Discordant Phenotypes of Nephritis in Patients with X-linked Agammaglobulinemia.

PURPOSE: To define the clinical and histological characteristics of nephritis in patients with X-linked agammaglobulinemia (XLA) and their immunological profiles. METHODS: The clinical, immunological, and histological findings of nine patients with XLA and nephritis were retrospectively analyzed. RESULTS: Based on kidney histological findings, patients with XLA and nephritis could be divided into two groups, viz., chronic glomerulonephritis (CGN) and tubulointerstitial nephritis (TIN). The two groups showed different immunological profiles. Patients in the CGN group exhibited an atypical immunological profile of XLA, with pathogenic leaky B cells producing immunoglobulins that may play a role in forming immune complexes and causing immune-mediated glomerulonephritis. In contrast, patients in the TIN group exhibited a typical immunological profile of XLA, suggesting that antibody-independent/other BTK-dependent mechanisms, or immunoglobulin replacement therapy (IgRT)-related immune/nonimmune-mediated nephrotoxicity causes TIN. CONCLUSION: Nephritis occurring in patients with XLA could have links between their renal pathology and immunological status. Careful observation is recommended to detect kidney pathology in patients with XLA on IgRT.

Allogeneic bone marrow transplantation appears to ameliorate IgA nephropathy in a patient with X-linked thrombocytopenia.

Wiskott-Aldrich syndrome (WAS) is caused by a mutation in the WAS gene, and it is clinically characterized by the triad of thrombocytopenia, eczema and immunodeficiency. X-linked thrombocytopenia (XLT), which is a clinically mild form of WAS, is also caused by a WAS gene mutation. Patients with WAS/XLT sometimes also have autoimmune diseases such as IgA nephropathy. Progression of IgA nephropathy may lead to chronic renal failure with a poor prognosis. Here, we describe an XLT patient who also had IgA nephropathy. The patient underwent bone marrow transplantation (BMT) because of an associated-lymphoproliferative disorder, and clinical and histological improvement in his IgA nephropathy was observed after BMT. The amount of galactose-deficient IgA in the patient's serum markedly decreased after BMT. Therefore, immunological reconstitution might improve autoimmune diseases in patients with WAS/XLT.

Role of Iron in Children With Immunoglobulin A Nephropathy and Macrohematuria-Induced Acute Kidney Injury.

Introduction: The role of iron in, and the prognosis of, pediatric Immunoglobulin A nephropathy (IgAN) with macrohematuria (MH)-induced acute kidney injury (AKI) (MH-AKI) have not been evaluated. Thirty percent of adults with MH-AKI, and especially those who are older, show progression to chronic kidney disease. Methods: We evaluated the immunohistopathologic characteristics of renal biopsy samples from pediatric patients with MH-AKI IgAN and controls, using Berlin Blue to identify iron, CD163 (a hemoglobin-scavenging receptor), and CD68 (a total macrophage marker), then compared the findings against the clinical characteristics of the patients. Results: We enrolled 44 children as follows: 19 with IgAN but no MH or AKI; 5 with IgAN and MH but no AKI (MH(+)AKI(-) IgAN); 11 with MH-AKI IgAN; and 9 with no IgAN, MH, or AKI, according to a renal biopsy. Berlin Blue staining was detected predominantly at the injured tubulointerstitium, and the areas of staining in children with MH(+)AKI(-) and MH-AKI IgAN were significantly more extensive. The areas of Berlin Blue and CD163 staining did not perfectly match; however, areas of Berlin Blue were surrounded by immunopositivity for CD163. No children with MH-AKI IgAN showed decreased renal function at their last visit. Conclusion: Children with IgAN and MH, with or without AKI, showed considerable iron deposition in their renal tubules. CD163-positive cells might scavenge hemoglobin in patients with MH-AKI IgAN, but not their roles as macrophages. The renal prognosis of pediatric MH-AKI IgAN is good.

Mizoribine treatment of young patients with severe lupus nephritis: a clinicopathologic study by the tohoku pediatric study group.

