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Purpose: Ureaplasma urealyticum is a rare pathogen associated with septic arthritis that predominantly affects patients with hypogammaglobulinemia. Bacterial identification of fastidious organisms is challenging because they are undetectable by routine culture testing. To the best of our knowledge, this is the first report of septic arthritis induced by U. urealyticum infection in Japan. Case description: We describe the case of a 23-year-old Japanese female with secondary hypogammaglobulinemia (serum immunoglobulin level < 500 mg/dL), identified 8 years after treatment with rituximab. The patient presented with persistent fever and polyarthritis that were unresponsive to ceftriaxone and prednisolone. Contrast-enhanced computed tomography and gallium-67 scintigraphy revealed effusion and inflammation in the left sternoclavicular, hip, wrist, knee, and ankle joints. Although Gram staining and bacterial culture of the drainage fluid from the left hip joint were negative, the condition exhibited characteristics of purulent bacterial infection. The patient underwent empirical treatment with doxycycline, and her symptoms promptly resolved. Subsequent 16S ribosomal RNA (rRNA) gene sequencing of the joint fluid confirmed the presence of U. urealyticum, leading to the diagnosis of septic arthritis. Combination therapy with doxycycline and azithromycin yielded a favorable recovery from the inflammatory status and severe arthritic pain. Conclusion: This case highlights U. urealyticum as a potential causative agent of disseminated septic arthritis, particularly in patients with hypogammaglobulinaemia. The 16S rRNA gene analysis proved beneficial for identifying pathogens in culture-negative specimens, such as synovial fluid, in suspected bacterial infections. [ABSTRACT FROM AUTHOR]

Background: Primary focal segmental glomerulosclerosis (FSGS) frequently recurs after kidney transplantation and is associated with poor graft survival. Patients who do not achieve remission (nonresponders) have an especially poor graft survival. However, the characteristics that may affect graft survival in nonresponders are unknown. This study aimed to determine the clinical characteristics associated with graft survival in nonresponders. Methods: We retrospectively collected the clinical records of patients with FSGS and an age at onset <16 years who experienced posttransplant recurrence of FSGS at six hospitals in Japan from 1993 to 2018. Results: Eight nonresponders with recurrent FSGS were enrolled in this study. The median time to recurrence after kidney transplantation was 1 day (interquartile range, 1–2 days). All patients received therapeutic plasma exchange and methylprednisolone pulse therapy. Rituximab was used as an add‐on therapy in three patients. Five patients lost their graft within 2 years after kidney transplantation (rapid group). In contrast, three patients had much longer graft survival (nonrapid group). We compared the clinical characteristics of the rapid and nonrapid groups. Proteinuria tended to be lower in the nonrapid group at the third and subsequent months of therapy. The rapid group had persistent nephrotic syndrome. The rate of reduction in proteinuria was lower in the rapid group than in the nonrapid group. Conclusions: Our study suggests that persistent nephrotic syndrome and a low rate of reduction in proteinuria may predict rapid progression to graft failure in nonresponders. [ABSTRACT FROM AUTHOR]

Background: International practice guidelines advocate for the use of anti-phospholipase A2 receptor (PLA2R) antibody testing to diagnose primary membranous nephropathy (pMN). This study aimed to clarify the current status of anti-PLA2R antibody testing in the diagnosis of pMN in Japan and to scrutinize the factors associated with the implementation of this antibody test. Methods: Utilizing a web-based questionnaire for nephrologists, responses were collected from 306 facilities and 427 nephrologists between November 2021 and December 2021. Preference for anti-PLA2R antibody testing was also investigated. Factors related to the experience of quantifying anti-PLA2R antibodies were estimated by generalized estimating equations using a robust analysis of variance with clusters of facilities of affiliation. Results: Of the 427 respondents, 140 (32.8%) had previous measurement experience at their current workplace and 165 (38.6%) had previous measurement experience overall. In pMN-suspected cases without contraindications to renal biopsy, 147 (34.4%) of the respondents opted to request anti-PLA2R antibody testing. The respondents' experience with anti-PLA2R antibody quantification at their current place of work was generally higher in university hospitals and increased with the annual number of kidney biopsies and the number of years since graduation. Conclusion: The results of this study suggest that a significant proportion of nephrologists in Japan have no experience in performing anti-PLA2R antibody assays, and that the assays may be hampered by the limited capabilities of the current workplace and the financial burden on facilities and patients. [ABSTRACT FROM AUTHOR]

Introduction: Disease subtyping and monitoring are essential for the management of nephrotic syndrome (NS). Although various biomarkers for NS have been reported, their clinical efficacy has not been comprehensively validated in adult Japanese patients. Methods: The Japanese Biomarkers in Nephrotic Syndrome (J-MARINE) study is a nationwide, multicenter, and prospective cohort study in Japan, enrolling adult (≥18 years) patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN), C3 glomerulopathy (C3G), and lupus nephritis (LN). Baseline clinical information and plasma and urine samples will be collected at the time of immunosuppressive therapy initiation or biopsy. Follow-up data and plasma and urine samples will be collected longitudinally based on the designated protocols. Candidate biomarkers will be measured: CD80, cytotoxic T-lymphocyte antigen 4, and soluble urokinase plasminogen activator receptor for MCD and FSGS; anti-phospholipase A2 receptor and thrombospondin type-1 domain-containing protein 7A antibodies for MN; fragment Ba, C3a, factor I, and properdin for MPGN/C3G; and CD11b, CD16b, and CD163 for LN. Outcomes include complete and partial remission, relapse of proteinuria, a 30% reduction in estimated glomerular filtration rate (eGFR), eGFR decline, and initiation of renal replacement therapy. The diagnostic accuracy and predictive ability for clinical outcomes will be assessed for each biomarker. Results: From April 2019 to April 2023, 365 patients were enrolled: 145, 21, 138, 10, and 51 cases of MCD, FSGS, MN, MPGN/C3G, and LN, respectively. Conclusion: This study will provide valuable insights into biomarkers for NS and serve as a biorepository for future studies. [ABSTRACT FROM AUTHOR]

Low‐density lipoprotein apheresis (LDL‐A) therapy has shown reasonable efficacy in treating nephrotic syndrome (NS) refractory to initial drug therapy and has been covered by National Health Insurance for the indication of drug‐resistant focal segmental glomerulosclerosis (FSGS) since 1992 in Japan and has contributed to liberating substantial number of patients of this disease from entering into end‐stage renal disease by easier practical application in actual clinical settings. Subsequently, various beneficial evidence of this treatment has accumulated on those other than FSGS, however, due to the limitation of covered disease insurance only for FSGS, patients with diseases other than FSGS are unlikely to benefit from this treatment in practice. This review summarizes the therapeutic evidence of the beneficial effect of LDL‐A accumulated to date and the mechanisms of action analyzed from multifaceted perspectives. examines the applicability of expanding insurance coverage for diseases other than FSGS. [ABSTRACT FROM AUTHOR]

The nationwide clinical features of Japanese patients with primary nephrotic syndrome (NS), including minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), or membranous nephropathy (MN), have not yet been reported. We collected the clinical personal records of patients with primary NS between 2015 and 2018 from the national registry organized by the Japanese Ministry of Health, Labour, and Welfare. Overall, the demographics, chronic kidney disease classification based on glomerular filtration rate and albuminuria, and treatment of 6036 patients were collected: 3394 (56.2%) with MCD, 677 (11.2%) with FSGS, 1455 (24.1%) with MN, and 510 (8.5%) with others. MN patients were older than MCD and FSGS patients (67 vs. 42 and 47 years, respectively). Steroid-dependent NS or frequently relapsing NS was found in 70.2%, 40.5%, and 24.6%, whereas steroid-resistant NS was found in 6.4%, 36.0%, and 37.9% of patients in the MCD, FSGS, and MN, respectively. The present oral prednisolone use (mean dose, mg/day) was 87.2% (21.2), 80.9% (20.0), and 77.5% (18.8) of patients in the MCD, FSGS, and MN, respectively. The national registry of clinical personal records of primary NS could provide an informative insight into the characteristics, clinical features, and treatment approaches for patients with primary NS in Japan. [ABSTRACT FROM AUTHOR]

