Response predictors and long-term outcomes of preprandial single-daily cyclosporine in children with steroid-dependent nephrotic syndrome caused by minimal change disease: a single-center experience

Response predictors and long-term outcomes of preprandial single-daily cyclosporine in children with steroid-dependent nephrotic syndrome caused by minimal change disease: a single-center experience | 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 Response predictors and long-term outcomes of preprandial single-daily cyclosporine in children with steroid-dependent nephrotic syndrome caused by minimal change disease: a single-center experience Yasuko Urushihara, Shuichiro Fujinaga, Tomohiko Nishino, Koji Sakuraya, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5921376/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Clinical practice guidelines for idiopathic nephrotic syndrome (NS) in children recommend twice-daily cyclosporine as a preferred steroid-sparing agent for steroid-dependent nephrotic syndrome (SDNS). Although single-daily cyclosporine (S-CS) may offer an effective therapeutic option with increased compliance and reduced nephrotoxicity, response predictors and long-term outcomes following this regimen remain unclear in this cohort. Methods A retrospective study was conducted on children with SDNS caused by minimal change disease (MCD) who were treated with preprandial S-CS to maintain 2-hour post-dose levels of 500–700 ng/mL between October 2005 and December 2021. The primary endpoint was the probability of SDNS-free survival during S-CS therapy. The secondary endpoint was the long-term outcome at the last visit. Results After initiating S-CS therapy in 48 children, 31 patients, including 18 who did not experience relapse during treatment, were able to discontinue steroid dependency (response group), while 17 patients experienced treatment failure. The median time to the first relapse after NS diagnosis was significantly longer in the response group than in the treatment failure group (4.3 vs . 2.1 months, p < 0.05). Multivariate logistic regression analysis identified a longer time until the first relapse (≥ 2.2 months) after NS diagnosis as an independent predictive factor for a favorable response to S-CS therapy (odds ratio: 21.0, p < 0.005). None of the patients progressed to chronic kidney disease Stage 3 or higher. Conclusions S-CS may offer a promising treatment option for children with SDNS caused by MCD who do not experience early relapse following NS diagnosis. Single-daily cyclosporine therapy C2 monitoring Response predictor Steroid-dependent nephrotic syndrome Minimal change disease Long-term Follow-up Figures Figure 1 Figure 2 Introduction The efficacy of twice-daily cyclosporine (T-CS) in maintaining remission in children with frequent-relapsing and steroid-dependent nephrotic syndrome (FR/SDNS) is well established [ 1 , 2 ]. Several studies suggest that administering CS before meals leads to more stable absorption compared to after meals [ 3 , 4 , 5 ]. Current guidelines for children with idiopathic nephrotic syndrome (NS) recommend splitting the dose of CS into two doses taken every 12 hours before meals by 15–30 minutes for FR/SDNS [ 6 , 7 ]. However, the practicality of long-term, twice-daily dosing before meals in children may be challenging. Previous studies in adult patients with NS indicate that single-daily cyclosporine (S-CS) may result in fewer side effects, lower dosage, improved adherence, and reduced costs compared to standard T-CS [ 8 , 9 ]. The 2023 clinical practice guideline for chronic kidney disease in Japan recommends once-daily CS administration for adult patients with NS [ 10 ]. However, there is limited information on the use of S-CS in children with SDNS, with only short-term retrospective studies on a small number of patients available [ 11 – 13 ]. Furthermore, the specific patient characteristics that may benefit from S-CS have not been clearly defined. Given that patients with childhood-onset SDNS often experience relapses into adulthood [ 14 ], differences in CS dosage and administration between adults and children present a significant challenge. In 2008, we demonstrated that treating children with SDNS caused by minimal change disease (MCD) with preprandial low-dose S-CS and monitoring 2-hour post-dose (C2) levels could help maintain remission [ 15 ]. We suggested conducting protocol kidney biopsies after more than 2 years of treatment to assess for chronic nephrotoxicity [ 16 ]. In this study, we assessed response predictors and long-term outcomes in children with SDNS treated with S-CS at a single center. Patients and methods Patients A retrospective review of the clinical outcomes of 48 patients diagnosed with MCD who were treated with S-CS for childhood-onset SDNS (1–15 years) between October 2005 and December 2021 was conducted. Short-term clinical data for 30 patients have been previously reported [ 15 – 17 ]. Patients with steroid-resistant NS, histological evidence of focal segmental glomerulosclerosis, prior CS treatment, and those with less than 3 years of follow-up were excluded from the study. This study was approved by the ethics committee of Saitama Children’s Medical Center (approval no. 2023-01-008-001) and Saitama Medical Center, Saitama Medical University (approval no. 2024-044). Definitions The definitions and criteria for NS, complete remission, relapse, frequent relapse, steroid dependency, and steroid resistance were adopted from the Clinical Practice Guideline for the International Pediatric Nephrology Association [ 7 ]. Treatment failure was defined as a condition where there is a switch from S-CS to conventional T-CS due to persistent steroid dependency. Steroid-dependent dose in SDNS was defined as the prednisolone dose (mg/kg/day) that maintained complete remission before a relapse occurred, categorized into low-dose (< 0.25 mg/kg/day), moderate-dose (0.25–0.5 mg/kg/day) and high-dose (≥ 0.5 mg/kg/day). Obesity was defined as a body mass index greater than 25 kg/m 2 , while short stature was defined as a height of less than − 2 standard deviation score compared to the normal stature for age and sex. Treatment protocol After the diagnosis of new-onset NS, all patients were treated with an 8-week steroid treatment regimen. This regimen comprised 4 weeks of daily prednisolone at a dose of 2 mg/kg or 60 mg/m 2 (up to a maximum of 60 mg), followed by 4 weeks of alternate-day treatment at a dose of 1.3 mg/kg or 40 mg/m 2 (up to a maximum of 40 mg). In case of relapse, prednisolone was administered at a dose of 1–2 mg/kg/day until proteinuria was undetectable for at least three consecutive days. Subsequently, prednisolone was administered on alternate days, and the dosage was gradually tapered off over a period of 6 months, reducing by 5–10 mg every 2–4 weeks. For children under 10 years old with low-dose SDNS, a single daily high-dose of mizoribine (10 mg/kg/day maximum, 300 mg/day; Bredinine, orally disintegrating tablet, Asahikasei, Tokyo, Japan) was used as a steroid-sparing agent (SSA) [ 18 ]. For young children who developed moderate-dose SDNS or failed mizoribine, cyclophosphamide (Endoxan, tablet or oral solution, Shionogi Co., Osaka, Japan) was administered at a single daily dose of 2–2.5 mg/kg/day for 12 weeks (cumulative dosage, 200 mg/kg) [ 19 ]. For younger children who developed high-dose SDNS or failed cyclophosphamide and/or mizoribine, or for older children (10 years and above) with SDNS, CS (Neoral, capsule or oral solution, Novartis Pharma Co., Tokyo, Japan) was initiated at a daily dose of 1.5–2 mg/kg before breakfast. The CS dosage was adjusted to maintain 2-hour post-dose (C2) levels of 500–700 ng/mL. In case of persistent steroid dependency after S-CS initiation, patients were switched to conventional T-CS, maintaining C2 levels of 400–600 ng/mL. After 2–3 years of CS treatment, the dosage was gradually tapered off within 6 months. For patients experiencing relapses and/or steroid toxicity after CS treatment, mycophenolate mofetil (MMF; 30–40 mg/kg/day or 1000–1200 mg/m 2 /day in two divided doses; maximum, 2000 mg/day; Cellcept, capsule or oral solution, Chugai Co. Tokyo, Japan) was offered as an alternative treatment [ 20 ]. Patients who achieved more than 12 months of prednisolone-free remission had MMF gradually tapered off. Since 2007, a single dose (375 mg/m 2 ; maximum, 500 mg) of rituximab (Rituxan, injection, Zenyaku Co., Tokyo, Japan) has been administered to patients experiencing relapse during treatment with CS or MMF [ 21 ]. To assess treatment outcomes and identify potential drug toxicity, clinical and laboratory parameters were monitored every 1–3 months. Clinical assessments included measurements of height, body weight, and blood pressure. Laboratory assessments included urine examination (dipstick and quantitative proteinuria), complete blood count, and serum urea, creatinine, electrolyte, albumin, cholesterol, transaminase, bilirubin, uric acid, C-reactive protein, and immunoglobulin levels, as well as drug levels in the blood, including CS, mizoribine, and mycophenolic acid. Histological evaluation In all patients, histological evidence of MCD was confirmed by kidney biopsy prior to initiating S-CS. After 2–3 years of CS treatment, protocol kidney biopsies were performed to confirm the presence of CS-related nephrotoxicity. Kidney specimens were examined using light, immunofluorescence, and electron microscopy. CS nephrotoxicity was graded based on the presence of arteriolar hyalinosis with accompanying interstitial fibrosis (Grade ±, 50%) [ 22 ]. Outcomes The primary endpoint was the probability of survival without regression to steroid dependency, defined as the time from starting S-CS to switching to T-CS. The secondary endpoint at the last visit included chronic kidney disease (CKD) defined as persistent estimated glomerular filtration rate (eGFR) 140/90 mmHg for more than three readings or ongoing antihypertensive treatment), obesity (body mass index > 25 kg/m 2 ), short stature ( < − 