Efficacy of rituximab and risk factors for poor prognosis in patients with childhood-onset steroid-resistant nephrotic syndrome: a multicenter study.

BACKGROUND: The efficacy of rituximab in steroid-resistant nephrotic syndrome (SRNS) is controversial. We previously reported that rituximab in combination with methylprednisolone pulse therapy (MPT) and immunosuppressants was associated with favorable outcomes. We determined risk factors for poor response following rituximab treatment, which remains unknown. METHODS: This retrospective study included 45 patients with childhood-onset SRNS treated with rituximab across four pediatric kidney facilities. Treatment effects were categorized as complete remission (CR), partial remission (PR), and no remission (NR) at one year after rituximab treatment. The primary outcome was the rate of CR, PR, and NR. Risk factors for non-CR were calculated with multivariate logistic regression. Adverse events and the relationship between disease status at one year and long-term prognosis were also evaluated. RESULTS: The rates of CR, PR, and NR at one year were 69%, 24%, and 7%, respectively. The median time from rituximab administration to CR was 90 days. The median follow-up period after rituximab administration was 7.4 years. In multivariate analysis, significant risk factors for poor response were the pathologic finding of focal segmental glomerular sclerosis and a long interval between SRNS diagnosis and rituximab administration. The rates of CR were 90.3% and 21.4% in patients receiving rituximab within and after 6 months following SRNS diagnosis, respectively (p < 0.001). Five patients developed chronic kidney disease stage G5, including 2 of the 11 patients with PR and all 3 patients with NR, whereas none of the 31 patients with CR developed chronic kidney disease stage G5. CONCLUSION: Early administration of rituximab in combination with MPT and immunosuppressants might achieve favorable outcomes in patients with SRNS.

Multinucleated podocytes as a clue to diagnosis of juvenile nephropathic cystinosis.

BACKGROUND  : Cystinosis is a rare autosomal recessive lysosomal disorder that mainly affects the kidney and eye. Early treatment with cysteamine significantly improves the prognosis. However, early diagnosis of cystinosis, especially the juvenile nephropathic form, remains challenging because typical symptoms only become apparent in adulthood. We herein describe a 13-year-old girl who presented with proteinuria only but was diagnosed with juvenile nephropathic cystinosis based on multinucleated podocytes in her kidney biopsy specimen. We also studied the nephropathology of another case to determine the features of the multinucleated podocytes. CASE DIAGNOSIS: A previously healthy 13-year-old girl presented to our hospital because proteinuria had been detected in her school urine screening. She had been noted to have proteinuria on her school urine screening when she was 11 years of age but there was no consultation with her physician at that time. She was asymptomatic and had no other abnormalities on examination other than a relatively high urinary ß-2 microglobulin level. Her kidney biopsy showed 15 multinucleated podocytes in 34 glomeruli, and the mean number of nuclei per multinucleated podocyte was 4.4. Ophthalmological examination showed cystine crystals in her cornea. Her white blood cell cystine level was high, and she was diagnosed with juvenile nephropathic cystinosis. She started oral cysteamine treatment and showed almost no progression of the disease after 2 years. In another patient with juvenile nephropathic cystinosis, there were 25 multinucleated podocytes in 63 glomeruli, and the mean number of nuclei per multinucleated podocyte was 2.9. CONCLUSION: Early diagnosis is crucial to improve the prognosis of patients with cystinosis. This report emphasizes the importance of recognizing the unique pathological feature of multinucleated podocytes as an essential clue to the diagnosis of cystinosis.

Rituximab in combination with cyclosporine and steroid pulse therapy for childhood-onset multidrug-resistant nephrotic syndrome: a multicenter single-arm clinical trial (JSKDC11 trial).

