Effect of pituitary microsurgery on acromegaly complicated nephrotic syndrome with focal segmental glomerulosclerosis: report of a rare clinical case.

A case of nephrotic syndrome complicated by acromegaly is presented. The first renal biopsy specimen showed minor glomerular abnormalities with glomerular hypertrophy, corresponding with minimal change nephrotic syndrome. Corticosteroid therapy led to a partial remission, followed by frequent relapses after reduction of the drug. A diagnosis of atypical focal segmental glomerulosclerosis (FSGS) was made based on the second renal biopsy results 6 months after the first. We combined steroid therapy with the administration of an anticoagulant, cytotoxic agents, angiotensin-converting enzyme inhibitor, and low-density lipoprotein adsorption. Except for the angiotensin-converting enzyme inhibitor, these medications were not effective in terms of allowing a reduction in the high dosage of steroid, which in turn threatened progressive osteoporosis and lumbar vertebrae fracture. Administering the steroid at a moderate dosage, treatment was focused on the complicating acromegaly from pituitary microadenoma. Subcutaneous injections of octreotide acetate, a somatostatin analogue, reduced proteinuria and increased urine volume. Subsequent transsphenoidal microsurgery of the adenoma resulted in the normalization of the elevated creatinine clearance and the further reduction in steroid dosage while maintaining a remission state. This is the first reported clinical case with acromegaly followed by FSGS, and it is suggested that hypersecretion of growth hormone participates in the development and progression of glomerular disease.

[Primary culture of proximal tubular cells (PTC) from normal mouse kidney as an in vitro model to study mechanisms of development of tubulointerstitial nephritis. Induction of ICAM-1 in PTC by antigen-primed lymphocytes].

Cultured PTC clearly expressed intercellular adhesion molecule-1 (ICAM-1) under the influence of tubular basement membrane antigen (TBM)-primed lymphocytes. These TBM-primed lymphocytes also demonstrated a high cytotoxic activity against cultured PTC. A pure preparation of isolated PTC from BALB/c mouse kidney was brought into primary culture. PTC was prepared by the method of Boogaard PJ et al, and our modification. Briefly, kidney was perfused with buffer containing 0.08% (w/v) collagenase. The cortical tissue was then filtered through nylon-gauze. Viable PTC were separated from other materials by isopycnic centrifugation on a discontinuous Nycodenz gradient. The confluent monolayer of PTC showed a typical epithelial morphology with cobblestone-like cells in the center of the cell-islands. Typical dome formation was observed in PTC cultures. These cells also strongly expressed gamma-glutamyl transpeptitase activity. Coculture of PTC with syngeneic lymphocytes primed with TBM antigen induced ICAM-1 expression in PTC. The TBM-primed lymphocytes had a cytotoxic activity without complement. However, neither virgin lymphocytes nor liver antigen-primed lymphocytes had cytotoxic activity. This simple syngeneic experimental model may allow us further molecular biological examination of renal tubulointerstitial diseases.

Protective effects of FUT-175 on acute massive hepatic necrosis induced in mice following endotoxin injection and immunization with liver proteins.

Experimental autoimmune hepatitis was induced in C57BL/6 mice by immunization with syngeneic liver protein and adjuvant. Hepatitis was characterized by marked cellular infiltrates, but hepatic necrosis was mild to moderate. A small dose of endotoxin (25 micrograms/mouse) produced lethal hepatitis with elevation of serum transaminase levels in these mice. The endotoxin-induced reactions were completely inhibited by i.p. administration of FUT-175 (5 mg/kg), a synthetic protease inhibitor, 1 h before the endotoxin injection. In vitro experiments showed that two-thirds of the inflammatory infiltrates were monocyte/macrophages. Cytotoxicity against syngeneic hepatocytes was significantly increased by the addition of endotoxin (25 micrograms/ml), but the same dose of endotoxin alone had no effect on the viability of hepatocytes. The endotoxin-induced increase in cytotoxicity was prominent in the glass-dish adherent (monocyte/macrophage enriched) fraction and was also demonstrated after depletion of T-cells. However, elevated cytotoxicity did not occur when FUT-175 (> 1 x 10(-7) M) was present throughout the assay period. These results seem to indicate that the hepatotoxic effects of endotoxin are mediated, at least in part, by monocytes or macrophages infiltrating the liver following immunization of liver proteins. Our results also suggest that FUT-175 has protective effects against endotoxin-induced hepatotoxic reactions.

[A case of Sweet's syndrome (acute febrile neutrophilic dermatosis) associated with mixed connective tissue disease].

Sweet's syndrome (acute febrile neutrophilic dermatosis) is an unusual condition characterized by fever, polymorphonuclear neutrophil leukocytosis of the blood, thick painful plaques on the face, neck and limbs, and a dense dermal infiltrate of mature neutrophils seen histologically. Recently, this disease has also been reported in association with various malignant neoplasms and chronic inflammatory disorders. In the literature, seven cases of Sweet's syndrome associated with collagen diseases have been reported, but no cases with mixed connective tissue disease (MCTD). The first case of Sweet's syndrome associated with MCTD was herein described and discussed. A 49-year-old man was admitted to our hospital with the complaints of high fever and painful erythema on his face, neck and limbs. Six months ago, MCTD was suspected, with the presence of limited cutaneous sclerosis of the hands, Raynaud's phenomenon, polyarthralgia, an elevation of CPK value and a positive anti-RNP antibody. Just before hospitalization, he suffered a prodromal infection of the upper respiratory tract for two weeks. He was diagnosed as Sweet's syndrome by the clinical and histological features. He began receiving corticosteroid therapy (prednisolone 60 mg/day), and within a week he showed dramatic improvement in the above symptoms.