2 standard deviation score), and treatment-free remission for more than 2 years. Statistical analysis Categorical variables were compared using Fisher's exact test and reported as frequencies and percentages, while continuous variables were expressed as medians with interquartile range (IQR) and compared using the non-parametric two-sample Wilcoxon signed-rank test or the non-parametric Mann–Whitney U test. Receiver-operating characteristics (ROC) curve analysis was utilized to determine the optimal cut-off point for time until the first relapse after NS diagnosis. The Kaplan–Meier method and log-rank test were employed to analyze the probability of SDNS-free survival post S-CS. Logistic regression was conducted to identify independent predictive factors for a favorable response to S-CS. Statistical analyses were conducted using R version 4.2.2 and EZR version 1.61 (Saitama Medical Center, Jichi Medical University), with p -values less than 0.05 considered statistically significant. Results Clinical course during single-daily cyclosporine therapy After initiating S-CS therapy, 31 out of 48 patients with SDNS (65%) were able to discontinue prednisolone use (response group), and 18 of these 31 patients did not experience a relapse of NS during treatment. In the response group, treatment with S-CS (median treatment period: 2.2 years, IQR: 2.1–2.3 years; median dose: 2.5 mg/kg/day, IQR: 2.1–2.9 mg/kg/day; median C2 level: 625 ng/mL, IQR: 547–667 ng/mL) resulted in a significant decrease in the median relapse rate from 3.9 (IQR: 2.6–5.1) to 0 (0.0–0.5) episodes per 12 months ( p < 0.0001). Although two of the 31 patients developed CS nephrotoxicity (Grade 1 and 2), there was no significant difference in eGFR before and after S-CS treatment. Conversely, 17 patients (35%) experienced treatment failure, and 11 of these patients received rituximab because of persistent steroid dependency after switching from S-CS to T-CS. Although six patients experienced transiently elevated transaminase levels and three patients had hypertension, no severe adverse events requiring treatment discontinuation were observed in any of the patients during S-CS treatment. Predictors of response to single-daily cyclosporine therapy The baseline characteristics and clinical course were compared between patients in the response group and those in the treatment failure group (Table 1 ). The median period from NS diagnosis to the first relapse was significantly longer in the response group than in the treatment failure group (4.3 vs . 2.1 months, p < 0.05). The ROC curve indicated that the optimal cut-off period from NS diagnosis to the first relapse for predicting a favorable response to S-CS therapy was 2.2 months or more, with an area under the curve of 0.716, sensitivity of 64.7%, and specificity of 87.1% (Fig. 1 ). Kaplan–Meier analysis demonstrated a significantly higher probability of SDNS-free survival in the non-early relapse group (≥ 2.2 months) than in the early relapse group (< 2.2 months) ( p < 0.005, log-rank test; Fig. 2 ). Furthermore, multivariate logistic regression analysis identified a longer period from NS diagnosis to the first relapse (≥ 2.2 months) as the only significant independent predictive factor for a favorable response to S-CS (odds ratio: 21.0, 95% confidence interval: 3.24–136.0, p < 0.005; Table 2 ). Table 1 Comparison of baseline characteristics and clinical course between the response and treatment failure groups Overall Response group Treatment failure group P –value ( n = 48) ( n = 31) ( n = 17) Male, n (%) 38 (79.2) 25 (80.6) 13 (76.5) 0.73 Age at nephrotic syndrome onset (years) 5.4 (3.2–10.3) 5.2 (3.1–9.6) 8.8 (3.7–11.0) 0.21 Days to remission after initial steroid treatment (days) 9 (8–10) ( n = 44) 8 (8–10) ( n = 29) 9 (9–12) ( n = 15) 0.10 Period from nephrotic syndrome diagnosis to the first relapse (months) 3.9 (2.2–5.5) 4.3 (3.0–5.7) 2.1 (1.4–4.1) 0.014 Period from nephrotic syndrome diagnosis to the first relapse (months) < 2.2 months/ ≥ 2.2 months 13/35 4/27 9/8 0.0055 Use of steroid-sparing agents before S-CS therapy, n (%) 23 (47.9) 15 (48.4) 8 (47.1) 1.00 Cyclophosphamide 17 (35.4) 12 (38.7) 5 (29.4) 0.75 Mizoribine 17 (35.4) 10 (32.3) 7 (41.2) 0.55 Number of relapse before S-CS therapy (per year) 4.2 (2.7–5.3) 3.9 (2.7–5.1) 4.8 (3.2–7.5) 0.095 Threshold dose of prednisolone before S-CS therapy (mg/kg/day) 0.53 (0.26–0.88) 0.51 (0.26–0.82) 0.59 (0.28–1.03) 0.55 Period from nephrotic syndrome diagnosis to S-CS initiation 1.0(0.5–2.7) 1.1(0.6–3.0) 0.7(0.3–1.7) 0.13 Age at S-CS initiation (years) 9.2 (4.5–12.1) 8.5 (4.5–11.9) 10.9 (4.8–12.4) 0.53 Data are shown as median (interquartile range) or as n (%). S-CS, single-daily cyclosporine Table 2 Predictive factors for favorable response to single-daily cyclosporine using a logistic regression model Odds ratio 95% CI P –value Older age at nephrotic syndrome diagnosis 0.88 0.72–1.09 0.25 Longer period from nephrotic syndrome diagnosis to the first relapse (≥ 2.2 months) 21.0 3.24–136.0 0.0014 Longer days to remission at new-onset nephrotic syndrome after initial steroid treatment 0.97 0.72–1.33 0.87 Long-term outcome after single-daily cyclosporine therapy After discontinuation of S-CS, 40 out of 48 patients with SDNS received additional SSA and/or rituximab, but none of them developed CKD Stage 3 or higher (Table 3 ). At the last visit, only 13 patients achieved long-term treatment-free remission for more than 2 years, while 29 patients continued to receive SSA and/or rituximab during the last 2 years. Table 3 Long-term outcomes of 48 patients after single-daily cyclosporine therapy Overall ( n = 48) Age at the last follow-up (years) 19.0 (13.3–22.8) Duration until the last follow-up from nephrotic syndrome diagnosis (years) 11.0 (7.8–14.8) Duration until the last follow-up from S–CS initiation (years) 9.8 (6.1–11.4) Relapse after S-CS discontinuation, n (%) 39 (81.3) Use of steroid-sparing agents after S-CS discontinuation, n (%) 43 (89.6) Mycophenolate mofetil 40 (83.3) Cyclophosphamide 5 (10.4) Cyclosporine 5 (10.4) Mizoribine 10 (20.8) Use of rituximab, n (%) 20 (41.7) Treatments states at the last follow-up, n (%) None 27 (56.3) Prednisolone 6 (12.5) Mycophenolate mofetil 7 (14.6) Cyclophosphamide 0 (0) Cyclosporine 1 (2.1) Mizoribine 1 (2.1) Rituximab 10 (20.8) Long-term complications at the last follow-up, n (%) Chronic kidney disease 7 (14.6) Estimated glomerular filtration rate, 60–90 mL/min/1.73 m 2 7 (14.6) Estimated glomerular filtration rate, < 60 mL/min/1.73 m 2 0 (0) Hypertension 2 (4.2) Short stature 2 (4.2) Obesity 3 (6.3) Cataract 2 (4.2) Data are shown as median (interquartile range) or as n (%). S-CS, single-daily cyclosporine Discussion In this study, we observed that S-CS enabled the discontinuation of prednisolone in 31 out of 48 patients with SDNS (65%) and maintained relapse-free survival in 18 patients (38%) during the treatment. In particular, S-CS was highly effective in patients without a history of early first relapse (< 2.2 months after NS diagnosis). Although two patients (6.5%) developed mild chronic nephrotoxicity after S-CS, none progressed to CKD Stage 3 or higher at the last visit. Therefore, initiating S-CS rather than T-CS is preferable in children with SDNS, especially in those without a history of early first relapse. Iijima et al . conducted a multicenter, randomized controlled trial comparing the efficacy and safety between high C2 and low C2 groups in 93 children with FRNS who received conventional T-CS therapy [ 2 ]. The relapse-free survival rate at 24 months of T-CS therapy was 64.4% in the high C2 group and 50% in the low C2 group, respectively, which was superior to the relapse-free remission rate of S-CS therapy in our study. The discrepancy in relapse-free rates between the two studies may be attributed to variations in disease activity at the time of CS initiation: 60% of their patients had SDNS, and only 20% had a history of SSA use such as cyclophosphamide and mizoribine before CS, while all our patients had SDNS, and 50% had a history of SSA use. Furthermore, 11 out of the 17 patients in the treatment failure group required rituximab because of persistent steroid dependency after T-CS therapy, and switching from S-CS to T-CS was effective in only 6 patients; the number needed to treat to achieve efficacy of T-CS for children with SDNS in this study was 8 patients. Thus, the proportion of children with SDNS who respond to T-CS but not to S-CS may be relatively limited. To the best of our knowledge, there have been no randomized controlled trials on the treatment with preprandial S-CS monitoring C2 levels in children with NS, and thus, the optimal target range for maintaining remission remains unknown. Saito et al . conducted a randomized multicenter trial comparing the efficacy of preprandial S-CS to that of T-CS in 48 adult patients with NS caused by idiopathic membranous nephropathy [ 23 ]. The authors concluded that the appropriate strategy for CS treatment is to maintain C2 levels above 600 ng/mL by preprandial S-CS, as the optimal cut-off level of C2 for achieving remission was determined to be 615 ng/mL by ROC analysis (sensitivity 75.6%, specificity 76.9%). However, three patients with S-CS maintaining high C2 levels above 900 ng/mL were withdrawn from the study because of CS-related adverse events. In our study, one patient with S-CS maintaining high C2 levels of approximately 700 ng/mL for over 2 years developed CS nephrotoxicity (Grade 2) at the age of 11 years. Despite discontinuation of CS, the patient progressed to CKD, with an eGFR of 70–80 mL/min/1.73 m 2 and hypertension at the last follow-up at the age of 28 years. Thus, a history of CS nephrotoxicity may be associated with kidney complications in adulthood. Furthermore, Shirai et al . conducted a single-center, randomized trial comparing the efficacy and safety between preprandial S-CS plus prednisolone and prednisolone-alone groups in 21 adult NS patients with new-onset MCD [ 24 ]. They found that the relapse rate during the 18-month treatment period was significantly lower in the S-CS plus prednisolone group maintaining C2 levels above 600 ng/mL than in the prednisolone-alone group (1/9 vs . 