Clinical significance of IgM and C1q deposition in the mesangium in pediatric idiopathic nephrotic syndrome.

BACKGROUND: In biopsy-proven idiopathic nephrotic syndrome (INS), immunoglobulin M (IgM) and C1q are occasionally deposited in the mesangium. In pediatric nephrology, the significance of mesangial IgM or C1q deposits is controversial, based on previous reports. The aim of this study was to explore the clinical significance of mesangial IgM and/or C1q deposits in pediatric INS patients, especially the initial responses to steroids and final outcomes. METHODS: We reviewed the clinical courses of 70 children with steroid-dependent or steroid-resistant INS who underwent a renal biopsy at our hospital from 1998 to 2010. There were 30 mesangial IgM immunofluorescence (IF)-positive (IgM+) children. The IgM+ group was compared with the IgM IF-negative (IgM-) group. In addition, we reviewed the clinical characteristics of 8 mesangial C1q IF-positive (C1q+) children. RESULTS: Of the 30 IgM+ children, 10 (33.3%) were steroid-dependent (IgM- group: 18/40, 45%) and 14 (46.7%) were steroid-resistant (IgM- group: 11/40, 27.5%; p<0.05). Although a high frequency of steroid-resistant INS was observed in the IgM+ group, the efficacy of cyclosporine (CyA) therapy was relatively good (all 14 steroid-resistant children obtained complete or partial remission). Moreover, all 8 C1q+ children obtained complete remission after CyA therapy, although they had a high frequency of steroid resistance (7/8, 87.5%), and 1 child was steroid-dependent. CONCLUSIONS: Our results indicate that, regardless of the histological pattern (minimal change disease, focal segmental glomerulosclerosis or diffuse mesangial hypercellularity), children with IgM+ and/or C1q+ INS have good responses to CyA. IgM+ and/or C1q+ may be markers of the initial disease severity of INS.

A case report of mediastinal seminoma arising after renal transplantation.

Recipients of organ transplantation on immunosuppressive medications are at increased risk for developing de novo malignancies, including skin cancer, Kaposi's sarcoma, in situ carcinomas of the uterine cervix, anogenital cancers, renal cell carcinoma, and post-transplant lymphoproliferative disorders (PTLD). However, there are few case reports of germ cell tumors after organ transplantation. There are some case reports of testicular seminoma, but not mediastinal seminoma. This case report is the first description of a mediastinal seminoma that developed de novo 28 months after renal transplantation and that was initially diagnosed as PTLD. To improve outcomes of organ transplant recipients, it is important to report rare cases of malignancies arising while on immunosuppressive medications. When we detect mediastinal tumor arising after organ transplantation while on immunosuppressive therapy, diseases other than PTLD should be considered in the differential diagnosis.

Expression of galectin-1, a new component of slit diaphragm, is altered in minimal change nephrotic syndrome.

Nephrin is an essential structural component of the glomerular slit diaphragm (SD), a highly organized intercellular junction that constitutes the ultrafiltration barrier of the kidney. Recent studies have identified two additional nephrin-interacting SD proteins (NEPH1 and NEPH2), suggesting that the zipper-like pattern of the SD is formed through complex intra- and intermolecular interactions of these proteins. However, the complexity of the SD structure suggests that additional SD components remain to be discovered. In this study, we identified galectin-1 (Gal-1) as a new component of the SD, binding to the ectodomain of nephrin. Using dual-immunofluorescence and confocal microscopy and dual-immunoelectron microscopy, we found Gal-1 co-localizing with the ectodomain of nephrin at the SD in normal human kidney. By immunoprecipitation and surface plasmon resonance, we confirmed a direct molecular interaction between Gal-1 and nephrin. Moreover, recombinant Gal-1 induced tyrosine phosphorylation of the cytoplasmic domain of nephrin and activation of the extracellular signal-regulated kinase 1/2 in podocytes. We also showed that podocytes are a major site of biosynthesis of Gal-1 in the glomerulus and that the normal expression patterns and levels of Gal-1 are altered in patients with minimal change nephrotic syndrome. Finally, in puromycin aminonucleoside-induced rat nephrosis, an apparent reduction in the levels of Gal-1 and nephrin around the onset of heavy proteinuria was also revealed. Our data present Gal-1 as a new extracellular ligand of nephrin localized at the glomerular SD, and provide further insight into the complex molecular organization, interaction, and structure of the SD, which is an active site of intracellular signaling necessary for podocyte function.

