Association between the time of initial relapse and subsequent relapses in patients with childhood-onset idiopathic nephrotic syndrome

Association between the time of initial relapse and subsequent relapses in patients with childhood-onset idiopathic nephrotic syndrome | 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 Association between the time of initial relapse and subsequent relapses in patients with childhood-onset idiopathic nephrotic syndrome Yuta Inoki, Kentaro Nishi, Kei Osaka, Tomoya Kaneda, Misaki Akiyama, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3425578/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 25 Jan, 2024 Read the published version in Pediatric Nephrology → Version 1 posted 5 You are reading this latest preprint version Abstract Background Nephrotic syndrome relapse within 6 months is a known risk factor for steroid-dependent nephrotic syndrome/frequently relapsing nephrotic syndrome (SDNS/FRNS), but the risk of early development of SDNS/FRNS and initiation of immunosuppression therapy remains unknown. Methods Patients with childhood-onset idiopathic nephrotic syndrome who had the first relapse within 6 months were enrolled. We analyzed the relationship between the time of the first and second relapse, incidence of SDNS/FRNS, and initiation of immunosuppression therapy. Results Forty-five patients were enrolled. Twenty out of 23 patients (87%) with a first relapse within 30 days after discontinuing initial steroid therapy experienced a second relapse within 30 days after discontinuing steroid therapy. Additionally, most patients in this group (96%) experienced a second relapse within 6 months after the onset and were diagnosed as SDNS/FRNS at this time. In this group, the incidence of SDNS/FRNS development within 6 months was 96%. In contrast, the incidence of SDNS/FRNS development within 6 months and 12 months was 18% and 41%, respectively, in patients with a first relapse more than 30 days after steroid discontinuation. The incidence of initiation of immunosuppressive agents within 6 months and 12 months was 83% and 91%, respectively, in the former group and 14% and 27%, respectively, in the latter group. Conclusions Most patients with a first relapse within 30 days after discontinuing steroid therapy developed SDNS/FRNS and were administered immunosuppressive agents within 6 months. Thus, it may be reasonable to start immunosuppression therapy in this group without waiting for the second relapse. children steroid-dependent nephrotic syndrome frequently relapsing nephrotic syndrome immunosuppressive agents relapse Figures Figure 1 Figure 2 Introduction Idiopathic nephrotic syndrome (INS) is the most common childhood glomerular disease, occurring in 1.15–16.9 per 100 000 children [ 1 ]. Although approximately 85% of patients achieve complete remission of proteinuria within 4 weeks of initial steroid therapy, 80% suffer from one or more relapses, and 50% develop steroid-dependent nephrotic syndrome/frequently relapsing nephrotic syndrome (SDNS/FRNS) [ 1 – 3 ]. Previous studies have reported that risk factors for relapse in INS patients were a young age (particularly those aged 1–3 years), the male sex, and those with delayed achievement of remission from the start of initial therapy, hypoalbuminemia, and hypertriglyceridemia [ 4 – 7 ]. The risk factors for SDNS/FRNS development include a time of at least 9–20 days to achieve remission, relapse within 6 months from initial treatment, and a younger age [ 3 , 6 , 8 – 11 ]. INS patients who relapse soon after completing initial steroid therapy are exposed to high doses of steroids for several months, which can cause severe side effects. Nakanishi et al. reported that the time to achieve remission was at least 9 days, and the occurrence of relapse within 6 months from the start of initial therapy was a risk of frequent relapses over the next 2 years [ 9 ]. However, in our clinical experience, the earlier patients experience a first relapse, the earlier they suffer from the second relapse, developing SDNS/FRNS. Thus, considering the effects of serious steroid toxicity in patients with a severe form of the disease, a precise, early prediction of SDNS/FRNS development based on the time from initial treatment to the first relapse will be advantageous. Additionally, the relationship between the time of the first relapse and the time of the second relapse has yet to be investigated. This study focused on INS patients who experienced a first relapse within 6 months after the start of initial treatment and investigated the association between the time of the first relapse and the incidence of early second relapse, early development of SDNS/FRNS, and initiation of immunosuppression therapy. Methods Study design and patient population In this retrospective observational study, the cohort included patients with childhood (aged 1-18 years)-onset INS who were treated at our center during the initial episode between May 1, 2005, and July 31, 2022. Patients who did not develop steroid-resistant nephrotic syndrome (SRNS) in the initial episode and at initial relapse and who experienced an initial relapse during the first 6 months from the start of initial treatment were included. Patients with secondary or congenital/infantile nephrotic syndrome (aged < 1 year), patients who were followed up for less than 6 months from clinical onset, and patients whose initial treatment was longer than 2 months due to a multicenter randomized study [ 12 ] and not in line with the Japanese clinical guidelines for pediatric INS were excluded [ 13 ]. The final follow-up occurred on May 1, 2023. Definitions INS was defined as nephrotic-range proteinuria (urine protein-creatinine ratio ≥ 2 g/g in the morning urine) and hypoalbuminemia (serum albumin of < 2.5 g/dL). Remission, relapse, frequent relapse, and steroid dependence were defined according to the Japanese clinical guidelines for pediatric INS [ 13 ]. Remission was defined as a urine protein-creatinine ratio of < 0.2 g/g in a spot urine test or a dipstick-negative result for proteinuria for ≥ 3 consecutive days. Steroid-sensitive nephrotic syndrome (SSNS) was defined as achieving remission during the initial 4 weeks of prednisolone therapy, and SRNS was defined as persistent proteinuria after 4 weeks of prednisolone therapy. FRNS was defined as ≥ 2 relapses within the first 6 months of remission or ≥ 4 relapses within a 12-month period. SDNS was defined as two consecutive relapses during steroid therapy or within 14 days of stopping steroid therapy. Hypertension was defined as systolic blood pressure > 95th percentile for age and sex or the use of antihypertensive medications [ 14 ]. Steroid-induced glaucoma was defined as intraocular pressure > 21 mmHg or the initiation of treatment for ocular hypertension [ 15 ]. Treatment protocol Patients were treated for 8 weeks as per the modified International Study of Kidney Diseases in Children protocol described in the Japanese pediatric INS guidelines [ 13 ]. Initial treatment consisted of 60 mg/m 2 /day prednisone (maximum, 60 mg) for 4 weeks, followed by 40 mg/m 2 /day (maximum, 40 mg) on alternate days for 4 weeks. Each relapse was treated with 60 mg/m 2 /day prednisone until remission, followed by tapering to 60 mg/m 2 every other day in a single dose for 2 weeks, 30 mg/m 2 every other day for 2 weeks, and 15 mg/m 2 every other day for 2 weeks. Data collection and analysis We extracted clinical data (sex, age at nephrotic syndrome onset, history of allergy, time of remission of the initial treatment, time of the first and second relapse and their remission, time of diagnosis of SDNS/FRNS and initiation of immunosuppressive agents, and steroid-related adverse events) and laboratory data (serum creatinine, albumin, and total cholesterol; urine protein-creatinine ratio; and urine red blood cell count) from the patients’ electronic medical records. To assess whether the timing of the first relapse affected the relapse frequency, the enrolled patients were divided into three groups according to the time from the end of initial treatment to the first relapse as follows: those who relapsed while taking a reduced dose of prednisolone (group A), those who relapsed within 30 days of prednisolone discontinuation (group B), and those who relapsed after 31 days (group C) of prednisolone discontinuation. The incidence of early progression to SDNS/FRNS, early immunosuppressant use, and steroid side effects, as well as the duration of steroid administration before immunosuppressant use, were compared among the groups. Statistical analysis Data were expressed as medians with interquartile ranges for continuous variables and percentages for categorical variables. The Mann–Whitney U test and Fisher exact test were used to compare continuous variables and categorical variables, respectively. A p -value of < 0.05 was defined as statistically significant. The Kaplan–Meier method was used to calculate the time from the start of initial therapy to the second relapse and to using immunosuppressive agents, and the log-rank test was used to compare the results. Statistical analyses were performed using JMP version 14.0 software (SAS Institute Japan, Tokyo, Japan). Results Patient characteristics Of the 151 patients with