BACKGROUND: Only 80% of children with idiopathic nephrotic syndrome respond well to glucocorticoid therapy. Multidrug-resistant nephrotic syndrome (MRNS) is associated with a poor kidney prognosis. Several retrospective studies have identified rituximab as an effective treatment for MRNS; however, prospective studies are required to assess its efficacy and safety. METHODS: We conducted a multicenter, non-blinded, single-arm trial to investigate the efficacy and safety of rituximab in patients with childhood-onset MRNS who were resistant to cyclosporine and more than three courses of steroid pulse therapy. The enrolled patients received four 375 mg/m2 doses of rituximab in combination with baseline cyclosporine and steroid pulse therapy. The primary endpoint was a > 50% reduction in the urinary protein/creatinine ratio from baseline on day 169. Complete and partial remissions were also evaluated. RESULTS: Six patients with childhood-onset MRNS were enrolled. All patients were negative for pathogenic variants of podocyte-related genes. On day 169, five patients (83.3%) showed a > 50% reduction in the urinary protein/creatinine ratio, two patients showed partial remission, and two patients showed complete remission. No deaths occurred and severe adverse events occurred in two patients (infection in one patient and acute kidney injury in one patient). Three patients needed treatment for moderate-to-severe infection. CONCLUSIONS: The study treatment effectively reduced the urinary protein/creatinine ratio in patients with childhood-onset MRNS. The adverse events in this study were within the expected range; however, attention should be paid to the occurrence of infections.

Aggressive immunotherapy combined with bortezomib and rituximab for membranous nephropathy associated with enzyme replacement therapy in Pompe disease.

BACKGROUND: Pompe disease (PD) is a lysosomal glycogen storage disorder caused by a deficiency in acid α-glucosidase (GAA) activity. Various organs, including the skeletal muscle, cardiac muscle, and liver, are commonly involved. Early initiation of enzyme replacement therapy (ERT) with recombinant human α-glucosidase (rhGAA) can improve the outcome. However, some patients experience a poor clinical course despite ERT because of the emergence of anti-rhGAA antibodies that neutralize rhGAA. Treatment against anti-rhGAA antibodies is challenging. CASE-DIAGNOSIS/TREATMENT: A 14-year-old boy with late-onset PD was referred to our hospital with proteinuria detected by school urinalysis screening. He was diagnosed with PD at the age of 4 years based on muscle biopsy and decreased GAA activity. Treatment with rhGAA was initiated, but anaphylaxis occurred frequently. Anti-rhGAA antibodies were detected and immune tolerance therapy was therefore given, but his antibody titer remained high. Kidney biopsy revealed stage II membranous nephropathy. Immunohistochemistry staining revealed anti-rhGAA antibody/rhGAA immune complexes along the glomerular capillary loop. Aggressive immunotherapy combined with bortezomib and rituximab was then initiated. Serum levels of anti-rhGAA antibodies decreased significantly and his proteinuria finally resolved. CONCLUSIONS: There have been few reports of membranous nephropathy associated with ERT for PD. We clarified the cause in the current patient. Bortezomib and rituximab effectively suppressed anti-rhGAA antibody production resulting in the resolution of proteinuria and maintenance of ERT efficacy.

New-onset pediatric nephrotic syndrome following Pfizer-BioNTech SARS-CoV-2 vaccination: a case report and literature review.

Various new vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been rapidly developed. The new onset and recurrence of nephrotic syndrome triggered by some vaccines have been documented and several adult cases of minimal change nephrotic syndrome newly developing after SARS-CoV-2 vaccination have been reported. However, no reports of pediatric cases have been published. Indications for SARS-CoV-2 vaccines have been expanded to those as young as 12 years old and vaccination of children has just started in Japan. We encountered a 15-year-old boy without underlying disease who newly developed nephrotic syndrome after SARS-CoV-2 vaccination with BNT162b2 (Pfizer-BioNTech). He developed eyelid edema 4 days after vaccination and peripheral edema of the lower extremities a further 4 days later. Twenty-one days after vaccination, 60 mg of oral daily prednisolone was started. He achieved complete remission in 12 days without complications such as hypertension or acute kidney injury. We clinicians should be aware of the possibility of nephrotic syndrome developing after SARS-CoV-2 vaccination, not only in adults, but also in children.

Epidemiology and clinical features of childhood-onset anti-neutrophil cytoplasmic antibody-associated vasculitis: a clinicopathological analysis.

