Clinicopathological features and prognosis in immunoglobulin light and heavy chain deposition disease.

BACKGROUND: There are three subtypes of monoclonal immunoglobulin deposition disease: light chain deposition disease (LCDD), light and heavy chain deposition disease (LHCDD), and heavy chain deposition disease (HCDD). Although it has been considered that LHCDD is a variant of LCDD, information on clinicopathological features and prognosis in LHCDD is presently limited. METHODS: We reviewed 5,443 renal biopsies, and evaluated clinicopathological features and outcomes in patients with LHCDD, in comparison with those in patients with LCDD and previously reported patients with HCDD. We also characterized paraprotein deposits in patients with LHCDD. RESULTS: We identified 6 patients with LHCDD, 6 patients with LCDD, and 1 patient with HCDD. The most common clinicopathological findings in patients with LHCDD were proteinuria, renal insufficiency, and nodular sclerosing glomerulopathy. Three patients had IgG-k deposits and 3 patients had IgG-l deposits. Heavy chain subclass analysis performed in 4 patients showed IgG3 deposits in all patients. Dual immunostaining revealed glomerular colocalization of light and heavy chains. In contrast with LCDD, glomerular C3 and C1q deposits were common findings in LHCDD and HCDD. All patients with LHCDD were treated with steroids and cytotoxic agents, but no effect on proteinuria was observed. Three patients developed end-stage renal disease requiring hemodialysis. The underlying hematological disorders in LHCDD and HCDD were milder than in LCDD. Early renal survival and overall patient survival in our patients appeared to be better in LHCDD than in LCDD. CONCLUSIONS: There are apparent differences in clinicopathological features and prognosis between LHCDD and LCDD. LHCDD is probably more similar to HCDD.

GATA-3 is upregulated in peripheral blood mononuclear cells from patients with minimal change nephrotic syndrome.

BACKGROUND: An imbalance of Th1 and Th2 cytokines has been reported in MCNS. Interleukin-13 (IL-13: Th2 cytokine) has been implicated in the pathogenesis of MCNS, but Th1/Th2 regulators such as T-bet (Th1-specific transcription factor) and GATA-3 (Th2-specific transcription factor) have not been examined. METHODS: We isolated PBMC from 25 patients with MCNS during nephrosis and remission phases, from 17 nephrotic patients with membranous nephropathy (MN), and from 25 healthy subjects. We measured mRNA expression levels of T-bet, GATA-3, Stat5A (regulator of Th2 priming), IFN-gamma (Th1 cytokine), IL-2 (Th1 cytokine and activator of Stat5), IL-4 (Th2 cytokine), and IL-13 in PBMC, using real-time RT-PCR. RESULTS: GATA-3, Stat5A, and IL-13 mRNA expression levels were higher in the nephrotic MCNS group compared to the others. IL-2 mRNA expression levels were higher in nephrotic patients with MCNS and MN than in MCNS patients in remission and healthy controls. There were no differences in mRNA expression levels of T-bet, IFN-gamma, and IL-4 between MCNS and MN patients and healthy controls. CONCLUSIONS: This study is the first to reveal increased mRNA expression levels of GATA-3 and Stat5A in PBMC from MCNS patients in nephrosis. This study also supports recent findings suggesting the role of IL-13 in the development of MCNS. A predominant Th2 type of T cell activation may be involved in the pathogenesis of MCNS.

Characteristics of proliferative glomerulo-nephritis with monoclonal IgG deposits associated with membranoproliferative features.

