Yasuo Nomoto

Sclerosing Encapsulating Peritonitis in Patients Undergoing Continuous Ambulatory Peritoneal Dialysis: A Report of the Japanese Sclerosing Encapsulating Peritonitis Study Group

Patients undergoing continuous ambulatory peritoneal dialysis (CAPD) who developed sclerosing encapsulating peritonitis (SEP) were retrospectively studied in 130 centers in Japan. Among 6,923 patients undergoing CAPD between 1980 and 1994 only 62 (0.9%) given CAPD developed SEP. There were 38 men and 24 women, ranging in age from 20 to 87 years (average age, 48.3 years). These 62 patients developed SEP 10 to 138 months (average, 65.4 months) after starting CAPD. The average frequency of peritonitis before developing SEP was 3.3 times. Five of the 62 patients with SEP had no history of peritonitis, and 27 (43.5%) of them died of various causes in the study period. The major causes of death were almost invariably related to problems concerning bowel obstruction or complications of surgery, such as malnutrition or septicemia. It was concluded that SEP is one of the most serious complications of CAPD, and constant surveillance is necessary to detect SEP in patients during CAPD.

Acute Hydrothorax in Continuous Ambulatory Peritoneal Dialysis – A Collaborative Study of 161 Centers

Follow-up studies on 3,195 patients from 161 centers in Japan undergoing continuous ambulatory peritoneal dialysis (CAPD) were performed for 1-104 months to clarify the incidence as well as the clinical features of acute hydrothorax. In these studies, 50 patients (1.6%) developed this complication. Twenty-seven (54%) were men, and 23 (46%) were women, ranging in age from 6 to 79 (average 49) years. The interval between onset of CAPD and hydrothorax ranged from 1 day to 8 years. Four had left-sided, and 2 had bilateral hydrothorax, but the majority (88%) were right-sided. Dyspnea was experienced by 37 of these 50 patients, but the remaining 13 (26%) patients were asymptomatic. Hydrothorax was fully resolved in 27 of them following a brief interruption of CAPD or the combined use of small exchange volumes in a semi-sitting position and pleurodesis with tetracycline or other agents. The remaining 23 patients (46%) were switched to hemodialysis permanently. Despite recurrence, 1 patient continued successfully on CAPD. It was concluded that acute hydrothorax is one important possible complication, although the risk may be low. Constant surveillance is necessary to detect pleural effusions in patients during CAPD.

In situ hybridization of interleukin 6 in diabetic nephropathy

Increased mesangial expansion is one of the most characteristic histological changes in diabetic nephropathy (DN). Although the pathogenesis of DN remains unclear, recent studies associate interleukin (IL) 6 with mesangial proliferative glomerulonephritis. To elucidate the expression and localization of IL-6 mRNA in renal tissues of patients with DN, a high-resolution in situ hybridization using digoxigenin-labeled oligonucleotide was performed. Patients were divided into three groups based on light microscopy findings: mild (group 1), moderate (group 2), and severe (group 3) mesangial expansion. The relationship between the expression of IL-6 mRNA and the degree of glomerular mesangial expansion in DN was examined. Individual cells positive for IL-6 mRNA were observed in glomeruli. These cells were mesangial cells, glomerular epithelial cells, and Bowmans capsule. The signal intensity was strongest in tissues from group 2 but was weak in those from groups 1 and 3. Most cells in the area of mesangial proliferation were strongly stained for IL-6 mRNA, and few positive cells were found in the Kimmelstiel-Wilson nodular lesion. In the interstitium, some tubules, particularly atrophic tubules, and some infiltrating cells were positively stained for IL-6 mRNA. The interstitial expression of IL-6 mRNA correlated significantly with the degree of interstitial injury and was remarkable in tissues from groups 2 and 3. We conclude that IL-6 mRNA is expressed by glomerular resident cells and interstitial cells in the renal tissue of patients with DN and that its expression may be associated with mesangial proliferation and may be involved in the tissue injury of DN.