BACKGROUND: This study was performed to determine the clinical features and outcomes of childhood-onset anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), particularly microscopic polyangiitis (MPA). METHODS: A retrospective Japanese multicenter study was performed in patients diagnosed with AAV before 16 years of age. RESULTS: Of 49 patients with AAV, 36 were female. The diagnoses were as follows: MPA (n = 38, 78%), granulomatosis with polyangiitis (GPA; n = 9, 18%), eosinophilic granulomatosis with polyangiitis (EGPA; n = 1, 2%), and other (n = 1, 2%). The median age at onset was 10.7 years, and median time to diagnosis was 2.0 months. Twenty-seven (55%) patients were identified through a school urinary screening program. Initial symptoms included fever and fatigue (45%), and renal (71%), pulmonary (29%), ocular (20%), and mucocutaneous involvement (22%). Although 27 (55%) patients achieved remission and none had died at the last follow-up, at least one recurrence occurred in 13 (48%) patients after a median of 48 months and was more common in patients with GPA (P < 0.01). After a median follow-up of 43 months, seven (14%) patients (all with MPA) progressed to end-stage renal disease (ESRD). CONCLUSIONS: Childhood-onset AAV has an estimated prevalence of 3.41-4.28 per million children and is characterized by female predominance and high frequency of detection in school urinary screening programs. More than 10% of patients with childhood-onset AAV still progress to ESRD without achieving remission. Histological chronicity is a factor associated with ESRD.

Long-term outcome of idiopathic steroid-resistant nephrotic syndrome in children.

BACKGROUND: Several recent studies have shown improved short-term outcome of steroid-resistant nephrotic syndrome (SRNS) in children; however, only a few studies have evaluated the long-term outcome. The aims of our study were to obtain detailed data and analyze the long-term outcome of children with SRNS. METHODS: Sixty-nine children with idiopathic SRNS were enrolled and divided into two groups based on initial histopathological patterns: focal segmental glomerulosclerosis (FSGS) and minimal change (MC)/diffuse mesangial proliferation (DMP). The effects of initial treatment with the immunosuppressant of choice (cyclosporine or cyclophosphamide) on renal survival, remission, and incidence of complications were analyzed in both groups (4 subgroups). RESULTS: The renal survival rate was significantly different among the four different subgroups based on different combinations of initial histopathological pattern (FSGS vs. MC/DMP) and initial immunosuppressant used for treating SRNS (cyclosporine vs. cyclophosphamide) (P = 0.013), with renal survival in the FSGS (cyclophosphamide) subgroup being especially low (54.6 %). Disease- and/or treatment-associated complications were relatively low; however, hypertension at last examination was observed in a considerable number of patients (31.9 %). CONCLUSIONS: Our results suggest that a recently developed therapeutic regimen with cyclosporine considerably improves both the initial remission rate and the long-term renal survival rate of children with idiopathic SRNS.

Elevated D-dimer level is a risk factor for coronary artery lesions accompanying intravenous immunoglobulin-unresponsive Kawasaki disease.

Although there are many reports on the resistance of Kawasaki disease (KD) to initial intravenous immunoglobulin (IVIg) therapy, risk factors for coronary artery lesions in such cases remain to be established. The objective of this study was to explore when additional therapies should be administered and to identify factors helpful for selecting a therapeutic option. Based on their written clinical records, we performed a retrospective review of KD patients who did not respond to initial IVIg therapy and who therefore then underwent plasma exchange (PE) therapy. This was a case-control study to compare the presence or absence of acute coronary lesions in patients treated by PE for IVIg-unresponsive KD at Yokohama City University Hospital or at Yokohama City University Medical Center. Fifteen of 44 patients had acute coronary artery lesions (CAL) correlating with high levels of white blood cells (WBC) (P = 0.045), D-dimer (P = 0.008), and fibrin/fibrinogen degradation products (P = 0.009) and lower levels of fibrinogen (P = 0.013) prior to PE therapy. There was a strong correlation between pre-PE levels of albumin and D-dimer (Pearson's correlation coefficient of 0.610). Multivariate analyses revealed that the odds ratio for CAL when D-dimer was ≥ 4.5 µg/mL was 25.06 (95% CI, 2.56-244.91, P = 0.006). D-dimer elevation and albumin decline in IVIg-unresponsive KD patients could be risk factors for acute CAL, suggesting the possibility that angitis has spread throughout the arterial system, as far as the coronary artery.

Soft glassy colloidal arrays in an ionic liquid: colloidal glass transition, ionic transport, and structural color in relation to microstructure.