5/10, p = 0.02). However, similar to adverse events in our study, liver dysfunction was frequently observed in the S-CS plus prednisolone group, necessitating a reduction in CS dosage. Although further prospective studies are needed, treatment with preprandial S-CS maintaining C2 levels of 500–700 ng/mL may be optimal for children with SDNS in terms of safety and efficacy. Previous studies have shown that a longer time until remission after initial treatment and a shorter time from disease onset to first relapse are significant predictors of FR/SDNS development [ 25 – 27 ]. In a prospective study of 145 children with new-onset steroid-sensitive NS who received the standard 8-week steroid treatment, Nakanishi et al . reported that a time until initial response of 9 days or above and a duration from initial treatment to first relapse of less than 6 months were significant predictors of FRNS progression [ 28 ]. These findings were supported by several studies, including ours [ 29 ]. Furthermore, we hypothesize that these two clinical characteristics following standard initial treatment may not only predict relapsing disease courses but also influence the necessity and response to SSA in children with FR/SDNS. In a retrospective study of 45 children with steroid-sensitive NS who experienced their first relapse within 6 months after NS diagnosis, Inoki et al . found that only four out of 22 patients (18%) who experienced the first relapse more than 3 months after initial treatment developed FR/SDNS within 6 months [ 30 ]. In contrast, 23 out of 24 patients (96%) who relapsed within 3 months developed FR/SDNS, with 19 of these patients requiring SSA within 6 months. Our recent study revealed that all seven patients with very early relapse during the initial 4-week full-dose prednisolone treatment required T-CS because of SR/SDNS progression [ 31 ]. In the present study, S-CS was effective in most patients with SDNS who experienced their first relapse ≥ 2.2 months after NS diagnosis. However, less than one-third of patients who relapsed earlier, within 2.2 months, responded to S-CS therapy. Overall, an earlier first relapse after standard initial steroid treatment for NS onset is associated with a higher likelihood of SDND with high disease activity. Although there is insufficient evidence to establish a first-line SSA in children with SDNS, we suggest that the selection of the agent should be guided by disease activity, such as the timing of the first relapse and steroid-dependent dose. Therefore, S-CS may be a promising treatment option prior to T-CS in children with SDNS who do not experience early relapse after NS onset. In a long-term follow-up study of 46 children with FRNS after the initiation of conventional T-CS (mean age, 18.7 years; median follow-up period, 10.3 years), only ten patients (22%) achieved treatment-free remission for more than 2 years, whereas half of the patients continued to experience frequent relapses or were receiving SSA at the last visit [ 32 ]. These unfavorable outcomes after T-CS therapy were similar to the long-term outcomes of S-CS therapy in our study. Based on the persistent disease activity in adulthood following both T-CS and S-CS, we suggest that low-dose S-CS may be a preferable initial regimen for children with SDNS, consistent with adult patients. There are several limitations to consider in this study. First, given the uncontrolled retrospective design, inherent selection and reporting biases could not be avoided. Second, the sample size was too small to draw robust conclusions. Third, the variability in the selection of SSA after S-CS and the duration of follow-up among patients may have impacted the outcomes. However, we focused on children with SDNS caused by biopsy-proven MCD to ensure a more homogeneous population. All patients underwent kidney biopsies before and after CS treatment, and the treatment protocols, including SSA use, were relatively homogeneous in this single-center study. Furthermore, to the best of our knowledge, this study represents the longest follow-up of children with SDNS after S-CS to date. In conclusion, our data suggest that preprandial S-CS prior to conventional T-CS could be a promising treatment option for children with SDNS caused by MCD and without a history of early relapse after NS onset. Although kidney complications at the last follow-up were mild in this study, long-term treatment-free remission was rarely achieved. Therefore, the development of novel treatment strategies, such as pre-emptive rituximab administration, is urgently required to prevent persistent active disease into adulthood following the initiation of S-CS [ 33 ]. Declarations Ethical approval: This study was conducted in accordance with the principles of the Declaration of Helsinki and the Ethical Guidelines for Medical and Biological Research Involving Human Subjects of the Ministry of Health, Labour and Welfare of Japan. This study was approved by the Ethics Committee of Saitama Children’s Medical Center (approval no. 2023-01-008-001) and Saitama Medical Center, Saitama Medical University (approval no. 2024-044). Informed consent The Institutional Review Board waived the requirement for informed consent due to the retrospective nature of this study. Competing interests: The authors declare no competing interests. Funding SF has received grants-in-aid for research from Saitama Children’s Medical Center. Author contribution YU and SF designed the study, drafted the manuscript, were responsible for the data integrity and analysis results. TN provided statistical support. YU and KS collected the data from the medical charts. All authors critically reviewed and approved the final manuscript. Acknowledgments We want to thank Enago for editing the draft of this manuscript. Data availability More detailed datasets are available from the corresponding author upon reasonable request. References Ishikura K, Yoshikawa N, Hattori S, Sasaki S, Iijima K, Nakanishi K, Matsuyama T, Yata N, Ando T, Honda M, for Japanese Study Group of Renal Disease in Children (2010) Treatment with microemulsified cyclosporine in children with frequently relapsing nephrotic syndrome. 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Pediatr Nephrol 22:71–76 Fujinaga S, Someya T, Watanabe T, Ito A, Ohtomo Y, Shimizu T, Kaneko K (2013) Cyclosporine versus mycophenolate mofetil for maintenance of remission of steroid-dependent nephrotic syndrome after a single infusion of rituximab. Eur J Pediatr 172:513–518 Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, Halloran PF, Baldwin W, Banfi G, Collins AB, Cosio F, David DS, Drachenberg C, Einecke G, Fogo AB, Gibson IW, Glotz D, Iskandar SS, Kraus E, Lerut E, Mannon RB, Mihatsch M, Nankivell BJ, Nickeleit V, Papadimitriou JC, Randhawa P, Regele H, Renaudin K, Roberts I, Seron D, Smith RN, Valente M (2008) Banff 07 classification of kidney allograft pathology: updates and future directions. Am J Transplan 8:753–760 Saito T, Iwano M, Matsumoto K, Mitarai T, Yokoyama H, Yorioka N, Nishi S, Yoshimura A, Sato H, Ogahara S, Shuto H, Kataoka Y, Ueda S, Koyama A, Maruyama S, Nangaku M, Imai E, Matsuo S, Tomino Y, Refractory Nephrotic Syndrome Study Group (2014) Significance of combined cyclosporine-prednisolone therapy and cyclosporine blood concentration monitoring for idiopathic membranous nephropathy with steroid-resistant nephrotic syndrome: a randomized controlled multicenter trial. Clin Exp Nephrol 18:784–794 Shirai S, Imai N, Sueki S, Matsui K, Tominaga N, Sakurada T, Yasuda T, Kimura K, Shibagaki Y (2018) Combined cyclosporine and prednisolone therapy using cyclosporine blood concentration monitoring for adult patients with new-onset minimal change nephrotic syndrome: a single-center pilot randomized trial. Clin Exp Nephrol 22:283–290 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 Harambat J, Godron A, Ernould S, Rigothier C, Llanas B, Leroy S (2013) Prediction of steroid-sparing agent use in childhood idiopathic nephrotic syndrome. Pediatr Nephrol 28:631–638 Sureshkumar P, Hodson EM, Willis NS, Barzi F, Craig JC (2014) Predictors of remission and relapse in idiopathic nephrotic syndrome: a prospective cohort study. Pediatr Nephrol 29:1039–1046 Nakanishi K, Iijima K, Ishikura K, Hataya H, Nakazato H, Sasaki S, Honda M, Yoshikawa N, Japanese Study Group of Renal Disease in Children (2013) Two-year outcome of the ISKDC regimen and frequent-relapsing risk in children with idiopathic nephrotic syndrome. Clin J Am Soc Nephrol 8:756–762 Fujinaga S, Hirano D, Nishizaki N (2011) Early identification of steroid dependency in Japanese children with steroid-sensitive nephrotic syndrome undergoing short-term initial steroid therapy. Pediatr Nephrol 26:485–486 Inoki Y, Nishi K, Osaka K, Kaneda T, Akiyama M, Sato M, Ogura M, Kamei K (2024) Association between the time of initial relapse and subsequent relapses in patients with childhood-onset idiopathic nephrotic syndrome. Pediatr Nephrol 39:2393–2401 Morishita T, Fujinaga S, Sakuraya K (2025) Necessity of cyclosporine for minimal change disease with transient remission during initial 4-week prednisolone treatment: is it steroid-sensitive or steroid-resistant nephrotic syndrome? Pediatr Nephrol 40:265–266 Ishikura K, Yoshikawa N, Nakazato H, Sasaki S, Nakanishi K, Matsuyama T, Ito S, Hamasaki Y, Yata N, Ando T, Iijima K, Honda M, Japanese Study Group of Renal Disease in Children (2015) Morbidity in children with frequently relapsing nephrosis: 10-year follow-up of a randomized controlled trial. Pediatr Nephrol 30:459–468 Fujinaga S (2024) Pre-emptive rituximab administration for discontinuation of steroid-sparing agents in patients with complicated frequently-relapsing or steroid-dependent nephrotic syndrome. Pediatr Nephrol 39:282 Supplementary Files