BACKGROUND: A novel purine synthesis inhibitor, mizoribine (MZR), with a similar activity to that of mycophenolate mofetil, was developed in Japan. We suspected that long-term oral MZR intermittent pulse therapy (MZR-P) might be more effective than the conventional daily MZR regimen due to the higher peak serum MZR levels that are achieved. Here, we examined the clinicopathologic efficacy of MZR-P treatment in 10 young patients with diffuse proliferative lupus nephritis (DPLN), including 3 patients who received MZR-P as their primary cytotoxic therapy. METHODS: After their most recent renal flare-ups, all the patients were treated using MZR-P combined with oral prednisolone (PDN). MZR was administered as a single daily dose of 6-10 mg/kg per day (maximum dose of 500 mg) on 2 days of the week (Monday and Thursday) for at least 12 months or longer. The concomitantly administered PDN dose was gradually reduced. RESULTS: The baseline characteristics of the patients were as follows: mean age 15 years; urinary protein/creatinine (Up/cr) ratio 1.57 +/- 1.05 mg/mg; serum C3 level 50.3 +/- 19.7 mg/dl; serum complement hemolytic activity (CH50) 18.1 +/- 9.9 U/ml; serum anti-dsDNA antibody titer 177.5 +/- 152.7 IU/ml; serum creatinine 0.6 +/- 0.1 mg/dl, and European Consensus Lupus Activity Measurement (ECLAM) index 4.9 +/- 2.6. Despite the gradual tapering of the PDN dose, marked improvements compared with the baseline values were observed at the last observation, mean interval of 29 months after the start of treatment: Up/cr ratio 0.19 +/- 0.14; ECLAM index 1.3 +/- 0.7 (p < 0.01); serum C3 level 76.5 +/- 22.1 mg/dl; serum CH50 value 31.9 +/- 8.7 U/ml, and anti-dsDNA antibody titer 34.2 +/- 20.5 IU/ml (p < 0.05). The serum creatinine level remained within the normal range in all study participants. Post-treatment renal biopsies were performed in 5 of the patients; histology showed a marked attenuation of lesion progression. No serious adverse effects were observed. CONCLUSION: We believe that long-term MZR-P may prove to be a treatment of choice for young patients with DPLN. However, confirmation is needed as this preliminary study is limited by the small number of subjects, lack of controls, and its retrospective nature.

Bruton's tyrosine kinase regulates B cell antigen receptor-mediated JNK1 response through Rac1 and phospholipase C-gamma2 activation.

Bruton's tyrosine kinase (Btk) is essential for B cell development and B cell antigen receptor (BCR) function. Recent studies have shown that Btk plays an important role in BCR-mediated c-Jun NH(2)-terminal kinase (JNK) 1 activation; however, the mechanism by which Btk participates in the JNK1 response remains elusive. Here we show that the BCR-mediated Rac1 activation is significantly inhibited by loss of Btk, while this Rac1 activation is not affected by loss of phospholipase C-gamma2 (PLC-gamma2). Since PLC-gamma2 is also required for BCR-mediated JNK1 response, our results suggest that Btk regulates Rac1 pathway as well as PLC-gamma2 pathway, both of which contribute to the BCR-mediated JNK1 response.

Effect of salt intake on bioavailability of mizoribine in healthy Japanese males.

Bioavailability of mizoribine in subjects with the concentrative nucleoside transporter 1 (CNT1, SLC28A1) 565-A/A allele is significantly lower than that in subjects with the SLC28A1 565-G/G allele. The aims of the present study were to investigate the cellular uptake of mizoribine in CNT1- and CNT2-expressing Madin-Darby canine kidney type II (MDCKII) cells, and to evaluate the effect of salt intake on bioavailability of mizoribine in healthy Japanese volunteers with SLC28A1 565-A/A and -G/A alleles. Eight healthy males participated in the present study, and took 150 mg mizoribine concomitantly with/without 300 mg salt. Bioavailability of mizoribine was estimated by total cumulative urinary excretion of the drug. Mizoribine was taken up Na(+)-dependently into not only CNT1-expressing but also CNT2-expressing MDCKII cells, indicating that mizoribine is a substrate for both CNT1 and CNT2. Mean bioavailability of mizoribine taken with salt (83.8%) was significantly higher than that taken without salt (73.0%). These findings suggest that the salt intake is expected to improve the bioavailability of mizoribine in patients with insufficient intestinal absorption.

Effect of genetic polymorphisms of SLC28A1, ABCG2, and ABCC4 on bioavailability of mizoribine in healthy Japanese males.

The aim of the present study was to investigate the genetic factors responsible for the interindividual variability in the bioavailability of mizoribine. Thirty healthy Japanese men aged 20-49 years and weighing 53-75 kg participated in the present study and took 150 mg of mizoribine. Urine samples were collected periodically for 12 h after the dose, and the bioavailability of mizoribine was calculated from the estimated total urinary excretion from time zero to infinity. The bioavailability of mizoribine in the 30 subjects ranged from 60.3% to 99.4%. The mean bioavailability of mizoribine in subjects with the concentrative nucleoside transporter 1 (SLC28A1) 565-A/A allele (75.4%) was significantly lower than that in subjects with the SLC28A1 565-G/G allele (90.1%). On the other hand, the bioavailability of mizoribine was not affected by polymorphisms of breast cancer resistance protein (ABCG2) C421A and multidrug resistance-associated protein 4 (ABCC4) G2269A. The findings in the present prospective study suggested that the genetic test for the SLC28A1 G565A polymorphism is promising for predicting the Japanese subjects with lower bioavailability of mizoribine.

Ocular findings in Japanese children with nephrotic syndrome receiving prolonged corticosteroid therapy.

