Clinical characteristics and long-term outcomes of immune-complex membranoproliferative glomerulonephritis and C3 glomerulopathy in Japanese children

Clinical characteristics and long-term outcomes of immune-complex membranoproliferative glomerulonephritis and C3 glomerulopathy in Japanese children | 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 Clinical characteristics and long-term outcomes of immune-complex membranoproliferative glomerulonephritis and C3 glomerulopathy in Japanese children Chika Ueda, Tomoko Horinouchi, Yuta Inoki, Yuta Ichikawa, Yu Tanaka, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3885158/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background Membranoproliferative glomerulonephritis (MPGN) can be divided into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G), which include dense deposit disease (DDD) and C3 glomerulonephritis (C3GN), respectively. These conditions result from abnormalities in different complement pathways and may lead to different prognoses. However, there are limited studies describing the respective clinical courses. Methods In this study, Japanese pediatric patients diagnosed with MPGN based on kidney biopsies conducted between February 2002 and December 2022 were reclassified as having IC-MPGN or C3G (DDD or C3GN). We retrospectively analyzed the clinical characteristics and outcomes of these patients. Results Out of 25 patients with MPGN, three (12.0%) were diagnosed with DDD, 20 (80.0%) with C3GN, and two (8.0%) with IC-MPGN. There were 13 (65.0%) patients and one (33.3%) patient in remission after treatment for C3GN and DDD, respectively, and no patients with IC-MPGN achieved remission. The median follow-up period was 5.3 (2.5-8.9) years, and none of the patients in either group progressed to an estimated glomerular filtration rate < 15 ml/min/1.73m 2 . Patients with C3GN presenting mild to moderate proteinuria (n=8) received a renin-angiotensin system inhibitor (RAS-I) alone, and these patients exhibited a significant decrease in the urinary protein creatinine ratio and a notable increase in serum C3 levels at the last follow-up. Conclusions The majority of patients with MPGN were diagnosed with C3GN. The remission rate for C3GN was high, and no patients developed kidney failure, indicating favorable outcomes. Additionally, it was suggested that patients with mild pediatric C3GN could be treated with RAS-I alone. Membranoproliferative glomerulonephritis immune-complex MPGN C3 glomerulopathy C3 glomerulonephritis Dense deposit disease Figures Figure 1 Figure 2 Introduction Membranoproliferative glomerulonephritis (MPGN) is a glomerular injury characterized by pathological findings of mesangial interposition and double contours of the capillary wall [ 1 ]. Historically, MPGN was morphologically classified into three subtypes based on the deposition site of electron-dense deposits (EDD) in the glomerulus, as observed by electron microscopy: type I with EDD in the subendothelial areas, dense deposit disease (DDD) with deposits in the basement membrane, and type III with deposits in both the subepithelial and subendothelial areas [ 2 , 3 ]. However, in a 2012 study, immunofluorescence images revealed strong positivity for C3 deposits in DDD, while types I and III had a mixture of C3 deposits and both C3 and immunoglobulin deposits, indicating potentially different etiologies [ 4 ]. Subsequently, based on immunofluorescence images, patients with predominant IgG staining were reclassified as having immune-complex MPGN (IC-MPGN), while those with predominant C3 deposition were reclassified as having C3 glomerulopathy (C3G) [ 4 , 5 ]. C3G was further classified into DDD and C3 glomerulonephritis (C3GN) as DDD characterized by linear intramembranous EDD according to electron microscopy, and C3GN was classified when there was absence of DDD [ 4 , 5 ]. IC-MPGN is caused by activation of the classical pathway due to immune complex formation associated with infections and autoimmune diseases [ 4 ]. On the other hand, C3G (DDD, C3GN) is caused by the dysregulation of alternative pathway activity [ 4 , 6 ]. Given the different complement pathways involved, IC-MPGN and C3G (DDD, C3GN) may exhibit distinct prognoses. However, limited reports exist on the respective clinical courses of IC-MPGN and C3G, especially in pediatric patients, in whom MPGN is rare. There is also a lack of evidence-based standard treatment for patients with IC-MPGN and C3G, particularly in the pediatric population [ 7 ]. To elucidate the clinical characteristics of MPGN and to identify appropriate treatments, we reclassified types of MPGN based on kidney biopsy findings in pediatric patients diagnosed with MPGN. We retrospectively analyzed demographic, clinical and laboratory findings, and therapeutic response in patients with IC-MPGN and C3G (DDD, C3GN). Methods Participants and Study Design This retrospective cohort study included Japanese pediatric patients diagnosed with MPGN via kidney biopsy between February 2002 and December 2022 at the pediatric nephrology departments of Kobe University Hospital, Wakayama Medical University Hospital, Hyogo Prefectural Kobe Children’s Hospital, Takatsuki General Hospital, Japanese Red Cross Society Himeji Hospital, and Kakogawa Central City Hospital. The exclusion criteria were patients with missing clinical or laboratory data, absence of immunofluorescence imaging, resolved proteinuria without therapeutic intervention, a brief follow-up period (< 6 months) and indications of secondary nephritis. The following data were retrospectively obtained from the patients’ medical records at the time of diagnosis (initial kidney biopsy) and subsequent regular outpatient visits, as well as at the last follow-up: patient demographic information (age, sex, height, and weight), clinical and laboratory data (proteinuria, hematuria, serum creatinine level, estimated glomerular filtration rate (eGFR), serum albumin level, serum C3 and C4 level and presence of nephrotic syndrome), and details of the treatment. For C3GN, the predominant subtype of MPGN, we examined the factors associated with remission and normalization of serum C3 levels. Additionally, we compared the differences in clinical and laboratory findings between patients treated with and without prednisolone. The Kaplan‒Meier method was used to assess the time to remission or normalization of the serum C3 levels. Pathology Kidney biopsies were performed for children exhibiting both hypocomplementemia and proteinuria. All kidney biopsy reports, including light microscopy, immunostaining, and electron microscopy results, were reviewed by one pathologist (N.Y.). MPGN was pathologically diagnosed based on mesangial hypercellularity, endocapillary proliferation, and double-contour formation along the glomerular capillary walls via light microscopy. Subsequently, based on immunofluorescence imaging of kidney biopsies, we reclassified these patients with MPGN as having IC-MPGN or C3G. C3-dominant deposits were categorized as C3G with ‘dominant’, defined as a C3 intensity two orders of magnitude higher than that of any other immune reactant (IgG, IgA, IgM or C1q) on a scale of zero to three [ 8 ], and the others were categorized as having IC-MPGN [ 4 , 5 ]. Further subclassification of C3G included DDD or C3GN: DDD was assigned when linear intramembranous electron-dense deposits were observed via electron microscopy, while those lacking DDD characteristics were classified as having C3GN [ 4 , 5 ]. In patients with multiple kidney biopsies, the initial biopsy was used for diagnosis. Treatment protocol Treatments were administered at the discretion of the clinicians. In general, patients exhibiting mild to moderate proteinuria (urine protein creatinine ratio 0.15-1.0 g/gCr) were treated with angiotensin-converting enzyme inhibitor (ACE-I), patients who did not respond adequately to ACE-I were additionally given an angiotensin II receptor blocker (ARB). Those facing challenges in continuing ACE-I medication due to side effects such as cough and dizziness were switched to an ARB. Patients diagnosed with nephrotic syndrome or severe proteinuria (urinary protein creatinine ratio ≥ 1.0 g/gCr) or those experiencing exacerbation after ACE-I or ARB treatment received either prednisolone or a combination of prednisolone and intravenous methylprednisolone at a dosage of 30 mg/kg/day (maximum dose, 1000 mg/day) for three consecutive days. This regimen is known as methylprednisolone pulse therapy (MPT) and was administered for two to three courses along with prednisolone. In cases of worsening or inadequate response, an additional two courses of MPT were administered, followed by prednisolone, and subsequently, immunosuppressants such as mizoribine (MZR) or mycophenolate mofetil (MMF) were added. Definitions Nephrotic syndrome was diagnosed based on the presence of both severe proteinuria (urine protein creatinine ratio ≥ 2 g/gCr) and hypoalbuminemia (serum albumin ≤ 2.5 g/dL). Hematuria was defined as the presence of ≥ 5 red blood cells per high-power field of a centrifuged urine specimen. Proteinuria was defined as a protein creatinine ratio ≥ 0.15 g/gCr. Remission was considered to be achieved when the protein creatinine ratio was 2.5 g/dL. Normalization of the serum C3 levels was considered to be achieved when the serum C3 levels was > 80 mg/dL. For patients aged between two and eighteen years, the eGFR was calculated by comparing the serum creatinine levels of patients with the reference serum creatinine levels of Japanese children based on the patients’ height and sex [ 9 ]. For patients aged > 18 years old, the eGFR was calculated based on the patients’ serum creatinine levels, age, and sex [ 10 ]. Statistical methods Statistical analysis was conducted using Easy R (EZR) [ 11 ], a modified version of the R Commander that is specifically tailored to include commonly-used statistical methods in biostatistics. Clinical and laboratory findings are presented as the median and interquartile range (IQR) for continuous variables and as percentages for qualitative variables. The Mann‒Whitney U test and Wilcoxon signed rank test were employed to assess differences between continuous variables, while Fisher's exact test and McNemar's test were utilized for comparing qualitative variables. The Kaplan-Meier method and log-rank tests were used to evaluate differences in the time to remission and serum C3 normalization among patients, comparing those with and without prednisolone use. P -values < 0.05 were considered to indicate statistical significance. Results Study cohort In this retrospective cohort study, 32 patients were diagnosed with idiopathic MPGN. We excluded seven patients: four patients due to inadequate clinical and laboratory data, one patient with no immunofluorescence imaging, one patient with resolved proteinuria without therapeutic intervention, and one patient with a short follow-up period (< 6 months). Among the remaining 25 patients with MPGN, three (12.0%) were reclassified as DDD, 20 (80.0%) were reclassified as C3GN, and two (8.0%) were reclassified as IC-MPGN (Fig. 1). Patient demographics and clinical characteristics The events that led to the diagnosis of MPGN in 25 patients were as follows: school urinalysis in 16 patients, abnormal