Background: Membranoproliferative glomerulonephritis (MPGN) is a rare glomerular injury that causes nephrotic syndrome and end-stage kidney disease. The nationwide demographics and treatment of Japanese patients with primary MPGN have not yet been reported. Methods: We collected clinical personal records of patients with primary MPGN between 2015 and 2018 from the national registry organized by the Japanese Ministry of Health, Labour, and Welfare and investigated the characteristics of primary MPGN throughout Japan. Results: Of 258 patients with primary MPGN, 199 and 59 showed nephrotic and non-nephrotic syndrome, respectively. The median age at onset was higher in patients with nephrotic syndrome than in those with non-nephrotic syndrome (45 [24–63] vs. 35 [14–53] years, respectively; P = 0.010). The use of oral prednisolone was significantly higher in patients with nephrotic syndrome than in those with non-nephrotic syndrome (73.9% vs. 59.3%, respectively; P = 0.032). When patients were divided into three age groups: adolescent and young adult group (≤ 39 years; n = 80), middle adult group (40–64 years; n = 111), and older adult group (≥ 65 years; n = 67), the use of oral prednisolone, cyclosporine, and mizoribine was significantly higher in the adolescent and young adult group than in the middle adult group. The mean dosage of oral prednisolone and mizoribine showed no differences among the three age groups. Conclusion: The national registry of clinical personal records of primary MPGN could provide an informative insight into the characteristics, clinical features, and treatment approaches for patients with primary MPGN in Japan. [ABSTRACT FROM AUTHOR]

Background: Glucocorticoids affect bone turnover. Little is known about how bone turnover changes when glucocorticoids are discontinued following long-term administration. Methods: This retrospective observational study was conducted on the relationship between discontinuation of long-term administration of glucocorticoid and bone turnover markers (BTMs) in patients with childhood-onset idiopathic nephrotic syndrome. Serum bone alkaline phosphatase (BAP), intact procollagen type 1 N-terminal propeptide (P1NP), and tartrate-resistant acid phosphatase-5b (TRACP-5b) were evaluated as BTMs. Results: Thirty-eight pairs of BTMs at glucocorticoid administration and after discontinuation were analyzed in 29 patients. The median age at baseline was 12.4 (interquartile range, 9.0–14.5) years, and the median time from the onset of nephrotic syndrome was 5.9 (3.3–9.7) years. The mean period from prednisolone discontinuation to the measurement of BTMs after glucocorticoid discontinuation was 3.5 ± 1.0 months. Changes in BTMs after glucocorticoid discontinuation were modest when the daily prednisolone dose was < 0.25 mg/kg/day (ln BAP standard deviation [SD] score, p = 0.19; log intact P1NP SD score, p = 0.70; TRACP-5b, p = 0.95). When the daily prednisolone dose was ≥ 0.25 mg/kg/day, all BTMs increased significantly after glucocorticoid discontinuation (ln BAP SD score, p < 0.01; log intact P1NP SD score, p < 0.01; TRACP-5b, p < 0.01). Conclusions: Decreased BTMs can rise within a few months of discontinuing long-term glucocorticoid administration. When the administered glucocorticoid dose is low, changes in BTMs may be small. [ABSTRACT FROM AUTHOR]

Background: Prospective research of children receiving heterogeneous vaccines has shown that immunization is not associated with pediatric idiopathic nephrotic syndrome (NS) relapses. However, prospective data concentrating only on influenza (flu) virus vaccines are not available. Methods: This multicenter prospective study was conducted in children with NS who received inactivated flu vaccines from June 2017 to July 2018. The day of flu vaccination was defined as day 0, and the period between prevaccination and postvaccination days was defined as − X to + Y (period from day − 180 to 0 as the precontrolled period). The primary outcome was the NS relapse rate from day 0 to + 30 as a direct association with vaccination compared with those in the precontrolled period. Exacerbation was defined as children experiencing more NS relapses after vaccination compared with those in the precontrolled period, or children starting any new immunosuppressants due to NS relapse after vaccination. Results: Sixty-three children were included. Relapse rates were not significantly different between the precontrolled period and 0 to + 30 periods (0.38 vs. 0.19 times/person-year, p = 0.95). Although the exacerbation rate during the 0 to + 180 period in children without NS relapse in the precontrolled period was very low (4/54 [7.4 %]), children with at least one NS relapse in the precontrolled period showed a remarkable increase in the rate (4/9 [44.4%]; p = 0.01). Conclusions: Flu vaccination did not significantly precipitate the direct relapse of NS in children. However, it might increase the disease activity in children with at least one NS relapse within a half year before vaccination. [ABSTRACT FROM AUTHOR]

The article focuses on the management of minimal change disease with transient remission during initial prednisolone treatment and whether cyclosporine is necessary. Topics include steroid-sensitive versus steroid-resistant nephrotic syndrome, the use of cyclosporine in patients with transient complete remission, and the long-term outcomes of children treated for steroid-resistant nephrotic syndrome.

Therapeutic options with immunosuppressive agents for glomerular diseases have widened with refinements to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines from 2012 to 2021. However, international guidelines do not necessarily match the reality in each country. Expensive therapies such as rituximab and calcineurin inhibitors are sometimes inaccessible to patients with refractory nephrotic syndrome due to cost or regulations. Under the Japanese medical insurance system, rituximab is accessible but still limited to steroid-dependent patients who developed idiopathic nephrotic syndrome in childhood. Based on international KDIGO guidelines and other national guidelines, possible applications of immunosuppressive agents for nephrotic syndrome are comprehensively examined in this review. While rituximab has become the mainstay of immunosuppressive therapy for nephrotic syndrome, clinical trials have indicated that options such as cyclophosphamide, calcineurin inhibitors, and mycophenolate mofetil would be preferable. Given the rising number of patients with nephrotic syndrome worldwide, KDIGO guidelines mention the need for further consideration of cost-effectiveness. If the new option of rituximab is to be the first choice in combination with steroids for nephrotic syndrome, its cost-effectiveness should also be verified. Among the few studies examining the cost-effectiveness of treatments for nephrotic syndrome, administration of rituximab to young adults has been shown to be cost-beneficial, at least in Japan. However, further large-scale studies involving multiple facilities are needed to verify such findings. Network meta-analyses have concluded that the efficacy of rituximab remains controversial and confirmation through high-quality studies of large cohorts is needed. To this end, the mechanisms of action underlying immunosuppressive agents, both old and new, need to be understood and experience must be accumulated to evaluate possible effects and side effects. [ABSTRACT FROM AUTHOR]

Background: Current treatment for frequently relapsing, steroid-dependent, or steroid-resistant nephrotic syndrome focuses on immunosuppressive therapies. Although the clinical guideline suggests the use of mycophenolate mofetil (MMF), limited information is available on patients with primary nephrotic syndrome who receive off-label treatment with MMF in Japan. Method: The dose, treatment duration, previous treatment, and characteristics of primary nephrotic syndrome patients receiving MMF were investigated using data from a Japanese hospital claims database (April 2008–September 2021). Results: Data on 424 primary nephrotic syndrome patients receiving MMF (146 patients < 18 years old; 278 patients ≥ 18 years old) were captured. The most common initial daily doses of MMF capsules (% of patients < 18 and ≥ 18 years old) were 1000 mg (31.9%, 36.8%), 1500 mg (16.0%, 23.8%), and 500 mg (23.6%, 17.3%), and the most common maximum daily doses were 1000 mg (43.8%, 32.9%), 1500 mg (23.6%, 28.9%), and 2000 mg (6.3%, 16.2%). Most patients (97.9%, 99.3%) were treated with a daily dose of 2000 mg or less. Among patients < 18 years old, the younger the patient, the lower the dose. MMF was used for more than 1 year in 30.8% of patients < 18 years old and in 28.8% of patients ≥ 18 years old. Conclusions: Our study suggested that off-label use of MMF for primary nephrotic syndrome has increased since 2012 in Japan. The dose of MMF used in patients with primary nephrotic syndrome was generally within the approved dose range for lupus nephritis and transplant-related diseases in Japan. [ABSTRACT FROM AUTHOR]