BACKGROUND: Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) associated with membranoproliferative features is an extremely rare entity. Information on clinicopathological features and prognosis in this entity is limited. METHODS: We reviewed 5,443 renal biopsies processed at our department, and identified 4 patients with PGNMID associated with membranoproliferative features. We evaluated clinicopathological features and outcomes in these patients, and characterized paraprotein deposits by immunofluorescence studies. RESULTS: Three out of 4 patients had nephrotic syndrome with renal insufficiency at presentation. Cryoglobulin or monoclonal protein in serum and urine was not detected. Renal biopsy showed membranoproliferative features with or without nodular formation. Tubulointerstitial and vascular alterations were mild in three patients. All patients had glomerular IgG-kappa deposits. Heavy chain subclass analysis performed in 3 patients showed IgG3 deposits. Immunofluorescence studies using antibodies specific for gamma-heavy chain C(H)1, C(H)2, and C(H)3 domains and gamma3 hinge did not show any apparent deletion. Confocal microscopy revealed glomerular colocalization of light and heavy chains. On electron microscopy, granular deposits were predominantly mesangial and subendothelial. All patients were treated with steroids and cytotoxic agents, but no effect on proteinuria was observed. The renal outcome was progressive in all patients. Early death was observed in two elder patients. No patient had overt myeloma or lymphoma at presentation or over the course of follow-up (mean 43 months). CONCLUSIONS: Our study suggests a predominance of IgG3-kappa glomerular deposits of nondeleted whole immunoglobulin molecules in PGNMID associated with membranoproliferative features. The clinical outcome in patients with this entity appears to be poor.

Up-regulated expression of Toll-like receptors mRNAs in peripheral blood mononuclear cells from patients with systemic lupus erythematosus.

Recent studies in animal models for systemic lupus erythematosus (SLE) have shown that Toll-like receptors (TLR-7 and TLR-9) and interferon (IFN)-alpha are involved in the pathogenesis of murine lupus. Recent studies using flow cytometry have also shown increased expression of TLR-9 in peripheral blood mononuclear cells (PBMCs) from SLE patients. In this study, we performed quantitative real-time reverse transcription-polymerase chain reaction analyses of PBMCs from 21 SLE patients and 21 healthy subjects, to estimate TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, IFN-alpha and LY6E (a type I IFN-inducible gene) mRNA expression levels. Expression levels of TLR2, TLR7, TLR9, IFN-alpha and LY6E mRNAs in SLE patients were significantly higher than those in healthy controls. Expression levels of TLR7 and TLR9 mRNAs correlated with that of IFN-alpha mRNA in SLE patients. These results suggest that up-regulated expression of TLR7 and TLR9 mRNAs together with increased expression of IFN-alpha mRNA in PBMCs may also contribute to the pathogenesis of human lupus.

Predominant tubulointerstitial nephritis in a patient with systemic lupus erythematosus: phenotype of infiltrating cells.

A 63-year-old man with systemic lupus erythematosus developed tubular proteinuria. All subclasses of serum IgG increased, and the largest IgG subclass increase was IgG4. A renal biopsy showed lupus nephritis (Class II) with severe tubulointerstitial nephritis (so-called predominant tubulointerstitial lupus nephritis, an unusual form of lupus nephritis). Immunofluorescence microscopy revealed positive granular staining for IgG, C3 and C1q in the mesangium and peritubular interstitium, and along the tubular basement membranes (TBM). Electron microscopy also showed electron-dense deposits in the mesangium and TBM. Immunophenotyping of interstitial infiltrating cells disclosed a predominance of T cells. CD8-positive cytotoxic T cells infiltrated the peritubular interstitium, and some of these cells infiltrated the tubules. B cell-rich lymphoid follicles were also observed. IgG subclass analyses showed glomerular IgG1, IgG2 and IgG4 deposition, positive staining of IgG4 in the peritubular interstitium and along the TBM, and abundant IgG1-, IgG3- and IgG4-positive plasma cells in the interstitium. The patient responded well to moderate-dose steroid therapy. This is the first report of immunophenotyping of interstitial infiltrates in predominant tubulointerstitial lupus nephritis. The results suggest CD8-positive cytotoxic T cell-mediated tubular injury. Furthermore, immune complexes containing IgG4 might be one of etiologic factors.

Successful treatment of post-MRSA infection glomerulonephritis with steroid therapy.