findings in a urine test conducted incidentally in five patients, onset of nephrotic syndrome in two patients, and gross hematuria in two patients. The baseline clinical characteristics are shown in Table 1 . The median age at diagnosis for the entire cohort was 10.2 (8.7–12.5) years, and 16 (64.0%) patients were male. Hematuria was observed in 24 (96.0%) patients. Among patients with C3GN, only two (10.0%) presented with nephrotic syndrome, while no patients with DDD presented nephrotic syndrome. Conversely, both patients with IC-MPGN exhibited nephrotic syndrome. The median urine protein creatinine ratio at diagnosis was 1.14 (0.47–1.72) g/gCr. The median eGFR for the entire cohort was 122.5 (103.1-137.6) mL/min/1.73 m 2 , with five (20.0%) patients showing an eGFR < 90 ml/min/1.73m 2 . The median serum C3 level was 18.0 (12.0-31.5) mg/dL, and the serum C3 levels were low at the time of diagnosis in all groups. Pathological findings The light microscopic findings are shown in Table 2 . Notably, crescents, global sclerosis and interstitial fibrosis were uncommon among our patients. Crescents were observed in five (25.0%) patients with C3GN, one (33.3%) patient with DDD, and one (50.0%) patient with IC-MPGN. Global sclerosis was present in one (5.0%) patient with C3GN, one (33.3%) patient with DDD, and one (50.0%) patient with IC-MPGN. Interstitial fibrosis was absent in patients with DDD but was observed in six (30.0%) patients with C3GN and one (50.0%) patient with IC-MPGN. Treatments As shown in Table 3 , 23 (92.0%) patients received RAS-I. Prednisolone was administered to all patients with DDD and IC-MPGN, but to just 12 (60.0%) patients with C3GN. Immunosuppressants were administered to all patients with IC-MPGN and to four patients (20.0%) with C3GN, but not to patients with DDD. Based on the clinicians’ decisions, some patients received treatments that deviated from the strategy described in the Methods section. Specifically, one patient with C3GN and with mild proteinuria was treated with prednisolone and MMF in addition to ACE-I. Another patient with C3GN and with initially mild proteinuria received ACE-I, but prednisolone and MMF were added due to an inadequate response. Subsequently, due to exacerbation, three courses of MPT were administered, followed by prednisolone. One patient with IC-MPGN with severe proteinuria received cyclosporine instead of MZR or MMF. Outcome The outcomes of this retrospective cohort study are shown in Table 3 . The follow-up period of the entire cohort was 5.3 (2.5–8.9) years. The incidence of hematuria at the last follow-up decreased in all groups (28%) compared with that at diagnosis. Thirteen (65.0%) patients with C3GN and one (33.3%) patient with DDD achieved remission, but none of the patients with IC-MPGN achieved remission. No patients in either group progressed to an eGFR < 15 ml/min/1.73m 2 . Notably, compared with those at the time of diagnosis, urinary protein at the last follow-up tended to decrease, and serum C3 levels tended to increase in all groups (Supplementary Figure S1 ). Clinical and pathological findings as well as treatments of patients with C3GN in remission and non-remission, are shown in Supplementary Table S1 . Clinical findings and treatments did not differ between the remission and non-remission groups. Pathology revealed that, in the non-remission group, no patients had crescents, endocapillary proliferation, or global sclerosis, and only one (14.3%) patient had interstitial fibrosis. Moreover, there was no significant difference between the remission and non-remission groups. Clinical and pathological findings and treatments for patients with C3GN with normalized and non-normalized serum C3 levels are shown in Supplementary Table S2. The age at diagnosis was significantly lower in patients with normalized serum C3 levels than in those with non-normalized serum C3 levels (8.7 vs 12.7 years, P = 0.02). There were no significant differences in other clinical findings, pathological findings, or treatments between the patients with normalized and non-normalized serum C3 levels. A comparison of clinical and laboratory findings based on the use of prednisolone in the C3GN group is shown in Table 4 . Hematuria, eGFR, urine protein creatinine ratio, and serum C3 levels were compared between the time of diagnosis and the time of the last follow-up within each group. There were no significant differences between the prednisolone-free group and the group in which prednisolone was used regarding the incidence of hematuria, eGFR, urinary protein creatinine ratio, remission rate, serum C3 levels, and pathological findings. In both groups, the urinary protein creatinine ratio significantly decreased and the serum C3 levels significantly increased at the last follow-up. Remission was achieved in 6 of the 8 (75.0%) patients in the prednisolone-free group and 7 of the 12 (58.3%) patients in the group in which prednisolone was used. Among the four patients with severe proteinuria who received MZR or MMF, only one achieved remission, and none of them had normalized serum C3 levels. A Kaplan–Meier analysis of remission and normalization of serum C3 levels in patients with C3GN is shown in Fig. 2. The median time to remission was 17.0 months in the prednisolone-free group and 57.7 months in the group in which prednisolone was used. There was no significant difference in the probability of remission between the two groups (log-rank, P = 0.58). Additionally, there was no significant difference in the probability of a normalized serum C3 level between the two groups (log-rank, P = 0.59). Discussion This retrospective cohort study reports the comprehensive clinical and laboratory data and outcomes of pediatric patients diagnosed with IC-MPGN and C3G (DDD, C3GN) at several pediatric facilities in Japan. Surprisingly, of the 25 patients diagnosed with MPGN in this study, 20 (80.0%) patients were classified as having C3GN. The percentage of C3GN in MPGN was previously reported as 29.5–35.7% in pediatric cohorts [ 12 , 13 ], 37.1–41.7% in mixed pediatric and adult cohorts [ 14 , 15 ], and 39.3% in an adult cohort [ 16 ]. The proportion of C3GN among the patients with MPGN in this study was thus greater than that in previous reports. In this study, the median age at diagnosis for patients with C3GN was 9.8 (8.6–13.0) years, which is similar to that reported in other pediatric reports (9.0-10.1 years) [ 6 , 12 , 13 ]. Furthermore, in this study, the prevalence of hematuria in patients with C3GN was 95.0%, which was present in most patients and comparable to previous reports of children and adults [ 12 – 14 ]. In patients with MPGN, the presence of nephrotic syndrome [ 17 ] and decreased eGFR at diagnosis [ 18 ] are considered to be poor prognostic signs. In previous reports, the complication rate of nephrotic syndrome in patients with C3GN range from 26.8–32.6% in mixed cohorts of children and adults [ 14 , 15 , 18 ] to 76.9% in a pediatric cohort [ 12 ]. However, in this study, the prevalence was 10.0%, which is clearly lower than those in these previous reports. Regarding kidney function, the eGFR at baseline in this study was 124.2 (105.2-139.3) ml/min/1.73m 2 and the percentage of eGFR < 90 ml/min/1.73m 2 was 20.0%. This indicates good kidney function, compared with previous reports of 65.9–75.7 ml/min/1.73m 2 in mixed cohorts of children and adults [ 15 , 18 ], and 101 ml/min/1.73m 2 [ 12 ] and 44.0% of eGFR < 90 ml/min/1.73m 2 [ 13 ] in children. Regarding the pathological findings of C3GN, the presence of crescents [ 19 – 22 ], tubulointerstitial disease [ 21 , 22 ] and sclerosis [ 20 ] are considered to be poor prognostic signs in patients with MPGN. In this study, 75.0% of the patients with C3GN had no crescents, 25.0% had less than 50% crescents, and none had 50% or more crescents. In addition, 30.0% of patients with C3GN had interstitial fibrosis. The complication rate of these findings was comparable to that of previous pediatric cohorts [ 13 ]. The complication rate of global sclerosis was 5.0% in this study, which was lower than that in previous pediatric cohorts [ 12 , 13 ]. Our Japanese cohort can be said to be predominantly composed of patients with mild symptoms overall. On the other hand, the serum C3 level in this study was 18.0 (12.0-31.5) mg/dL, which was relatively low compared with previous reports of 27.5–39.0 mg/dL in a pediatric cohort [ 12 , 13 ] and 44.0 mg/dL in a mixed cohort of adults and children [ 14 ]. In this study, remission occurred in 13 of the 20 (65.0%) patients with C3GN. Previous papers [ 12 , 13 , 18 ] have reported remission rates of 11.5–60.0% for patients with C3GN, and although the definition of remission in this study was stricter than those previously reported, the remission rate was similar or greater. In addition, in previous reports [ 12 , 18 ], 7.7–9.2% of patients with C3GN progressed to an eGFR < 15 ml/min/1.73m 2 at the last follow-up, compared with no patients in this study. The patients with C3GN in this study had a lower complication rate of nephrotic syndrome and better kidney function and pathological findings of the kidneys, suggesting a greater proportion of mild cases than previously reported. In Japan, a school urinalysis system is widespread, and regular urinalysis allows early diagnosis of C3GN. This may have resulted in a greater percentage of mild cases in this study than in previous reports that were based outside of Japan. In fact, 14 of the 20 patients with C3GN in our study were diagnosed following an abnormality detected in a school urinalysis. In this study, the prednisolone-free group exhibited a significant decrease in urinary protein and a significant increase in serum C3 at the last follow-up. In addition, remission was achieved in six of the eight (75.0%) patients, suggesting a good response to treatment. In a previous report [ 13 ], all seven pediatric patients with C3GN treated with ACE-I or ARB alone also achieved remission. Therefore, patients with C3GN with mild to moderate proteinuria may have favorable outcomes when treated with ACE-I or ARB alone. In the current study, the group in which prednisolone was used also had a significant decrease in urinary protein and a significant increase in serum C3 levels at the last follow-up, suggesting that even patients with C3GN with nephrotic syndrome or severe proteinuria (urinary protein creatinine ratio ≥ 1.0 g/gCr) may have favorable outcomes with prednisolone. However, there was no statistically significant difference in urinary protein and serum C3 levels between pre- and post-treatment in patients treated with MZR or MMF. These immunosuppressants were added when patients had worsening or inadequate response to prednisolone. Treatment response is therefore limited in such severe cases in which immunosuppressants are needed. This study has several limitations. First, the investigation was retrospective, and we did not include a control group to compare outcomes with those of other treatments. Second, all patients in this study were Japanese children. Third, we could not obtain information on autoantibodies and genetic variants related to the alternative pathway of the complement system. Fourth, because the sample sizes of patients with DDD and IC-MPGN were relatively small, it was not