The colloidal glass transition, ionic transport, and optical properties of soft glassy colloidal arrays (SGCAs) that consist of poly(methyl methacrylate) (PMMA)-grafted silica nanoparticles (PMMA-g-NPs) and a room-temperature ionic liquid, 1-ethyl-3-methylimidazolium bis(trifluoromethane sulfonyl)amide ([C(2)mim][NTf(2)]), were investigated. At lower particle concentrations, PMMA-g-NPs were well-suspended in the IL without any aggregation or sedimentation, and the dilute suspensions showed liquid-like behavior. However, above a certain particle concentration, the suspensions became solidified and exhibited different structural colors depending on the particle concentrations. The liquid-solid transition of the SGCAs was essentially caused by colloidal glass transition. Due to the soft repulsive interaction between the particles, the effective volume fraction of the particle (ϕ(eff)) required for colloidal glass transition was higher than that of the hard sphere system and found to be approximately 0.70-0.74. The SGCA had sufficient ionic conductivity, which was greater than 10(-3) S cm(-1) at room temperature, even in the highly concentrated region. For ionic transport of the cation and the anion in the SGCAs, the decrease in diffusivity observed with the addition of the particles (D(g)/D(0)) was slightly greater for the [NTf(2)] anion than that of the [C(2)mim] cation, suggesting that the [NTf(2)] anion preferentially interacts with the PMMA chains. The SGCAs showed homogeneous, nonbrilliant, and angle-independent structural colors above the glass transition volume fraction. In addition, the color of the SGCAs changed from red to green to blue as the particle concentration increased. A linear relationship was found between the maximum wavelength of the reflection spectra and the center-to-center distance in the SGCAs.

Thermosensitive, soft glassy and structural colored colloidal array in ionic liquid: colloidal glass to gel transition.

A novel soft material comprising thermosensitive poly(benzyl methacrylate)-grafted silica nanoparticles (PBnMA-g-NPs) and the ionic liquid (IL), 1-ethyl-3-methylimidazolium bis(trifluoromethane sulfonyl)amide ([C(2)mim][NTf(2)]), was fabricated. The thermosensitive properties were studied over a wide range of particle concentrations and temperatures. PBnMA-g-NPs in the IL underwent the lower critical solution temperature (LCST) phase transition at lower temperatures with a broader transition temperature range as compared to the free PBnMA solution. Highly concentrated suspensions formed soft glassy colloidal arrays (SGCAs) exhibiting a soft-solid behavior and angle-independent structural color. For the first time, we report a discrete change in the angle-independent structural color of SGCAs with temperature because of a temperature-induced colloidal glass-to-gel transition. The interparticle interaction changed from repulsive to attractive at the LCST temperature, and it was characterized by a V-shaped rheological response and a direct electron microscope observation of the colloidal suspension in the IL. With unique rheological and optical properties as well as properties derived from the IL itself, the thermosensitive SGCAs may be of interest as a new material for a wide range of applications such as electrochemical devices and color displays.

Long-term remission of nephrotic syndrome with etanercept for concomitant juvenile idiopathic arthritis.

Etanercept is a tumor necrosis factor (TNF)-alpha inhibitor that has been applied beneficially for juvenile idiopathic arthritis (JIA). We experienced long-term remission of nephrotic syndrome (NS) in a boy treated with etanercept, which was initially used for concomitant JIA. He developed NS at age 3 years 7 months and had mostly been treated with cyclosporine because of steroid dependency and frequent relapses. Cyclosporine was halted at 10 years 7 months because of nephrotoxicity, and he was subsequently treated with mizoribine. However, he had three relapses in the first year and developed JIA at 11 years 7 months. He was treated with sulfasalazine, methotrexate, and prednisolone, but his arthritis persisted. Etanercept was started at 12 years 3 months. Thereafter, his arthritis went into complete remission. Surprisingly, he has remained relapse-free for both NS and JIA for more than 3 years with etanercept and mizoribine. It is difficult to know whether the NS remission after initiating etanercept was coincidental. However, there are many reports of increased TNF-alpha or soluble TNF-alpha receptor in NS relapse. To date, there are two reports of the efficacy of TNF-alpha inhibitors against NS. It is possible that TNF-alpha inhibitors may have potential as therapeutic agents for NS.

Acute encephalopathy of Bacillus cereus mimicking Reye syndrome.