Background: Recent clinical reports indicate a correlation between new-onset and relapse of nephrotic syndrome (NS) following coronavirus 2019 (COVID-19) vaccination in patients with glomerular diseases. However, there are no reports of a nationwide survey on NS following COVID-19 vaccination in Japan. Methods: We conducted a web-based survey of council members of the Japanese Society of Nephrology (581 members, 382 facilities) to elucidate the relationship between COVID-19 vaccination and new-onset and relapse of NS. Results: Following COVID-19 vaccination, 27 patients (male: 15, 55.6%) with new-onset (n = 6) and relapse (n = 21) of NS were reported. Of them, 12 (44.4%) patients were diagnosed with minimal change disease at the occurrence of NS. Five patients developed a slight increase in serum creatinine levels; however, none progressed to severe renal dysfunction. Conclusion: Our findings clarify the clinical features of new-onset and relapse of NS following COVID-19 vaccination. Although there was no obvious progression to severe renal dysfunction, clinicians and pathologists should be aware that NS is a potential adverse effect of the vaccines. [ABSTRACT FROM AUTHOR]

Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. We previously reported that the prevalence of phospholipase A2 receptor (PLA2R)- and thrombospondin type 1 domain containing 7A (THSD7A)-associated MN patients in Japan is 52.7% and 9.1%, respectively. In addition to PLA2R and THSD7A, we assessed the presence of newly discovered target antigens, neural epidermal growth factor-like 1 (NELL-1), semaphorin 3B (SEMA3B), and exostosin 1/exostosin 2 (Ext1/Ext2), in renal specimens from patients with primary and secondary MN by immunohistochemistry. We found enhanced glomerular staining of PLA2R, THSD7A, NELL-1, and Ext1/Ext2 in 53.6%, 8.7%, 1.5%, and 13.0% of the renal samples, respectively, in patients with primary MN. None of the patient specimens showed enhanced staining of SEMA3B. Enhanced glomerular staining of PLA2R, NELL-1, and Ext1/Ext2 was detected in 5.7%, 8.6%, and 22.9% of the patients with secondary MN, respectively. Based on our findings, we recommend the assessment of PLA2R, THSD7A and NELL-1 in addition to clinical information and IgG4 staining to differentiate between primary and secondary MN. This would aid in distinguishing secondary MN patients from primary MN patients who coincidentally have some secondary characteristics. [ABSTRACT FROM AUTHOR]

Background: Rituximab is conditionally approved in Japan for use in patients with refractory nephrotic syndrome. To meet the conditions of approval, an all-case post-marketing surveillance study was conducted to confirm the real-world safety and efficacy of rituximab in patients of all ages with refractory nephrotic syndrome. Methods: All patients scheduled to receive rituximab treatment for refractory nephrotic syndrome were eligible to register (registration: August 29, 2014 through April 15, 2016); the planned observation period was 2 years from the initiation of rituximab treatment (intravenous infusion, 375 mg/m2 once weekly for four doses). The study was conducted at 227 hospitals throughout Japan. Adverse drug reactions (ADRs) were collected for safety outcomes. The efficacy outcomes were relapse-free period and the degree of growth in pediatric (< 15 years) patients. Results: In total, 997 (447 pediatric) patients were registered; 981 (445) were included in the safety analysis set; 852 (402) completed the 2-year observation period; and 810 (429) were included in the efficacy analysis set. Refractory nephrotic syndrome had developed in childhood for 85.0% of patients, and 54.6% were aged ≥15 years. ADRs were observed in 527 (53.7%) patients, treatment-related infection/infestation in 235 (24.0%) patients, and infusion reactions in 313 (31.9%) patients. The relapse-free period was 580 days (95% confidence interval, 511–664). There was a significant change in height standard deviation score (pediatric patients; mean change, 0.093; standard deviation, 0.637; P = 0.009). Conclusion: The safety and efficacy of rituximab treatment in patients with refractory nephrotic syndrome were confirmed in the real-world setting. Clinical trial registration: UMIN000014997. [ABSTRACT FROM AUTHOR]

Focal segmental glomerulosclerosis (FSGS) is a serious condition leading to kidney failure. We aimed to investigate the clinical characteristics of FSGS and its differences compared with minimal change disease (MCD) using cross-sectional data from the Japan Renal Biopsy Registry. In Analysis 1, primary FSGS (n = 996) were stratified by age into three groups: pediatric (< 18 years), adult (18–64 years), and elderly (≥ 65 years), and clinical characteristics were compared. Clinical diagnosis of nephrotic syndrome (NS) was given to 73.5% (97/132) of the pediatric, 41.2% (256/622) of the adult, and 65.7% (159/242) of the elderly group. In Analysis 2, primary FSGS (n = 306) and MCD (n = 1303) whose clinical diagnosis was nephrotic syndrome (NS) and laboratory data were consistent with NS, were enrolled. Logistic regression analysis was conducted to elucidate the variables which can distinguish FSGS from MCD. On multivariable analysis, higher systolic blood pressure, higher serum albumin, lower eGFR, and presence of hematuria associated with FSGS. In Japanese nationwide registry, primary FSGS patients aged 18–64 years showed lower rate of NS than those in other ages. Among primary nephrotic cases, FSGS showed distinct clinical features from MCD. [ABSTRACT FROM AUTHOR]

Background: The aim of the present study was to clarify the prevalence of immunosuppressive drug use and outcomes in elderly and non-elderly patients with primary membranous nephropathy (MN) in nationwide real-world practice in Japan. Patients and methods: Between 2009 and 2010, 374 patients with primary nephrotic syndrome were enrolled in the cohort study (The Japan Nephrotic Syndrome Cohort Study, JNSCS), including 126 adult patients with MN. Their clinical characteristics were compared with those of nephrotic patients with primary MN registered in a large nationwide registry (The Japan Renal Biopsy Registry, J-RBR). Outcomes and predictors in the elderly (≥ 65 years) and non-elderly groups were identified. Results: Similar clinical characteristics were observed in JNSCS patients and J-RBR patients (n = 1808). At the early stage of 1 month, 84.1% of patients were treated with immunosuppressive therapies. No significant differences were observed in therapies between age groups. However, elderly patients achieved complete remission (CR) more frequently than non-elderly patients, particularly those treated with therapies that included corticosteroids. No significant differences were noted in serum creatinine (sCr) elevations at 50 or 100%, end-stage kidney disease, or all-cause mortality between age groups. Corticosteroids were identified as an independent predictor of CR (HR 2.749, 95%CI 1.593–4.745, p = 0.000) in the multivariate Cox's model. sCr levels, hemoglobin levels, immunosuppressants, clinical remission, and relapse after CR were independent predictors of sCr × 1.5 or × 2.0. Conclusion: Early immunosuppressive therapy including corticosteroids for primary MN showed better remission rates in elderly patients in a nationwide cohort study. [ABSTRACT FROM AUTHOR]

Background: Kikuchi-Fujimoto disease (KFD) or necrotizing histiocytic lymphadenitis, was described separately by both Kikuchi and Fujimoto in Japan in the early 1970's. Despite its rarity in the pediatric population, it is an important differential in persistent lymphadenopathy. Familial cases of KFD in the literature are rare. Here we describe the first reported case of KFD in non-identical twin sisters. Case presentation: Twin 1 presented with a 3-week history of worsening right-sided cervical lymphadenopathy, daily fevers, significant lethargy, weight loss and arthralgia of her knees and ankles at the age of 12 years in 2015. She had had an unremarkable medical history. A biopsy of her lymph nodes showed histiocytic necrosis consistent with KFD. Twin 2 presented with a three-week history of lethargy, fatigue, weight loss and left-sided posterior cervical chain lymphadenopathy at 16 years of age in 2018. She had a history of frequently relapsing nephrotic syndrome and celiac disease. A biopsy of her lymph nodes was undertaken and showed histiocytic necrosis consistent with KFD. Conclusions: KFD is a rare but self-limiting pathological process of necrotizing histiocytic lymphadenitis. Although further research is needed, there is an increasing amount of evidence which suggests a multifactorial pathological basis of disease. The two cases we document here are the first reported cases of familial KFD in dizygotic HLA-identical twins which reinforces the likely HLA-linkage in the etiology of KFD. [ABSTRACT FROM AUTHOR]