A 48-year-old man without underlying disease developed mediastinitis and was treated by mediastinal drainage. Methicillin-resistant Staphylococcus aureus (MRSA) was detected in a culture of the abscess material. He was treated with anti-MRSA antibiotics and the MRSA infection improved. Four weeks after the onset of MRSA infection, he developed rapidly progressive glomerulonephritis (RPGN) with nephrotic syndrome (NS). A renal biopsy showed endocapillary proliferative glomerulonephritis with IgA-predominant glomerular deposition. These clinicopathological findings were consistent with those in glomerulonephritis following MRSA infection (post-MRSA infection glomerulonephritis). The level of serum creatinine increased to 6.3 mg/dl, 7 weeks after the onset of RPGN. At that time, the eradication of MRSA infection was considered. He was given middle-dose steroid therapy. Thereafter, his RPGN with NS improved. MRSA infection did not recur. If the disease activity of post-MRSA infection glomerulonephritis persists after the disappearance of MRSA infection, the application of immunosuppressive therapy with steroids may be useful.

Renal amyloidosis associated with extracapillary glomerulonephritis and vasculitis in a patient with inflammatory bowel disease treated with infliximab.

A 70-year-old woman with an 11-year history of indeterminate inflammatory bowel disease developed rapidly progressive glomerulonephritis (RPGN) 3 months after the initiation of infliximab therapy. A renal biopsy showed Congo red-positive homogenous deposits in the mesangial area, glomerular capillary walls and arterial walls. Cellular and fibrocellular crescents were observed in 7 of 28 functioning glomeruli. There were findings of active tubulointerstitial nephritis and vasculitis of the small arteries. On electron microscopy, amyloid fibrils were observed in the deposits. Immunohistochemistry showed positive staining for amyloid A (AA) protein. After cessation of infliximab therapy, she was treated with methylprednisolone pulse therapy followed by oral prednisolone therapy. Thereafter, her RPGN was improved. This is a rare case of co-existent focal extracapillary glomerulonephritis with vasculitis and AA renal amyloidosis. Considering the temporal association of drug use with new onset of RPGN in our patient, we suggest a causal link between infliximab and RPGN due to extracapillary glomerulonephritis and vasculitis.

Focal segmental glomerulosclerosis associated with polycythemia vera: report of a case and review of the literature.

A 69-year-old female with a 3-year history of polycythemia vera (PV) developed nephrotic syndrome. A renal biopsy showed focal and segmental glomerulosclerosis (FSGS). The patient was treated with prednisolone and myelosuppressive agents. Thereafter, parallel improvement of the two conditions was observed. After 4-year treatment, proteinuria disappeared. To our knowledge, there are five reported cases of FSGS associated with PV. Among them, three patients suffered from progressive azotemia. We suggest that steroid therapy with myelosuppressive agents can resolve the renal lesion in patients with PV.

Analysis of the NPHP genes in two Japanese patients with suspected sporadic juvenile or adolescent nephronophthisis.

BACKGROUND: Mutations in 3 genes (NPHP1, NPHP3 and NPHP4) have been identified in patients with juvenile or adolescent nephronophthisis (NPHP) without extrarenal involvement, mainly in patients from western countries. In this study, we analyzed mutations in the NPHP genes of 2 Japanese patients with suspected sporadic juvenile or adolescent NPHP without extrarenal involvement. METHODS: A renal biopsy was performed in the 2 patients. Genomic DNA was prepared from peripheral blood mononuclear cells of the patients and their family members. The above NPHP genes were examined by deletion analysis or direct automated sequencing of polymerase chain reaction-amplified DNA products. RESULTS: Histological findings in the patients were compatible with those of NPHP. In 1 patient, we identified a novel deletion mutation including about half of exons of the NPHP1 gene. In another patient, there was no mutation in the NPHP genes examined. CONCLUSIONS: We found a novel NPHP1 deletion in 1 patient. To our knowledge, this is the second Japanese NPHP case in which genetic diagnosis was made.