GraphicalabstractSCS.pptx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-5921376","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":409064489,"identity":"49bd884a-b8f7-4ee8-bc75-5352a9018f18","order_by":0,"name":"Yasuko Urushihara","email":"","orcid":"","institution":"Saitama Medical Center: Saitama Ika Daigaku Sogo Iryo Center","correspondingAuthor":false,"prefix":"","firstName":"Yasuko","middleName":"","lastName":"Urushihara","suffix":""},{"id":409064490,"identity":"8a6fc01f-8406-450d-a2c9-dd6b691484d8","order_by":1,"name":"Shuichiro Fujinaga","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIie2RsYoCMRRFryxo82DbBIX9hQfCyILoryQEphIV/IGA4Ja2Fn7EwoJYRgRt5gMsRwSrKbS30JFZtnHj2smSU4Tw4JB784BA4AmpWJQBhnqFcSAuxsKjkCsUaWP1iAIodh0G/SUYobLfUb/Vra8VI+s3u6gOHd7nPoUadWIziJJUlaYcD1BbKcjkd6UNKleJnZ5tlHshXmorLgnlyB/sqnxNtC2U3uGOguiqfAqD71dwR6FITtnoSbLH4tJFj0TMztclDyayU0uPP3rHNDs19ViY7U56fgxv6c/d5Ue+pqW0HuUmpePDSiAQCPxjzkLiSkqZdh38AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-2957-3705","institution":"Saitama children's medical center","correspondingAuthor":true,"prefix":"","firstName":"Shuichiro","middleName":"","lastName":"Fujinaga","suffix":""},{"id":409064491,"identity":"ce2c7882-7cb5-4345-9dc0-fc64ff3a8fb5","order_by":2,"name":"Tomohiko Nishino","email":"","orcid":"","institution":"Nishino child clinic","correspondingAuthor":false,"prefix":"","firstName":"Tomohiko","middleName":"","lastName":"Nishino","suffix":""},{"id":409064492,"identity":"a316af2f-bff5-4790-99bf-88a86a2e7cae","order_by":3,"name":"Koji Sakuraya","email":"","orcid":"","institution":"saitama children's medical center","correspondingAuthor":false,"prefix":"","firstName":"Koji","middleName":"","lastName":"Sakuraya","suffix":""},{"id":409064493,"identity":"6fc0d8ea-de8f-4359-8937-26ea39d74e47","order_by":4,"name":"Yoshiyuki Ohtomo","email":"","orcid":"","institution":"Juntendo Daigaku Igakubu Fuzoku Nerima Byoin","correspondingAuthor":false,"prefix":"","firstName":"Yoshiyuki","middleName":"","lastName":"Ohtomo","suffix":""},{"id":409064494,"identity":"867a1e87-7de2-46cf-917a-be3edc3d39dd","order_by":5,"name":"Satoshi Masutani","email":"","orcid":"","institution":"Saitama Medical Center: Saitama Ika Daigaku Sogo Iryo Center","correspondingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Masutani","suffix":""}],"badges":[],"createdAt":"2025-01-29 01:40:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5921376/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5921376/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":75314671,"identity":"7f2eddfc-bb41-457b-a890-1dfe801e3037","added_by":"auto","created_at":"2025-02-03 09:32:30","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":31491,"visible":true,"origin":"","legend":"\u003cp\u003eReceiver operating curve for discriminating between the response and treatment failure groups based onthe timing of the first relapse after nephrotic syndrome diagnosis\u003c/p\u003e","description":"","filename":"Slide1.png","url":"https://assets-eu.researchsquare.com/files/rs-5921376/v1/1ed48af1dbc6b8ba225feeed.png"},{"id":75314672,"identity":"8801e646-be8e-446c-8cc6-d8435911f679","added_by":"auto","created_at":"2025-02-03 09:32:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":36863,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meir curves showing the probability of survival without regression to steroid dependency according to the timing of the first relapse after nephrotic syndrome diagnosis\u003c/p\u003e\n\u003cp\u003eThe probability of steroid-dependent nephrotic syndrome-free survival was significantly higher in the non-early relapse group (≥ 2.2 months) than in the early relapse group (\u0026lt;2.2 months) (\u003cem\u003ep\u003c/em\u003e\u0026lt; 0.005, log-rank test).\u003c/p\u003e","description":"","filename":"Slide2.png","url":"https://assets-eu.researchsquare.com/files/rs-5921376/v1/24e9cd78e94fa76f51f3d8cb.png"},{"id":75926867,"identity":"32915c0e-03ae-4f09-992c-ccf3cff09b84","added_by":"auto","created_at":"2025-02-10 15:23:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":790960,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5921376/v1/e4610fdf-d288-4ede-9b1b-564ce2c09ea1.pdf"},{"id":75316444,"identity":"2b247738-dcc1-46ca-8cb6-23bea5a74911","added_by":"auto","created_at":"2025-02-03 09:40:30","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":79056,"visible":true,"origin":"","legend":"","description":"","filename":"GraphicalabstractSCS.pptx","url":"https://assets-eu.researchsquare.com/files/rs-5921376/v1/cf4c50cee33b616bf94fbb97.pptx"}],"financialInterests":"","formattedTitle":"Response predictors and long-term outcomes of preprandial single-daily cyclosporine in children with steroid-dependent nephrotic syndrome caused by minimal change disease: a single-center experience","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe efficacy of twice-daily cyclosporine (T-CS) in maintaining remission in children with frequent-relapsing and steroid-dependent nephrotic syndrome (FR/SDNS) is well established [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Several studies suggest that administering CS before meals leads to more stable absorption compared to after meals [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Current guidelines for children with idiopathic nephrotic syndrome (NS) recommend splitting the dose of CS into two doses taken every 12 hours before meals by 15\u0026ndash;30 minutes for FR/SDNS [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, the practicality of long-term, twice-daily dosing before meals in children may be challenging.\u003c/p\u003e \u003cp\u003ePrevious studies in adult patients with NS indicate that single-daily cyclosporine (S-CS) may result in fewer side effects, lower dosage, improved adherence, and reduced costs compared to standard T-CS [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The 2023 clinical practice guideline for chronic kidney disease in Japan recommends once-daily CS administration for adult patients with NS [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, there is limited information on the use of S-CS in children with SDNS, with only short-term retrospective studies on a small number of patients available [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Furthermore, the specific patient characteristics that may benefit from S-CS have not been clearly defined. Given that patients with childhood-onset SDNS often experience relapses into adulthood [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], differences in CS dosage and administration between adults and children present a significant challenge.\u003c/p\u003e \u003cp\u003eIn 2008, we demonstrated that treating children with SDNS caused by minimal change disease (MCD) with preprandial low-dose S-CS and monitoring 2-hour post-dose (C2) levels could help maintain remission [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. We suggested conducting protocol kidney biopsies after more than 2 years of treatment to assess for chronic nephrotoxicity [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In this study, we assessed response predictors and long-term outcomes in children with SDNS treated with S-CS at a single center.\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003e A retrospective review of the clinical outcomes of 48 patients diagnosed with MCD who were treated with S-CS for childhood-onset SDNS (1\u0026ndash;15 years) between October 2005 and December 2021 was conducted. Short-term clinical data for 30 patients have been previously reported [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Patients with steroid-resistant NS, histological evidence of focal segmental glomerulosclerosis, prior CS treatment, and those with less than 3 years of follow-up were excluded from the study. This study was approved by the ethics committee of Saitama Children\u0026rsquo;s Medical Center (approval no. 2023-01-008-001) and Saitama Medical Center, Saitama Medical University (approval no. 2024-044).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDefinitions\u003c/h3\u003e\n\u003cp\u003eThe definitions and criteria for NS, complete remission, relapse, frequent relapse, steroid dependency, and steroid resistance were adopted from the Clinical Practice Guideline for the International Pediatric Nephrology Association [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Treatment failure was defined as a condition where there is a switch from S-CS to conventional T-CS due to persistent steroid dependency. Steroid-dependent dose in SDNS was defined as the prednisolone dose (mg/kg/day) that maintained complete remission before a relapse occurred, categorized into low-dose (\u0026lt;\u0026thinsp;0.25 mg/kg/day), moderate-dose (0.25\u0026ndash;0.5 mg/kg/day) and high-dose (\u0026ge;\u0026thinsp;0.5 mg/kg/day). Obesity was defined as a body mass index greater than 25 kg/m\u003csup\u003e2\u003c/sup\u003e, while short stature was defined as a height of less than \u0026minus;\u0026thinsp;2 standard deviation score compared to the normal stature for age and sex.\u003c/p\u003e\n\u003ch3\u003eTreatment protocol\u003c/h3\u003e\n\u003cp\u003eAfter the diagnosis of new-onset NS, all patients were treated with an 8-week steroid treatment regimen. This regimen comprised 4 weeks of daily prednisolone at a dose of 2 mg/kg or 60 mg/m\u003csup\u003e2\u003c/sup\u003e (up to a maximum of 60 mg), followed by 4 weeks of alternate-day treatment at a dose of 1.3 mg/kg or 40 mg/m\u003csup\u003e2\u003c/sup\u003e (up to a maximum of 40 mg). In case of relapse, prednisolone was administered at a dose of 1\u0026ndash;2 mg/kg/day until proteinuria was undetectable for at least three consecutive days. Subsequently, prednisolone was administered on alternate days, and the dosage was gradually tapered off over a period of 6 months, reducing by 5\u0026ndash;10 mg every 2\u0026ndash;4 weeks.