childhood-onset INS treated at our center during the study period, 45 were included in our study (Fig. 1 ). Patient characteristics are presented in Table 1 . The median age at diagnosis of childhood-onset INS was 3.7 years. The median time from the start of initial treatment to remission achievement was 10.0 days. The number of patients in each group stratified by the time from the end of initial steroid treatment to the first relapse was 14, 9, and 22 in groups A, B, and C, respectively. Table 1 Patient characteristics Patient characteristics Total (n = 45) Male gender 33 (73) Age at onset of nephrotic syndrome (years) 3.7 [2.4–8.2] History of allergy 15 (33) Laboratory data at onset of nephrotic syndrome Protein-creatinine ratio, (g/g) 14.3 [10.0–22.2] Hematuria 7 (16) Cr-eGFR (mL/min/1.73 m 2 ) 105 [97.2–122] Serum albumin (g/dL) 1.1 [0.9–1.4] Total cholesterol (mg/dL) 497 [389.5–554] Time to achieve remission from start of the initial treatment (days) 10.0 [7.0–20.0] Number of patients stratified by the time from the end of the initial treatment to the first relapse Group A (relapse during steroid therapy tapering) 14 (31) Group B (relapse 1–30 days after steroid therapy cessation) 9 (20) Group C (relapse more than 31 days after steroid therapy cessation) 22 (49) Data are expressed as medians [interquartile ranges] or numbers (%) Cr-eGFR, estimated glomerular filtration rate based on serum creatinine Table 2 compares the clinical course stratified by the time from the end of initial treatment to the first relapse. There was no significant difference according to sex or age at onset between the three groups. The time to achieve remission of the initial episode was significantly longer in group A (median, 23.0 days) and group B (median, 12.0 days) compared with group C (median, 8.5 days) ( p = 0.002 and 0.037, respectively). On the other hand, there was no significant difference in the time to remission of the first relapse in each group. Proteinuria reoccurred in six patients after remission during initial full course of prednisolone therapy, and all of them relapsed within 30 days from the end of the initial treatment. Table 2 Comparison of clinical courses stratified by the time from the end of the initial steroid treatment to the first relapse Variable Total Group A Group B Group C Number of patients 45 14 9 22 Number of males 33 (73) 11 (79) 8 (89) 14 (64) Age at onset of nephrotic syndrome (years) 3.7 [2.4–8.2] 2.6 [1.9–8.9] 3.6 [2.5–5.8] 4.6 [2.9–12.4] History of allergy 15 (33) 3 (21) 4 (44) 8 (36) Laboratory data at disease onset Protein-creatinine ratio, (g/g) 14.3 [10.0–22.2] 18.0 [10.4–29.1] 15.2 [14.3–27.4] ∗1 11.0 [7.8–25.9] ∗1 Hematuria 7 (16) 4 (29) 0 (0) 3 (14) Cr-eGFR (mL/min/1.73 m 2 ) 105 [97–122] 102 [93–112] 102 [99–122] 118 [98–133] Serum albumin (g/dL) 1.1 [0.9–1.4] 1.1 [1.0–1.4] †1 0.9 [0.8–0.9] †1 1.2 [0.9–1.7] Total cholesterol (mg/dL) 497 [390–554] 439 [397–534] 384 [343–494] ‡1 530 [440–589] ‡1 Time from the start of initial treatment to achieving remission (days) 10.0 [7.0–20.0] 23.0 [10.0–28.3] §1 12.0 [7.5–26.0] §2 8.5 [6.8–11.3] §1,2 Reoccurrence of proteinuria during the initial full-dose steroid therapy 6 (13) 4 (29) ‖1 2 (22) 0 (0) ‖1 Time from the first relapse treatment to achieving remission (days) 8.0 [7.0–11.0] 9.5 [5.8–16.5] 10.0 [7.5–12.0] 8.0 [6.8–9.5] SRNS at second relapse 2 (4) 2 (14) 0 (0) 0 (0) Steroid-related adverse events Hypertension 9 (20) 5 (36) 1 (11) 3 (14) Glaucoma 23 (51) 4 (29) ¶1 7 (78) ¶1 12 (55) Data are expressed as medians [interquartile ranges] or numbers (%) Cr-eGFR, estimated glomerular filtration rate based on serum creatinine; SRNS, steroid-resistant nephrotic syndrome Group A was defined as those who relapse during steroid therapy tapering. Group B was defined as those who relapse 1–30 days after steroid therapy cessation. Group C was defined as those who relapse more than 31 days after steroid therapy cessation. P -value: ∗1, 0.011; †1, 0.002; ‡1, 0.027; § 1, 0.002; § 2, 0.037; ‖1, 0.01; ¶1, 0.036 The incidence of steroid-induced glaucoma in group B was significantly higher than in group A. There were no other significant differences in the rates of side effects of steroid therapy. However, two patients in group A developed SRNS at the second relapse. Analysis of the time of the second relapse stratified by the time from the end of the initial treatment to the first relapse Approximately two-thirds of patients in group A suffered a second relapse during steroid therapy tapering (Table 3 ). Twenty out of 23 (87%) patients who experienced a first relapse within 30 days (groups A and B) experienced a second relapse within 30 days after cessation of the steroid therapy for the first relapse. In these groups, 22 out of 23 patients (96%) experienced a second relapse within 6 months after the onset and were diagnosed as SDNS/FRNS at this time. Kaplan–Meier curves and log-rank tests were used to compare the time from the start of treatment to the second relapse between those who experienced a first relapse within 30 days and those who relapsed after 31 days (Fig. 2 a), revealing a statistically significant difference between the two groups (50% survival: 93 and 250 days, respectively, p < 0.001). Table 3 The second relapses, SDNS/FRNS development, and initiation of immunosuppression therapy stratified by the time from the end of the initial treatment to the first relapse Variable Total (n = 45) Group A (n = 14) Group B (n = 9) Group C (n = 22) Time from end of the first relapse treatment to the second relapse 0 days a 20 (44) 9 (64) 7 (78) 4 (18) 1–30 days 9 (20) 4 (29) 0 (0) 5 (23) > 30 days 14 (31) 1 (7) 2 (22) 11 (50) No second relapse during follow-up period 2 (4) 0 (0) 0 (0) 2 (9) Time to SDNS/FRNS development from start of initial treatment 0–6 months 26 (58) 14 (100) 8 (89) 4 (18) 6–12 months 5 (11) 0 (0) 0 (0) 5 (23) 1–2 years 6 (13) 0 (0) 0 (0) 6 (27) > 2 years 1 (2) 0 (0) 1(11) 0 (0) No progression 7 (16) 0 (0) 0 (0) 7 (32) Development of SDNS/FRNS on second relapse 26 (58) 14 (100) ∗1 8 (89) ∗2 4 (18) ∗1,2 Time from the start of initial treatment to administration of immunosuppressive agents 0–6 months 22 (49) 12 (86) 7 (78) 3 (14) 6–12 months 5 (11) 1 (7) 1 (11) 3 (14) 1–2 years 8 (18) 1 (7) 0 (0) 7 (32) > 2 years 1 (2) 0 (0) 1 (11) 0 (0) No initiation 9 (20) 0 (0) 0 (0) 9 (41) Rate of days on oral steroids between the start of initial treatment and the start of immunosuppression therapy (%) 84.0 [59.4–100] 100 [97.1–100] †1,2 84.0 [73.7–86.9] †1,3 56.7 [44.5–69.2] †,2,3 Data are expressed as medians [interquartile ranges] or number (%). SDNS/FRNS, steroid-dependent nephrotic syndrome/frequently relapsing nephrotic syndrome a , 0 days refers to relapse during tapering of steroid therapy Group A was defined as those who relapse during steroid therapy tapering. Group B was defined as those who relapse 1–30 days after steroid therapy cessation. Group C was defined as those who relapse more than 31 days after steroid therapy cessation. P -value: ∗1 , < 0.001; ∗2 , < 0.001; †1 , 0.005; †2 , < 0.001; †3 , < 0.001 Development of SDNS/FRNS stratified by the time from the end of the initial treatment to the first relapse All 14 patients in group A developed SDNS/FRNS within 6 months after nephrotic syndrome onset (Table 3 ). Additionally, 22 out of 23 patients (96%) who experienced the first relapse within 30 days (groups A and B) developed SDNS/FRNS within 6 months, with SDNS/FRNS diagnosis at their second relapse. On the other hand, 18% and 41% of patients in group C developed SDNS/FRNS within 6 months and 12 months, respectively. In this group, 41% did not develop SDNS/FRNS during the follow-up period. Figure 2 b shows the SDNS/FRNS-free survival curve, revealing a statistically significant difference between those who had a first relapse within 30 days and those who relapsed after 31 days (50% survival: 93 and 408 days, respectively; p < 0.001). Administration of immunosuppressive agents stratified by the time from the end of the initial treatment to the first relapse Twelve patients in group A (86%) were administered immunosuppressive agents within 6 months after the onset of nephrotic syndrome (Table 3 ). Of the patients who had an initial relapse within 30 days (groups A and B), 19 out of 23 (83%) started treatment with immunosuppressive agents within 6 months after the start of initial treatment, 21 out of 23 (91%) within 12 months, and 23 out of 23 (100%) during the follow-up period. On the other hand, 3 out of 22 (14%) and 6 out of 22 (27%) patients in group C commenced treatment with immunosuppressive agents within 6 months and within 12 months, respectively, and 41% of patients did not commence immunosuppression therapy during the follow-up period. Figure 2 c shows the immunosuppressive agent-free survival curve, revealing a statistically significant difference between those who had a first relapse within 30 days and those who relapsed after 31 days (50% survival: 111 and 491 days, respectively; p < 0.001). Association between time to first remission and incidence of relapse Eleven patients took over 20 days to achieve initial remission, all of whom experienced an initial relapse within 30 days after initial treatment. On the other hand, 12 out of 34 patients (35%) who achieved