Background: Despite recent advances in immunosuppressive therapy for patients with primary nephrotic syndrome, its effectiveness and safety have not been fully studied in recent nationwide real-world clinical data in Japan. Methods: A 5-year cohort study, the Japan Nephrotic Syndrome Cohort Study, enrolled 374 patients with primary nephrotic syndrome in 55 hospitals in Japan, including 155, 148, 38, and 33 patients with minimal change disease (MCD), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and other glomerulonephritides, respectively. The incidence rates of remission and relapse of proteinuria, 50% and 100% increases in serum creatinine, end-stage kidney disease (ESKD), all-cause mortality, and other major adverse outcomes were compared among glomerulonephritides using the Log-rank test. Incidence of hospitalization for infection, the most common cause of mortality, was compared using a multivariable-adjusted Cox proportional hazard model. Results: Immunosuppressive therapy was administered in 339 (90.6%) patients. The cumulative probabilities of complete remission within 3 years of the baseline visit was ≥ 0.75 in patients with MCD, MN, and FSGS (0.95, 0.77, and 0.79, respectively). Diabetes was the most common adverse events associated with immunosuppressive therapy (incidence rate, 71.0 per 1000 person-years). All-cause mortality (15.6 per 1000 person-years), mainly infection-related mortality (47.8%), was more common than ESKD (8.9 per 1000 person-years), especially in patients with MCD and MN. MCD was significantly associated with hospitalization for infection than MN. Conclusions: Patients with MCD and MN had a higher mortality, especially infection-related mortality, than ESKD. Nephrologists should pay more attention to infections in patients with primary nephrotic syndrome. [ABSTRACT FROM AUTHOR]

Background: Patients with refractory nephrotic syndrome (NS) are at high risk of medication-induced glucose metabolism disorders, because of their long-term use of diabetogenic medications, particularly glucocorticoids and calcineurin inhibitors (CNIs). However, there have been no comprehensive evaluations of glucose metabolism disorders in pediatric patients with refractory NS. Moreover, glucocorticoids and CNIs could not be discontinued in these patients until the effectiveness of rituximab on refractory NS was shown, and therefore, there has been limited opportunity to evaluate glucose metabolism disorders after discontinuation of these medications. Methods: Consecutive pediatric patients who started rituximab treatment for refractory NS were enrolled. Their glucose metabolism conditions were evaluated using the oral glucose tolerance tests (OGTT) and HbA1c levels at the initiation of rituximab treatment. Patients with glucose metabolism disorders at the first evaluation were reevaluated after approximately 2 years. Results: Overall, 57% (20/35) of study patients had glucose metabolism disorders, and 40% (8/20) of these patients were detected only by their 2-h OGTT blood glucose levels and not by their fasting blood glucose or HbA1c levels. Non-obese/non-overweight patients had significantly more glucose metabolism disorders than obese/overweight patients (p = 0.019). In addition, glucose metabolism disorders in 71% (10/14) of patients persisted after the discontinuation of glucocorticoids and CNIs. Conclusions: Whether the patient is obese/overweight or not, patients with refractory NS are at high risk of developing glucose metabolism disorders, even in childhood. Non-obese/non-overweight patients who are at high risk of diabetes need extra vigilance. [ABSTRACT FROM AUTHOR]

The authors offer a response to commentary made on their article "High prevalence of pathogenic variants in Japanese children with steroid-resistant nephrotic syndrome without edema detected by urine screening program." Topics include their agreement about their opinion on causality of generic variants for a given people, how asymptomatic proteinuria (ASP) is usually detected in Japan, and the unlikeliness of nephrotic syndrome (NS) to respond to any immunosuppressive treatment.

Idiopathic nephrotic syndrome (INS) is characterized by three different entities, namely minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and membranous nephropathy (MN). While there is an increasing understanding of primary MN with the discovery of antibodies directed against phospholipase A2 receptor (PLA2R Ab) and thrombospondin type 1 domain-containing 7A, circulatory factors causative of inducing MCD and FSGS remain in part elusive. Extracorporeal treatment forms (mostly plasma exchange) have been reserved for patients with either a disease course refractory to commonly prescribed immunosuppressive drugs or to patients with recurrence after kidney transplantation. There is a paucity of data supporting the use of immunoadsorption (IAS) in the management of MCD and MN and evidence to perform LDL-apheresis in the former is limited to reports from Japan. Treatment with IAS in primary FSGS has shown mixed responses, possibly biased by including treatment-resistant cases in the absence of genetic testing. In those with recurrence of the disease following kidney transplantation, IAS has shown high remission rates with an acceptable safety profile. There is a need to compare IAS to plasma exchange (PLEX) in this indication and due to a higher amount of plasma processed during one session, IAS may have advantages over PLEX. Removal of PLA2R Ab by IAS is currently being tested in a phase II clinical trial. More clinical trials in a prospective and randomized fashion need to be designed to prove the concept that IAS may be a treatment option for INS. While PLEX is still the leading extracorporeal treatment form in these indications, this review aims to highlight the efficacy and safety of IAS in the management of INS. [ABSTRACT FROM AUTHOR]

Low‐density lipoprotein apheresis (LDL‐A) has been used for nephrotic syndrome (NS) caused by focal segmental glomerulosclerosis in Japan. Idiopathic membranous nephropathy (iMN) can also cause treatment‐resistant NS. Therefore, we investigated the effect of LDL‐A during initial induction for it. This retrospective, observational, and single‐center study enrolled consecutive iMN patients who received steroids from March 2000 to May 2015. We compared data between 11 patients treated with LDL‐A (LDL‐A group) and 27 patients without (non‐LDL‐A group) at baseline and 4 and 8 weeks later. Reduction rate of proteinuria and increase rate of serum albumin in LDL‐A group were significantly higher than the other after 4 weeks (P = 0.036 and 0.030) and 8 weeks (P = 0.030 and <0.001), respectively. There was no adverse event caused by LDL‐A and immunosuppressant dose was not significantly different. In conclusion, LDL‐A may be an effective choice for initial induction of nephrotic iMN. [ABSTRACT FROM AUTHOR]

Background: Few good-quality clinical trials on adults with nephrotic syndrome exist. Thus, there are discrepancies between real-world practice and clinical practice guidelines. We conducted a questionnaire-based survey to investigate potential discrepancies and the factors associated with variations in clinical practice. Methods: A questionnaire was administered electronically to all board-certified nephrologists in Japan. To examine clinical practice variations in relation to physician characteristics, we estimated the ratio of the mean duration of steroid therapy using a generalized linear model, and the odds ratio of higher level ordinal variables using an ordered logistic regression model. Results: Responses of the 116 participants showed some variation for the majority of questions. Most participants (94.8%) indicated that screening for malignant tumors was "Conducted for almost all patients". The duration of steroid therapy was found to be longer among physicians seeing ≥ 30 patients with nephrotic syndrome per month, both for minimal-change disease (ratio of mean 1.69; 95% CI 1.07–2.66) and membranous nephropathy (ratio of mean 1.71; 95% CI 1.09–2.69). Conclusions: We identified practice patterns for nephrotic syndrome and discrepancies between clinical practice guidelines and actual practice. Defining the standard therapy for nephrotic syndrome may be necessary to generate high-quality evidence and develop clinical guidelines. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to investigate possible differences in treatment responses between two categories for the onset of lupus nephritis. Methods: We performed a multicentre, retrospective cohort study of class III–V lupus nephritis patients diagnosed between 1997 and 2014. The renal responses to initial induction therapy were compared between patients who developed lupus nephritis within one year from diagnosis of systemic lupus erythematosus (early (E-) LN) and the remainder (delayed (D-) LN) using the Kaplan–Meier method. We determined the predictors of renal response as well as renal flares and long-term renal outcomes using multivariate Cox regression analyses. Results: A total of 107 E-LN and 70 D-LN patients were followed up for a median of 10.2 years. Log-rank tests showed a lower cumulative incidence of complete response in D-LN compared with E-LN patients. Multivariate analysis identified D-LN (hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.33–0.70), nephrotic syndrome at baseline, and a chronicity index greater than 2 as negative predictors of complete response. D-LN patients were more likely to experience renal flares. D-LN (HR 2.54, 95% CI 1.10–5.83) and decreased renal function were significant predictors of chronic kidney disease at baseline. Conclusion: D-LN was a predictor of poorer treatment outcomes, in addition to renal histology and severity of nephritis at lupus nephritis onset. [ABSTRACT FROM AUTHOR]