OBJECTIVE: To examine ocular findings in Japanese children with nephrotic syndrome who receive prolonged corticosteroid treatment. METHODS: Information was retrospectively obtained from each patient's record. RESULTS: A total of 45 children (30 boys and 15 girls) were enrolled. Twenty-one patients (46.7%) had epiblepharon with inverted eyelashes. The incidence of epiblepharon was associated with overweight and obesity. Fifteen patients (33.3%) developed posterior subcapsular cataract in both eyes. Of the 15 patients, 4 had visual acuity less than 0.4 and underwent cataract extraction in both eyes. Nine patients (20%) developed intraocular pressure higher than 22 mm Hg during corticosteroid treatment. The total dose and duration of corticosteroid treatment were associated with cataract formation but were unassociated with elevated intraocular pressure. One boy had elevated intraocular pressure after cessation of corticosteroid therapy and underwent trabeculectomy. One patient had repeated hordeolum in the left eyelid. Three patients had bilateral bacterial conjunctivitis. CONCLUSION: Children with nephrotic syndrome who receive corticosteroid treatment may have epiblepharon, cataract, ocular hypertension, hordeolum and bacterial conjunctivitis.

Membranoproliferative glomerulonephritis in a patient with X-linked agammaglobulinemia.

Immune complex and complement systems play an important role in membranoproliferative glomerulonephritis (MPGN). X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by severe hypogammaglobulinemia. We report the case of an XLA patient who developed MPGN during an intravenous immunoglobulin (IVIG) treatment. In this patient, the serum IgG level was maintained at more than 400 mg/dl of regular IVIG administration (2.5 g/dose/month). The patient presented with microscopic hematuria, proteinuria (U-pro/Cr: 4.0-4.2) and low serum complement levels (C3: 57.8 mg/dl) 3 years after IVIG treatment and was diagnosed histopathologically as having MPGN type III. Both hematuria and proteinuria significantly improved, and the serum complement level returned to a normal level following methylprednisolone pulse therapy. To our knowledge, this is the first case report of MPGN associated with XLA. Although it is unclear how MPGN occurred in this XLA patient, we suggest that residual humoral immunity in the patient could be associated with the development of MPGN.

Autoimmune lymphoproliferative syndrome presenting with glomerulonephritis.

Autoimmune lymphoproliferative syndrome (ALPS) is characterized clinically by chronic non-malignant lymphoproliferation and autoimmunity and is caused by a genetic defect in programmed cell death (apoptosis). Most patients with ALPS have heterozygous mutations in the Fas gene. We describe an 11-year-old Brazilian boy with hepatosplenomegaly, lymphadenopathy, hemolytic anemia, and hypergammaglobulinemia since early infancy. T cell lines from the patient were defective in Fas-mediated apoptosis. He was diagnosed as having ALPS and found to have a novel Fas gene mutation (IVS4+1G>A). In addition, he presented with glomerulonephritis in infancy. An aunt and uncle who had the same Fas mutations also had histories of glomerulonephritis. Although glomerulonephritis is common in Fas-deficient mice, it is infrequent in human ALPS. Corticosteroid therapy ameliorated the glomerulonephritis in our patient, as well as his lymphoproliferation, anemia, and hypergammaglobulinemia. This study suggests that glomerulonephritis is one of the characteristic features of ALPS.

Activation-dependent T cell expression of the X-linked lymphoproliferative disease gene product SLAM-associated protein and its assessment for patient detection.

X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterized by extreme vulnerability to Epstein-Barr virus (EBV) infection, resulting in fatal infectious mononucleosis, dysgammaglobulinemia and malignant lymphoma. Recently, mutations in the SH2D1A gene, which encodes SLAM-associated protein (SAP), have been found to cause XLP. Although the molecular events behind XLP are largely unknown, there is evidence that affected males exhibited some immunohematological abnormalities, such as hypogammaglobulinemia or lymphoma, even prior to EBV infection. Because of the poor prognosis in XLP, an early diagnosis to patients and families is clinically of great importance. A glutathione-S-transferase-SAP fusion protein was used to immunize rats and generate mAb against human SAP to investigate its pathogenic role in XLP and develop a flow cytometric assay for detection of XLP. By flow cytometric and Western immunoblot analyses using an established anti-SAP mAb, termed KST-3, we determined that SAP was expressed intensely in thymocytes, but at lower levels in peripheral T cells and NK cells. In contrast, expression of SAP was negligible in B cells, monocytes or granulocytes. We found that SAP expression in T cells increased upon in vivo as well as in vitro activation. In two XLP survivors with SH2D1A mutations, a flow cytometric evaluation of activated T cells using KST-3 could demonstrate SAP deficiency as a diagnostic indicator of XLP. Through this approach, we identified three novel XLP families with SH2D1A mutations in Japan. A flow cytometric assessment of SAP expressed in activated T cells would lead to easy detection of XLP patients.