remission within 20 days experienced an initial relapse within 30 days after the initial treatment. All 11 patients who took over 20 days to achieve initial remission developed SDNS/FRNS within 6 months of starting initial therapy. Immunosuppression therapy commenced in 10 out of 11 (91%) patients within 6 months and in the remaining patient within 6–7 months. There were significant differences in the ratio of SDNS/FRNS development within 6 months of starting initial therapy between the group that took over 20 days to achieve initial remission and the group that achieved remission within 20 days (100% and 38%, respectively; p < 0.001). There were also significant differences in the ratio of immunosuppressant use within 6 months of starting initial therapy between these two groups (91% and 35%, respectively; p < 0.001). Discussion This study investigated the association between the time to first relapse and the incidence of early second relapse, early development of SDNS/FRNS, and early initiation of immunosuppressive agents among patients with childhood-onset INS who experienced a first relapse within 6 months after disease onset. Almost all patients (96%) who experienced a first relapse within 30 days after initial steroid treatment experienced a second relapse within 6 months after initial treatment and developed SDNS/FRNS at the second relapse, which was significantly higher than patients who experienced a first relapse after 31 days. Of the patients who experienced an initial relapse within 30 days, 83% and 91% commenced immunosuppression therapy within 6 months and 12 months after the start of initial treatment, respectively. Previous large prospective studies reported that 18–28% of INS patients frequently relapsed 6 months after initial therapy [ 2 , 16 ]. This correlates with our study findings of SDNS/FRNS development in 30% (45/151) of patients 6 months after the start of initial therapy. Thus, our result suggests that although this was a single-center study, the proportion of severe patients was not high compared with the general population. Relapse within 6 months after initiating initial therapy has been reported as predictive of SDNS/FRNS development within a follow-up period of 1 or 2 years, or even longer [ 6 , 8 , 9 , 11 ]. However, few studies have investigated the risk of earlier development of SDNS/FRNS and earlier initiation of immunosuppressive agents among INS patients. In our study, a small number of patients in those who experienced the first relapse within 30 days after initial treatment did not commence immunosuppression therapy after remission of the second relapse, but all of them started to use immunosuppressive agents during the follow-up period. Considering previous reports, our findings suggest that early recurrence may be associated with a greater tendency toward early and frequent relapse. Although it is crucial to manage INS patients who are trying to use immunosuppressive agents only if necessary and to initiate treatment with appropriate timing, our results suggest that commencing immunosuppression therapy after remission of the first relapse may be considered for patients who relapsed within 30 days after initial treatment. There are many reports that a long time to achieve initial remission predicts the development of SDNS/FRNS over more than 2 years [ 3 , 6 , 9 , 10 , 17 – 20 ]. An Italian cohort study reported a significant association between the time from the onset of steroid therapy and the risk of relapsing within 3 months after initial treatment [ 18 ]. Several studies revealed that most patients who achieved remission after more than 20 days developed SDNS/FRNS during the follow-up period [ 10 , 19 , 20 ]. Although the patients in our study were at high risk of developing SDNS/FRNS because we only included patients with a first relapse within 6 months, our results were in line with previous reports. All patients who achieved initial remission after more than 20 days started immunosuppressive agents earlier than patients who achieved remission within 20 days. Thus, achieving initial remission after more than 20 days could be a predictor of SDNS/FRNS development or the initiation of immunosuppressive agents within 6 months, but this measure appears to have very high specificity and low sensitivity. Our findings suggest that a combination of the time to first remission and time to first relapse may help to identify patients at risk of SDNS/FRNS development very early in their clinical course. To the best of our knowledge, ours is the first study demonstrating the risk of earlier SDNS/FRNS development and earlier initiation of immunosuppression therapy among INS patients with a high risk of developing SRNS/SDNS. Although there were no significant differences in steroid side effects between the group with a first relapse within 30 days after cessation of steroid therapy and the group with a first relapse after 31 days, commencement of immunosuppression therapy after the first relapse remission instead of waiting for the second relapse may prevent patients from SRNS development at the second relapse. Moreover, a recent study has suggested that nephrin autoantibodies may be a potential factor in INS etiology and disease severity in some patients [ 21 ]. These findings may lead to more personalized treatment in the future, and it will become even more critical to predict patients with a high risk of early SDNS/FRNS development in the early stages of INS. Further large-scale studies are necessary to investigate whether patients with early relapse within 30 days soon relapse again and to assess whether immunosuppression therapy should commence in such patients after confirming the first relapse and without waiting for the second relapse. Our study has several limitations. First, due to its retrospective design, the timing of initiation of immunosuppression therapy was not protocolized and depended on each physician. For example, if a patient relapsed following an upper respiratory tract infection or a gastrointestinal tract infection, some physicians waited before administering immunosuppressive agents, even if they met the diagnostic criteria for SDNS/FRNS. However, since none of the patients started immunosuppressive agents prior to two or more relapses, it is unlikely that that the incidence of immunosuppressant initiation is highly estimated. Second, our study only included patients admitted to a single large children’s hospital, which could affect the applicability of our study findings to the general population. However, since our study population comprised patients with SSNS at initial relapse, our findings are less likely to be influenced by the institution and may be generalizable. As mentioned above, the incidence of patients in our study developing SDNS/FRNS within 6 months after initial therapy agreed with previous studies, suggesting that our patients were not unique with the absence of bias. In conclusion, our findings suggest that most INS patients who experienced an initial relapse within 30 days developed SDNS/FRNS and commenced immunosuppression therapy within 6 months. Additionally, it is likely that these patients will continue to be exposed to high doses of steroids until the commencement of immunosuppression therapy. Thus, it may be reasonable to start immunosuppression therapy in such patients without waiting for the second relapse. Declarations Funding: No external funding was received for this work. Competing Interests: Koichi Kamei has obtained research funding from the Public Foundation of Vaccination Research Center, the Terumo Foundation for Life Sciences and Arts, and the Taiju Life Social Welfare Foundation; donations from Chugai Pharmaceutical Co. Ltd., Astellas Pharma Inc., Ono Pharmaceutical Co. Ltd., Teijin Pharma Ltd., Shionogi Co. Ltd., and Otsuka Pharmaceutical Co. Ltd.; and lecture fees from Tanabe Mitsubishi Pharma, Baxter Ltd., and Zenyaku Kogyo Co. Ltd. All other authors have no potential conflicts of interest to disclose. Availability of data and materials: The data supporting the findings of this study are available from the corresponding author upon reasonable request. Author contributions: All authors were physicians who treated the patients in this study. Yuta Inoki conducted the study, collected the clinical and laboratory data, and wrote the manuscript. Kentaro Nishi, Kei Osaka, Tomoya Kaneda, Misaki Akiyama, Mai Sato, and Masao Ogura reviewed and edited the manuscript. Koichi Kamei supervised the work and revised the manuscript. All authors read and approved the final manuscript. Ethics approval: This study was approved by the Ethics Committee of the National Center for Child Health and Development (approval no. 2022–210). It was conducted according to the principles of the Declaration of Helsinki and the ethics guidelines of the Japanese Ministry of Health, Labor and Welfare. Consent to participate: Due to the retrospective nature of this study, informed consent for participation was waived. Consent to publish: Due to the retrospective nature of this study, informed consent to publish was waived. References Noone DG, Iijima K, Parekh R (2018) Idiopathic nephrotic syndrome in children. 