We present an 11-year-old boy diagnosed as having acute encephalopathy and liver failure with the underlying condition of a metabolic dysfunction. He developed convulsions and severe consciousness disturbance following gastroenteritis after the ingestion of some fried rice. He showed excessive elevation of transaminases, non-ketotic hypoglycemia and hyperammonemia, which were presumed to reflect a metabolic dysfunction of the mitochondrial beta-oxidation, and he exhibited severe brain edema throughout the 5th hospital day. He was subjected to mild hypothermia therapy for encephalopathy, and treated with high-dose methylprednisolone, cyclosporine and continuous hemodiafiltration for liver failure, systemic organ damage and hyperammonemia. The patient recovered with the sequela of just mild intelligence impairment. In this case, Bacillus cereus, producing emetic toxin cereulide, was detected in a gastric fluid specimen, a stool specimen and the fried rice. It was suggested that the cereulide had toxicity to mitochondria and induced a dysfunction of the beta-oxidation process. The patient was considered as having an acute encephalopathy mimicking Reye syndrome due to food poisoning caused by cereulide produced by B. cereus.

A soft glassy colloidal array in ionic liquid, which exhibits homogeneous, non-brilliant and angle-independent structural colours.

A soft glassy colloidal array that was prepared from polymer-grafted silica particles and an ionic liquid showed homogeneous, non-brilliant, angle-independent structural colours.

A report of two cases of Kawasaki disease treated with plasma exchange.

Kawasaki disease is a generalized vasculitis of unknown etiology that occurs predominantly in infants and young children. It is very important to prevent its cardiovascular manifestations, especially coronary artery lesions. Early treatment with intravenous immunoglobulin reduces cardiovascular sequelae, but some patients do not respond to this treatment, and they have a high incidence of coronary artery lesions. On the other hand, acute heart failure is rare in Kawasaki disease. We report on the cases of two patients with persistent fever and shock even after intravenous immunoglobulin therapy. In both cases, plasma exchange may have reduced the risk of coronary artery lesions and proved effective against acute heart failure with catecholamine-refractory shock; yet the mechanism of this improvement remains unclear.

Colloidal stability of bare and polymer-grafted silica nanoparticles in ionic liquids.

The colloidal stability of bare and poly(methyl methacrylate) (PMMA)-grafted silica nanoparticles was studied in 1-alkyl-3-methylimidazolium ([C(n)mim])-based ionic liquids (ILs) with different anionic structures. The theoretical estimation of the colloidal interaction between monodispersed bare silica particles by using the Derjaguin-Landau-Verwey-Overbeek theory indicates that bare silica particles cannot be stabilized and they rapidly form aggregates in all the ILs used in this study. The instability of bare silica particles was experimentally confirmed by dynamic light scattering measurement and in situ transmission electron microscopy observations by utilizing the negligible vapor pressure of ILs. This evidence suggests that electrostatic stabilization is inefficient in ILs because of the high ionic atmosphere and the resulting surface-charge screening. The PMMA-grafted silica particles exhibited long-term colloidal stability in [C(4)mim][PF(6)] and [C(n)mim][NTf(2)], which are compatible with the grafted PMMA. On the other hand, the PMMA-grafted particles could not be stabilized in [C 4mim][BF 4] due to the poor solubility of the grafted PMMA in the IL. Effective steric stabilization is important for obtaining stable colloidal particles in ILs.

Amelioration of steroids and cyclosporine-resistant nephrotic syndrome by pravastatin.

We report the case of a girl with steroids and cyclosporine (CsA) resistant focal segmental glomerulosclerosis (FSGS) whose proteinuria and hypoproteinaemia were dramatically resolved by pravastatin. She had been in a nephrotic condition for 6 years. Prednisolone, pulse methylprednisolone therapy, low-density lipoprotein (LDL) apheresis, CsA, cyclophosphamide and mizoribine (MZR) had proved to be ineffective. She was started on pravastatin for her hyperlipidaemia 6 and a half years from onset, in addition to the baseline therapy, which included CsA; remission of the nephrotic syndrome was unexpectedly attained after 10 months of treatment. The baseline therapy has not been changed since the inclusion of pravastatin. This case suggests that, in patients with hyperlipidaemia, the response to CsA could be restored by lowering cholesterol levels with statins. The decrease of cholesterol levels might have improved the pharmacokinetics of CsA in this patient. Furthermore, the anti-inflammatory and immuno-modulatory effects, recently attributed to statins, may also have been involved in the improvement experienced by our patient.