possible to properly compare the clinical characteristics of the two diseases. However, the study included a relatively large number of patients despite the rarity of the disease. In addition, the diagnosis and classification of the MPGNs were performed by a single pathologist, which ensured consistency in the diagnosis. In summary, the majority of pediatric patients in this study had C3GN. Overall, 65.0% of patients with C3GN achieved remission, and no patients with C3GN progressed to an eGFR < 15 ml/min/1.73m 2 at the last follow-up, indicating good outcomes. In particular, patients with C3GN with mild to moderate proteinuria had good outcomes, and ACE-I or ARB alone seemed to be effective in patients with mild C3GN. Treatment response was limited in severe cases in which immunosuppressants were induced. Table 1 Baseline clinical characteristics in patients with MPGN Total (N = 25) C3G IC-MPGN (N = 2) C3GN (N = 20) DDD (N = 3) Age at diagnosis (year) 10.2 (8.7–12.5) 9.8 (8.6–13.0) 10.6 (9.6–11.2) 10.1 (9.4–10.9) Male, N (%) 16 (64.0) 14 (70.0) 1 (33.3) 1 (50.0) Height (cm) 132.2 (126.2-156.6) 134.4 (126.2-159.1) 132.2 (131.6-139.1) 134.1 (129.1-139.2) Weight (kg) 28.1 (24.0-45.9) 27.9 (24.0-50.1) 28.1 (27.3–30.3) 27.9 (25.4–30.5) Hematuria, N (%) 24 (96.0) 19 (95.0) 3 (100) 2 (100) Nephrotic syndrome, N (%) 4 (16.0) 2 (10.0) 0 (0) 2 (100) Urine protein creatinine ratio (g/gCr) 1.14* (0.47–1.72) 0.86 (0.42–1.28) 2.86 (1.96–4.28) 4.50* eGFR (ml/min/1.73m 2 ) 122.5 (103.1-137.6) 124.2 (105.2-139.3) 122.5 (101.3-124.5) 182.7 (140.6-224.8) eGFR < 90 ml/min/1.73m 2 , N (%) 5 (20.0) 4 (20.0) 1 (33.3) 0 (0) Serum albumin (g/dL) 4.0 (3.6–4.2) 4.0 (3.7–4.2) 4.1 (3.9–4.4) 2.3 (2.3–2.4) Serum C3 (mg/dL) 18.0* (12.0-31.5) 18.0 (12.0-31.8) 12.0 (8.6–16.5) 33.0* Serum C4 (mg/dL) 15.1* (11.8–18.2) 16.0 (12.8–19.0) 11.0 (10.0–12.0) 7.0* * Lack of data for 1 patient. MPGN membranoproliferative glomerulonephritis, C3G C3 glomerulopathy, C3GN C3 glomerulonephritis, DDD dense deposit disease, IC-MPGN immune-complex MPGN, eGFR estimated glomerular filtration rate Table 2 Light microscopic findings in patients with MPGN C3G IC-MPGN (N = 2) C3GN (N = 20) DDD (N = 3) Crescents, N (%) None 15 (75.0) 2 (66.7) 1 (50.0) < 50% glomeruli 5 (25.0) 1 (33.3) 1 (50.0) ≥ 50% glomeruli 0 (0) 0 (0) 0 (0) Endocapillary proliferation, N (%) 3 (15.0) 2 (66.7) 0 (0) Global sclerosis, N (%) 1 (5.0) 1 (33.3) 1 (50.0) Interstitial fibrosis, N (%) 6 (30.0) 0 (0) 1 (50.0) MPGN membranoproliferative glomerulonephritis, C3G C3 glomerulopathy, C3GN C3 glomerulonephritis, DDD dense deposit disease, IC-MPGN immune-complex MPGN Table 3 Treatments and outcomes in patients with MPGN Total (N = 25) C3G (N = 23) IC-MPGN (N = 2) C3GN (N = 20) DDD (N = 3) Therapy during the follow-up period RAS-I, N (%) 23 (92.0) 18 (90.0) 3 (100) 2 (100) Prednisolone, N (%) 17 (68.0) 12 (60.0) 3 (100) 2 (100) Immunosuppressants, N (%) 6 (24.0) 4 (20.0) 0 (0) 2 (100.0) Therapy at the last follow-up RAS-I, N (%) 15 (60.0) 11 (55.0) 2 (66.7) 2 (100) Prednisolone, N (%) 6 (24.0) 4 (20.0) 2 (66.7) 0 (0) Immunosuppressants, N (%) 5 (20.0) 4 (20.0) 0 (0) 1 (50.0) Clinical parameters at the last follow-up Hematuria, N (%) 7 (28.0) 5 (25.0) 1 (33.3) 1 (50.0) Urine protein creatinine ratio (g/gCr) 0.12 (0.06–0.25) 0.10 (0.05–0.23) 0.17 (0.13–0.31) 0.28 (0.24–0.31) Remission, N (%) 14 (56.0) 13 (65.0) 1 (33.3) 0 (0) eGFR (ml/min/1.73m 2 ) 110.1* (103.7-121.5) 107.8* (102.8-121.3) 113.3 (112.6-119.9) 99.7 (88.7-110.7) eGFR < 90 ml/min/1.73m 2 , N (%) 3* (12.0) 2* (10.0) 0 (0) 1 (50.0) Serum albumin (g/dL) 4.3 (4.1–4.6) 4.3 (4.1–4.6) 4.6 (4.1–4.8) 4.3 (4.2–4.4) Serum C3 (mg/dL) 76.0** (47.5–92.5) 72.0* (47.5–89.0) 46.0* (28.0-63.9) 97.5 (95.3–99.8) Serum C4 (mg/dL) 16.0** (14.9–22.0) 16.0* (14.9–21.0) 14.6* (12.8–16.4) 24.0 (23.5–24.5) * Lack of data for one patient. **Lack of data for two patients. MPGN membranoproliferative glomerulonephritis, C3G C3 glomerulopathy, C3GN C3 glomerulonephritis, DDD dense deposit disease, IC-MPGN immune-complex MPGN, RAS-I renin-angiotensin system inhibitor, eGFR estimated glomerular filtration rate Table 4 Comparison based on the use of prednisolone in the C3GN group Prednisolone-free (N = 8) Prednisolone-used (N = 12) P value Hematuria at diagnosis, N (%) 8 (100) 11 (91.7) 1 Hematuria at the last follow-up, N (%) 1 (12.5) 4 (33.3) 1 P value NA 0.02 eGFR at diagnosis (ml/min/1.73m 2 ) 126.8 (104.1-135.9) 121.6 (105.2-144.7) 0.97 eGFR at the last follow-up (ml/min/1.73m 2 ) 110.7 (106.1-126.6) 106.3* (100.6-121.3) 0.44 P value 0.84 0.12 eGFR < 90 ml/min/1.73m 2 at diagnosis, N (%) 2 (25.0) 2 (16.7) 1 eGFR < 90 ml/min/1.73m 2 at the last follow-up, N (%) 1 (12.5) 1* (9.1) 1 P value 1 1 Urine protein creatinine ratio at diagnosis (g/gCr) 0.54 (0.43–0.79) 1.27 (0.42–1.72) 0.13 Urine protein creatinine ratio at the last follow-up (g/gCr) 0.09 (0.06–0.15) 0.10 (0.05–0.43) 0.62 P value 0.02 0.03 Remission, N (%) 6 (75.0) 7 (58.3) 0.64 Serum C3 (mg/dL) at diagnosis 18.0 (15.8–31.5) 15.5 (10.5–31.8) 0.44 Serum C3 (mg/dL) at the last follow-up 70.5 (64.3–88.8) 76.0 * (28.0-88.5) 0.72 P value 0.02 0.004 Normalization of serum C3, N (%) 3 (37.5) 4* (36.4) 1 Crescents, N (%) 3 (37.5) 2 (16.7) 0.35 Endocapillary proliferation, N (%) 1 (12.5) 2 (16.7) 1 Global sclerosis, N (%) 0 (0) 1 (8.3) 1 Interstitial fibrosis, N (%) 1 (12.5) 5 (41.7) 0.33 * Lack of data for one patient. C3GN C3 glomerulonephritis, eGFR estimated glomerular filtration rate, NA not available Declarations Acknowledgments We wish to thank all the participants who were included in this study and all the attending physicians for their contributions. Finally, we thank Benjamin Phillis for editing a draft of this manuscript. Author contributions CU, TH, YIno, YIchi, YT, HK, AK, NS, CN, TY, JF, NK, SI, TN, HK, and YS managed the patients and conceptualized this study. CU and TH designed the study concept, interpreted the data, and wrote the manuscript. NY performed the pathological evaluation. KI and KN critically reviewed the manuscript. All the authors have read and approved the final manuscript. Data availability Data from this study can be obtained from the corresponding author upon reasonable request. Ethics approval This study, which involved human participants, was conducted in accordance with the Declaration of Helsinki. Ethics approval was obtained from the Kobe University Graduate School of Medicine Ethics Review Committee (IRB number: B190137). Consent to participate/consent for publication Informed consent for kidney biopsy was obtained from guardians of all patients, but the need for informed consent to publish the detailed data of the patients was waived due to the retrospective nature of this study. Competing Interest The authors declare no conflicts of interest. References Habib R, Kleinknecht C, Gubler MC, Levy M (1973) Idiopathic membranoproliferative glomerulonephritis in children. Report of 105 cases. Clin Nephrol 1:194-214. Anders D, Agricola B, Sippel M, Thoenes W (1977) Basement membrane changes in membranoproliferative glomerulonephritis. II. Characterization of a third type by silver impregnation of ultra thin sections. Virchows Arch A Pathol Anat Histol 376:1-19. https://doi.org/10.1007/BF00433081 Burkholder PM, Marchand A, Krueger RP (1970) Mixed membranous and proliferative glomerulonephritis. A correlative light, immunofluorescence, and electron microscopic study. Lab Invest 23:459-479. Sethi S, Fervenza FC (2012) Membranoproliferative glomerulonephritis--a new look at an old entity. N Engl J Med 366:1119-1131. https://doi.org/10.1056/NEJMra1108178 Bomback AS, Appel GB (2012) Pathogenesis of the C3 glomerulopathies and reclassification of MPGN. Nat Rev Nephrol 8:634-642. https://doi.org/10.1038/nrneph.2012.213 Kirpalani A, Jawa N, Smoyer WE, Licht C, Midwest Pediatric Nephrology C (2020) Long-Term Outcomes of C3 Glomerulopathy and Immune-Complex Membranoproliferative Glomerulonephritis in Children. Kidney Int Rep 5:2313-2324. https://doi.org/10.1016/j.ekir.2020.09.019 Licht C, Vivarelli M, Riedl Khursigara M, Pickering MC, Walker PD (2021) Membranoproliferative Glomerulonephritis and C3 Glomerulopathy in Children. Pediatric Nephrology, pp 1-31. https://doi.org/10.1007/978-3-642-27843-3_29-2 Pickering MC, D'Agati VD, Nester CM, Smith RJ, Haas M, Appel GB, Alpers CE, Bajema IM, Bedrosian C, Braun M, Doyle M, Fakhouri F, Fervenza FC, Fogo AB, Fremeaux-Bacchi V, Gale DP, Goicoechea de Jorge E, Griffin G, Harris CL, Holers VM, Johnson S, Lavin PJ, Medjeral-Thomas N, Paul Morgan B, Nast CC, Noel LH, Peters DK, Rodriguez de Cordoba S, Servais A, Sethi S, Song WC, Tamburini P, Thurman JM, Zavros M, Cook HT (2013) C3 glomerulopathy: consensus report. Kidney Int 84:1079-1089. https://doi.org/10.1038/ki.2013.377 Uemura O, Nagai T, Ishikura K, Ito S, Hataya H, Gotoh Y, Fujita N, Akioka Y, Kaneko T, Honda M (2014) Creatinine-based equation to estimate the glomerular filtration rate in Japanese children and adolescents with chronic kidney disease. Clin Exp Nephrol 18:626-633. https://doi.org/10.1007/s10157-013-0856-y Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A, Collaborators developing the Japanese equation for estimated GFR (2009) Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 53:982-992. https://doi.org/10.1053/j.ajkd.2008.12.034 Kanda Y (2013) Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 48:452-458. https://doi.org/10.1038/bmt.2012.244 Khandelwal P, Bhardwaj S, Singh G, Sinha A, Hari P, Bagga A (2021) Therapy and outcomes of C3 glomerulopathy and immune-complex membranoproliferative glomerulonephritis. Pediatr Nephrol 36:591-600. https://doi.org/10.1007/s00467-020-04736-8 Wong EKS, Marchbank KJ, Lomax-Browne H, Pappworth IY, Denton H, Cooke K, Ward S, McLoughlin AC, Richardson G, Wilson V, Harris CL, Morgan BP, Hakobyan S, McAlinden P, Gale DP, Maxwell H, Christian M, Malcomson R, Goodship THJ, Marks SD, Pickering MC, Kavanagh D, Cook HT, Johnson SA, Group MDCGRD, National Study of MDDDCGI (2021) C3 Glomerulopathy and Related Disorders in Children: Etiology-Phenotype Correlation and Outcomes. Clin J Am Soc Nephrol 16:1639-1651. https://doi.org/10.2215/CJN.00320121 Iatropoulos P, Noris M, Mele C, Piras R, Valoti E, Bresin E, Curreri M, Mondo E, Zito A, Gamba S, Bettoni S, Murer L, Fremeaux-Bacchi V, Vivarelli M, Emma F, Daina E, Remuzzi G (2016) Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome. Mol Immunol 71:131-142. https://doi.org/10.1016/j.molimm.2016.01.010 Servais A, Noel LH, Roumenina LT, Le Quintrec M, Ngo S, Dragon-Durey MA, Macher MA, Zuber J, Karras A, Provot F, Moulin B, Grunfeld JP, Niaudet P, Lesavre P, Fremeaux-Bacchi V (2012) Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int 82:454-464. https://doi.org/10.1038/ki.2012.63 Iatropoulos P, Daina E, Curreri M, Piras R, Valoti E, Mele C, Bresin E, Gamba S, Alberti M, Breno M, Perna A, Bettoni S, Sabadini E, Murer L, Vivarelli M, Noris M, Remuzzi G, Registry of Membranoproliferative Glomerulonephritis CG, Nastasi (2018) Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies/Immune Complex-Mediated Membranoproliferative GN. J Am Soc Nephrol 29:283-294. https://doi.org/10.1681/ASN.2017030258 Somers M, Kertesz S, Rosen S, Herrin J, Colvin R, Palacios de Carreta N, Kim M (1995) Non-nephrotic children with membranoproliferative glomerulonephritis: are