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J Pediatr 156:965–971. https://doi.org/10.1016/j.jpeds.2009.12.020 Yap HK, Han EJ, Heng CK, Gong WK (2001) Risk factors for steroid dependency in children with idiopathic nephrotic syndrome. Pediatr Nephrol 16:1049–1052. https://doi.org/10.1007/s004670100024 Abdel-Hafez MA, Abou-El-Hana NM, Erfan AA, El-Gamasy M, Abdel-Nabi H (2017) Predictive risk factors of steroid dependent nephrotic syndrome in children. J Nephropathol 6:180–186. https://doi.org/10.15171/jnp.2017.31 Watts AJB, Keller KH, Lerner G, Rosales I, Collins AB, Sekulic M, Waikar SS, Chandraker A, Riella LV, Alexander MP, Troost JP, Chen J, Fermin D, Yee JL, Sampson MG, Beck LH Jr., Henderson JM, Greka A, Rennke HG, Weins A (2022) Discovery of Autoantibodies Targeting Nephrin in Minimal Change Disease Supports a Novel Autoimmune Etiology. J Am Soc Nephrol 33:238–252. https://doi.org/10.1681/ASN.2021060794 Supplementary Files GraphicalAbstract.pptx Cite Share Download PDF Status: Published Journal Publication published 25 Jan, 2024 Read the published version in Pediatric Nephrology → Version 1 posted Editorial decision: Major Revisions Needed 30 Oct, 2023 Reviewers agreed at journal 12 Oct, 2023 Reviewers invited by journal 12 Oct, 2023 Editor assigned by journal 10 Oct, 2023 First submitted to journal 09 Oct, 2023 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3425578","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":239698584,"identity":"5e11ed0b-7c37-45ae-b72b-0a35d35f3603","order_by":0,"name":"Yuta Inoki","email":"","orcid":"","institution":"Department of Pediatrics, Kobe University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuta","middleName":"","lastName":"Inoki","suffix":""},{"id":239698585,"identity":"b55cff3c-0b1c-41cf-a29b-c6a9efaa50f9","order_by":1,"name":"Kentaro Nishi","email":"","orcid":"","institution":"Division of Nephrology and Rheumatology, National Center for Child Health and Development","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kentaro","middleName":"","lastName":"Nishi","suffix":""},{"id":239698586,"identity":"990a2b86-e759-4521-8948-89d95e3836a0","order_by":2,"name":"Kei Osaka","email":"","orcid":"","institution":"Department of Pediatrics, Tokyo Medical and Dental University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kei","middleName":"","lastName":"Osaka","suffix":""},{"id":239698587,"identity":"08c7f50f-0063-43ad-8fae-2c7ddac4d762","order_by":3,"name":"Tomoya Kaneda","email":"","orcid":"","institution":"Division of Nephrology and Rheumatology, National Center for Child Health and Development","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tomoya","middleName":"","lastName":"Kaneda","suffix":""},{"id":239698588,"identity":"f7e33707-f785-4920-b8c5-ee6b89802640","order_by":4,"name":"Misaki Akiyama","email":"","orcid":"","institution":"Division of Nephrology and Rheumatology, National Center for Child Health and Development","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Misaki","middleName":"","lastName":"Akiyama","suffix":""},{"id":239698589,"identity":"81d35ee8-2834-4695-a6d4-d0e2e5a71d00","order_by":5,"name":"Mai Sato","email":"","orcid":"","institution":"Division of Nephrology and Rheumatology, National Center for Child Health and Development","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mai","middleName":"","lastName":"Sato","suffix":""},{"id":239698590,"identity":"24c99da3-ebf1-48f1-b317-df1bf3390df6","order_by":6,"name":"Masao Ogura","email":"","orcid":"","institution":"Division of Nephrology and Rheumatology, National Center for Child Health and Development","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Masao","middleName":"","lastName":"Ogura","suffix":""},{"id":239698591,"identity":"7fafdafb-379f-43bb-95b2-4d644f3cac76","order_by":7,"name":"Koichi Kamei","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYBACCRCRwJAgB6TYGHjAYgeI02JMohagpsQGhBYCQLL9dOKDBwxp6dvZDz978IahVo6B8Sx+a6R5cjcbJDDk5O7sSTM3nMNwHOjCcwl4tcgx5G6TSPxXkbvhBg+bNA/DMaALzxjg18L/dvuPBIaKdAOitUhL5G4DhlhOAlRLDWEtkjPebpZIYEgz3HAmzUxyjsEBYzZCfpE4n7vx4w+GZHmD44efSbypqJPjlyAQYmjA4DADm8QZUnQwMNQxMPD3kKZlFIyCUTAKhj0AACAeQ6wBOp/+AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-3528-6961","institution":"Division of Nephrology and Rheumatology, National Center for Child Health and Development","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Koichi","middleName":"","lastName":"Kamei","suffix":""}],"badges":[],"createdAt":"2023-10-10 01:12:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3425578/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3425578/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00467-024-06286-9","type":"published","date":"2024-01-25T15:18:39+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":44739917,"identity":"7c43ee36-05a7-43f6-b1fe-aedd6cd52ee0","added_by":"auto","created_at":"2023-10-16 23:12:17","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":100284,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of the study population.\u003c/p\u003e\n\u003cp\u003eINS, idiopathic nephrotic syndrome; SSNS, steroid-sensitive nephrotic syndrome; SRNS, steroid-resistant nephrotic syndrome\u003c/p\u003e","description":"","filename":"Slide1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3425578/v1/2fc31bd4dbd610ec1367321e.jpg"},{"id":44739919,"identity":"3bb40f06-004c-45a0-9caf-b689d45fa494","added_by":"auto","created_at":"2023-10-16 23:12:18","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":100463,"visible":true,"origin":"","legend":"\u003cp\u003eSecond relapse-free ratio and immunosuppressant-free ratio after initial treatment.\u003c/p\u003e\n\u003cp\u003e(a) Kaplan–Meier curves for the time from the start of initial steroid therapy to the second relapse.\u003c/p\u003e\n\u003cp\u003e(b) Kaplan–Meier curves for the time from the start of initial steroid therapy to SDNS/FRNS development.\u003c/p\u003e\n\u003cp\u003e(c) Kaplan–Meier curves for the time from the start of initial steroid therapy to initiation of immunosuppression therapy.\u003c/p\u003e\n\u003cp\u003eSDNS/FRNS, steroid-dependent nephrotic syndrome/frequently relapsing nephrotic syndrome; IM, immunosuppressant\u003c/p\u003e","description":"","filename":"Slide2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3425578/v1/25340474b2e9621131a26b3a.jpg"},{"id":50314307,"identity":"8c5f2717-f4a7-4978-b4d1-f4617a38d573","added_by":"auto","created_at":"2024-01-29 15:30:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":555045,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3425578/v1/00de681b-d439-4aa1-8c0b-dfee19ecf1fb.pdf"},{"id":44739918,"identity":"dddf55e9-4c30-4dc1-ae22-6e52e8f21cd0","added_by":"auto","created_at":"2023-10-16 23:12:18","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":283299,"visible":true,"origin":"","legend":"","description":"","filename":"GraphicalAbstract.pptx","url":"https://assets-eu.researchsquare.com/files/rs-3425578/v1/d76c08357398dbddb60a9942.pptx"}],"financialInterests":"","formattedTitle":"Association between the time of initial relapse and subsequent relapses in patients with childhood-onset idiopathic nephrotic syndrome","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIdiopathic nephrotic syndrome (INS) is the most common childhood glomerular disease, occurring in 1.15\u0026ndash;16.9 per 100 000 children [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although approximately 85% of patients achieve complete remission of proteinuria within 4 weeks of initial steroid therapy, 80% suffer from one or more relapses, and 50% develop steroid-dependent nephrotic syndrome/frequently relapsing nephrotic syndrome (SDNS/FRNS) [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrevious studies have reported that risk factors for relapse in INS patients were a young age (particularly those aged 1\u0026ndash;3 years), the male sex, and those with delayed achievement of remission from the start of initial therapy, hypoalbuminemia, and hypertriglyceridemia [\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The risk factors for SDNS/FRNS development include a time of at least 9\u0026ndash;20 days to achieve remission, relapse within 6 months from initial treatment, and a younger age [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eINS patients who relapse soon after completing initial steroid therapy are exposed to high doses of steroids for several months, which can cause severe side effects. Nakanishi et al. reported that the time to achieve remission was at least 9 days, and the occurrence of relapse within 6 months from the start of initial therapy was a risk of frequent relapses over the next 2 years [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, in our clinical experience, the earlier patients experience a first relapse, the earlier they suffer from the second relapse, developing SDNS/FRNS. Thus, considering the effects of serious steroid toxicity in patients with a severe form of the disease, a precise, early prediction of SDNS/FRNS development based on the time from initial treatment to the first relapse will be advantageous. Additionally, the relationship between the time of the first relapse and the time of the second relapse has yet to be investigated.