Increased serum levels of S100A12 in patients with MPO-ANCA-associated glomerulonephritis.

BACKGROUND: Increased serum levels of S100A12, a proinflammatory protein secreted by activated neutrophils, have recently been shown in patients with active inflammatory diseases, such as rheumatoid arthritis and Kawasaki disease. In this study, we investigated serum levels of S100A 12 in patients with small-vessel vasculitis, myeloperoxidase anti-neutrophil cytoplasmic antibodies- (MPO-ANCA) associated pauci-immune glomerulonephritis. METHODS: Serum S100A12 concentrations were measured by a sandwich enzyme-linked immunosorbent assay (ELISA) in 46 patients with MPO-ANCA-associated glomerulonephritis and 29 healthy controls. We analyzed correlations between serum S100A12 levels and a clinical index of vasculitis activity, the Birmingham Vasculitis Activity Score (BVAS), various laboratory parameters, and pathological activity scores in the patients. We also analyzed changes of serum S100A12 levels in 10 patients after treatment. RESULTS: ELISA showed about 4-fold higher levels of serum S100A12 in patients with MPO-ANCA-associated glomerulonephritis than healthy controls. Serum S100A12 levels correlated with the BVAS scores, the peripheral white blood cell count, levels of serum C-reactive protein and creatinine, and pathological activity scores in the patients, but did not correlate with serum MPO-ANCA titers. Serum S100A12 levels after treatment decreased in all the 10 patients examined. CONCLUSION: We demonstrated that increased serum S100A12 levels correlate with clinical, laboratory and pathological parameters of disease activity in patients with MPO-ANCA-associated glomerulonephritis. Serum S100A12 level may be one of the useful markers of disease activity in MPO-ANCA-associated glomerulonephritis.

Regulation of glucocorticoid receptor activity by 14--3-3-dependent intracellular relocalization of the corepressor RIP140.

Proteins belonging to the 14--3-3 family interact with various regulatory proteins involved in cellular signaling, cell cycle regulation, or apoptosis. 14--3-3 proteins have been suggested to act by regulating the cytoplasmic/nuclear localization of their target proteins or by acting as molecular scaffolds or chaperones. We have previously shown that overexpression of 14--3-3 enhances the transcriptional activity of the glucocorticoid receptor (GR), which is a member of the nuclear receptor family. In this study, we show that 14--3-3 interacts with the nuclear receptor corepressor RIP140. In transfection assays, RIP140 antagonizes 14--3-3- enhanced GR transactivation. Using colocalization studies we demonstrate that 14--3-3 can export RIP140 out of the nucleus and, interestingly, can also change its intranuclear localization. Moreover, we also observed that 14--3-3 can bind various other nuclear receptors and cofactors. In summary, our findings suggest that 14--3-3-mediated intracellular relocalization of the GR corepressor RIP140 might be a novel mechanism to enhance glucocorticoid responsiveness of target genes. They furthermore indicate a more general role for 14--3-3 protein by influencing the nuclear availability of nuclear receptor-associated cofactors.

Angiotensin II Type 1 Receptor Binding Molecule ATRAP as a Possible Modulator of Renal Sodium Handling and Blood Pressure in Pathophysiology.

Exaggerated activation of the renin-angiotensin system via tissue angiotensin II (Ang II) type 1 receptor (AT1R) signaling exerts detrimental effects on cardiovascular, renal and endocrine systems to provoke hypertension and related target organ damage. On the other hand, accumulated research evidence of both basic and clinical studies shows that physiological AT1R signaling also plays an indispensable role for the normal organ development such as the kidney and the maintenance of cardiovascular and renal homeostasis. Such functional diversity of AT1R signaling prompts us to seek a new strategy of selective modulation of AT1R signaling in pathophysiology. In the course of an investigational search for a means to functionally and selectively modulate AT1R signaling for that purpose, a molecule directly interacting with the carboxyl-terminal cytoplasmic domain of AT1R was identified by employing yeast two-hybrid screening of a mouse kidney cDNA library and named AT1R-associated protein (ATRAP). The results of functional analysis showed that ATRAP promotes constitutive AT1R internalization in cultured cells and inhibits Ang II-mediated pathological response in mouse distal convoluted cells. The ATRAP is expressed in a variety of tissues including the kidney where ATRAP is abundantly distributed in epithelial cells along the renal tubules. The results employing genetic engineered mice with modified ATRAP expression showed that ATRAP plays a key role in the regulation of renal sodium handling and the modulation of blood pressure in response to pathological stimuli such as chronic Ang II infusion, and suggest ATRAP to be a target of interest.