steroids indicated? Pediatr Nephrol 9:140-144. https://doi.org/10.1007/BF00860727 Bomback AS, Santoriello D, Avasare RS, Regunathan-Shenk R, Canetta PA, Ahn W, Radhakrishnan J, Marasa M, Rosenstiel PE, Herlitz LC, Markowitz GS, D'Agati VD, Appel GB (2018) C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy. Kidney Int 93:977-985. https://doi.org/10.1016/j.kint.2017.10.022 Bennett WM, Fassett RG, Walker RG, Fairley KF, d'Apice AJ, Kincaid-Smith P (1989) Mesangiocapillary glomerulonephritis type II (dense-deposit disease): clinical features of progressive disease. Am J Kidney Dis 13:469-476. https://doi.org/10.1016/s0272-6386(89)80004-6 Cameron JS, Turner DR, Heaton J, Williams DG, Ogg CS, Chantler C, Haycock GB, Hicks J (1983) Idiopathic mesangiocapillary glomerulonephritis. Comparison of types I and II in children and adults and long-term prognosis. Am J Med 74:175-192. https://doi.org/10.1016/0002-9343(83)90606-x Little MA, Dupont P, Campbell E, Dorman A, Walshe JJ (2006) Severity of primary MPGN, rather than MPGN type, determines renal survival and post-transplantation recurrence risk. Kidney Int 69:504-511. https://doi.org/10.1038/sj.ki.5000084 Lomax-Browne HJ, Medjeral-Thomas NR, Barbour SJ, Gisby J, Han H, Bomback AS, Fervenza FC, Cairns TH, Szydlo R, Tan SJ, Marks SD, Waters AM, Appel GB, D'Agati VD, Sethi S, Nast CC, Bajema I, Alpers CE, Fogo AB, Licht C, Fakhouri F, Cattran DC, Peters JE, Cook HT, Pickering MC (2022) Association of Histologic Parameters with Outcome in C3 Glomerulopathy and Idiopathic Immunoglobulin-Associated Membranoproliferative Glomerulonephritis. Clin J Am Soc Nephrol 17:994-1007. https://doi.org/10.2215/CJN.16801221 Supplementary Files renamede7865.pptx renamedd1454.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major Revisions Needed 13 Feb, 2024 Reviewers agreed at journal 23 Jan, 2024 Reviewers invited by journal 22 Jan, 2024 Editor assigned by journal 22 Jan, 2024 First submitted to journal 20 Jan, 2024 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-3885158","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":268858253,"identity":"ec947997-f640-4f62-a40c-a5aeddf59453","order_by":0,"name":"Chika Ueda","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Chika","middleName":"","lastName":"Ueda","suffix":""},{"id":268858254,"identity":"823da741-ecdd-4996-90be-6f3b2fcf484d","order_by":1,"name":"Tomoko 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15:59:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3885158/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3885158/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50182114,"identity":"bc0e7d94-a5aa-4887-9ebf-d2342431e686","added_by":"auto","created_at":"2024-01-25 18:52:50","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":64234,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow chart showing the distribution of pediatric patients with MPGN\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study included 32 pediatric patients diagnosed with MPGN based on kidney biopsies conducted between February 2002 and December 2022. Patients with inadequate clinical and laboratory data (n=4), no immunofluorescence imaging (n=1), resolved proteinuria without therapeutic intervention(n=1), and short follow-up (\u0026lt; 6 months) (n=1) were excluded from the analysis. Of the remaining patients, 23 with C3 dominant deposits were classified as C3G, and the other two patients were classified as IC-MPGN. Furthermore, among the patients with C3G, three patients exhibiting linear intramembranous electron dense deposits on electron microscopy were classified as DDD, while the remaining 20 patients were classified as having C3GN\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3885158/v1/23071d9b29d86c86fd27a2ca.jpg"},{"id":50182113,"identity":"c4e3a3f8-05d5-45c1-bb47-e65635ec58f7","added_by":"auto","created_at":"2024-01-25 18:52:50","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":74239,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier analysis of remission by the last follow-up and normalized serum C3 levels in patients with C3GN\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe solid line indicates the prednisolone-free group, and the dotted line indicates the group in which prednisolone was used. (a) The median time to remission by the last follow-up was 17.0 months in the prednisolone-free group and 57.7 months in the group in which prednisolone was used. Moreover, there was no significant difference in the probability of remission between the two groups (log-rank, \u003cem\u003eP\u003c/em\u003e = 0.58). (b) The median time to normalized serum C3 levels was not available for either group because the rate of normalization did not reach 50%. There was no significant difference in the probability of normalized serum C3 levels between the two groups (log-rank, \u003cem\u003eP\u003c/em\u003e = 0.59)\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3885158/v1/1a7633b8ca5bbf81c85194ee.jpg"},{"id":50182814,"identity":"51af8337-0ac2-4fd6-a702-eeb155331e66","added_by":"auto","created_at":"2024-01-25 19:00:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":508805,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3885158/v1/2478c48a-80c0-40bd-ac7f-f81002e3f405.pdf"},{"id":50182116,"identity":"98ea2b6a-015b-4ba9-ae85-fa266777322a","added_by":"auto","created_at":"2024-01-25 18:52:51","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":63868,"visible":true,"origin":"","legend":"","description":"","filename":"renamede7865.pptx","url":"https://assets-eu.researchsquare.com/files/rs-3885158/v1/aa58af4d83505090f03e27bb.pptx"},{"id":50182115,"identity":"5e0e6ce7-61cc-4554-bad2-1b8d6a08ccda","added_by":"auto","created_at":"2024-01-25 18:52:51","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":46678,"visible":true,"origin":"","legend":"","description":"","filename":"renamedd1454.docx","url":"https://assets-eu.researchsquare.com/files/rs-3885158/v1/61032436269c0ddd28102301.docx"}],"financialInterests":"","formattedTitle":"Clinical characteristics and long-term outcomes of immune-complex membranoproliferative glomerulonephritis and C3 glomerulopathy in Japanese children","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMembranoproliferative glomerulonephritis (MPGN) is a glomerular injury characterized by pathological findings of mesangial interposition and double contours of the capillary wall [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Historically, MPGN was morphologically classified into three subtypes based on the deposition site of electron-dense deposits (EDD) in the glomerulus, as observed by electron microscopy: type I with EDD in the subendothelial areas, dense deposit disease (DDD) with deposits in the basement membrane, and type III with deposits in both the subepithelial and subendothelial areas [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, in a 2012 study, immunofluorescence images revealed strong positivity for C3 deposits in DDD, while types I and III had a mixture of C3 deposits and both C3 and immunoglobulin deposits, indicating potentially different etiologies [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Subsequently, based on immunofluorescence images, patients with predominant IgG staining were reclassified as having immune-complex MPGN (IC-MPGN), while those with predominant C3 deposition were reclassified as having C3 glomerulopathy (C3G) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. C3G was further classified into DDD and C3 glomerulonephritis (C3GN) as DDD characterized by linear intramembranous EDD according to electron microscopy, and C3GN was classified when there was absence of DDD [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. IC-MPGN is caused by activation of the classical pathway due to immune complex formation associated with infections and autoimmune diseases [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. On the other hand, C3G (DDD, C3GN) is caused by the dysregulation of alternative pathway activity [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Given the different complement pathways involved, IC-MPGN and C3G (DDD, C3GN) may exhibit distinct prognoses. However, limited reports exist on the respective clinical courses of IC-MPGN and C3G, especially in pediatric patients, in whom MPGN is rare. There is also a lack of evidence-based standard treatment for patients with IC-MPGN and C3G, particularly in the pediatric population [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. To elucidate the clinical characteristics of MPGN and to identify appropriate treatments, we reclassified types of MPGN based on kidney biopsy findings in pediatric patients diagnosed with MPGN. We retrospectively analyzed demographic, clinical and laboratory findings, and therapeutic response in patients with IC-MPGN and C3G (DDD, C3GN).\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eParticipants and Study Design\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study included Japanese pediatric patients diagnosed with MPGN via kidney biopsy between February 2002 and December 2022 at the pediatric nephrology departments of Kobe University Hospital, Wakayama Medical University Hospital, Hyogo Prefectural Kobe Children\u0026rsquo;s Hospital, Takatsuki General Hospital, Japanese Red Cross Society Himeji Hospital, and Kakogawa Central City Hospital. The exclusion criteria were patients with missing clinical or laboratory data, absence of immunofluorescence imaging, resolved proteinuria without therapeutic intervention, a brief follow-up period (\u0026lt;\u0026thinsp;6 months) and indications of secondary nephritis. The following data were retrospectively obtained from the patients\u0026rsquo; medical records at the time of diagnosis (initial kidney biopsy) and subsequent regular outpatient visits, as well as at the last follow-up: patient demographic information (age, sex, height, and weight), clinical and laboratory data (proteinuria, hematuria, serum creatinine level, estimated glomerular filtration rate (eGFR), serum albumin level, serum C3 and C4 level and presence of nephrotic syndrome), and details of the treatment. For C3GN, the predominant subtype of MPGN, we examined the factors associated with remission and normalization of serum C3 levels. Additionally, we compared the differences in clinical and laboratory findings between patients treated with and without prednisolone. The Kaplan‒Meier method was used to assess the time to remission or normalization of the serum C3 levels.