\u003c/p\u003e \u003cp\u003eThis study focused on INS patients who experienced a first relapse within 6 months after the start of initial treatment and investigated the association between the time of the first relapse and the incidence of early second relapse, early development of SDNS/FRNS, and initiation of immunosuppression therapy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and patient population\u003c/h2\u003e \u003cp\u003eIn this retrospective observational study, the cohort included patients with childhood (aged 1-18 years)-onset INS who were treated at our center during the initial episode between May 1, 2005, and July 31, 2022. Patients who did not develop steroid-resistant nephrotic syndrome (SRNS) in the initial episode and at initial relapse and who experienced an initial relapse during the first 6 months from the start of initial treatment were included. Patients with secondary or congenital/infantile nephrotic syndrome (aged\u0026thinsp;\u0026lt;\u0026thinsp;1 year), patients who were followed up for less than 6 months from clinical onset, and patients whose initial treatment was longer than 2 months due to a multicenter randomized study [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] and not in line with the Japanese clinical guidelines for pediatric INS were excluded [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The final follow-up occurred on May 1, 2023.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDefinitions\u003c/h2\u003e \u003cp\u003eINS was defined as nephrotic-range proteinuria (urine protein-creatinine ratio\u0026thinsp;\u0026ge;\u0026thinsp;2 g/g in the morning urine) and hypoalbuminemia (serum albumin of \u0026lt;\u0026thinsp;2.5 g/dL). Remission, relapse, frequent relapse, and steroid dependence were defined according to the Japanese clinical guidelines for pediatric INS [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRemission was defined as a urine protein-creatinine ratio of \u0026lt;\u0026thinsp;0.2 g/g in a spot urine test or a dipstick-negative result for proteinuria for \u0026ge;\u0026thinsp;3 consecutive days. Steroid-sensitive nephrotic syndrome (SSNS) was defined as achieving remission during the initial 4 weeks of prednisolone therapy, and SRNS was defined as persistent proteinuria after 4 weeks of prednisolone therapy. FRNS was defined as \u0026ge;\u0026thinsp;2 relapses within the first 6 months of remission or \u0026ge;\u0026thinsp;4 relapses within a 12-month period. SDNS was defined as two consecutive relapses during steroid therapy or within 14 days of stopping steroid therapy.\u003c/p\u003e \u003cp\u003eHypertension was defined as systolic blood pressure\u0026thinsp;\u0026gt;\u0026thinsp;95th percentile for age and sex or the use of antihypertensive medications [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Steroid-induced glaucoma was defined as intraocular pressure\u0026thinsp;\u0026gt;\u0026thinsp;21 mmHg or the initiation of treatment for ocular hypertension [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eTreatment protocol\u003c/h2\u003e \u003cp\u003ePatients were treated for 8 weeks as per the modified International Study of Kidney Diseases in Children protocol described in the Japanese pediatric INS guidelines [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Initial treatment consisted of 60 mg/m\u003csup\u003e2\u003c/sup\u003e/day prednisone (maximum, 60 mg) for 4 weeks, followed by 40 mg/m\u003csup\u003e2\u003c/sup\u003e/day (maximum, 40 mg) on alternate days for 4 weeks. Each relapse was treated with 60 mg/m\u003csup\u003e2\u003c/sup\u003e/day prednisone until remission, followed by tapering to 60 mg/m\u003csup\u003e2\u003c/sup\u003e every other day in a single dose for 2 weeks, 30 mg/m\u003csup\u003e2\u003c/sup\u003e every other day for 2 weeks, and 15 mg/m\u003csup\u003e2\u003c/sup\u003e every other day for 2 weeks.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eData collection and analysis\u003c/h2\u003e \u003cp\u003eWe extracted clinical data (sex, age at nephrotic syndrome onset, history of allergy, time of remission of the initial treatment, time of the first and second relapse and their remission, time of diagnosis of SDNS/FRNS and initiation of immunosuppressive agents, and steroid-related adverse events) and laboratory data (serum creatinine, albumin, and total cholesterol; urine protein-creatinine ratio; and urine red blood cell count) from the patients\u0026rsquo; electronic medical records.\u003c/p\u003e \u003cp\u003eTo assess whether the timing of the first relapse affected the relapse frequency, the enrolled patients were divided into three groups according to the time from the end of initial treatment to the first relapse as follows: those who relapsed while taking a reduced dose of prednisolone (group A), those who relapsed within 30 days of prednisolone discontinuation (group B), and those who relapsed after 31 days (group C) of prednisolone discontinuation. The incidence of early progression to SDNS/FRNS, early immunosuppressant use, and steroid side effects, as well as the duration of steroid administration before immunosuppressant use, were compared among the groups.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eData were expressed as medians with interquartile ranges for continuous variables and percentages for categorical variables. The Mann\u0026ndash;Whitney U test and Fisher exact test were used to compare continuous variables and categorical variables, respectively. A \u003cem\u003ep\u003c/em\u003e-value of \u0026lt;\u0026thinsp;0.05 was defined as statistically significant. The Kaplan\u0026ndash;Meier method was used to calculate the time from the start of initial therapy to the second relapse and to using immunosuppressive agents, and the log-rank test was used to compare the results. Statistical analyses were performed using JMP version 14.0 software (SAS Institute Japan, Tokyo, Japan).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eOf the 151 patients with childhood-onset INS treated at our center during the study period, 45 were included in our study (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Patient characteristics are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median age at diagnosis of childhood-onset INS was 3.7 years. The median time from the start of initial treatment to remission achievement was 10.0 days. The number of patients in each group stratified by the time from the end of initial steroid treatment to the first relapse was 14, 9, and 22 in groups A, B, and C, respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;45)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale gender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (73)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at onset of nephrotic syndrome (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.7 [2.4\u0026ndash;8.2]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of allergy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (33)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLaboratory data at onset of nephrotic syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProtein-creatinine ratio, (g/g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.3 [10.0\u0026ndash;22.2]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematuria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCr-eGFR (mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e105 [97.2\u0026ndash;122]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum albumin (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.1 [0.9\u0026ndash;1.4]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal cholesterol (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e497 [389.5\u0026ndash;554]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to achieve remission from start of the initial treatment (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.0 [7.0\u0026ndash;20.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of patients stratified by the time from the end of the initial treatment to the first relapse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup A (relapse during steroid therapy tapering)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (31)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup B (relapse 1\u0026ndash;30 days after steroid therapy cessation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (20)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup C (relapse more than 31 days after steroid therapy cessation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (49)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eData are expressed as medians [interquartile ranges] or numbers (%)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eCr-eGFR, estimated glomerular filtration rate based on serum creatinine\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e compares the clinical course stratified by the time from the end of initial treatment to the first relapse. There was no significant difference according to sex or age at onset between the three groups. The time to achieve remission of the initial episode was significantly longer in group A (median, 23.0 days) and group B (median, 12.0 days) compared with group C (median, 8.5 days) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002 and 0.037, respectively). On the other hand, there was no significant difference in the time to remission of the first relapse in each group. Proteinuria reoccurred in six patients after remission during initial full course of prednisolone therapy, and all of them relapsed within 30 days from the end of the initial treatment.