Hemoperitoneum due to acute cytomegalovirus infection in a patient receiving peritoneal dialysis.

A 27-year-old man receiving continuous ambulatory peritoneal dialysis (CAPD) developed high-grade fever, dyspnea, and hemoperitoneum 32 months after the start of CAPD. A chest computed tomograph showed fine reticular shadows in the bilateral lower lung fields. Cytomegalovirus (CMV) antigenemia were detected, and immunoglobulin (Ig) M and IgG antibodies for CMV were also positive. The absolute counts of helper T cells (478/microL) and the ratio of helper T cells/suppressor T cells (0.25) decreased, despite no evidence of hematologic or immunologic diseases, including human immunodeficiency virus (HIV) or human T cell lymphoma virus-1 (HTLV-1) infection, or the use of immunosuppressive drugs. All symptoms, including hemoperitoneum and the ratio of helper T cells/suppressor T cells, improved gradually and spontaneously. Acute and primary cytomegalovirus (CMV) infection induced hemoperitoneum in a patient who was receiving CAPD.

Endocapillary proliferative glomerulonephritis in a patient with parvovirus B19 infection.

A 45-year-old woman developed acute nephritic syndrome after erythema infectiosum. Laboratory data on admission showed decreased serum C3, C4, and CH50 levels and the presence of both immunoglobulin (Ig) M and IgG antibodies to human parvovirus B19 (HPV). A renal biopsy showed diffuse endocapillary proliferative glomerulonephritis. Immunofluorescence microscopy indicated 2+ granular staining for IgG, IgM, and C3 over the mesangial area and along glomerular capillary walls. HPV antigen was also detected in glomeruli by immunohistochemistry. Electron microscopy showed electron-dense deposits in the subendothelial space and the paramesangial area. These findings suggest that immune complex-type glomerulonephritis is caused by glomerular deposition of HPV antigen-antibody complexes in some patients with HPV infection.

Collagenofibrotic glomerulopathy: a systemic disease.

Collagenofibrotic glomerulopathy is a recently discovered entity that is characterized by massive accumulation of spiraled and frayed collagen fibrils in mesangial and subendothelial areas, and elevated serum levels of procollagen III peptide. We report the autopsy of a patient who received continuous ambulatory peritoneal dialysis (CAPD) therapy for 7 years. Autopsy disclosed that massive accumulation of peculiar collagen fibers was found not only in the kidney, but also in many organs including spleen, liver, myocardium, and thyroid gland. Although the possibility remains that CAPD for 7 years might change or aggravate the deposition of abnormal collagen, the current case suggests a possibility that collagenofibrotic glomerulopathy is a systemic disorder with abnormal metabolism of type III collagen.

Disappearance of nodular mesangial lesions in a patient with light chain nephropathy after long-term chemotherapy.

A 64-year-old man developed multiple myeloma (kappa light chain type), nephrotic syndrome, and renal insufficiency in 1993. A renal biopsy showed typical histological findings of light chain nephropathy: nodular glomerulosclerosis with deposition of kappa light chains in the mesangial area and subendothelial space of the glomerular capillary walls. Long-term intermittent MEVP chemotherapy (melphalan, 4 mg/d for 4 days; cyclophosphamide, 100 mg/d for 4 days; vincristine, 1 mg/d; prednisolone, 40 mg/d for 4 days) diminished proteinuria and improved renal function. In April 1999, a follow-up biopsy showed remarkable diminution of nodular lesions and disappearance of kappa light chain deposits. Although the prognosis of light chain nephropathy has been considered poor, long-term successful chemotherapy can clear light chain deposits and restore renal function.

