndash; 10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e5.5 (3.5 \u0026ndash; 7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e0.32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePathological findings\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eOxford Classification of IgA nephropathy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003eNumber of Glomeruli\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e20 (14 \u0026ndash; 30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e23 (14 \u0026ndash; 38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e16 (12 \u0026ndash; 28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003eM1 / M0 (M1; %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e319 / 244 (56.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e67 / 8 (89.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e12 / 4 (75.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003eE1 / E0 (E1; %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e235 / 196 (54.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e39 / 16 (70.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e13 / 3 (81.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003eS1 / S0 (S1; %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e239 / 327 (42.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e38 / 39 (49.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e6 / 10 (37.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e0.39\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003eT2 /T1 / T0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e0 / 2 / 539\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e0 / 1 / 69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e0 / 0 / 16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003eT present / absent (T present; %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e283 / 258 (52.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e42 / 28 (60.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e10 / 6 (62.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003eC2 / C1 / C0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e71 / 257 / 238\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e13 / 42 / 22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e5 / 11 / 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003eC2+C1 / C0 (C1+2; %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e328 / 238 (58.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e55 / 22 (71.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e16 / 0 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003eC2 / C1+C0 (C2;%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e71 / 495 (12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e13 / 64 (16.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e5 / 11 (31.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 27.7533%;\"\u003e\n \u003cp\u003eG present / absent (G present; %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e105 / 461 (18.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1733%;\"\u003e\n \u003cp\u003e16 / 61 (20.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.8517%;\"\u003e\n \u003cp\u003e5 / 11 (31.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.37004%;\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eThe previous treatment (prednisolone + mizoribine + warfarin + dipyridamole)\u003c/p\u003e\n\u003cp\u003eThe new treatment (prednisolone + mizoribine + lisinopril)\u003c/p\u003e\n\u003cp\u003eM mesangial hypercellularity, E endocapillary hypercellularity, S segmental glomerulosclerossis or adhesion, T tubular atrophy/interstitial fibrosis, C crescent, G global glomerulosclerosis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Baseline characteristics after propensity matching\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"652\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30.0613%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.7546%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eThe previous treatment\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(n=15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.9939%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eThe new treatmen\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(n=15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1902%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30.0613%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical findings\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.7546%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.9939%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1902%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30.0613%;\"\u003e\n \u003cp\u003eMale (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.7546%;\"\u003e\n \u003cp\u003e5 (33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.9939%;\"\u003e\n \u003cp\u003e9 (60.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1902%;\"\u003e\n \u003cp\u003e0.27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30.0613%;\"\u003e\n \u003cp\u003eAge at onset\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.7546%;\"\u003e\n \u003cp\u003e11.1 (9.4 \u0026ndash; 12.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.9939%;\"\u003e\n \u003cp\u003e11.0 (7.1 \u0026ndash; 13.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1902%;\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30.0613%;\"\u003e\n \u003cp\u003eEpisode of gross hematuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.7546%;\"\u003e\n \u003cp\u003e7 (46.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.9939%;\"\u003e\n \u003cp\u003e6 (40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1902%;\"\u003e\n \u003cp\u003e0.71\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30.0613%;\"\u003e\n \u003cp\u003eDuration from onset to biopsy (m)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.7546%;\"\u003e\n \u003cp\u003e5.8 (3.6 \u0026ndash; 14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.9939%;\"\u003e\n \u003cp\u003e1.9 (1.3 \u0026ndash; 6.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1902%;\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30.0613%;\"\u003e\n \u003cp\u003eProteinuria (g/gCr)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.7546%;\"\u003e\n \u003cp\u003e1.9 (1.0 \u0026ndash; 2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.9939%;\"\u003e\n \u003cp\u003e1.8 (1.2 \u0026ndash; 3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1902%;\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30.0613%;\"\u003e\n \u003cp\u003emBp (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.7546%;\"\u003e\n \u003cp\u003e83 (69 \u0026ndash; 87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.9939%;\"\u003e\n \u003cp\u003e83 (80 \u0026ndash; 90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1902%;\"\u003e\n \u003cp\u003e0.30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30.0613%;\"\u003e\n \u003cp\u003eeGFR (ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.7546%;\"\u003e\n \u003cp\u003e117 (90 \u0026ndash; 120)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.9939%;\"\u003e\n \u003cp\u003e120 (103 \u0026ndash; 120)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1902%;\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30.0613%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePathological findings\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eOxford Classification of IgA nephropathy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.7546%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.9939%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1902%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30.0613%;\"\u003e\n \u003cp\u003eNumber of glomeruli\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.7546%;\"\u003e\n \u003cp\u003e19 (10 \u0026ndash; 23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.9939%;\"\u003e\n \u003cp\u003e14 (11 \u0026ndash; 23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1902%;\"\u003e\n \u003cp\u003e0.64\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30.0613%;\"\u003e\n \u003cp\u003eM1/M0 (M1 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.7546%;\"\u003e\n \u003cp\u003e14 / 1 (93.