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of clinical courses stratified by the time from the end of the initial steroid treatment to the first relapse\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup A\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup B\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGroup C\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of patients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of males\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14 (64)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at onset of nephrotic syndrome (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.7 [2.4\u0026ndash;8.2]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.6 [1.9\u0026ndash;8.9]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.6 [2.5\u0026ndash;5.8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.6 [2.9\u0026ndash;12.4]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of allergy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8 (36)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLaboratory data at disease onset\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProtein-creatinine ratio, (g/g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.3 [10.0\u0026ndash;22.2]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.0 [10.4\u0026ndash;29.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15.2 [14.3\u0026ndash;27.4] \u003csup\u003e\u0026lowast;1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11.0 [7.8\u0026ndash;25.9] \u003csup\u003e\u0026lowast;1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematuria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCr-eGFR (mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e105 [97\u0026ndash;122]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e102 [93\u0026ndash;112]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e102 [99\u0026ndash;122]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e118 [98\u0026ndash;133]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum albumin (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.1 [0.9\u0026ndash;1.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.1 [1.0\u0026ndash;1.4] \u003csup\u003e\u0026dagger;1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.9 [0.8\u0026ndash;0.9] \u003csup\u003e\u0026dagger;1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.2 [0.9\u0026ndash;1.7]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal cholesterol (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e497 [390\u0026ndash;554]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e439 [397\u0026ndash;534]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e384 [343\u0026ndash;494] \u003csup\u003e\u0026Dagger;1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e530 [440\u0026ndash;589] \u003csup\u003e\u0026Dagger;1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime from the start of initial treatment to achieving remission (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.0 [7.0\u0026ndash;20.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.0 [10.0\u0026ndash;28.3] \u003csup\u003e\u0026sect;1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.0 [7.5\u0026ndash;26.0] \u003csup\u003e\u0026sect;2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.5 [6.8\u0026ndash;11.3] \u003csup\u003e\u0026sect;1,2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReoccurrence of proteinuria during the initial full-dose steroid therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (29) \u003csup\u003e‖1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0) \u003csup\u003e‖1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime from the first relapse treatment to achieving remission (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.0 [7.0\u0026ndash;11.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.5 [5.8\u0026ndash;16.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.0 [7.5\u0026ndash;12.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.0 [6.8\u0026ndash;9.5]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSRNS at second relapse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSteroid-related adverse events\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlaucoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (29) \u003csup\u003e\u0026para;1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (78) \u003csup\u003e\u0026para;1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 (55)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eData are expressed as medians [interquartile ranges] or numbers (%)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eCr-eGFR, estimated glomerular filtration rate based on serum creatinine; SRNS, steroid-resistant nephrotic syndrome\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eGroup A was defined as those who relapse during steroid therapy tapering.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eGroup B was defined as those who relapse 1\u0026ndash;30 days after steroid therapy cessation.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eGroup C was defined as those who relapse more than 31 days after steroid therapy cessation.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eP\u003c/em\u003e-value: \u0026lowast;1, 0.011; \u0026dagger;1, 0.002; \u0026Dagger;1, 0.027; \u0026sect;\u0026nbsp;1, 0.002; \u0026sect;\u0026nbsp;2, 0.037; ‖1, 0.01; \u0026para;1, 0.036\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe incidence of steroid-induced glaucoma in group B was significantly higher than in group A. There were no other significant differences in the rates of side effects of steroid therapy. However, two patients in group A developed SRNS at the second relapse.\u003c/p\u003e \u003cp\u003e \u003cb\u003eAnalysis of the time of the second relapse stratified by the time from the end of the initial treatment to the first relapse\u003c/b\u003e \u003c/p\u003e \u003cp\u003eApproximately two-thirds of patients in group A suffered a second relapse during steroid therapy tapering (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Twenty out of 23 (87%) patients who experienced a first relapse within 30 days (groups A and B) experienced a second relapse within 30 days after cessation of the steroid therapy for the first relapse. In these groups, 22 out of 23 patients (96%) experienced a second relapse within 6 months after the onset and were diagnosed as SDNS/FRNS at this time. Kaplan\u0026ndash;Meier curves and log-rank tests were used to compare the time from the start of treatment to the second relapse between those who experienced a first relapse within 30 days and those who relapsed after 31 days (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea), revealing a statistically significant difference between the two groups (50% survival: 93 and 250 days, respectively, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe second relapses, SDNS/FRNS development, and initiation of immunosuppression therapy stratified by the time from the end of the initial treatment to the first relapse\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;45)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup A\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;14)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup B\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGroup C\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;22)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime from end of the first relapse treatment to the second relapse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0 days\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (18)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u0026ndash;30 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (23)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;30 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11 (50)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo second relapse during follow-up period\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to SDNS/FRNS development from start of initial treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (18)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u0026ndash;12 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (23)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u0026ndash;2 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 (27)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;2 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo progression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (32)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDevelopment of SDNS/FRNS on second relapse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (100) \u003csup\u003e\u0026lowast;1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (89) \u003csup\u003e\u0026lowast;2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (18) \u003csup\u003e\u0026lowast;1,2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime from the start of initial treatment to administration of immunosuppressive agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u0026ndash;12 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u0026ndash;2 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (32)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;2 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo initiation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 (41)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRate of days on oral steroids between the start of initial treatment and the start of immunosuppression therapy (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e84.0 [59.4\u0026ndash;100]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100 [97.1\u0026ndash;100] \u003csup\u003e\u0026dagger;1,2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e84.0 [73.7\u0026ndash;86.9] \u003csup\u003e\u0026dagger;1,3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e56.7 [44.5\u0026ndash;69.2] \u003csup\u003e\u0026dagger;,2,3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eData are expressed as medians [interquartile ranges] or number (%).