Idiopathic membranous nephropathy is the most common cause of nephrotic syndrome in nondiabetic adults. The antibody most often implicated is the M‐type phospholipase A2 receptor (PLA2R) antibody, found in >70% of primary membranous nephropathy cases. First‐line therapy is immunosuppressive in nature, but for patients who are treatment‐resistant there is a significant risk of end‐stage renal disease and mortality. Hypercholesterolemia is not only a side effect of nephrotic syndrome, but also its presence may worsen renal function. A recent single‐arm observational study in Japan found that low‐density lipoprotein apheresis (LDL‐A) was able to ameliorate nephrotic syndrome in half of patients who were resistant to medication. We present a case of treatment resistant PLA2R negative membranous nephropathy who had significant improvement following two courses of LDL‐A. To our knowledge, this is the first such reported case in the United States. [ABSTRACT FROM AUTHOR]

Background: In pediatric patients with steroid-sensitive nephrotic syndrome, recent trials have revealed that a 2-month, short-term steroid regimen is not inferior to an extended steroid course. However, the optimal duration of initial steroid therapy for adult steroid-sensitive minimal change disease (MCD) remains unclear.Objectives: The aim of present study was to evaluate the effectiveness of a 2-month, short-term steroid regimen in the treatment of adult steroid-sensitive MCD patients.Method: This was a prospective observational study. Adult patients with steroid-sensitive MCD (n = 35) who were initiated on a short-term steroid regimen between January 2015 and June 2016 were included. The details of the regimen are as follows: (1) prednisolone was administered at an initial dose of 0.8-1.0 mg/kg/day and continued for 4-6 weeks and (2) dosage was reduced to 0.5-0.6 mg/kg/alternate day and continued for 4 weeks. Control patients (n = 140), who were treated using conventional steroid administration, were selected from our previous adult MCD cohort. All patients fulfilled the following criteria: biopsy-proven MCD, age ≥20 years, first episode of nephrotic syndrome, and attainment of complete remission within 4 weeks. The following parameters of patients who received short-term treatment regimen and control patients were compared: any relapse and frequent relapse, adverse events caused by steroid treatment and cumulative steroid dose.Results: Throughout the observation period (median: 17.3 months), 24 (68.6%) patients in the short-term group developed at least one relapse. The short-term regimen showed earlier occurrence of any relapse than the conventional regimen (adjusted hazard ratio [aHR] 2.45; 95% CI 1.51-3.97; p < 0.001), but there was no difference in frequent relapse (aHR 1.31; 95% CI 0.43-3.99; p = 0.63). None of the patients showed any symptoms of adrenal insufficiency after discontinuation of corticosteroids. The cumulative steroid dose during the observational period was significantly lower in the short-term group than in the conventional group.Conclusions: The short-term steroid regimen may represent an effective treatment option that ensures lower steroid exposure when treating adult steroid-sensitive MCD patients. [ABSTRACT FROM AUTHOR]

Background: This study analysed the trend in mortality from nephrotic syndrome in Japan from 1995 to 2013. Moreover, to better understand premature death from nephrotic syndrome, the average years of life lost due to nephrotic syndrome were estimated.Methods: National death certificate data were evaluated. Age-standardised mortality rates from nephrotic syndrome were calculated by direct standardisation using the World Standard Population. Trends for average annual changes in percentages were determined by joinpoint regression analysis. Average years of life lost were estimated by dividing total years of life lost by the number of deaths from nephrotic syndrome. Years of life lost were estimated by the constant end-point method, with 65 years as the endpoint. Average years of life lost due to malignant neoplasms, the leading cause of death in Japan, were estimated for comparison.Results: There were 9945 deaths (4872 men and 5073 women) during the study period. The numbers of deaths and crude overall mortality rates increased, while age-standardised mortality rates continuously decreased, for both sexes. The annual percentage changes were −1.9% [95% confidence interval (CI), −2.3 to −1.4%] for men and −3.5% (95% CI −4.1 to −2.9%) for women. The average years of life lost due to nephrotic syndrome decreased during the study period, but were greater than for patients who died of malignant neoplasm.Conclusions: Mortality and premature mortality rates from nephrotic syndrome significantly decreased in Japan between 1995 and 2014. Despite these improvements, nephrotic syndrome patients ≤65 years of age still have a poor prognosis. [ABSTRACT FROM AUTHOR]

Background: Despite a low incidence, nephrotic syndrome (NS) can present with IgA nephropathy (IgAN). The clinical characteristics and long-term outcomes of pediatric patients with IgAN presenting with NS (NS-IgAN) at onset have not been fully elucidated. Methods: We retrospectively analyzed 426 patients, and compared clinical and pathological (Oxford) findings between those with NS-IgAN and those with non-NS-IgAN. Results: Among 426 patients, 30 (7.0 %) had NS-IgAN. Logistic analyses showed that male sex (OR: 7.6, p = 0.0002), M1 (OR: 10.3, p = 0.002), and E1 (OR: 15.2, p = 0.0001) were significantly related to NS. The mean observation period was 6.2 ± 3.2 years. Although NS-IgAN was associated with significantly lower renal survival than non-NS-IgAN according to Kaplan-Meier analysis ( p = 0.02), renal survival of NS-IgAN was good (92.4 % at 10 years). The most significant prognostic factor for renal survival was remission of proteinuria after treatment, and NS at onset is also a significant prognostic factor for renal survival after adjusting for remission of proteinuria. Twenty children with NS-IgAN were treated with prednisolone alone, or prednisolone and immunosuppressant. Remission of proteinuria occurred in 21 patients. Three cases of NS-IgAN progressed to stage III-V chronic kidney disease at the most recent observation. They all demonstrated heavy proteinuria after the 2-year initial treatment. The significant factor for persistent proteinuria at 5 years was S1 in NS-IgAN. Conclusions: The most significant factor for renal survival was responsiveness to treatment, not NS itself. As modifiable acute lesions are the dominant pathological findings in NS-IgAN, histological improvements achieved by appropriate treatments can result in a favorable prognosis. [ABSTRACT FROM AUTHOR]

Introduction: The Japan Renal Biopsy Registry (J-RBR) was started in 2007 by the Committee for the Standardization of Renal Pathological Diagnosis and the Committee for the Kidney Disease Registry of the Japanese Society of Nephrology. The purpose of this report is to clarify drug-induced kidney disease (DIKD) of renal biopsied cases in Japan. Subjects and methods: We analyzed the data of 26,535 cases that were registered in the J-RBR from 2007 to 2015. Results: Based on clinical and pathological diagnoses, 328 cases (176 males and 152 females) of renal biopsy-proven DIKD were registered in the J-RBR from 2007 to 2015 (1.24 % of all cases). The frequency of DIKD increased with age. The number of cases peaked in the 6th-8th decade in all pathological categories, except for the number of chronic tubulointerstitial lesions (CTIL), which peaked in the 4th-5th decade. Overall, the frequency of DIKD was 3 times higher in the 7th decade than in the 2nd decade (1.86 vs. 0.62 %). The main clinical diagnoses were DIKD in 150 cases (45.7 %), nephrotic syndrome in 66 cases (20.1 %), chronic nephritic syndrome in 55 cases (16.8 %), and rapidly progressive glomerulonephritis in 30 cases (9.1 %). DIKD was registered as a secondary diagnosis in 136 cases (41.5 %). The pathological findings of these cases were glomerular lesions in 105 cases (32.0 %), acute tubulointerstitial lesions (ATIL) in 87 cases (26.5 %), CTIL in 72 cases (22.0 %), and sclerotic glomerular lesions and/or nephrosclerosis in 18 cases (5.5 %). ATIL and CTIL were mainly found in cases in which DIKD was diagnosed on the basis of the patient's clinical findings. In addition, nephrotic syndrome-related membranous nephropathy (MN) was the major cause of renal damage in 59.4 % of the cases involving glomerular injuries. According to the CGA risk classification, high-risk (red zone) cases accounted for 56.1 % of all cases of DIKD and 75.9, 64.9, and 33.3 % of the cases involving ATIL, CTIL, and glomerular injuries, respectively. The causative drugs were identified in 102 cases, including bucillamine in 38 cases of MN, gemcitabine in 3 cases of thrombotic microangiopathy, and other anticancer drugs in 14 cases (anti-vascular endothelial growth factor drugs in 3 cases and propyl thiouracil in 3 cases of anti-neutrophil cytoplasmic antibody-related nephritis). Conclusion: Our analysis of the J-RBR revealed that DIKD mainly affects elderly people in Japan. ATIL or CTIL were found in approximately half of the biopsied cases of DIKD, and one-third involved glomerular lesions, mainly MN or clinical nephrotic syndrome. [ABSTRACT FROM AUTHOR]