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePathology\u003c/h2\u003e \u003cp\u003eKidney biopsies were performed for children exhibiting both hypocomplementemia and proteinuria. All kidney biopsy reports, including light microscopy, immunostaining, and electron microscopy results, were reviewed by one pathologist (N.Y.). MPGN was pathologically diagnosed based on mesangial hypercellularity, endocapillary proliferation, and double-contour formation along the glomerular capillary walls via light microscopy. Subsequently, based on immunofluorescence imaging of kidney biopsies, we reclassified these patients with MPGN as having IC-MPGN or C3G. C3-dominant deposits were categorized as C3G with \u0026lsquo;dominant\u0026rsquo;, defined as a C3 intensity two orders of magnitude higher than that of any other immune reactant (IgG, IgA, IgM or C1q) on a scale of zero to three [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], and the others were categorized as having IC-MPGN [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Further subclassification of C3G included DDD or C3GN: DDD was assigned when linear intramembranous electron-dense deposits were observed via electron microscopy, while those lacking DDD characteristics were classified as having C3GN [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In patients with multiple kidney biopsies, the initial biopsy was used for diagnosis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eTreatment protocol\u003c/h2\u003e \u003cp\u003eTreatments were administered at the discretion of the clinicians. In general, patients exhibiting mild to moderate proteinuria (urine protein creatinine ratio 0.15-1.0 g/gCr) were treated with angiotensin-converting enzyme inhibitor (ACE-I), patients who did not respond adequately to ACE-I were additionally given an angiotensin II receptor blocker (ARB). Those facing challenges in continuing ACE-I medication due to side effects such as cough and dizziness were switched to an ARB. Patients diagnosed with nephrotic syndrome or severe proteinuria (urinary protein creatinine ratio\u0026thinsp;\u0026ge;\u0026thinsp;1.0 g/gCr) or those experiencing exacerbation after ACE-I or ARB treatment received either prednisolone or a combination of prednisolone and intravenous methylprednisolone at a dosage of 30 mg/kg/day (maximum dose, 1000 mg/day) for three consecutive days. This regimen is known as methylprednisolone pulse therapy (MPT) and was administered for two to three courses along with prednisolone. In cases of worsening or inadequate response, an additional two courses of MPT were administered, followed by prednisolone, and subsequently, immunosuppressants such as mizoribine (MZR) or mycophenolate mofetil (MMF) were added.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eDefinitions\u003c/h2\u003e \u003cp\u003eNephrotic syndrome was diagnosed based on the presence of both severe proteinuria (urine protein creatinine ratio\u0026thinsp;\u0026ge;\u0026thinsp;2 g/gCr) and hypoalbuminemia (serum albumin\u0026thinsp;\u0026le;\u0026thinsp;2.5 g/dL). Hematuria was defined as the presence of \u0026ge;\u0026thinsp;5 red blood cells per high-power field of a centrifuged urine specimen. Proteinuria was defined as a protein creatinine ratio\u0026thinsp;\u0026ge;\u0026thinsp;0.15 g/gCr. Remission was considered to be achieved when the protein creatinine ratio was \u0026lt;\u0026thinsp;0.15 g/gCr and the serum albumin levels was \u0026gt;\u0026thinsp;2.5 g/dL. Normalization of the serum C3 levels was considered to be achieved when the serum C3 levels was \u0026gt;\u0026thinsp;80 mg/dL. For patients aged between two and eighteen years, the eGFR was calculated by comparing the serum creatinine levels of patients with the reference serum creatinine levels of Japanese children based on the patients\u0026rsquo; height and sex [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. For patients aged\u0026thinsp;\u0026gt;\u0026thinsp;18 years old, the eGFR was calculated based on the patients\u0026rsquo; serum creatinine levels, age, and sex [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical methods\u003c/h2\u003e \u003cp\u003eStatistical analysis was conducted using Easy R (EZR) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], a modified version of the R Commander that is specifically tailored to include commonly-used statistical methods in biostatistics. Clinical and laboratory findings are presented as the median and interquartile range (IQR) for continuous variables and as percentages for qualitative variables. The Mann‒Whitney U test and Wilcoxon signed rank test were employed to assess differences between continuous variables, while Fisher's exact test and McNemar's test were utilized for comparing qualitative variables. The Kaplan-Meier method and log-rank tests were used to evaluate differences in the time to remission and serum C3 normalization among patients, comparing those with and without prednisolone use. \u003cem\u003eP\u003c/em\u003e-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered to indicate statistical significance.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStudy cohort\u003c/h2\u003e \u003cp\u003eIn this retrospective cohort study, 32 patients were diagnosed with idiopathic MPGN. We excluded seven patients: four patients due to inadequate clinical and laboratory data, one patient with no immunofluorescence imaging, one patient with resolved proteinuria without therapeutic intervention, and one patient with a short follow-up period (\u0026lt;\u0026thinsp;6 months). Among the remaining 25 patients with MPGN, three (12.0%) were reclassified as DDD, 20 (80.0%) were reclassified as C3GN, and two (8.0%) were reclassified as IC-MPGN (Fig.\u0026nbsp;1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003ePatient demographics and clinical characteristics\u003c/h2\u003e \u003cp\u003eThe events that led to the diagnosis of MPGN in 25 patients were as follows: school urinalysis in 16 patients, abnormal findings in a urine test conducted incidentally in five patients, onset of nephrotic syndrome in two patients, and gross hematuria in two patients. The baseline clinical characteristics are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median age at diagnosis for the entire cohort was 10.2 (8.7\u0026ndash;12.5) years, and 16 (64.0%) patients were male. Hematuria was observed in 24 (96.0%) patients. Among patients with C3GN, only two (10.0%) presented with nephrotic syndrome, while no patients with DDD presented nephrotic syndrome. Conversely, both patients with IC-MPGN exhibited nephrotic syndrome. The median urine protein creatinine ratio at diagnosis was 1.14 (0.47\u0026ndash;1.72) g/gCr. The median eGFR for the entire cohort was 122.5 (103.1-137.6) mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e, with five (20.0%) patients showing an eGFR\u0026thinsp;\u0026lt;\u0026thinsp;90 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e. The median serum C3 level was 18.0 (12.0-31.5) mg/dL, and the serum C3 levels were low at the time of diagnosis in all groups.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePathological findings\u003c/h2\u003e \u003cp\u003eThe light microscopic findings are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Notably, crescents, global sclerosis and interstitial fibrosis were uncommon among our patients. Crescents were observed in five (25.0%) patients with C3GN, one (33.3%) patient with DDD, and one (50.0%) patient with IC-MPGN. Global sclerosis was present in one (5.0%) patient with C3GN, one (33.3%) patient with DDD, and one (50.0%) patient with IC-MPGN. Interstitial fibrosis was absent in patients with DDD but was observed in six (30.0%) patients with C3GN and one (50.0%) patient with IC-MPGN.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eTreatments\u003c/h2\u003e \u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, 23 (92.0%) patients received RAS-I. Prednisolone was administered to all patients with DDD and IC-MPGN, but to just 12 (60.0%) patients with C3GN. Immunosuppressants were administered to all patients with IC-MPGN and to four patients (20.0%) with C3GN, but not to patients with DDD. Based on the clinicians\u0026rsquo; decisions, some patients received treatments that deviated from the strategy described in the \u003cspan refid=\"Sec2\" class=\"InternalRef\"\u003eMethods\u003c/span\u003e section. Specifically, one patient with C3GN and with mild proteinuria was treated with prednisolone and MMF in addition to ACE-I. Another patient with C3GN and with initially mild proteinuria received ACE-I, but prednisolone and MMF were added due to an inadequate response. Subsequently, due to exacerbation, three courses of MPT were administered, followed by prednisolone. One patient with IC-MPGN with severe proteinuria received cyclosporine instead of MZR or MMF.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eOutcome\u003c/h2\u003e \u003cp\u003eThe outcomes of this retrospective cohort study are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The follow-up period of the entire cohort was 5.3 (2.5\u0026ndash;8.9) years. The incidence of hematuria at the last follow-up decreased in all groups (28%) compared with that at diagnosis. Thirteen (65.0%) patients with C3GN and one (33.3%) patient with DDD achieved remission, but none of the patients with IC-MPGN achieved remission. No patients in either group progressed to an eGFR\u0026thinsp;\u0026lt;\u0026thinsp;15 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e. Notably, compared with those at the time of diagnosis, urinary protein at the last follow-up tended to decrease, and serum C3 levels tended to increase in all groups (Supplementary Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eClinical and pathological findings as well as treatments of patients with C3GN in remission and non-remission, are shown in Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e. Clinical findings and treatments did not differ between the remission and non-remission groups. Pathology revealed that, in the non-remission group, no patients had crescents, endocapillary proliferation, or global sclerosis, and only one (14.3%) patient had interstitial fibrosis. Moreover, there was no significant difference between the remission and non-remission groups. Clinical and pathological findings and treatments for patients with C3GN with normalized and non-normalized serum C3 levels are shown in Supplementary Table S2. The age at diagnosis was significantly lower in patients with normalized serum C3 levels than in those with non-normalized serum C3 levels (8.7 vs 12.7 years, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02). There were no significant differences in other clinical findings, pathological findings, or treatments between the patients with normalized and non-normalized serum C3 levels.\u003c/p\u003e \u003cp\u003eA comparison of clinical and laboratory findings based on the use of prednisolone in the C3GN group is shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. Hematuria, eGFR, urine protein creatinine ratio, and serum C3 levels were compared between the time of diagnosis and the time of the last follow-up within each group. There were no significant differences between the prednisolone-free group and the group in which prednisolone was used regarding the incidence of hematuria, eGFR, urinary protein creatinine ratio, remission rate, serum C3 levels, and pathological findings. In both groups, the urinary protein creatinine ratio significantly decreased and the serum C3 levels significantly increased at the last follow-up. Remission was achieved in 6 of the 8 (75.0%) patients in the prednisolone-free group and 7 of the 12 (58.3%) patients in the group in which prednisolone was used. Among the four patients with severe proteinuria who received MZR or MMF, only one achieved remission, and none of them had normalized serum C3 levels.\u003c/p\u003e \u003cp\u003eA Kaplan\u0026ndash;Meier analysis of remission and normalization of serum C3 levels in patients with C3GN is shown in Fig.