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eSDNS/FRNS, steroid-dependent nephrotic syndrome/frequently relapsing nephrotic syndrome\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003e, 0 days refers to relapse during tapering of steroid therapy\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eGroup A was defined as those who relapse during steroid therapy tapering.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eGroup B was defined as those who relapse 1\u0026ndash;30 days after steroid therapy cessation.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eGroup C was defined as those who relapse more than 31 days after steroid therapy cessation.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eP\u003c/em\u003e-value: \u003csup\u003e\u0026lowast;1\u003c/sup\u003e, \u0026lt;\u0026thinsp;0.001; \u003csup\u003e\u0026lowast;2\u003c/sup\u003e, \u0026lt;\u0026thinsp;0.001; \u003csup\u003e\u0026dagger;1\u003c/sup\u003e, 0.005; \u003csup\u003e\u0026dagger;2\u003c/sup\u003e, \u0026lt;\u0026thinsp;0.001; \u003csup\u003e\u0026dagger;3\u003c/sup\u003e, \u0026lt;\u0026thinsp;0.001\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eDevelopment of SDNS/FRNS stratified by the time from the end of the initial treatment to the first relapse\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAll 14 patients in group A developed SDNS/FRNS within 6 months after nephrotic syndrome onset (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Additionally, 22 out of 23 patients (96%) who experienced the first relapse within 30 days (groups A and B) developed SDNS/FRNS within 6 months, with SDNS/FRNS diagnosis at their second relapse. On the other hand, 18% and 41% of patients in group C developed SDNS/FRNS within 6 months and 12 months, respectively. In this group, 41% did not develop SDNS/FRNS during the follow-up period. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb shows the SDNS/FRNS-free survival curve, revealing a statistically significant difference between those who had a first relapse within 30 days and those who relapsed after 31 days (50% survival: 93 and 408 days, respectively; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003cb\u003eAdministration of immunosuppressive agents stratified by the time from the end of the initial treatment to the first relapse\u003c/b\u003e \u003c/p\u003e \u003cp\u003eTwelve patients in group A (86%) were administered immunosuppressive agents within 6 months after the onset of nephrotic syndrome (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Of the patients who had an initial relapse within 30 days (groups A and B), 19 out of 23 (83%) started treatment with immunosuppressive agents within 6 months after the start of initial treatment, 21 out of 23 (91%) within 12 months, and 23 out of 23 (100%) during the follow-up period. On the other hand, 3 out of 22 (14%) and 6 out of 22 (27%) patients in group C commenced treatment with immunosuppressive agents within 6 months and within 12 months, respectively, and 41% of patients did not commence immunosuppression therapy during the follow-up period. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec shows the immunosuppressive agent-free survival curve, revealing a statistically significant difference between those who had a first relapse within 30 days and those who relapsed after 31 days (50% survival: 111 and 491 days, respectively; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eAssociation between time to first remission and incidence of relapse\u003c/h2\u003e \u003cp\u003eEleven patients took over 20 days to achieve initial remission, all of whom experienced an initial relapse within 30 days after initial treatment. On the other hand, 12 out of 34 patients (35%) who achieved remission within 20 days experienced an initial relapse within 30 days after the initial treatment.\u003c/p\u003e \u003cp\u003eAll 11 patients who took over 20 days to achieve initial remission developed SDNS/FRNS within 6 months of starting initial therapy. Immunosuppression therapy commenced in 10 out of 11 (91%) patients within 6 months and in the remaining patient within 6\u0026ndash;7 months. There were significant differences in the ratio of SDNS/FRNS development within 6 months of starting initial therapy between the group that took over 20 days to achieve initial remission and the group that achieved remission within 20 days (100% and 38%, respectively; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). There were also significant differences in the ratio of immunosuppressant use within 6 months of starting initial therapy between these two groups (91% and 35%, respectively; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study investigated the association between the time to first relapse and the incidence of early second relapse, early development of SDNS/FRNS, and early initiation of immunosuppressive agents among patients with childhood-onset INS who experienced a first relapse within 6 months after disease onset. Almost all patients (96%) who experienced a first relapse within 30 days after initial steroid treatment experienced a second relapse within 6 months after initial treatment and developed SDNS/FRNS at the second relapse, which was significantly higher than patients who experienced a first relapse after 31 days. Of the patients who experienced an initial relapse within 30 days, 83% and 91% commenced immunosuppression therapy within 6 months and 12 months after the start of initial treatment, respectively.\u003c/p\u003e \u003cp\u003ePrevious large prospective studies reported that 18\u0026ndash;28% of INS patients frequently relapsed 6 months after initial therapy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. This correlates with our study findings of SDNS/FRNS development in 30% (45/151) of patients 6 months after the start of initial therapy. Thus, our result suggests that although this was a single-center study, the proportion of severe patients was not high compared with the general population.\u003c/p\u003e \u003cp\u003eRelapse within 6 months after initiating initial therapy has been reported as predictive of SDNS/FRNS development within a follow-up period of 1 or 2 years, or even longer [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, few studies have investigated the risk of earlier development of SDNS/FRNS and earlier initiation of immunosuppressive agents among INS patients. In our study, a small number of patients in those who experienced the first relapse within 30 days after initial treatment did not commence immunosuppression therapy after remission of the second relapse, but all of them started to use immunosuppressive agents during the follow-up period. Considering previous reports, our findings suggest that early recurrence may be associated with a greater tendency toward early and frequent relapse. Although it is crucial to manage INS patients who are trying to use immunosuppressive agents only if necessary and to initiate treatment with appropriate timing, our results suggest that commencing immunosuppression therapy after remission of the first relapse may be considered for patients who relapsed within 30 days after initial treatment.\u003c/p\u003e \u003cp\u003eThere are many reports that a long time to achieve initial remission predicts the development of SDNS/FRNS over more than 2 years [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. An Italian cohort study reported a significant association between the time from the onset of steroid therapy and the risk of relapsing within 3 months after initial treatment [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Several studies revealed that most patients who achieved remission after more than 20 days developed SDNS/FRNS during the follow-up period [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Although the patients in our study were at high risk of developing SDNS/FRNS because we only included patients with a first relapse within 6 months, our results were in line with previous reports. All patients who achieved initial remission after more than 20 days started immunosuppressive agents earlier than patients who achieved remission within 20 days. Thus, achieving initial remission after more than 20 days could be a predictor of SDNS/FRNS development or the initiation of immunosuppressive agents within 6 months, but this measure appears to have very high specificity and low sensitivity. Our findings suggest that a combination of the time to first remission and time to first relapse may help to identify patients at risk of SDNS/FRNS development very early in their clinical course.