Childhood nephrotic syndrome, in which steroid-dependence occurs concurrently with steroid-resistance, requires aggressive therapy to prevent relapse. Predictive biomarkers that can be used to stratify treatment are urgently needed. Here we report that reciprocal regulation of the glucocorticoid metabolizing enzymes, 11β-hydroxysteroid dehydrogenase types 1 and 2, is associated with steroid-responsiveness and disease remission in childhood nephrotic syndrome, potentially providing a marker to identify patients in which aggressive therapy is required. [ABSTRACT FROM AUTHOR]

Background: Rituximab (RTX) is known to be effective for the treatment of refractory steroid-dependent nephrotic syndrome (SDNS). However, there are insufficient data on the risk factors for relapse and long-term outcome after RTX treatment. Methods: We administered a single dose of RTX to patients with refractory SDNS from November 2007 to December 2013 and continued with immunosuppressants. The risk factors for early relapse and long-term outcome were analyzed. Results: Eighty-one patients were included and the observation period was 13-90 months. Seventy-six patients (94 %) discontinued steroids. Median duration of B-cell depletion was 160 days and 50 % relapse-free survival was 482 days. In multivariate analyses, only a history of steroid-resistant nephrotic syndrome (SRNS) was a statistically significant risk factor (hazard ratio, 2.44; p = 0.048). Fifty percent relapse-free survival in patients without a history of SRNS was 615 days, longer than that of patients with one relapse (393 days; p = 0.005). Fifty-one patients (63 %) received additional RTX treatments for relapses. At last observation, patients using calcineurin inhibitors decreased from 89 % to 23 %, and 12 patients (15 %) discontinued immunosuppressants. Conclusions: Rituximab treatment followed by immunosuppressants is an effective option for patients with SDNS, although a history of SRNS is a risk factor for early relapse. [ABSTRACT FROM AUTHOR]

Background and objectives: There are very little data available regarding nephrotic syndrome (NS) in elderly (aged ≥65 years) Japanese. The aim of this study was to examine the causes and outcomes of NS in elderly patients who underwent renal biopsies between 2007 and 2010. Design, setting, participants, and measurements: From July 2007 to June 2010, all of the elderly (aged ≥65 years) Japanese primary NS patients who underwent native renal biopsies and were registered in the Japan renal biopsy registry (J-RBR; 438 patients including 226 males and 212 females) were identified. From this cohort, 61 patients [28 males and 33 females including 29, 19, 6, 4, and 3 patients with membranous nephropathy (MN), minimal change nephrotic syndrome (MCNS), focal segmental glomerulosclerosis (FSGS), membranoproliferative glomerulonephritis (MPGN), and other conditions, respectively] were registered from the representative multi-centers over all districts of Japan, and analyzed retrospectively. The treatment outcome was assessed using proteinuria-based criteria; i.e., complete remission (CR) was defined as urinary protein level of <0.3 g/day or g/g Cr, and incomplete remission type I (ICR-I) was defined as urinary protein level of <1.0-0.3 g/day or g/g Cr, and renal dysfunction was defined as a serum creatinine (Cr) level of 1.5 times the baseline level. Results: In this elderly primary NS cohort, MN was the most common histological type of NS (54.8 %), followed by MCNS (19.4 %), FSGS (17.4 %), and MPGN (8.4 %). Of the patients with MN, MCNS, or FSGS, immunosuppressive therapy involving oral prednisolone was performed in 25 MN patients (86.2 %), 18 MCNS patients (94.7 %), and all 6 FSGS patients (100 %). CR was achieved in all 19 (100 %) MCNS patients. In addition, CR and ICR-I were achieved in 16 (55.2 %) and 18 (62.1 %) MN patients and 4 (66.7 %) and 5 (83.3 %) FSGS patients, respectively. There were significant differences in the median time to CR among the MCNS, FSGS, and MN patients (median: 26 vs. 271 vs. 461 days, respectively, p < 0.001), and between the elderly (65-74 years, n = 7) and very elderly (aged ≥75 years, n = 12) MCNS patients (7 vs. 22 days, p = 0.037). Relapse occurred in two (6.9 %) of the MN and nine (47.4 %) of the MCNS patients. Renal dysfunction was observed in five (7.2 %) of the MN patients. Serious complications developed in eight (14.8 %) patients, i.e., two (3.7 %) patients died, four (7.4 %, including three MCNS patients) were hospitalized due to infectious disease, and two (3.7 %) developed malignancies. The initiation of diabetic therapy was necessary in 14 of the 61 patients (23.0 %) with much higher initial steroid dosage. Conclusion: Renal biopsy is a valuable diagnostic tool for elderly Japanese NS patients. In this study, most of elderly primary NS patients respond to immunosuppressive therapy with favorable clinical outcomes. On the other hand, infectious disease is a harmful complication among elderly NS patients, especially those with MCNS. In future, modified clinical guidelines for elderly NS patients should be developed. [ABSTRACT FROM AUTHOR]

Background: Hyperlipidemia is not merely a complication but a major exacerbating factor in longstanding nephrotic syndrome (NS). Low-density lipoprotein apheresis (LDL-A) has been reported to ameliorate dyslipidemia and induce rapid remission of NS. Several clinical studies have suggested the therapeutic efficacy of LDL-A, but the level of clinical evidence is insufficient. Therefore, a multicenter prospective study, POLARIS (Prospective Observational Survey on the Long-Term Effects of LDL Apheresis on Drug-Res istant Nephrotic Syndrome), was initiated in Japan. Method: Patients with drug-resistant NS were prospectively recruited into the study and treated with LDL-A in facilities that were registered in advance. In the POLARIS study design, the clinical data are to be followed up for 2 years. In the current study, we aimed at evaluating the short-term efficacy based on the treatment outcome of LDL-A immediately after completion of treatment. Results: Along with rapid improvement of hyperlipidemia, LDL-A significantly improved proteinuria and hypoproteinemia after treatment. More than half of the patients showed remission of NS based on the urinary protein level at the completion of LDL-A. The duration of NS before the start of treatment was significantly shorter in patients who responded to LDL-A. Conclusions: An analysis of patients registered in the POLARIS study indicated that LDL-A has short-term efficacy for drug-resistant NS. Rapid relief of dyslipidemia by LDL-A may provide early remission in about half of the NS patients who are resistant to conventional medication. Completion of the POLARIS study may reveal additional long-term effects of LDL-A in these patients. [ABSTRACT FROM AUTHOR]

Background: Recent randomized studies indicate that mycophenolate mofetil (MMF) is inferior to cyclosporine (CsA) in preventing relapses of nephrotic syndrome (NS). During the last decade, rituximab (RTX) has emerged as a rescue therapy in patients with complicated, frequently relapsing, or steroid-dependent NS. Case-Diagnosis/Treatment: After introducing RTX in our single center, we analyzed 26 patients with steroid-dependent NS who had relapses while receiving long-term CsA and who were subsequently switched to MMF. MMF was adjusted to maintain a targeted predose mycophenolic acid (MPA) level of 2-5 μg/ml. Moreover, for patients who required MMF and high-dose prednisolone (PSL) to maintain remission, a single infusion of RTX (375 mg/m) was added. The primary endpoint was the probability of achieving PSL-free remission for >1 year. At a mean follow-up of 28.8 ± 9.9 months, 11 of 26 patients (42 %) required RTX treatment, and 22 of those patients (85 %) achieved PSL-free sustained remission. The mean predose MPA levels for patients who achieved PSL-free sustained remission were significantly higher compared with those for patients who did not (3.1 μg/ml vs. 1.7 μg/ml, p < 0.05). Conclusions: After RTX introduction, most patients were able to switch from CsA to MMF and achieve sustained PSL-free remission. [ABSTRACT FROM AUTHOR]