[Possible role of cellular immunity against tubular basement membrane antigen (TBM) in gold nephropathy in rheumatoid arthritis patients].

Autoantibody formation and lymphocytes proliferative response to tubular basement membrane (TBM) antigen were examined to clarify the pathogenesis of gold nephropathy, in rheumatoid arthritis patients. The existence of tubulopathy was ascertained by urine protein analysis, electrophoresis and urine TBM antigen titration. Circulating antibody to human TBM antigen titrated by enzyme immunoassay was significantly elevated in patients with gold tubulopathy, and mitogenic stimulation with TBM antigen of peripheral lymphocytes specifically responded in the early stage after receiving gold, but then clearly decreased after the cessation of gold. But, when the lymphocytes had been passed through a nylon wool column, the reaction was remarkably high even in the later stage after receiving gold, suggesting that another suppressive population of lymphocytes became trapped in the nylon wool column. This evidence suggests that gold compounds definitely act as initiating and promoting agents, and the development of tubular disorders induced by gold are likely related to the cellular recognition of effector T cells to the TBM antigen, following the strong effect of gold on the cellular immune system.

[Intrarenal arterial Doppler sonography in patients with various renal disease: correlation of resistive index with biopsy findings].

Duplex Doppler sonography (ultrasonic equipment: Toshiba SSA-270A) were performed in the patients with various renal disease (male 44, female 32) admitted to our hospital between June 1990 and August 1991. Interlobar arterial blood flow velocity was measured at the side of renal pyramid through a longitudinal scan. Both the maximum blood flow velocity (Vmax) and the minimum blood flow velocity (Vmin) were measured quantitatively and resistive index (RI: defined as (Vmax-Vmin)/Vmax) were calculated. Vmax and Vmin correlated well with the creatinine clearance (Ccr) (r = 0.56, r = 0.66 respectively), whereas RI, by which we can detect Doppler waveform changes, correlated weak with Ccr (r = 0.39). We found twenty-nine patients (40%) with an elevated RI (greater than or equal to 0.70). They had severe renal dysfunction and active pathologic findings in the tubulo-interstitial or vascular compartment of the kidney. Doppler examination of renal blood flow velocity was valuable not only to estimate renal function but also to assess pathophysiology of renal disease.

Effect of glycyrrhizin on lysis of hepatocyte membranes induced by anti-liver cell membrane antibody.

Studies were made on why glycyrrhizin injection decreases the plasma aspartate aminotransferase (AST) and alanine aminotransferase activities in patients with chronic hepatitis. For this, rat hepatocytes were isolated, and incubated with antibody raised against rat liver cell membranes, and the effect of glycyrrhizin on their release of transaminase was investigated. Isolated rat hepatocytes released AST on incubation with anti-liver cell antibody in the presence of complement. At this time, their endogenous phospholipase A2 activity was increased. Cultured hepatocytes also released the transaminase in the presence of venom phospholipase A2. Glycyrrhizin suppressed the release of transaminase in the presence of either anti-liver cell membrane antibody or phospholipase A2. These results suggest that antibody treatment raised the phospholipase A2 activity in liver cell membranes, resulting in release of transaminases, and that glycyrrhizin suppressed this increase in phospholipase A2 activity and so inhibited the release of transaminase.

Study on chronic renal injuries induced by carbon tetrachloride: selective inhibition of the nephrotoxicity by irradiation.

Carbon tetrachloride (CCl4) was intraperitoneally injected into Balb/c mice 4 times at biweekly intervals, and the morphological changes of the liver and kidney were examined during 12 weeks after the last injection. The renal injuries progressed in spite of cessation of CCl4 treatment; microcysts with tubular-cell degeneration were manifest on day 42 after the last injection of CCl4. At the end of the experiment, however, interstitial fibrosis with inflammatory cell infiltration was much more prominent. Glomerular changes with IgG deposits also developed following the tubulointerstitial changes. The CCl4 treatment induced liver damage as well, but it promptly subsided without formation of cirrhosis. The CCl4 nephrotoxicity was completely inhibited by whole body irradiation (200 rad) exposed at each injection of CCl4. In contrast, the hepatic damage was not changed by irradiation. These results seem to indicate etiologic independence of renal and hepatic events induced by CCl4 treatment. It is also suggested that chronic CCl4 nephrotoxicity is mediated, at least in part, by radiosensitive responses of the mice themselves.

Pneumothorax in a patient with Wegener's granulomatosis during treatment with immunosuppressive agents.