\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, ours is the first study demonstrating the risk of earlier SDNS/FRNS development and earlier initiation of immunosuppression therapy among INS patients with a high risk of developing SRNS/SDNS. Although there were no significant differences in steroid side effects between the group with a first relapse within 30 days after cessation of steroid therapy and the group with a first relapse after 31 days, commencement of immunosuppression therapy after the first relapse remission instead of waiting for the second relapse may prevent patients from SRNS development at the second relapse. Moreover, a recent study has suggested that nephrin autoantibodies may be a potential factor in INS etiology and disease severity in some patients [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. These findings may lead to more personalized treatment in the future, and it will become even more critical to predict patients with a high risk of early SDNS/FRNS development in the early stages of INS. Further large-scale studies are necessary to investigate whether patients with early relapse within 30 days soon relapse again and to assess whether immunosuppression therapy should commence in such patients after confirming the first relapse and without waiting for the second relapse.\u003c/p\u003e \u003cp\u003eOur study has several limitations. First, due to its retrospective design, the timing of initiation of immunosuppression therapy was not protocolized and depended on each physician. For example, if a patient relapsed following an upper respiratory tract infection or a gastrointestinal tract infection, some physicians waited before administering immunosuppressive agents, even if they met the diagnostic criteria for SDNS/FRNS. However, since none of the patients started immunosuppressive agents prior to two or more relapses, it is unlikely that that the incidence of immunosuppressant initiation is highly estimated. Second, our study only included patients admitted to a single large children\u0026rsquo;s hospital, which could affect the applicability of our study findings to the general population. However, since our study population comprised patients with SSNS at initial relapse, our findings are less likely to be influenced by the institution and may be generalizable. As mentioned above, the incidence of patients in our study developing SDNS/FRNS within 6 months after initial therapy agreed with previous studies, suggesting that our patients were not unique with the absence of bias.\u003c/p\u003e \u003cp\u003eIn conclusion, our findings suggest that most INS patients who experienced an initial relapse within 30 days developed SDNS/FRNS and commenced immunosuppression therapy within 6 months. Additionally, it is likely that these patients will continue to be exposed to high doses of steroids until the commencement of immunosuppression therapy. Thus, it may be reasonable to start immunosuppression therapy in such patients without waiting for the second relapse.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e No external funding was received for this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u003c/strong\u003e Koichi Kamei has obtained research funding from the Public Foundation of Vaccination Research Center, the Terumo Foundation for Life Sciences and Arts, and the Taiju Life Social Welfare Foundation; donations from Chugai Pharmaceutical Co. Ltd., Astellas Pharma Inc., Ono Pharmaceutical Co. Ltd., Teijin Pharma Ltd., Shionogi Co. Ltd., and Otsuka Pharmaceutical Co. Ltd.; and lecture fees from Tanabe Mitsubishi Pharma, Baxter\u0026nbsp;Ltd., and\u0026nbsp;Zenyaku Kogyo Co. Ltd.\u0026nbsp;All other authors have no potential conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e The data supporting the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e All authors were physicians who treated the patients in this study. Yuta Inoki conducted the study, collected the clinical and laboratory data, and wrote the manuscript. Kentaro Nishi, Kei Osaka, Tomoya Kaneda, Misaki Akiyama, Mai Sato, and Masao Ogura reviewed and edited the manuscript. Koichi Kamei supervised the work and revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e This study was approved by the Ethics Committee of the National Center for Child Health and Development\u0026nbsp;(approval no. 2022\u0026ndash;210). It was conducted according to the principles of the Declaration of Helsinki and the ethics guidelines of the Japanese Ministry of Health, Labor and Welfare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u003c/strong\u003e Due to the retrospective nature of this study, informed consent for participation was waived.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish:\u003c/strong\u003e Due to the retrospective nature of this study, informed consent to publish was waived.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNoone DG, Iijima K, Parekh R (2018) Idiopathic nephrotic syndrome in children. 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J Am Soc Nephrol 33:238\u0026ndash;252. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1681/ASN.2021060794\u003c/span\u003e\u003cspan address=\"10.1681/ASN.2021060794\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"children, steroid-dependent nephrotic syndrome, frequently relapsing nephrotic syndrome, immunosuppressive agents, relapse","lastPublishedDoi":"10.21203/rs.3.rs-3425578/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3425578/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eNephrotic syndrome relapse within 6 months is a known risk factor for steroid-dependent nephrotic syndrome/frequently relapsing nephrotic syndrome (SDNS/FRNS), but the risk of early development of SDNS/FRNS and initiation of immunosuppression therapy remains unknown.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003ePatients with childhood-onset idiopathic nephrotic syndrome who had the first relapse within 6 months were enrolled. We analyzed the relationship between the time of the first and second relapse, incidence of SDNS/FRNS, and initiation of immunosuppression therapy.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eForty-five patients were enrolled. Twenty out of 23 patients (87%) with a first relapse within 30 days after discontinuing initial steroid therapy experienced a second relapse within 30 days after discontinuing steroid therapy. Additionally, most patients in this group (96%) experienced a second relapse within 6 months after the onset and were diagnosed as SDNS/FRNS at this time. In this group, the incidence of SDNS/FRNS development within 6 months was 96%. In contrast, the incidence of SDNS/FRNS development within 6 months and 12 months was 18% and 41%, respectively, in patients with a first relapse more than 30 days after steroid discontinuation. The incidence of initiation of immunosuppressive agents within 6 months and 12 months was 83% and 91%, respectively, in the former group and 14% and 27%, respectively, in the latter group.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eMost patients with a first relapse within 30 days after discontinuing steroid therapy developed SDNS/FRNS and were administered immunosuppressive agents within 6 months. Thus, it may be reasonable to start immunosuppression therapy in this group without waiting for the second relapse.\u003c/p\u003e","manuscriptTitle":"Association between the time of initial relapse and subsequent relapses in patients with childhood-onset idiopathic nephrotic syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-10-16 23:12:13","doi":"10.21203/rs.3.rs-3425578/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revisions Needed","date":"2023-10-30T16:59:37+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2023-10-12T15:10:21+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-10-12T14:59:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-10-10T07:16:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Nephrology","date":"2023-10-09T21:01:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b9976d15-2afb-4f42-a9dd-ae75e9de48dc","owner":[],"postedDate":"October 16th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-01-29T15:27:58+00:00","versionOfRecord":{"articleIdentity":"rs-3425578","link":"https://doi.org/10.1007/s00467-024-06286-9","journal":{"identity":"pediatric-nephrology","isVorOnly":false,"title":"Pediatric Nephrology"},"publishedOn":"2024-01-25 15:18:39","publishedOnDateReadable":"January 25th, 2024"},"versionCreatedAt":"2023-10-16 23:12:13","video":"","vorDoi":"10.1007/s00467-024-06286-9","vorDoiUrl":"https://doi.org/10.1007/s00467-024-06286-9","workflowStages":[]},"version":"v1","identity":"rs-3425578","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3425578","identity":"rs-3425578","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}