Background: To investigate the long-term outcome in children with frequently relapsing nephrotic syndrome (FRNS) we conducted a follow-up of a previous randomized controlled trial (RCT) 10 years after the initiation of the treatment protocol. Methods: We previously conducted an RCT on the efficacy of cyclosporine for treating children with FRNS. After 2 years of treatment, a recommended a management protocol of steroids, and immunosuppressants was provided. Results: Valid information was available for 46 of the 56 patients (82.1 %) enrolled in the original RCT. The median follow-up period was 10.3 years from the start of protocol treatment with cyclosporine. At last follow-up (mean age 18.7 years), only ten patients (21.7 %) showed disease-free remission (no relapse for at least 2 years). In contrast, 23 (50.0 %) continued to relapse frequently or were on immunosuppressants, eight patients (17.4 %) had infrequent relapses without immunosuppressants. Adverse effects attributable to treatment included short stature (6 patients), osteoporosis (six patients), obesity (4 patients), cataracts (3 patients) and hypertension (3 patients). No lethal event or renal dysfunction occurred during follow-up. Conclusions: This 10-year follow-up study shows that most children with FRNS experience relapses after 2 years of cyclosporine treatment, in adolescence and into adulthood. Outcomes in terms of life expectancy and renal function are favorable. [ABSTRACT FROM AUTHOR]

Background: The criterion for performing a renal biopsy in children with idiopathic nephrotic syndrome (NS) showing microscopic hematuria at onset remains controversial. Methods: To determine an adequate renal biopsy criterion in children with NS showing hematuria, the optimal cutoff for the maximum red blood cell (RBC) range in urine sediment to separate minimal change disease (MCD) from other glomerular changes was obtained by receiver operating characteristic analysis. We studied 29 children with NS showing hematuria who were screened from 1,320 patients who underwent renal biopsies between January 2001 and September 2011. Patients were divided into two groups according to the cutoff value to verify its validity. Results: The optimal maximum RBC range was 30-49/high-power field (HPF). In group 1 (RBC ≤29/HPF, n = 14), 3 patients showed nephritis and the other 11 patients showed MCD. In group 2 (RBC ≥30/HPF, n = 15), 1 patient showed focal segmental glomerulosclerosis, 12 showed nephritis, and the other 2 showed MCD. These findings indicated that the ratio of non-MCD/MCD was significantly higher in group 2 than in group 1 ( P < 0.01). Conclusions: The use of maximum RBC range (30-49/HPF) for a criterion of renal biopsy in patients with NS showing hematuria may be reasonable for clinical practice. [ABSTRACT FROM AUTHOR]

Background Angiotensinogen ( AGT) and angiotensin-converting enzyme ( ACE) are recognized as important regulators of body mass index ( BMI) and systemic blood pressure ( BP). An association between these single nucleotide polymorphisms ( SNP) of AGT and ACE genes and obesity or hypertension has been established. This study examined relationships between the molecular variants of the AGT and ACE genes and bodyweight or BP in children treated with glucocorticoids for nephrotic syndrome. Methods Twenty Japanese children (male, n = 14; female, n = 6; age, 2-13 years) were genotyped for AGT polymorphisms ( M235T and A-6G) and the ACE polymorphisms (insertion/deletion: I/ D and rs4341). All of the children studied were treated with daily prednisolone 2 mg/kg for 4 weeks and thereafter alternate-day prednisolone for 8 weeks. BMI, BMI z-scores, blood lipids, renal function and BP in each group were evaluated during the study period. Results BMI and BMI z-scores during the glucocorticoid therapy were significantly higher in the TT genotype of the AGT M235T polymorphisms and the AA genotype of the AGT A-6G polymorphisms compared to other genotypes ( P < 0.05). In contrast, the molecular variant of ACE I/D and rs4341 genotypes did not change bodyweight during the glucocorticoid exposure. It was evident, however, that the BP and blood lipids and renal function were not significantly influenced by the AGT and ACE polymorphisms. Conclusions The TT genotype of the AGT M235T and the AA genotype of the A-6G polymorphisms may predispose children to bodyweight gain when initially treated with glucocorticoids for nephrotic syndrome. [ABSTRACT FROM AUTHOR]

Background: Prednisolone, the first-line treatment for children with nephrotic syndrome, causes severe side effects. One of these side effects is ocular hypertension, which can result in severe and permanent visual disturbance. However, the exact prevalence, severity and timing of development of ocular hypertension have yet to be fully explored in this pediatric patient group. Methods: In this retrospective cohort study, children with nephrotic syndrome treated with prednisolone for their first episode were analyzed. Intraocular pressure was screened with an iCare® tonometer and confirmed with Goldmann applanation tonometry before the initiation of prednisolone treatment and at 1 and 4 weeks thereafter. Results: A total of 26 children with nephrotic syndrome were included in this study, of whom eight (30.8 %) required treatment with eye drops for ocular hypertension. The median time interval between the diagnosis of ocular hypertension and start of treatment was 9 (range 5-31) days. At relapse of nephrotic syndrome, all children who had undergone treatment for ocular hypertension in their first episode again required treatment for ocular hypertension. Conclusions: Routine ophthalmologic examination should be conducted from the early phase after the start of prednisolone treatment. In addition, children with episodes of ocular hypertension may be at greater risk of its reappearance with relapse of the nephrotic syndrome. [ABSTRACT FROM AUTHOR]

The objective of this study was to clarify the long-term outcome in patients with lupus nephritis (LN) according to the International Society of Nephrology and Renal Pathology Society classification. This retrospective analysis comprised 186 Japanese patients given a diagnosis of LN by renal specimen with a mean observation period of 12 years. Primary end point was defined as death or end-stage renal disease, and standardized mortality ratios were calculated. Five patients presented with histopathological class I, 62 with II, 21 with III or III+V, 73 with IV or IV+V and 25 with V. Fourteen deaths occurred, corresponding to an overall standardized mortality ratio of 3.59 (95% confidence interval 2.02–5.81, p < 0.0001). Kaplan-Meier analysis revealed a 10-year overall survival of 95.7%. Nephrotic proteinuria (≥3.5 g/day) at baseline was identified as an independent poor prognostic factor for overall survival in Cox regression analysis. Kaplan-Meier analysis revealed a 10-year renal survival as 94.3%. Male gender and nephrotic proteinuria at baseline were identified as independent poor prognostic factors for renal survival in Cox regression analysis. In conclusion, LN was associated with a 3.59-fold increase in mortality compared with the general population. Male gender and nephrotic proteinuria were predictive for poor renal outcome. [ABSTRACT FROM AUTHOR]

Background: Calcineurin inhibitors (CIs) with/without intravenous methylprednisolone pulse therapy (MPT) constitute the standard treatment for childhood-onset, steroid-resistant nephrotic syndrome (SRNS). However, some patients fail to achieve remission. We treated SRNS patients resistant to CIs and MPT with additional rituximab combined with MPT and immunosuppressive agents. Methods: Ten patients (aged 2-14 years) with CI- and MPT-resistant SRNS were enrolled. Patients were administered rituximab (1-4 doses; 375 mg/m) followed by MPT (30 mg/kg/day of methylprednisolone for 3 consecutive days) once every 2-4 weeks until complete remission (CR). We analyzed clinical outcome and safety. Results: Six patients received a single dose of rituximab, 2 received two doses, and 2 received four doses. Seven patients achieved CR, 1 achieved partial remission, and 2 showed no response. Although 2 patients with no response progressed to end-stage renal failure, 7 patients with CR preserved normal renal function without proteinuria at the last observation. There were two serious adverse events. Conclusions: Additional rituximab combined with conventional MPT and immunosuppressive agents is a promising option for overcoming refractory SRNS. Aggressive B cell suppression by rituximab may ameliorate resistance to conventional treatments and a cocktail of other immunosuppressive agents, such as CIs, MMF, mizoribine, may be beneficial. However, as intense immunosuppression may cause serious adverse events, further evaluation is necessary. [ABSTRACT FROM AUTHOR]

LDL-apheresis is a method to correct dyslipidemia rapidly. It is expected to alleviate the tissue toxicity of persistent dyslipidemia in not only primary, but also in secondary dyslipidemia associated with refractory nephrotic syndrome, and to have a protective effect against glomerular and tubular injury as expected in atherosclerosis. In addition, the effectiveness of LDL-apheresis to promote the remission of nephrotic syndrome has been recognized. In Japan, LDL-A to control hyperlipidemia in patients with refractory nephrotic syndrome associated with focal segmental glomerulosclerosis is covered by national health insurance. Here, the hypothetical mechanism behind its effect and the evidence for its effectiveness over a long period are reviewed. [ABSTRACT FROM AUTHOR]