Extramedullary megakaryoblastic tumors following an indolent phase of myelofibrosis.

A 59-year-old man developed multiple subcutaneous and bone tumors after 2 years' duration of indolent myelofibrosis. These tumors exhibited a diffuse proliferation of pleomorphic blast cells. The skeletal x-rays showed disseminated osteolysis and osteosclerosis. Blast cells obtained from the pleural effusion did not react with myeloperoxidase, sudan black B or non-specific esterase. Genotypic analysis of DNA samples at autopsy did not demonstrate rearrangements of T-cell receptor beta-chain or immunoglobulin heavy-chain genes. Frozen-section immunohistochemical studies revealed that the neoplastic cells were derived from megakaryocytic lineage. The present case represents a novel and unusual subtype of megakaryocytic neoplasm.

Glomerular deposition of complex-forming glycoprotein heterogenous in charge (protein HC) in IgA nephropathy.

IgA immune complexes and polymeric IgA are presumed to play important roles in the development and progression of IgA nephropathy. Complex-forming glycoprotein heterogenous in charge (protein HC), being inhibitors of neutrophilic chemotaxis, has been reported as binding to IgA. As a working hypothesis it was assumed that complexes of protein HC and IgA are present in glomeruli from IgA nephropathy patient in stable state. In this study, we examined the glomerular deposition of protein HC in 40 patients with IgA nephropathy and in 10 patients with non-IgA nephropathy. We used highly specific antibody against protein HC, that does not cross-react with alpha-1-microglobulin. An immunofluorescent study revealed that 10 out of the 40 patients (25%) showed an intensity of 1+, 16 (40%) showed weak positive (+/-), and the other 14 (35%) were negative. There was no deposition of protein HC in non-IgA nephropathy patients. Histopathological analysis demonstrated a significant correlation between the intensity of glomerular-deposited protein HC and pathological activity (p less than 0.005); the latter was defined as having either crescents in more than 15% of the remaining glomeruli (excluding global sclerotic glomeruli), or segmental necrosis or sclerosis in more than 30% of the remaining glomeruli. A significant correlation was observed between pathological activity and the intensity of deposited IgG, IgA and IgM (p = 0.01), and lambda chain (p less than 0.005). Considering anti-inflammatory activity of protein HC, these results suggest that protein HC cannot protect sufficiently acute inflammation or tissue damages due to co-deposited IgG and IgM and/or other factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Tubulointerstitial nephritis with renal tubular acidosis and asymptomatic primary biliary cirrhosis accompanied by antibody to a 52-kDa mitochondrial protein alone.

We report a patient presenting with a mixed type of renal tubular acidosis, who demonstrated anti-mitochondrial antibodies on immunofluorescent study. However, study of anti-M2 antibody (enzyme immunoassay) was negative. Renal biopsy revealed lymphocyte infiltration in the interstitium compatible with chronic tubulointerstitial nephritis. Liver biopsy demonstrated a mild degree of primary biliary cirrhosis (PBC) but biochemical liver function tests were normal, resulting in a diagnosis of asymptomatic PBC. Using affinity chromatography conjugated with the patient's IgG, we purified a 52-kDa protein from a porcine renal mitochondrial fraction. This protein was identified as a component of a mitochondrial multienzyme complex such as dihydrolipoamide acyltransferase of the branched-chain alpha-keto acid dehydrogenase complex (BCKD), based on the molecular mass analysis and partial amino acid sequence of the purified protein. This is the first report of the detection of antibody to 52-kDa mitochondrial protein alone in a patient who showed predominantly tubulointerstitial damage in the kidney rather than liver damage.