\u003c/p\u003e \u003cp\u003eFor children under 10 years old with low-dose SDNS, a single daily high-dose of mizoribine (10 mg/kg/day maximum, 300 mg/day; Bredinine, orally disintegrating tablet, Asahikasei, Tokyo, Japan) was used as a steroid-sparing agent (SSA) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. For young children who developed moderate-dose SDNS or failed mizoribine, cyclophosphamide (Endoxan, tablet or oral solution, Shionogi Co., Osaka, Japan) was administered at a single daily dose of 2\u0026ndash;2.5 mg/kg/day for 12 weeks (cumulative dosage, 200 mg/kg) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. For younger children who developed high-dose SDNS or failed cyclophosphamide and/or mizoribine, or for older children (10 years and above) with SDNS, CS (Neoral, capsule or oral solution, Novartis Pharma Co., Tokyo, Japan) was initiated at a daily dose of 1.5\u0026ndash;2 mg/kg before breakfast. The CS dosage was adjusted to maintain 2-hour post-dose (C2) levels of 500\u0026ndash;700 ng/mL. In case of persistent steroid dependency after S-CS initiation, patients were switched to conventional T-CS, maintaining C2 levels of 400\u0026ndash;600 ng/mL. After 2\u0026ndash;3 years of CS treatment, the dosage was gradually tapered off within 6 months. For patients experiencing relapses and/or steroid toxicity after CS treatment, mycophenolate mofetil (MMF; 30\u0026ndash;40 mg/kg/day or 1000\u0026ndash;1200 mg/m\u003csup\u003e2\u003c/sup\u003e/day in two divided doses; maximum, 2000 mg/day; Cellcept, capsule or oral solution, Chugai Co. Tokyo, Japan) was offered as an alternative treatment [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Patients who achieved more than 12 months of prednisolone-free remission had MMF gradually tapered off. Since 2007, a single dose (375 mg/m\u003csup\u003e2\u003c/sup\u003e; maximum, 500 mg) of rituximab (Rituxan, injection, Zenyaku Co., Tokyo, Japan) has been administered to patients experiencing relapse during treatment with CS or MMF [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo assess treatment outcomes and identify potential drug toxicity, clinical and laboratory parameters were monitored every 1\u0026ndash;3 months. Clinical assessments included measurements of height, body weight, and blood pressure. Laboratory assessments included urine examination (dipstick and quantitative proteinuria), complete blood count, and serum urea, creatinine, electrolyte, albumin, cholesterol, transaminase, bilirubin, uric acid, C-reactive protein, and immunoglobulin levels, as well as drug levels in the blood, including CS, mizoribine, and mycophenolic acid.\u003c/p\u003e\n\u003ch3\u003eHistological evaluation\u003c/h3\u003e\n\u003cp\u003eIn all patients, histological evidence of MCD was confirmed by kidney biopsy prior to initiating S-CS. After 2\u0026ndash;3 years of CS treatment, protocol kidney biopsies were performed to confirm the presence of CS-related nephrotoxicity. Kidney specimens were examined using light, immunofluorescence, and electron microscopy. CS nephrotoxicity was graded based on the presence of arteriolar hyalinosis with accompanying interstitial fibrosis (Grade \u0026plusmn;, \u0026lt;\u0026thinsp;5%; Grade 1, 5\u0026ndash;25%; Grade 2, 26\u0026ndash;50%; Grade 4, \u0026gt;\u0026thinsp;50%) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint was the probability of survival without regression to steroid dependency, defined as the time from starting S-CS to switching to T-CS. The secondary endpoint at the last visit included chronic kidney disease (CKD) defined as persistent estimated glomerular filtration rate (eGFR)\u0026thinsp;\u0026lt;\u0026thinsp;90 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e for more than three months, hypertension (blood pressure\u0026thinsp;\u0026gt;\u0026thinsp;140/90 mmHg for more than three readings or ongoing antihypertensive treatment), obesity (body mass index\u0026thinsp;\u0026gt;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e), short stature (\u0026thinsp;\u0026lt;\u0026thinsp;\u0026minus;\u0026thinsp;2 standard deviation score), and treatment-free remission for more than 2 years.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eCategorical variables were compared using Fisher's exact test and reported as frequencies and percentages, while continuous variables were expressed as medians with interquartile range (IQR) and compared using the non-parametric two-sample Wilcoxon signed-rank test or the non-parametric Mann\u0026ndash;Whitney \u003cem\u003eU\u003c/em\u003e test. Receiver-operating characteristics (ROC) curve analysis was utilized to determine the optimal cut-off point for time until the first relapse after NS diagnosis. The Kaplan\u0026ndash;Meier method and log-rank test were employed to analyze the probability of SDNS-free survival post S-CS. Logistic regression was conducted to identify independent predictive factors for a favorable response to S-CS. Statistical analyses were conducted using R version 4.2.2 and EZR version 1.61 (Saitama Medical Center, Jichi Medical University), with \u003cem\u003ep\u003c/em\u003e-values less than 0.05 considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eClinical course during single-daily cyclosporine therapy\u003c/h2\u003e \u003cp\u003eAfter initiating S-CS therapy, 31 out of 48 patients with SDNS (65%) were able to discontinue prednisolone use (response group), and 18 of these 31 patients did not experience a relapse of NS during treatment. In the response group, treatment with S-CS (median treatment period: 2.2 years, IQR: 2.1\u0026ndash;2.3 years; median dose: 2.5 mg/kg/day, IQR: 2.1\u0026ndash;2.9 mg/kg/day; median C2 level: 625 ng/mL, IQR: 547\u0026ndash;667 ng/mL) resulted in a significant decrease in the median relapse rate from 3.9 (IQR: 2.6\u0026ndash;5.1) to 0 (0.0\u0026ndash;0.5) episodes per 12 months (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Although two of the 31 patients developed CS nephrotoxicity (Grade 1 and 2), there was no significant difference in eGFR before and after S-CS treatment. Conversely, 17 patients (35%) experienced treatment failure, and 11 of these patients received rituximab because of persistent steroid dependency after switching from S-CS to T-CS. Although six patients experienced transiently elevated transaminase levels and three patients had hypertension, no severe adverse events requiring treatment discontinuation were observed in any of the patients during S-CS treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePredictors of response to single-daily cyclosporine therapy\u003c/h2\u003e \u003cp\u003eThe baseline characteristics and clinical course were compared between patients in the response group and those in the treatment failure group (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The median period from NS diagnosis to the first relapse was significantly longer in the response group than in the treatment failure group (4.3 \u003cem\u003evs\u003c/em\u003e. 2.1 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The ROC curve indicated that the optimal cut-off period from NS diagnosis to the first relapse for predicting a favorable response to S-CS therapy was 2.2 months or more, with an area under the curve of 0.716, sensitivity of 64.7%, and specificity of 87.1% (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Kaplan\u0026ndash;Meier analysis demonstrated a significantly higher probability of SDNS-free survival in the non-early relapse group (\u0026ge;\u0026thinsp;2.2 months) than in the early relapse group (\u0026lt;\u0026thinsp;2.2 months) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.005, log-rank test; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Furthermore, multivariate logistic regression analysis identified a longer period from NS diagnosis to the first relapse (\u0026ge;\u0026thinsp;2.2 months) as the only significant independent predictive factor for a favorable response to S-CS (odds ratio: 21.0, 95% confidence interval: 3.24\u0026ndash;136.0, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.005; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\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\u003eComparison of baseline characteristics and clinical course between the response and treatment failure groups\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=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eResponse group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTreatment failure group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026ndash;value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;48)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;31)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;17)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (79.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (80.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (76.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at nephrotic syndrome onset (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.4 (3.2\u0026ndash;10.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.2 (3.1\u0026ndash;9.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.8 (3.7\u0026ndash;11.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDays to remission after initial steroid treatment (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (8\u0026ndash;10)\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (8\u0026ndash;10)\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (9\u0026ndash;12)\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeriod from nephrotic syndrome diagnosis to the first relapse (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.9 (2.2\u0026ndash;5.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.3 (3.0\u0026ndash;5.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.1 (1.4\u0026ndash;4.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeriod from nephrotic syndrome diagnosis to the first relapse (months)\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;2.2 months/ \u0026ge; 2.2 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13/35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4/27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9/8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.0055\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUse of steroid-sparing agents before S-CS therapy, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (47.