Phenotypic Characterization of Cytokine Expression in Patients With IgA Nephropathy

To identify the cytokines that play a relevant role in the pathogenesis of IgA nephropathy, we analyzed and compared the gene expression of proinflammatory cytokines, immuno-regulatory cytokines, and growth factors in peripheral blood mononuclear cells (PBMC). Expression of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IFN-γ, TGF-β, TNF-α, and PDGF was examined in 28 patients with IgA nephropathy (IgAN), 20 patients with non-IgA mesangial proliferative glomerulo-nephritis (mesPGN), and 19 healthy controls. Compared with healthy controls, a significant number of IgAN and mesPGN patients showed increased expression of IL-1β, IL-4, IL-10, IL-12, and IFN-γ. The cytokine profile of renal tissue of 10 IgAN and 5 mesPGN biopsies was simultaneously analyzed and compared with that of PBMC. The proinflammatory IL-1α and growth factor PDGF-B were expressed more in renal tissues than in PBMC. Furthermore, the renal profile of IL-α, IFN-γ, and TNF-α expression was associated with the expression of IFN-γ PBMC. The serum level of IFN-γ of IgAN correlated significantly (P = 0.0003) with that of IL-12, suggesting a potential role for cross-stimulation. More importantly, expression of IFN-γ in PBMC and the elevated serum level correlated with the decline in glomerular filtration rate (P = 0.0012) and severity of renal histopathologic grade. To elucidate the role of leukocytes in renal cytokine expression, surface markers of T cells (CD3), monocytes (CD14), natural killer cells (CD16), and B cells (CD19) were also examined in renal tissues. The prominent renal expression of CD3, CD14, and CD16 implicates the leukocytes as the major source of proinflammatory cytokines in IgAN. Collectively, these findings indicate that IFN-γ plays a prominent role in an interactive network of cytokines that contribute to the pathogenesis and progression of IgA nephropathy.

Detection of immune complexes in polymorphonuclear leukocytes by double immunofluorescence in patients with IgA nephropathy.

Abstract The amounts of cytoplasmic inclusion bodies in peripheral blood polymorphonuclear cells (PMN) were determined in patients with IgA nephropathy and other glomerular diseases to elucidate whether or not IgA-dominant immune complexes were phagocytized by PMN in these patients. Fifteen patients with IgA nephropathy, 8 patients with other glomerular diseases, and 10 healthy adults were examined. The amounts of cytoplasmic inclusion bodies were measured by a double immunofluorescence technique. It was demonstrated that the percentages of IgA with C3 and IgA without C3 cytoplasmic inclusion bodies were significantly increased in patients with IgA nephropathy compared with those obtained in other glomerular diseases and healthy adults. There was a significant correlation between the levels of serum IgA and the percentage of IgA with C3 cytoplasmic inclusion bodies in PMN from patients with IgA nephropathy. It was suggested that IgA-dominant immune complexes are phagocytized by peripheral blood PMN in patients with IgA nephropathy.

Differential distribution of type IV collagen chains in patients with diabetic nephropathy in non-insulin-dependent diabetes mellitus

Thickening of the glomerular basement membrane (GBM) and expansion of the mesangial matrix are hallmarks of human diabetic nephropathy. Renal tissues from 15 patients with type II (non-insulin-dependent) diabetes (NIDDM) were studied by immunofluorescence (IF) and immunogold electron microscopy (IEM) for the distribution of 2 type IV collagen peptides [alpha 3(IV) noncollagenous (NC) domain and alpha 4(IV) NC domain] and 2 classical type IV collagen chains [alpha 1(IV) NC domain and alpha 2(IV) domain]. There was intense staining for alpha 3(IV) NC and alpha 4(IV) NC domain in the GBM but not in the mesangial matrix of patients with overt diabetic nephropathy. In contrast, staining with antibodies to alpha 1(IV) NC and alpha 2(IV) NC domain reacted with mesangial matrix but was significantly decreased in the GBM in the patients with overt diabetic nephropathy. IEM confirmed the IF findings. These data suggest that expansion of the mesangial matrix and thickening of GBM in NIDDM involves separate and distinct type IV collagen components and that the site-specific matrix alterations in NIDDM and type I (insulin-dependent) diabetes are parallel.