\u0026nbsp;2. The median time to remission was 17.0 months in the prednisolone-free group and 57.7 months in the group in which prednisolone was used. There was no significant difference in the probability of remission between the two groups (log-rank, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.58). Additionally, there was no significant difference in the probability of a normalized serum C3 level between the two groups (log-rank, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.59).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis retrospective cohort study reports the comprehensive clinical and laboratory data and outcomes of pediatric patients diagnosed with IC-MPGN and C3G (DDD, C3GN) at several pediatric facilities in Japan.\u003c/p\u003e \u003cp\u003eSurprisingly, of the 25 patients diagnosed with MPGN in this study, 20 (80.0%) patients were classified as having C3GN. The percentage of C3GN in MPGN was previously reported as 29.5\u0026ndash;35.7% in pediatric cohorts [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], 37.1\u0026ndash;41.7% in mixed pediatric and adult cohorts [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], and 39.3% in an adult cohort [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The proportion of C3GN among the patients with MPGN in this study was thus greater than that in previous reports.\u003c/p\u003e \u003cp\u003eIn this study, the median age at diagnosis for patients with C3GN was 9.8 (8.6\u0026ndash;13.0) years, which is similar to that reported in other pediatric reports (9.0-10.1 years) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Furthermore, in this study, the prevalence of hematuria in patients with C3GN was 95.0%, which was present in most patients and comparable to previous reports of children and adults [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In patients with MPGN, the presence of nephrotic syndrome [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and decreased eGFR at diagnosis [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] are considered to be poor prognostic signs. In previous reports, the complication rate of nephrotic syndrome in patients with C3GN range from 26.8\u0026ndash;32.6% in mixed cohorts of children and adults [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] to 76.9% in a pediatric cohort [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, in this study, the prevalence was 10.0%, which is clearly lower than those in these previous reports. Regarding kidney function, the eGFR at baseline in this study was 124.2 (105.2-139.3) ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e and the percentage of eGFR\u0026thinsp;\u0026lt;\u0026thinsp;90 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e was 20.0%. This indicates good kidney function, compared with previous reports of 65.9\u0026ndash;75.7 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e in mixed cohorts of children and adults [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], and 101 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] and 44.0% of eGFR\u0026thinsp;\u0026lt;\u0026thinsp;90 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] in children. Regarding the pathological findings of C3GN, the presence of crescents [\u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], tubulointerstitial disease [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] and sclerosis [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] are considered to be poor prognostic signs in patients with MPGN. In this study, 75.0% of the patients with C3GN had no crescents, 25.0% had less than 50% crescents, and none had 50% or more crescents. In addition, 30.0% of patients with C3GN had interstitial fibrosis. The complication rate of these findings was comparable to that of previous pediatric cohorts [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The complication rate of global sclerosis was 5.0% in this study, which was lower than that in previous pediatric cohorts [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Our Japanese cohort can be said to be predominantly composed of patients with mild symptoms overall. On the other hand, the serum C3 level in this study was 18.0 (12.0-31.5) mg/dL, which was relatively low compared with previous reports of 27.5\u0026ndash;39.0 mg/dL in a pediatric cohort [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and 44.0 mg/dL in a mixed cohort of adults and children [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study, remission occurred in 13 of the 20 (65.0%) patients with C3GN. Previous papers [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] have reported remission rates of 11.5\u0026ndash;60.0% for patients with C3GN, and although the definition of remission in this study was stricter than those previously reported, the remission rate was similar or greater. In addition, in previous reports [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], 7.7\u0026ndash;9.2% of patients with C3GN progressed to an eGFR\u0026thinsp;\u0026lt;\u0026thinsp;15 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e at the last follow-up, compared with no patients in this study. The patients with C3GN in this study had a lower complication rate of nephrotic syndrome and better kidney function and pathological findings of the kidneys, suggesting a greater proportion of mild cases than previously reported. In Japan, a school urinalysis system is widespread, and regular urinalysis allows early diagnosis of C3GN. This may have resulted in a greater percentage of mild cases in this study than in previous reports that were based outside of Japan. In fact, 14 of the 20 patients with C3GN in our study were diagnosed following an abnormality detected in a school urinalysis.\u003c/p\u003e \u003cp\u003eIn this study, the prednisolone-free group exhibited a significant decrease in urinary protein and a significant increase in serum C3 at the last follow-up. In addition, remission was achieved in six of the eight (75.0%) patients, suggesting a good response to treatment. In a previous report [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], all seven pediatric patients with C3GN treated with ACE-I or ARB alone also achieved remission. Therefore, patients with C3GN with mild to moderate proteinuria may have favorable outcomes when treated with ACE-I or ARB alone. In the current study, the group in which prednisolone was used also had a significant decrease in urinary protein and a significant increase in serum C3 levels at the last follow-up, suggesting that even patients with C3GN with nephrotic syndrome or severe proteinuria (urinary protein creatinine ratio\u0026thinsp;\u0026ge;\u0026thinsp;1.0 g/gCr) may have favorable outcomes with prednisolone. However, there was no statistically significant difference in urinary protein and serum C3 levels between pre- and post-treatment in patients treated with MZR or MMF. These immunosuppressants were added when patients had worsening or inadequate response to prednisolone. Treatment response is therefore limited in such severe cases in which immunosuppressants are needed.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, the investigation was retrospective, and we did not include a control group to compare outcomes with those of other treatments. Second, all patients in this study were Japanese children. Third, we could not obtain information on autoantibodies and genetic variants related to the alternative pathway of the complement system. Fourth, because the sample sizes of patients with DDD and IC-MPGN were relatively small, it was not possible to properly compare the clinical characteristics of the two diseases. However, the study included a relatively large number of patients despite the rarity of the disease. In addition, the diagnosis and classification of the MPGNs were performed by a single pathologist, which ensured consistency in the diagnosis.\u003c/p\u003e \u003cp\u003eIn summary, the majority of pediatric patients in this study had C3GN. Overall, 65.0% of patients with C3GN achieved remission, and no patients with C3GN progressed to an eGFR\u0026thinsp;\u0026lt;\u0026thinsp;15 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e at the last follow-up, indicating good outcomes. In particular, patients with C3GN with mild to moderate proteinuria had good outcomes, and ACE-I or ARB alone seemed to be effective in patients with mild C3GN. Treatment response was limited in severe cases in which immunosuppressants were induced.\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\u003eBaseline clinical characteristics in patients with MPGN\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTotal (N\u0026thinsp;=\u0026thinsp;25)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eC3G\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eIC-MPGN (N\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eC3GN (N\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDDD (N\u0026thinsp;=\u0026thinsp;3)\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 diagnosis (year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.2 (8.7\u0026ndash;12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.8 (8.6\u0026ndash;13.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.6 (9.6\u0026ndash;11.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.1 (9.4\u0026ndash;10.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (64.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (70.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e132.2 (126.2-156.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e134.4 (126.2-159.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e132.2 (131.6-139.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e134.1 (129.1-139.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28.1 (24.0-45.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.9 (24.0-50.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28.1 (27.3\u0026ndash;30.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27.9 (25.4\u0026ndash;30.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematuria, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (96.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (95.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNephrotic syndrome, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (16.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrine protein creatinine ratio (g/gCr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.14* (0.47\u0026ndash;1.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.86 (0.42\u0026ndash;1.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.86 (1.96\u0026ndash;4.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.50*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR (ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e122.5 (103.1-137.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e124.2 (105.2-139.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e122.5 (101.3-124.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e182.7 (140.6-224.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR\u0026thinsp;\u0026lt;\u0026thinsp;90 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum albumin (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.0 (3.6\u0026ndash;4.