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (48.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (47.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCyclophosphamide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (35.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (38.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (29.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMizoribine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (35.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (32.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (41.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of relapse before S-CS therapy (per year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.2 (2.7\u0026ndash;5.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.9 (2.7\u0026ndash;5.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.8 (3.2\u0026ndash;7.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.095\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThreshold dose of prednisolone before S-CS therapy (mg/kg/day)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.53 (0.26\u0026ndash;0.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.51 (0.26\u0026ndash;0.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.59 (0.28\u0026ndash;1.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeriod from nephrotic syndrome diagnosis to S-CS initiation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.0(0.5\u0026ndash;2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.1(0.6\u0026ndash;3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.7(0.3\u0026ndash;1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at S-CS initiation (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.2 (4.5\u0026ndash;12.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.5 (4.5\u0026ndash;11.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.9 (4.8\u0026ndash;12.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eData are shown as median (interquartile range) or as \u003cem\u003en\u003c/em\u003e (%).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eS-CS, single-daily cyclosporine\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 \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\u003ePredictive factors for favorable response to single-daily cyclosporine using a logistic regression model\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOdds ratio\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026ndash;value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOlder age at nephrotic syndrome diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.72\u0026ndash;1.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLonger period from nephrotic syndrome diagnosis to the first relapse (\u0026ge;\u0026thinsp;2.2 months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.24\u0026ndash;136.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0014\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLonger days to remission at new-onset nephrotic syndrome after initial steroid treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.72\u0026ndash;1.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eLong-term outcome after single-daily cyclosporine therapy\u003c/h2\u003e \u003cp\u003eAfter discontinuation of S-CS, 40 out of 48 patients with SDNS received additional SSA and/or rituximab, but none of them developed CKD Stage 3 or higher (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). At the last visit, only 13 patients achieved long-term treatment-free remission for more than 2 years, while 29 patients continued to receive SSA and/or rituximab during the last 2 years.\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\u003eLong-term outcomes of 48 patients after single-daily cyclosporine therapy\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\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;48)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at the last follow-up (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19.0 (13.3\u0026ndash;22.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration until the last follow-up from nephrotic syndrome diagnosis (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.0 (7.8\u0026ndash;14.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration until the last follow-up from S\u0026ndash;CS initiation (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.8 (6.1\u0026ndash;11.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelapse after S-CS discontinuation, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (81.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUse of steroid-sparing agents after S-CS discontinuation, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43 (89.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMycophenolate mofetil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (83.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCyclophosphamide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (10.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCyclosporine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (10.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMizoribine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (20.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUse of rituximab, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (41.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatments states at the last follow-up, \u003cem\u003en\u003c/em\u003e (%)\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\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (56.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrednisolone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (12.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMycophenolate mofetil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (14.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCyclophosphamide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCyclosporine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMizoribine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRituximab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (20.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLong-term complications at the last follow-up, \u003cem\u003en\u003c/em\u003e (%)\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\u003eChronic kidney disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (14.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstimated glomerular filtration rate, 60\u0026ndash;90 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (14.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstimated glomerular filtration rate, \u0026lt;\u0026thinsp;60 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \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\u003e2 (4.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShort stature\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObesity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (6.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCataract\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eData are shown as median (interquartile range) or as \u003cem\u003en\u003c/em\u003e (%).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eS-CS, single-daily cyclosporine\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we observed that S-CS enabled the discontinuation of prednisolone in 31 out of 48 patients with SDNS (65%) and maintained relapse-free survival in 18 patients (38%) during the treatment. In particular, S-CS was highly effective in patients without a history of early first relapse (\u0026lt;\u0026thinsp;2.2 months after NS diagnosis). Although two patients (6.5%) developed mild chronic nephrotoxicity after S-CS, none progressed to CKD Stage 3 or higher at the last visit. Therefore, initiating S-CS rather than T-CS is preferable in children with SDNS, especially in those without a history of early first relapse.\u003c/p\u003e \u003cp\u003eIijima \u003cem\u003eet al\u003c/em\u003e. conducted a multicenter, randomized controlled trial comparing the efficacy and safety between high C2 and low C2 groups in 93 children with FRNS who received conventional T-CS therapy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The relapse-free survival rate at 24 months of T-CS therapy was 64.4% in the high C2 group and 50% in the low C2 group, respectively, which was superior to the relapse-free remission rate of S-CS therapy in our study. The discrepancy in relapse-free rates between the two studies may be attributed to variations in disease activity at the time of CS initiation: 60% of their patients had SDNS, and only 20% had a history of SSA use such as cyclophosphamide and mizoribine before CS, while all our patients had SDNS, and 50% had a history of SSA use. Furthermore, 11 out of the 17 patients in the treatment failure group required rituximab because of persistent steroid dependency after T-CS therapy, and switching from S-CS to T-CS was effective in only 6 patients; the number needed to treat to achieve efficacy of T-CS for children with SDNS in this study was 8 patients. Thus, the proportion of children with SDNS who respond to T-CS but not to S-CS may be relatively limited.