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.9939%;\"\u003e\n \u003cp\u003e11 / 4 (73.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1902%;\"\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30.0613%;\"\u003e\n \u003cp\u003eE1 / E0 (E1 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.7546%;\"\u003e\n \u003cp\u003e7 / 5 (58.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.9939%;\"\u003e\n \u003cp\u003e13 / 2 (86.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1902%;\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30.0613%;\"\u003e\n \u003cp\u003eS1 / S0 (S1 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.7546%;\"\u003e\n \u003cp\u003e10 / 5 (66.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.9939%;\"\u003e\n \u003cp\u003e6 / 9 (40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1902%;\"\u003e\n \u003cp\u003e0.27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30.0613%;\"\u003e\n \u003cp\u003eT present / absent (T present %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.7546%;\"\u003e\n \u003cp\u003e9 / 3 (75.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.9939%;\"\u003e\n \u003cp\u003e10 / 5 (66.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1902%;\"\u003e\n \u003cp\u003e0.70\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30.0613%;\"\u003e\n \u003cp\u003eC2 /C1 /C0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.7546%;\"\u003e\n \u003cp\u003e5 / 10 / 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.9939%;\"\u003e\n \u003cp\u003e5 / 10 / 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1902%;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30.0613%;\"\u003e\n \u003cp\u003eG present/absent (G present %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29.7546%;\"\u003e\n \u003cp\u003e3 / 12 (20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.9939%;\"\u003e\n \u003cp\u003e5 / 10 (33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1902%;\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eThe previous treatment (prednisolone + mizoribine + warfarin + dipyridamole)\u003c/p\u003e\n\u003cp\u003eThe new treatment (prednisolone + mizoribine + lisinopril)\u003c/p\u003e\n\u003cp\u003eM mesangial hypercellularity, E endocapillary hypercellularity, S segmental glomerulosclerossis or adhesion, T tubular atrophy/interstitial fibrosis, C crescent, G global glomerulosclerosis\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3: Comparison of efficacy of treatments after propensity matching\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"652\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 39.1104%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0736%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eThe previous treatment\u0026nbsp;\u003c/strong\u003e(n=15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eThe new treatment\u0026nbsp;\u003c/strong\u003e(n=15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.0368%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 39.1104%;\"\u003e\n \u003cp\u003eRemission of proteinuria\u003c/p\u003e\n \u003cp\u003e[P (-) or P/Cr\u0026lt;0.2]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0736%;\"\u003e\n \u003cp\u003e8 (53.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e13 (86.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.0368%;\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 39.1104%;\"\u003e\n \u003cp\u003eDuration from start of treatment to remission (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0736%;\"\u003e\n \u003cp\u003e4.0 (2.0 \u0026ndash; 10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e1.0 (1.0 \u0026ndash; 4.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.0368%;\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 39.1104%;\"\u003e\n \u003cp\u003eDuration of prednisolone use (months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0736%;\"\u003e\n \u003cp\u003e24 (24 \u0026ndash; 24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e14 (6 \u0026ndash; 22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.0368%;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 39.1104%;\"\u003e\n \u003cp\u003eObservation period (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0736%;\"\u003e\n \u003cp\u003e8 (3 \u0026ndash; 10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e5 (3 \u0026ndash; 8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.0368%;\"\u003e\n \u003cp\u003e0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 39.1104%;\"\u003e\n \u003cp\u003eRecurrence of proteinuria at the latest observation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0736%;\"\u003e\n \u003cp\u003e3/8 (37.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.7791%;\"\u003e\n \u003cp\u003e3/13 (23.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.0368%;\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eThe previous treatment (prednisolone + mizoribine + warfarin + dipyridamole)\u003c/p\u003e\n\u003cp\u003eThe new treatment (prednisolone + mizoribine + lisinopril)\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"childhood IgA nephropathy, angiotensin-converting enzyme inhibitors, prednisolone, proteinuria remission, chronic kidney disease","lastPublishedDoi":"10.21203/rs.3.rs-7587733/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7587733/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eAngiotensin-converting enzyme inhibitors such as lisinopril have long been used for childhood IgA Nephropathy (cIgAN). A two-year combined regimen including prednisolone\u0026thinsp;+\u0026thinsp;mizoribine\u0026thinsp;+\u0026thinsp;warfarin\u0026thinsp;+\u0026thinsp;dipyridamole was shown in our previous randomized control trial to be better for severe cIgAN than prednisolone\u0026thinsp;+\u0026thinsp;mizoribine (without warfarin or dipyridamole) in proteinuria remission. However, to avoid warfarin nephropathy and to shorten the duration of prednisolone use, we consider a new two-year combined regimen of prednisolone\u0026thinsp;+\u0026thinsp;mizoribine\u0026thinsp;+\u0026thinsp;lisinopril.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eBetween July 1976 and December 2022, among 567 biopsy-proven cases of cIgAN, there were 93 cases of severe cIgAN treated with prednisolone\u0026thinsp;+\u0026thinsp;mizoribine. We investigated clinicopathological differences between the 77 cases of cIgAN (82.8%) with the previous treatment and the other 16 patients with the new treatment regimen. After 1:1 propensity score matching was performed to account for between-group differences (amount of proteinuria, eGFR, and the percentage of patients with C0, C1, and C2), we analyzed 15 matched pairs.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eClinicopathological presentations did not significantly differ between the groups. Kaplan-Meier analysis of proteinuria remission showed that the patients with the new treatment achieved significantly higher (90.0 vs. 64.1% at 11 yrs, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01), and faster (1.0 vs. 4.0 yrs, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03) proteinuria remission than those with the previous treatment. Proteinuria recurrence was not significantly different between the groups.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eWe suggested the superiority of 2-year combined regimen of prednisolone\u0026thinsp;+\u0026thinsp;mizoribine\u0026thinsp;+\u0026thinsp;lisinopril for severe cIgAN in achieving early proteinuria remission and shortening prednisolone use without recurrence of proteinuria.\u003c/p\u003e","manuscriptTitle":"Safety and efficacy of prednisolone, mizoribine and lisinopril combination therapy for severe childhood IgA Nephropathy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-23 06:51:49","doi":"10.21203/rs.3.rs-7587733/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8d0ef875-11a3-431f-9eb7-5e02fc2d6a3d","owner":[],"postedDate":"September 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-02T14:09:20+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-23 06:51:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7587733","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7587733","identity":"rs-7587733","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}