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.0 (3.7\u0026ndash;4.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.1 (3.9\u0026ndash;4.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.3 (2.3\u0026ndash;2.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum C3 (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.0* (12.0-31.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.0 (12.0-31.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.0 (8.6\u0026ndash;16.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e33.0*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum C4 (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.1* (11.8\u0026ndash;18.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.0 (12.8\u0026ndash;19.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11.0 (10.0\u0026ndash;12.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.0*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003csup\u003e*\u003c/sup\u003eLack of data for 1 patient.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eMPGN membranoproliferative glomerulonephritis, C3G C3 glomerulopathy, C3GN C3 glomerulonephritis, DDD dense deposit disease, IC-MPGN immune-complex MPGN, eGFR estimated glomerular filtration rate\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\u003eLight microscopic findings in patients with MPGN\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=\"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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eC3G\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eIC-MPGN (N\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC3GN (N\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDDD (N\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCrescents, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \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\u003e15 (75.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt; 50% glomeruli\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge; 50% glomeruli\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndocapillary proliferation, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (15.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlobal sclerosis, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterstitial fibrosis, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eMPGN membranoproliferative glomerulonephritis, C3G C3 glomerulopathy, C3GN C3 glomerulonephritis, DDD dense deposit disease, IC-MPGN immune-complex MPGN\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\u003eTreatments and outcomes in patients with MPGN\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\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\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTotal (N\u0026thinsp;=\u0026thinsp;25)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eC3G (N\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c6\" namest=\"c5\" rowspan=\"2\"\u003e \u003cp\u003eIC-MPGN (N\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eC3GN (N\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDDD (N\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eTherapy during the follow-up period\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRAS-I, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (92.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (90.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e2 (100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrednisolone, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (68.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e2 (100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmunosuppressants, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (24.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e2 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eTherapy at the last follow-up\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRAS-I, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (55.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e2 (100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrednisolone, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (24.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmunosuppressants, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e1 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eClinical parameters at the last follow-up\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematuria, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (28.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e1 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrine protein creatinine ratio (g/gCr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.12 (0.06\u0026ndash;0.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.10 (0.05\u0026ndash;0.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.17 (0.13\u0026ndash;0.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.28 (0.24\u0026ndash;0.31)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRemission, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (56.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (65.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR (ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e110.1* (103.7-121.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e107.8* (102.8-121.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e113.3 (112.6-119.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e99.7 (88.7-110.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR\u0026thinsp;\u0026lt;\u0026thinsp;90 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3* (12.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2* (10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e1 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum albumin (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.3 (4.1\u0026ndash;4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.3 (4.1\u0026ndash;4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.6 (4.1\u0026ndash;4.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e4.3 (4.2\u0026ndash;4.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum C3 (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76.0** (47.5\u0026ndash;92.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72.0* (47.5\u0026ndash;89.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e46.0* (28.0-63.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e97.5 (95.3\u0026ndash;99.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum C4 (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.0** (14.9\u0026ndash;22.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.0* (14.9\u0026ndash;21.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.6* (12.8\u0026ndash;16.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e24.0 (23.5\u0026ndash;24.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003csup\u003e*\u003c/sup\u003eLack of data for one patient. **Lack of data for two patients.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c6\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eMPGN membranoproliferative glomerulonephritis, C3G C3 glomerulopathy, C3GN C3 glomerulonephritis, DDD dense deposit disease, IC-MPGN immune-complex MPGN, RAS-I renin-angiotensin system inhibitor, eGFR estimated glomerular filtration rate\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison based on the use of prednisolone in the C3GN group\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=\"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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePrednisolone-free (N\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePrednisolone-used (N\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematuria at diagnosis, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (91.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematuria at the last follow-up, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR at diagnosis (ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e126.8 (104.1-135.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e121.6 (105.2-144.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR at the last follow-up (ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e110.7 (106.1-126.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e106.3* (100.6-121.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR\u0026thinsp;\u0026lt;\u0026thinsp;90 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e at diagnosis, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR\u0026thinsp;\u0026lt;\u0026thinsp;90 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e at the last follow-up, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1* (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrine protein creatinine ratio at diagnosis (g/gCr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.54 (0.43\u0026ndash;0.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.27 (0.42\u0026ndash;1.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrine protein creatinine ratio at the last follow-up (g/gCr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.09 (0.06\u0026ndash;0.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.10 (0.05\u0026ndash;0.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRemission, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (75.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (58.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum C3 (mg/dL) at diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.0 (15.8\u0026ndash;31.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.5 (10.5\u0026ndash;31.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum C3 (mg/dL) at the last follow-up\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70.5 (64.3\u0026ndash;88.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76.0\u003csup\u003e*\u003c/sup\u003e (28.0-88.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNormalization of serum C3, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (37.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4* (36.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCrescents, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (37.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndocapillary proliferation, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlobal sclerosis, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterstitial fibrosis, N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (41.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003csup\u003e*\u003c/sup\u003eLack of data for one patient.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eC3GN C3 glomerulonephritis, eGFR estimated glomerular filtration rate, NA not available\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e We wish to thank all the participants who were included in this study and all the attending physicians for their contributions. Finally, we thank Benjamin Phillis for editing a draft of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e CU, TH, YIno, YIchi, YT, HK, AK, NS, CN, TY, JF, NK, SI, TN, HK, and YS managed the patients and conceptualized this study.