\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, there have been no randomized controlled trials on the treatment with preprandial S-CS monitoring C2 levels in children with NS, and thus, the optimal target range for maintaining remission remains unknown. Saito \u003cem\u003eet al\u003c/em\u003e. conducted a randomized multicenter trial comparing the efficacy of preprandial S-CS to that of T-CS in 48 adult patients with NS caused by idiopathic membranous nephropathy [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The authors concluded that the appropriate strategy for CS treatment is to maintain C2 levels above 600 ng/mL by preprandial S-CS, as the optimal cut-off level of C2 for achieving remission was determined to be 615 ng/mL by ROC analysis (sensitivity 75.6%, specificity 76.9%). However, three patients with S-CS maintaining high C2 levels above 900 ng/mL were withdrawn from the study because of CS-related adverse events. In our study, one patient with S-CS maintaining high C2 levels of approximately 700 ng/mL for over 2 years developed CS nephrotoxicity (Grade 2) at the age of 11 years. Despite discontinuation of CS, the patient progressed to CKD, with an eGFR of 70\u0026ndash;80 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e and hypertension at the last follow-up at the age of 28 years. Thus, a history of CS nephrotoxicity may be associated with kidney complications in adulthood. Furthermore, Shirai \u003cem\u003eet al\u003c/em\u003e. conducted a single-center, randomized trial comparing the efficacy and safety between preprandial S-CS plus prednisolone and prednisolone-alone groups in 21 adult NS patients with new-onset MCD [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. They found that the relapse rate during the 18-month treatment period was significantly lower in the S-CS plus prednisolone group maintaining C2 levels above 600 ng/mL than in the prednisolone-alone group (1/9 \u003cem\u003evs\u003c/em\u003e. 5/10, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02). However, similar to adverse events in our study, liver dysfunction was frequently observed in the S-CS plus prednisolone group, necessitating a reduction in CS dosage. Although further prospective studies are needed, treatment with preprandial S-CS maintaining C2 levels of 500\u0026ndash;700 ng/mL may be optimal for children with SDNS in terms of safety and efficacy.\u003c/p\u003e \u003cp\u003ePrevious studies have shown that a longer time until remission after initial treatment and a shorter time from disease onset to first relapse are significant predictors of FR/SDNS development [\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In a prospective study of 145 children with new-onset steroid-sensitive NS who received the standard 8-week steroid treatment, Nakanishi \u003cem\u003eet al\u003c/em\u003e. reported that a time until initial response of 9 days or above and a duration from initial treatment to first relapse of less than 6 months were significant predictors of FRNS progression [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. These findings were supported by several studies, including ours [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Furthermore, we hypothesize that these two clinical characteristics following standard initial treatment may not only predict relapsing disease courses but also influence the necessity and response to SSA in children with FR/SDNS. In a retrospective study of 45 children with steroid-sensitive NS who experienced their first relapse within 6 months after NS diagnosis, Inoki \u003cem\u003eet al\u003c/em\u003e. found that only four out of 22 patients (18%) who experienced the first relapse more than 3 months after initial treatment developed FR/SDNS within 6 months [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In contrast, 23 out of 24 patients (96%) who relapsed within 3 months developed FR/SDNS, with 19 of these patients requiring SSA within 6 months. Our recent study revealed that all seven patients with very early relapse during the initial 4-week full-dose prednisolone treatment required T-CS because of SR/SDNS progression [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. In the present study, S-CS was effective in most patients with SDNS who experienced their first relapse\u0026thinsp;\u0026ge;\u0026thinsp;2.2 months after NS diagnosis. However, less than one-third of patients who relapsed earlier, within 2.2 months, responded to S-CS therapy. Overall, an earlier first relapse after standard initial steroid treatment for NS onset is associated with a higher likelihood of SDND with high disease activity. Although there is insufficient evidence to establish a first-line SSA in children with SDNS, we suggest that the selection of the agent should be guided by disease activity, such as the timing of the first relapse and steroid-dependent dose. Therefore, S-CS may be a promising treatment option prior to T-CS in children with SDNS who do not experience early relapse after NS onset.\u003c/p\u003e \u003cp\u003eIn a long-term follow-up study of 46 children with FRNS after the initiation of conventional T-CS (mean age, 18.7 years; median follow-up period, 10.3 years), only ten patients (22%) achieved treatment-free remission for more than 2 years, whereas half of the patients continued to experience frequent relapses or were receiving SSA at the last visit [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. These unfavorable outcomes after T-CS therapy were similar to the long-term outcomes of S-CS therapy in our study. Based on the persistent disease activity in adulthood following both T-CS and S-CS, we suggest that low-dose S-CS may be a preferable initial regimen for children with SDNS, consistent with adult patients.\u003c/p\u003e \u003cp\u003eThere are several limitations to consider in this study. First, given the uncontrolled retrospective design, inherent selection and reporting biases could not be avoided. Second, the sample size was too small to draw robust conclusions. Third, the variability in the selection of SSA after S-CS and the duration of follow-up among patients may have impacted the outcomes. However, we focused on children with SDNS caused by biopsy-proven MCD to ensure a more homogeneous population. All patients underwent kidney biopsies before and after CS treatment, and the treatment protocols, including SSA use, were relatively homogeneous in this single-center study. Furthermore, to the best of our knowledge, this study represents the longest follow-up of children with SDNS after S-CS to date.\u003c/p\u003e \u003cp\u003eIn conclusion, our data suggest that preprandial S-CS prior to conventional T-CS could be a promising treatment option for children with SDNS caused by MCD and without a history of early relapse after NS onset. Although kidney complications at the last follow-up were mild in this study, long-term treatment-free remission was rarely achieved. Therefore, the development of novel treatment strategies, such as pre-emptive rituximab administration, is urgently required to prevent persistent active disease into adulthood following the initiation of S-CS [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eEthical approval:\u003c/strong\u003e \u003cp\u003e This study was conducted in accordance with the principles of the Declaration of Helsinki and the Ethical Guidelines for Medical and Biological Research Involving Human Subjects of the Ministry of Health, Labour and Welfare of Japan. This study was approved by the Ethics Committee of Saitama Children\u0026rsquo;s Medical Center (approval no. 2023-01-008-001) and Saitama Medical Center, Saitama Medical University (approval no. 2024-044).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eInformed consent\u003c/strong\u003e \u003cp\u003e The Institutional Review Board waived the requirement for informed consent due to the retrospective nature of this study.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCompeting interests:\u003c/strong\u003e \u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eSF has received grants-in-aid for research from Saitama Children\u0026rsquo;s Medical Center.\u003c/p\u003e\u003ch2\u003eAuthor contribution\u003c/h2\u003e \u003cp\u003eYU and SF designed the study, drafted the manuscript, were responsible for the data integrity and analysis results. TN provided statistical support. YU and KS collected the data from the medical charts. All authors critically reviewed and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e \u003cp\u003eWe want to thank Enago for editing the draft of this manuscript.\u003c/p\u003e\u003ch2\u003eData availability\u003c/h2\u003e \u003cp\u003eMore detailed datasets are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eIshikura K, Yoshikawa N, Hattori S, Sasaki S, Iijima K, Nakanishi K, Matsuyama T, Yata N, Ando T, Honda M, for Japanese Study Group of Renal Disease in Children (2010) Treatment with microemulsified cyclosporine in children with frequently relapsing nephrotic syndrome. Nephrol Dial Transpl 25:3956\u0026ndash;3962\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIijima K, Sako M, Oba MS, Ito S, Hataya H, Tanaka R, Ohwada Y, Kamei K, Ishikura K, Yata N, Nozu K, Honda M, Nakamura H, Nagata M, Ohashi Y, Nakanishi K, Yoshikawa N, Japanese Study Group of Kidney Disease in Children (2014) Cyclosporine C2 monitoring for the treatment of frequently relapsing nephrotic syndrome in children: a multicenter randomized phase II trial. Clin J Am Soc Nephrol 9:271\u0026ndash;278\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFujinaga S, Kaneko K, Takada M, Ohtomo Y, Akashi S, Yamashiro Y (2005) Preprandial C2 monitoring of cyclosporine treatment in children with nephrotic syndrome. Pediatr Nephrol 20:1359\u0026ndash;1360\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKusaba T, Konno Y, Hatta S, Fujino T, Yasuda T, Miura H, Sasaki H, Okabayashi J, Murao M, Sakurada T, Imai G, Shirai S, Kuboshima S, Shima Y, Ogimoto G, Sato T, Masuhara K, Kimura K (2005) More stable and reliable pharmacokinetics with preprandial administration of cyclosporine compared with postprandial administration in patients with refractory nephrotic syndrome. Pharmacotherapy 25:52\u0026ndash;58\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShirai S, Yasuda T, Tsuchida H, Kuboshima S, Konno Y, Shima Y, Sato T, Hatta S, Masuhara K, Kimura K (2009) Preprandial microemulsion cyclosporine administration is effective for patients with refractory nephrotic syndrome. Clin Exp Nephrol 13:123\u0026ndash;129\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIshikura K, Matsumoto S, Sako M, Tsuruga K, Nakanishi K, Kamei K, Saito H, Fujinaga