Background: Prognosis of nephrotic syndrome has been evaluated based on pathological diagnosis, whereas its clinical course is monitored using objective items and the treatment strategy is largely the same. We examined whether the entire natural history of nephrotic syndrome could be evaluated using objective common clinical items., Methods: Machine learning clustering was performed on 205 cases from the Japan Nephrotic Syndrome Cohort Study, whose clinical parameters, serum creatinine, serum albumin, dipstick hematuria, and proteinuria were traceable after kidney biopsy at 5 measured points up to 2 years. The clinical patterns of time-series data were learned using long short-term memory (LSTM)-encoder-decoder architecture, an unsupervised machine learning classifier. Clinical clusters were defined as Gaussian mixture distributions in a two-dimensional scatter plot based on the highest log-likelihood., Results: Time-series data of nephrotic syndrome were classified into four clusters. Patients in the fourth cluster showed the increase in serum creatinine in the later part of the follow-up period. Patients in both the third and fourth clusters were initially high in both hematuria and proteinuria, whereas a lack of decline in the urinary protein level preceded the worsening of kidney function in fourth cluster. The original diseases of fourth cluster included all the disease studied in this cohort., Conclusions: Four kinds of clinical courses were identified in nephrotic syndrome. This classified clinical course may help objectively grasp the actual condition or treatment resistance of individual patients with nephrotic syndrome., (© 2022. The Author(s).)

Background: A prolonged change in the rate of primary membranoproliferative glomerulonephritis (MPGN) was identified using a Japanese database of renal biopsies. Methods: We retrospectively investigated 6,369 renal biopsies that were performed between 1976 and 2009. Primary MPGN patients were selected, and the clinical and pathological findings were examined. We also statistically analyzed the changing rate of the onset of primary MPGN according to each decade. Results: Seventy-nine cases with primary MPGN (1.2 % of total biopsies) were diagnosed. The age of the patients ranged from 6-79 years (average 34.6 years). There were 24 children and 55 adults, including 37 male and 42 female patients. Thirty-six cases of primary MPGN (45.6 %) showed nephrotic syndrome-8 childhood and 28 adult cases. In the pathological classification of 44 samples using electron microscopy, 29 cases were MPGN type I, 1 case was MPGN type II, and 14 cases were MPGN type III. The secular change of the rate of primary MPGN onset showed a statistically significant reduction from the 1970s to the 2000s. The rate of primary MPGN onset in the child population also significantly decreased, but not in the adult population. Among the clinical parameters, disease severity and prognosis remained unchanged. Regarding treatment in recent years, steroid pulse therapy became more available but the administration of warfarin and anti-platelet drugs significantly decreased. Conclusion: We concluded that the rate of total primary MPGN and that of pediatric patients with primary MPGN decreased. [ABSTRACT FROM AUTHOR]

Background: Rituximab (RTX) is a promising option for treating childhood-onset steroid-dependent (SDNS), frequently relapsing (FRNS), and steroid-resistant (SRNS) nephrotic syndrome. Methods: We retrospectively surveyed RTX treatment for these conditions to evaluate its indications, efficacy and adverse events. Questionnaires were sent to 141 hospitals in Japan. Results: Seventy-four patients (52 SDNS; 3 FRNS; 19 SRNS) were treated with RTX because of resistance to various immunosuppressive agents. Most patients received a single administration of RTX (85%). Forty-one of 53 SDNS/FRNS (77%) and 5 of 17 SRNS (29%) patients successfully discontinued prednisolone (16 SDNS/FRNS and 6 SRNS achieved their first discontinuation since onset), and 17 out of 53 SDNS/FRNS patients (31%) discontinued cyclosporine. However, 28 of the 53 patients (51%) relapsed. Although immunosuppressive agents did not extend B cell depletion, relapses were significantly less if immunosuppressive agents were continued after RTX ( P = 0.006; hazard ratio = 0.2). Among the SRNS patients, complete ( n = 6) and partial remission ( n = 6) were achieved. No life-threatening adverse events were experienced. Conclusions: Although this was a multi-center survey where treatment of nephrotic syndrome varied between centers, the steroid-sparing effect of RTX in SDNS/FRNS was excellent. If single administration of RTX is chosen, continuation of immunosuppressive agents is recommended for prevention of relapse. [ABSTRACT FROM AUTHOR]

Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults. The J-RBR/J-KDR registry developed by the Japanese Society of Nephrology provides nationwide cohort data for epidemiological studies of MN. MN was present in 36.8% of 1,203 primary nephrotic syndrome patients in Japan. In addition, 633 (77.9%) out of 813 MN patients were referred to as 'idiopathic,' whereas 22.1% were classified as 'secondary' and involved conditions such as systemic lupus erythematosus, drug exposure, infections, cancer, and various collagen diseases. The mean age of the MN patients was 62.2 (2-88) years old, their mean eGFR was 76.7 (7.6-154.6) ml/min/1.73 m, and 63.3% had hypertension at the time of renal biopsy. On the basis of these findings, half of Japanese idiopathic MN patients have risk factors (age >60, male, or lower eGFR) for end-stage renal failure, and 10% belong to the high-risk group (daily proteinuria of over 8.0 g). Further studies with high-grade evidence should resolve the natural history and therapeutic problems of idiopathic MN in elderly Japanese. [ABSTRACT FROM AUTHOR]

Background: Although once-daily cyclosporine (CsA) therapy may have greater nephrotoxic-sparing effects than standard twice-daily therapy, little information is available in children with steroid-dependent minimal change nephrotic syndrome (MCNS) regarding histological analysis after long-term once-daily administration. Case-Diagnosis/Treatment: A prospective study of the clinical efficacy and comparison between pre- and post-treatment renal biopsy findings in ten children (mean age, 8.8 years) with steroid-dependent MCNS who were administered once-daily CsA therapy for more than 24 months (mean ± SD, 30 ± 3.7) was performed in Saitama Children's Medical Center. Administration of once-daily CsA therapy (mean dose, 2.8 ± 0.6 mg/kg/day; mean C2 levels, 670 ± 64 ng/ml) resulted in a significant reduction in the median relapse rate from 4.6 to 0.2 times per year, and five patients did not experience a relapse of NS. Furthermore, mean threshold of prednisolone dose significantly reduced from 1.2 to 0.02 mg/kg on alternate days. However, two patients showed evidence of chronic CsA nephrotoxicity (CsAN). Conclusions: Once-daily CsA therapy appears to be effective in children with steroid-dependent MCNS. However, follow-up renal biopsies should be performed to investigate the presence of CsAN after more than 24 months of treatment with once-daily regimen as well as with the conventional twice-daily regimen. [ABSTRACT FROM AUTHOR]

It remains elusive what factors affect posterior reversible encephalopathy syndrome (PRES). Eleven PRES children, all with acute glomerulonephritis, Alport syndrome, and lupus nephritis, 5 with nephrosis, and 3 renal transplant recipients, were studied. PRES recurred in 1 patient. Neurological symptoms were graded as 1: mild (headache, nausea/vomiting, or tremor), 2: moderate (vision change), and 3: severe (mental dysfunction, cerebellar symptoms, seizures, recurrence of seizures, and coma). Magnetic resonance imaging was graded as 1: subtle change, 2: abnormal large areas, and 3: complete involvement of the regions. The common symptoms were seizures (100%), headache (82%), nausea/vomiting (73%), coma (55%), and vision change (46%). Seizures recurred in 7 (64%). All but one (91%) developed hypertension and 7 (64%) received calcineurin inhibitors (CNI). Edema occurred in 7 (64%) and renal insufficiency/end-stage renal disease (ESRD) in 4 (36%). Seizures recurred frequently in younger patients. Symptoms were severe in girls. Duration or severity of the condition with predisposing factors (hypertension, CNI, nephrosis or renal insufficiency/ERSD) did not make a difference in the symptoms and neuroimaging. Two patients developed chronic epilepsy. Age and gender may affect PRES symptoms. Our results are limited by small sample size and should be determined using larger numbers of patients. [ABSTRACT FROM AUTHOR]