Glomerular FcαR expression and disease activity in IgA nephropathy

In this study, we examined the receptors for the Fc portion of immunoglobulin A (IgA) (Fc alphaR) in the glomeruli as well as circulating polymorphonuclear leukocytes and monocytes at the mRNA level by reverse transcription-polymerase chain reaction (RT-PCR) assay and at the protein level by an immunohistochemistry/flow cytometry technique using a specific anti-Fc alphaR monoclonal antibody (My 43). Glomeruli were isolated from biopsy specimens of renal tissues from IgA nephropathy (IgAN; 20 cases) and non-IgA mesangial proliferative glomerulonephritis (PGN; 13 cases) patients, and from normal renal tissue specimens obtained from kidneys removed because of malignancies (five cases) applying the microdissection method. There was a relative increase in Fc alphaR in the circulating phagocytes from IgAN patients compared with those from PGN and healthy controls. Fc alphaR expression was present in approximately 40% of glomeruli samples from IgAN patients at the message levels. Fc alphaR-positive specimens were also strongly positive for expression of tumor necrosis factor-alpha, interleukin-1, and interleukin-6 mRNA. Specimens from PGN patients and healthy controls did not show any detectable Fc alphaR message. Serum IgA levels and severity of hematuria were significantly higher in patients with positive Fc alphaR expression. A message for Fc alphaR was detected in the tissues that were more damaged histologically. Our data suggest that there is some in vivo induction of glomerular Fc alphaR expression, possibly mediated by a synergistic stimulus from IgA and inflammatory cytokines, and the expressed receptor is likely to be involved in the disease process of IgAN.

Mesangial deposition of J chain-linked polymeric IgA in IgA nephropathy.

Renal biopsy specimens from 8 patients with IgA nephropathy (Bergers disease) were examined immunocytochemically at the light and electron microscopic levels with peroxidase-labeled antibodies to IgA, IgM, J chain and secretory component. In 2 of the 8 specimens heavy deposits of IgA, but no IgM, were found in the mesangium. After acid-urea treatment of these tissue sections, J chain, a subunit of polymeric immunoglobulins, was identified in a distribution similar to that of IgA. In the remaining 6 specimens, small amounts of IgM in addition to denser deposits of IgA and J chains were found. We conclude that the IgA deposits in at least some patients with Bergers disease consist of IgA polymers linked by J chain.

A Case of IgA Nephropathy Associated with Adeno- and Herpes Simplex Viruses

We report here an adult case of IgA nephropathy associated with episodes of recurrent tonsillitis. Various kinds of viral antigens were examined in the renal and tonsillar tissues by immunofluorescence. Granular depositions of adeno- and herpes simplex viral antigens were detected in the glomerular mesangial areas and in the tonsillar epithelial cells by immunofluorescence. IgA and IgA1 deposits were also observed in the glomerular mesangial areas. It was suggested that IgA nephropathy might be caused by multiple antigenic substances, including adeno- and/or herpes simplex viruses, located in the tonsillar regions.

Altered production of IgE and IgA induced by IL-4 in peripheral blood mononuclear cells from patients with IgA nephropathy.

In order to elucidate the factors responsible for altered immunoglobulin production in patients with IgA nephropathy (IgAN). the in vitro effects oHL‐4 and intcrferon‐gamma (IFN‐γ) on the synthesis of IgE and IgA by peripheral blood mononuclear cells (PBMC) were studied. Spontaneous IgE and IgA synthesis by PBMC was significantly increased in patients with IgA nephropathy compared with controls. The maximum amounts of IgA and IgE synthesis by PBMC after stimulation with IL‐4 were almost the same both in patients with IgAN and in controls. The enhancement rate of IL‐4‐induccd IgE and IgA synthesis was significantly lower in IgAN than in the controls, suggesting in vivo preactivation of PBMC in IgAN patients. IFN‐γ suppressed IgA and IgE synthesis by PBMC from IgAN patients as well as controls. However, the suppressive effect on IgE synthesis was less prominent in patients with IgAN. These results suggested that altered IL‐4 action might be involved in the development of IgA ncphropathy.