S, Hamasaki Y, Chikamoto H, Ohtsuka Y, Komatsu Y, Ohta T, Nagai T, Kaito H, Kondo S, Ikezumi Y, Tanaka S, Kaku Y, Iijima K (2015) Clinical practice guideline for pediatric idiopathic nephrotic syndrome 2013: medical therapy. Clin Exp Nephrol 19:6\u0026ndash;33Japanese Society for Pediatric Nephrology; Japanese Society for Pediatric Nephrology\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTrautmann A, Boyer O, Hodson E, Bagga A, Gipson DS, Samuel S, Wetzels J, Alhasan K, Banerjee S, Bhimma R, Bonilla-Felix M, Cano F, Christian M, Hahn D, Kang HG, Nakanishi K, Safouh H, Trachtman H, Xu H, Cook W, Vivarelli M, Haffner D, International Pediatric Nephrology Association (2023) IPNA clinical practice recommendations for the diagnosis and management of children with steroid-sensitive nephrotic syndrome. Pediatr Nephrol 38:877\u0026ndash;919\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRasche FM, Keller F, Kunze G, Boesler B, Czock D (2007) Single daily dose of cyclosporine in patients with primary glomerulonephritis and nephrotic syndrome. Clin Nephrol 67:285\u0026ndash;292\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTakeda A, Horike K, Onoda H, Ohtsuka Y, Yoshida A, Uchida K, Morozumi K (2007) Benefits of cyclosporine absorption profiling in nephrotic syndrome: preprandial once-daily administration of cyclosporine microemulsion improves slow absorption and can standardize the absorption profile. Nephrol (Carlton) 12:197\u0026ndash;204\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJapanese Society of Nephrology (2024) Essential points from evidence-based clinical practice guideline for chronic kidney disease 2023. Clin Exp Nephrol 28:473\u0026ndash;495\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChishti AS, Sorof JM, Brewer ED, Kale AS (2001) Long-term treatment of focal segmental glomerulosclerosis in children with cyclosporine given as a single daily dose. Am J Kidney Dis 38:754\u0026ndash;760\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTanaka H, Nakahata T, Ito E (2004) Single-dose daily administration of cyclosporin A for relapsing nephrotic syndrome. Pediatr Nephrol 19:1055\u0026ndash;1058\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSuzuki K, Oki E, Tsuruga K, Aizawa-Yashiro T, Ito E, Tanaka H (2010) Benefits of once-daily administration of cyclosporine a for children with steroid-dependent, relapsing nephrotic syndrome. Tohoku J Exp Med 220:183\u0026ndash;186\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTakemasa Y, Fujinaga S, Nakagawa M, Sakuraya K, Hirano D (2024) Adult survivors of childhood-onset steroid-dependent and steroid-resistant nephrotic syndrome treated with cyclosporine: a long-term single-center experience. Pediatr Nephrol 39:473\u0026ndash;482\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFujinaga S, Ohtomo Y, Someya T, Shimizu T, Yamashiro Y, Kaneko K (2008) Is single-daily low-dose cyclosporine therapy really effective in children with idiopathic frequent-relapsing nephrotic syndrome? Clin Nephrol 69:84\u0026ndash;89\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFujinaga S, Hirano D, Murakami H, Ohtomo Y, Shimizu T, Kaneko K (2012) Nephrotoxicity of once-daily cyclosporine A in minimal change nephrotic syndrome. Pediatr Nephrol 27:671\u0026ndash;674\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFujinaga S, Nishino T, Urushihara Y (2021) Efficacy of once-daily cyclosporine in Japanese children with steroid-dependent minimal change nephrotic syndrome. Clin Exp Nephrol 25:213\u0026ndash;214\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFujinaga S, Hirano D, Nishizaki N, Someya T, Ohtomo Y, Ohtsuka Y, Shimizu T, Kaneko K (2011) Single daily high-dose mizoribine therapy for children with steroid-dependent nephrotic syndrome prior to cyclosporine administration. Pediatr Nephrol 26:479\u0026ndash;483\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMizutani A, Fujinaga S, Sakuraya K, Hirano D, Shimizu T (2019) Positive effects of single-daily high-dose mizoribine therapy after cyclophosphamide in young children with steroid-dependent nephrotic syndrome. Clin Exp Nephrol 23:244\u0026ndash;250\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFujinaga S, Ohtomo Y, Umino D, Takemoto M, Shimizu T, Yamashiro Y, Kaneko K (2007) A prospective study on the use of mycophenolate mofetil in children with cyclosporine-dependent nephrotic syndrome. Pediatr Nephrol 22:71\u0026ndash;76\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFujinaga S, Someya T, Watanabe T, Ito A, Ohtomo Y, Shimizu T, Kaneko K (2013) Cyclosporine versus mycophenolate mofetil for maintenance of remission of steroid-dependent nephrotic syndrome after a single infusion of rituximab. Eur J Pediatr 172:513\u0026ndash;518\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSolez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, Halloran PF, Baldwin W, Banfi G, Collins AB, Cosio F, David DS, Drachenberg C, Einecke G, Fogo AB, Gibson IW, Glotz D, Iskandar SS, Kraus E, Lerut E, Mannon RB, Mihatsch M, Nankivell BJ, Nickeleit V, Papadimitriou JC, Randhawa P, Regele H, Renaudin K, Roberts I, Seron D, Smith RN, Valente M (2008) Banff 07 classification of kidney allograft pathology: updates and future directions. Am J Transplan 8:753\u0026ndash;760\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaito T, Iwano M, Matsumoto K, Mitarai T, Yokoyama H, Yorioka N, Nishi S, Yoshimura A, Sato H, Ogahara S, Shuto H, Kataoka Y, Ueda S, Koyama A, Maruyama S, Nangaku M, Imai E, Matsuo S, Tomino Y, Refractory Nephrotic Syndrome Study Group (2014) Significance of combined cyclosporine-prednisolone therapy and cyclosporine blood concentration monitoring for idiopathic membranous nephropathy with steroid-resistant nephrotic syndrome: a randomized controlled multicenter trial. Clin Exp Nephrol 18:784\u0026ndash;794\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShirai S, Imai N, Sueki S, Matsui K, Tominaga N, Sakurada T, Yasuda T, Kimura K, Shibagaki Y (2018) Combined cyclosporine and prednisolone therapy using cyclosporine blood concentration monitoring for adult patients with new-onset minimal change nephrotic syndrome: a single-center pilot randomized trial. Clin Exp Nephrol 22:283\u0026ndash;290\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYap HK, Han EJ, Heng CK, Gong WK (2001) Risk factors for steroid dependency in children with idiopathic nephrotic syndrome. Pediatr Nephrol 16:1049\u0026ndash;1052\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarambat J, Godron A, Ernould S, Rigothier C, Llanas B, Leroy S (2013) Prediction of steroid-sparing agent use in childhood idiopathic nephrotic syndrome. Pediatr Nephrol 28:631\u0026ndash;638\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSureshkumar P, Hodson EM, Willis NS, Barzi F, Craig JC (2014) Predictors of remission and relapse in idiopathic nephrotic syndrome: a prospective cohort study. 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Pediatr Nephrol 39:282\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Single-daily cyclosporine therapy, C2 monitoring, Response predictor, Steroid-dependent nephrotic syndrome, Minimal change disease, Long-term, Follow-up","lastPublishedDoi":"10.21203/rs.3.rs-5921376/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5921376/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical practice guidelines for idiopathic nephrotic syndrome (NS) in children recommend twice-daily cyclosporine as a preferred steroid-sparing agent for steroid-dependent nephrotic syndrome (SDNS). Although single-daily cyclosporine (S-CS) may offer an effective therapeutic option with increased compliance and reduced nephrotoxicity, response predictors and long-term outcomes following this regimen remain unclear in this cohort.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA retrospective study was conducted on children with SDNS caused by minimal change disease (MCD) who were treated with preprandial S-CS to maintain 2-hour post-dose levels of 500–700 ng/mL between October 2005 and December 2021. The primary endpoint was the probability of SDNS-free survival during S-CS therapy. The secondary endpoint was the long-term outcome at the last visit.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter initiating S-CS therapy in 48 children, 31 patients, including 18 who did not experience relapse during treatment, were able to discontinue steroid dependency (response group), while 17 patients experienced treatment failure. The median time to the first relapse after NS diagnosis was significantly longer in the response group than in the treatment failure group (4.3 \u003cem\u003evs\u003c/em\u003e. 2.1 months, \u003cem\u003ep \u003c/em\u003e\u0026lt; 0.05). Multivariate logistic regression analysis identified a longer time until the first relapse (≥ 2.2 months) after NS diagnosis as an independent predictive factor for a favorable response to S-CS therapy (odds ratio: 21.0, \u003cem\u003ep \u003c/em\u003e\u0026lt; 0.005). None of the patients progressed to chronic kidney disease Stage 3 or higher.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eS-CS may offer a promising treatment option for children with SDNS caused by MCD who do not experience early relapse following NS diagnosis.\u003c/p\u003e","manuscriptTitle":"Response predictors and long-term outcomes of preprandial single-daily cyclosporine in children with steroid-dependent nephrotic syndrome caused by minimal change disease: a single-center experience","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-03 09:32:25","doi":"10.21203/rs.3.rs-5921376/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d96a8597-b177-4f4e-acd0-81ac95e99953","owner":[],"postedDate":"February 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-02-10T15:15:22+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-03 09:32:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5921376","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5921376","identity":"rs-5921376","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}