Clinical features and outcomes in children with antineutrophil cytoplasmic autoantibody-positive glomerulonephritis associated with propylthiouracil treatment.

A retrospective investigation was conducted by members of the Japanese Society for Pediatric Nephrology from 1990 to 1997 to define the clinical features and outcomes in children with antineutrophil cytoplasmic autoantibody (ANCA)-positive glomerulonephritis associated with propylthiouracil treatment. Seven Japanese pediatric patients who had myeloperoxidase-specific ANCA-positive biopsy-proven pauci-immune necrotizing crescentic glomerulonephritis associated with propylthiouracil administration were entered in the study. Three patients had nephritis alone, and four had nephritis and extrarenal organ system vasculitis. Females predominated, and the mean age at onset was 14 yr. Propylthiouracil was reduced or discontinued in all patients and was switched to methimazole in three patients. For the treatment of nephritis, five patients received corticosteroids; three had pulse methylprednisolone, one had plasma exchange, and one had plasma exchange and pulse methylprednisolone before initiating oral prednisolone. The remaining two patients received cyclophosphamide and corticosteroids, one of whom had pulse methylprednisolone before initiating oral prednisolone and cyclophosphamide. All patients achieved remission. In general, ANCA titers correlated with the response to treatment and disease activity, with some exceptions. No patient progressed to end-stage renal disease, renal dysfunction, or death during the follow-up period (58 +/- 25 mo; range, 32 to 108 mo). All but one patient remained euthyroid. In conclusion, this experience suggests that the clinical disease spectrum of ANCA-positive disease associated with propylthiouracil treatment is similar in pediatric and adult patients and that the overall prognosis may be better than that in the non-drug-induced ANCA-positive disease.

Antineutrophil cytoplasmic autoantibody-associated glomerulonephritis in children.

Aretrospective investigation was conducted by members of the Japanese Society for Pediatric Nephrology from 1990 to 1997 to define the clinical features and outcome of antineutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis in children. Thirty-four ANCA-seropositive Japanese pediatric patients with biopsy-proven pauci-immune necrotizing crescentic glomerulonephritis were identified. Of these, 3 cases associated with Wegener's granulomatosis were excluded because of the small sample size. Among the 31 patients studied, 10 had a diagnosis of necrotizing crescentic glomerulonephritis alone and 21 had microscopic polyangiitis. Females predominated (87%), and the median age at onset was 12 yr. Twenty-six patients received treatment with cyclophosphamide and corticosteroids, and five patients received treatment with corticosteroids alone; 84% of patients achieved remission, and 39% of responders relapsed in a median of 24 mo. ANCA titers correlated with response to treatment and disease activity, with some exceptions. Patients were followed for a median of 42 mo (range, 3 to 96 mo). Nine of 31 patients (29.0%) progressed to end-stage renal disease, 6 (19.4%) had reduced renal function, and 15 (48.4%) had normal renal function at the last observation. One patient (3.2%) died from cytomegalovirus infection 3 mo after initiation of therapy. Life-table analysis showed 75% renal survival at 39 mo. Patients who subsequently developed end-stage renal disease (n = 9) had significantly higher average peak serum creatinine levels and more chronic pathologic lesions at diagnosis compared with patients with favorable renal outcome (n = 15). In conclusion, our clinical experience suggests that the clinical disease spectrum of ANCA-associated glomerulonephritis is similar in pediatric and adult patients, but there is a female predominance in children.