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eCU and TH designed the study concept, interpreted the data, and wrote the manuscript. NY performed the pathological evaluation. KI and KN critically reviewed the manuscript. All the authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e Data from this study can be obtained from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u0026nbsp;\u003c/strong\u003eThis study, which involved human participants, was conducted in accordance with the Declaration of Helsinki. Ethics approval was obtained from the Kobe University Graduate School of Medicine Ethics Review Committee (IRB number: B190137).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate/consent for publication\u003c/strong\u003e Informed consent for kidney biopsy was obtained from guardians of all patients, but the need for informed consent to publish the detailed data of the patients was waived due to the retrospective nature of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interest\u003c/strong\u003e The authors declare no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHabib R, Kleinknecht C, Gubler MC, Levy M (1973) Idiopathic membranoproliferative glomerulonephritis in children. Report of 105 cases. Clin Nephrol 1:194-214.\u003c/li\u003e\n\u003cli\u003eAnders D, Agricola B, Sippel M, Thoenes W (1977) Basement membrane changes in membranoproliferative glomerulonephritis. II. Characterization of a third type by silver impregnation of ultra thin sections. Virchows Arch A Pathol Anat Histol 376:1-19. https://doi.org/10.1007/BF00433081\u003c/li\u003e\n\u003cli\u003eBurkholder PM, Marchand A, Krueger RP (1970) Mixed membranous and proliferative glomerulonephritis. A correlative light, immunofluorescence, and electron microscopic study. Lab Invest 23:459-479.\u003c/li\u003e\n\u003cli\u003eSethi S, Fervenza FC (2012) Membranoproliferative glomerulonephritis--a new look at an old entity. N Engl J Med 366:1119-1131. https://doi.org/10.1056/NEJMra1108178\u003c/li\u003e\n\u003cli\u003eBomback AS, Appel GB (2012) Pathogenesis of the C3 glomerulopathies and reclassification of MPGN. Nat Rev Nephrol 8:634-642. https://doi.org/10.1038/nrneph.2012.213\u003c/li\u003e\n\u003cli\u003eKirpalani A, Jawa N, Smoyer WE, Licht C, Midwest Pediatric Nephrology C (2020) Long-Term Outcomes of C3 Glomerulopathy and Immune-Complex Membranoproliferative Glomerulonephritis in Children. Kidney Int Rep 5:2313-2324. https://doi.org/10.1016/j.ekir.2020.09.019\u003c/li\u003e\n\u003cli\u003eLicht C, Vivarelli M, Riedl Khursigara M, Pickering MC, Walker PD (2021) Membranoproliferative Glomerulonephritis and C3 Glomerulopathy in Children. Pediatric Nephrology, pp 1-31. https://doi.org/10.1007/978-3-642-27843-3_29-2\u003c/li\u003e\n\u003cli\u003ePickering MC, D\u0026apos;Agati VD, Nester CM, Smith RJ, Haas M, Appel GB, Alpers CE, Bajema IM, Bedrosian C, Braun M, Doyle M, Fakhouri F, Fervenza FC, Fogo AB, Fremeaux-Bacchi V, Gale DP, Goicoechea de Jorge E, Griffin G, Harris CL, Holers VM, Johnson S, Lavin PJ, Medjeral-Thomas N, Paul Morgan B, Nast CC, Noel LH, Peters DK, Rodriguez de Cordoba S, Servais A, Sethi S, Song WC, Tamburini P, Thurman JM, Zavros M, Cook HT (2013) C3 glomerulopathy: consensus report. Kidney Int 84:1079-1089. https://doi.org/10.1038/ki.2013.377\u003c/li\u003e\n\u003cli\u003eUemura O, Nagai T, Ishikura K, Ito S, Hataya H, Gotoh Y, Fujita N, Akioka Y, Kaneko T, Honda M (2014) Creatinine-based equation to estimate the glomerular filtration rate in Japanese children and adolescents with chronic kidney disease. Clin Exp Nephrol 18:626-633. https://doi.org/10.1007/s10157-013-0856-y\u003c/li\u003e\n\u003cli\u003eMatsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A, Collaborators developing the Japanese equation for estimated GFR (2009) Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 53:982-992. https://doi.org/10.1053/j.ajkd.2008.12.034\u003c/li\u003e\n\u003cli\u003eKanda Y (2013) Investigation of the freely available easy-to-use software \u0026apos;EZR\u0026apos; for medical statistics. Bone Marrow Transplant 48:452-458. https://doi.org/10.1038/bmt.2012.244\u003c/li\u003e\n\u003cli\u003eKhandelwal P, Bhardwaj S, Singh G, Sinha A, Hari P, Bagga A (2021) Therapy and outcomes of C3 glomerulopathy and immune-complex membranoproliferative glomerulonephritis. Pediatr Nephrol 36:591-600. https://doi.org/10.1007/s00467-020-04736-8\u003c/li\u003e\n\u003cli\u003eWong EKS, Marchbank KJ, Lomax-Browne H, Pappworth IY, Denton H, Cooke K, Ward S, McLoughlin AC, Richardson G, Wilson V, Harris CL, Morgan BP, Hakobyan S, McAlinden P, Gale DP, Maxwell H, Christian M, Malcomson R, Goodship THJ, Marks SD, Pickering MC, Kavanagh D, Cook HT, Johnson SA, Group MDCGRD, National Study of MDDDCGI (2021) C3 Glomerulopathy and Related Disorders in Children: Etiology-Phenotype Correlation and Outcomes. Clin J Am Soc Nephrol 16:1639-1651. https://doi.org/10.2215/CJN.00320121\u003c/li\u003e\n\u003cli\u003eIatropoulos P, Noris M, Mele C, Piras R, Valoti E, Bresin E, Curreri M, Mondo E, Zito A, Gamba S, Bettoni S, Murer L, Fremeaux-Bacchi V, Vivarelli M, Emma F, Daina E, Remuzzi G (2016) Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome. Mol Immunol 71:131-142. https://doi.org/10.1016/j.molimm.2016.01.010\u003c/li\u003e\n\u003cli\u003eServais A, Noel LH, Roumenina LT, Le Quintrec M, Ngo S, Dragon-Durey MA, Macher MA, Zuber J, Karras A, Provot F, Moulin B, Grunfeld JP, Niaudet P, Lesavre P, Fremeaux-Bacchi V (2012) Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int 82:454-464. https://doi.org/10.1038/ki.2012.63\u003c/li\u003e\n\u003cli\u003eIatropoulos P, Daina E, Curreri M, Piras R, Valoti E, Mele C, Bresin E, Gamba S, Alberti M, Breno M, Perna A, Bettoni S, Sabadini E, Murer L, Vivarelli M, Noris M, Remuzzi G, Registry of Membranoproliferative Glomerulonephritis CG, Nastasi (2018) Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies/Immune Complex-Mediated Membranoproliferative GN. J Am Soc Nephrol 29:283-294. https://doi.org/10.1681/ASN.2017030258\u003c/li\u003e\n\u003cli\u003eSomers M, Kertesz S, Rosen S, Herrin J, Colvin R, Palacios de Carreta N, Kim M (1995) Non-nephrotic children with membranoproliferative glomerulonephritis: are steroids indicated? Pediatr Nephrol 9:140-144. https://doi.org/10.1007/BF00860727\u003c/li\u003e\n\u003cli\u003eBomback AS, Santoriello D, Avasare RS, Regunathan-Shenk R, Canetta PA, Ahn W, Radhakrishnan J, Marasa M, Rosenstiel PE, Herlitz LC, Markowitz GS, D\u0026apos;Agati VD, Appel GB (2018) C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy. Kidney Int 93:977-985. https://doi.org/10.1016/j.kint.2017.10.022\u003c/li\u003e\n\u003cli\u003eBennett WM, Fassett RG, Walker RG, Fairley KF, d\u0026apos;Apice AJ, Kincaid-Smith P (1989) Mesangiocapillary glomerulonephritis type II (dense-deposit disease): clinical features of progressive disease. Am J Kidney Dis 13:469-476. https://doi.org/10.1016/s0272-6386(89)80004-6\u003c/li\u003e\n\u003cli\u003eCameron JS, Turner DR, Heaton J, Williams DG, Ogg CS, Chantler C, Haycock GB, Hicks J (1983) Idiopathic mesangiocapillary glomerulonephritis. Comparison of types I and II in children and adults and long-term prognosis. Am J Med 74:175-192. https://doi.org/10.1016/0002-9343(83)90606-x\u003c/li\u003e\n\u003cli\u003eLittle MA, Dupont P, Campbell E, Dorman A, Walshe JJ (2006) Severity of primary MPGN, rather than MPGN type, determines renal survival and post-transplantation recurrence risk. Kidney Int 69:504-511. https://doi.org/10.1038/sj.ki.5000084\u003c/li\u003e\n\u003cli\u003eLomax-Browne HJ, Medjeral-Thomas NR, Barbour SJ, Gisby J, Han H, Bomback AS, Fervenza FC, Cairns TH, Szydlo R, Tan SJ, Marks SD, Waters AM, Appel GB, D\u0026apos;Agati VD, Sethi S, Nast CC, Bajema I, Alpers CE, Fogo AB, Licht C, Fakhouri F, Cattran DC, Peters JE, Cook HT, Pickering MC (2022) Association of Histologic Parameters with Outcome in C3 Glomerulopathy and Idiopathic Immunoglobulin-Associated Membranoproliferative Glomerulonephritis. Clin J Am Soc Nephrol 17:994-1007. https://doi.org/10.2215/CJN.16801221\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Membranoproliferative glomerulonephritis, immune-complex MPGN, C3 glomerulopathy, C3 glomerulonephritis, Dense deposit disease","lastPublishedDoi":"10.21203/rs.3.rs-3885158/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3885158/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003eMembranoproliferative glomerulonephritis (MPGN) can be divided into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G), which include dense deposit disease (DDD) and C3 glomerulonephritis (C3GN), respectively. These conditions result from abnormalities in different complement pathways and may lead to different prognoses. However, there are limited studies describing the respective clinical courses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eIn this study, Japanese pediatric patients diagnosed with MPGN based on kidney biopsies conducted between February 2002 and December 2022 were reclassified as having IC-MPGN or C3G (DDD or C3GN). We retrospectively analyzed the clinical characteristics and outcomes of these patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003eOut of 25 patients with MPGN, three (12.0%) were diagnosed with DDD, 20 (80.0%) with C3GN, and two (8.0%) with IC-MPGN. There were 13 (65.0%) patients and one (33.3%) patient in remission after treatment for C3GN and DDD, respectively, and no patients with IC-MPGN achieved remission. The median follow-up period was 5.3 (2.5-8.9) years, and none of the patients in either group progressed to an estimated glomerular filtration rate \u0026lt; 15 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e. Patients with C3GN presenting mild to moderate proteinuria (n=8) received a renin-angiotensin system inhibitor (RAS-I) alone, and these patients exhibited a significant decrease in the urinary protein creatinine ratio and a notable increase in serum C3 levels at the last follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions \u003c/strong\u003eThe majority of patients with MPGN were diagnosed with C3GN. The remission rate for C3GN was high, and no patients developed kidney failure, indicating favorable outcomes. Additionally, it was suggested that patients with mild pediatric C3GN could be treated with RAS-I alone.\u003c/p\u003e","manuscriptTitle":"Clinical characteristics and long-term outcomes of immune-complex membranoproliferative glomerulonephritis and C3 glomerulopathy in Japanese children","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-25 18:52:46","doi":"10.21203/rs.3.rs-3885158/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revisions Needed","date":"2024-02-13T10:02:52+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-01-23T05:40:25+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-23T03:50:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-22T18:20:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Nephrology","date":"2024-01-20T19:12:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"635564b1-2c9b-4583-bec4-da4b731c7d7a","owner":[],"postedDate":"January 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-04-01T16:26:13+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-25 18:52:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3885158","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3885158","identity":"rs-3885158","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}