We present the case of a 16-year-old woman with Wegener's granulomatosis, who developed a pneumothorax while receiving treatment with cyclophosphamide and glucocorticoids. The lung was re-expanded by tube drainage, and the patient recovered completely while the immunosuppressive treatment was continued in combination with sulphamethoxazole-trimethoprim. A possible role for this antimicrobial drug in the treatment of Wegener's granulomatosis is briefly discussed.

Detection of nephritogenic antigen from the Lewis rat renal tubular basement membrane.

Immunopathogenicity of trypsin-solubilized or non-solubilized renal tubular basement membrane (TBM) of the Lewis (LEW) rat was investigated. Autoimmune tubulointerstitial nephritis (TIN) was induced in BALB/c mice by immunization with trypsin-solubilized LEW rat TBM, while immunization with non-solubilized TBM did not produce the disease. Based on this preliminary experiment we studied the characterization of immunogenic and nephritogenic TBM antigen of the LEW rat. TIN was characterized by severe mononuclear cell infiltrates with multi-nucleated giant cells in the interstitium, tubular destruction and intensive IgG and C3 deposits along the TBM. Anti-TBM antisera and eluate from the nephritic mouse kidneys reacted with the TBM of normal LEW rat kidney by immunofluorescence. LEW rat TBM was also detected immunofluorescently by using antisera from BALB/c mice immunized with autologous trypsin-solubilized TBM. A competitive inhibition test revealed a higher titer of anti-TBM antibody in the eluate than in the adsorption-treated antisera per microgram IgG. Immunoblotting showed one reactive band with a molecular weight of 45,000 daltons, and the blotting patterns in tryptic TBM of the Brown Norway (BN) and LEW rats appeared similar. Amino acid analysis of nephritogenic LEW rat tryptic TBM showed that it contained no hydroxyproline and hydroxylysine, suggesting that this TBM preparation was not collagenous. These findings suggest that tryptic digestion contributes to the release of nephritogenic antigen from the LEW rat TBM and that this antigen system might participate in the immune system involved in the anti-TBM associated TIN that is well known to be induced by non-digested TBM of TBM antigen positive animals.

[Effects of FUT-175 on mouse model of acute hepatic necrosis induced by endotoxin following immunological procedure].

Acute hepatic necrosis was induced by a single i.v. injection of lipopolysaccharide (LPS) into C57BL/6 mice following immunization with syngeneic liver protein and adjuvant. Sixty percent of the mice died of massive hepatocyte necrosis within 48 hours of LPS injection. The serum lactate dehydrogenase and aspartate aminotransferase levels were markedly elevated. The fatal and hepatotoxic action of LPS was prevented by pretreatment with FUT-175 (1.6 mg/kg), a synthetic protease-inhibitor. The inhibitory effects of FUT-175 was not demonstrated when the agent was given to the mice 2 h after the administration of LPS. These results seem to indicate that the hepatotoxic effects of LPS are mediated by endogenous host mechanisms in which proteases play an important role.

Autoimmune interstitial nephritis induced in inbred mice. Analysis of mouse tubular basement membrane antigen and genetic control of immune response to it.

Purified murine tubular basement membrane (TBM) antigen (molecular weight, 32,000) induced interstitial lesions in Brown Norway (BN) rats. TBM antigen prepared from mice of 3 inbred strains--BALB/c, C3H/He, and C57BL/6--and outbred ddY mice possessed both antigenicity and nephritogenecity. Using these TBM antigens, the roles of humoral and cellular immunity in the development of interstitial nephritis (IN) and the genetic control of the induction of IN in inbred mice were investigated. BALB/c mice were highly susceptible to IN and showed a high antibody response and a high lymphocyte proliferative response to syngeneic and allogeneic TBM antigen, whereas C57BL/6 mice did not. C3H/He mice, in which minimal interstitial lesions developed, showed a high antibody response but a low proliferative response of T cells to TBM antigen. TBM antigen sensitized T cells induced interstitial lesions, but anti-TBM antisera did not do so. Thus, the development of IN seemed to be related closely to cellular immunity. Further studies with their hybrids, backcrosses, congenic mice, and recombinant mice suggested that the induction of IN and the immune response to TBM antigen are controlled by 1 or a few dominant genes, whose loci are within, or closely linked to, the H-2 complex.

Adoptive transfer of experimental autoimmune hepatitis in mice--cellular interaction between donor and recipient mice.

This report extends our previous study on experimental autoimmune hepatitis in C57BL/6(B6) mice. Cellular immunity involved in the induction of liver injury in this model was studied by transfer of primed spleen cells from hepatitis donor mice to syngeneic normal recipient mice. The most prominent liver damage in recipient B6 mice was induced by transfer of nylon wool adherent spleen cells from hepatitis donor mice, and T cells in this fraction were the essential requirement for the liver damage in the recipient mice. Nylon wool adherent spleen cells from hepatitis donor mice after depletion of the suppressor T-cell function by low-dose (300 rad) irradiation induced more severe liver injury compared to the same cells without irradiation. When the recipient mice were depleted of lymphocytes by low or high dose (700 rad) whole body irradiation, transfer of primed spleen cells from hepatitis donor mice did not induce liver lesion in the lymphocyte-depleted mice. This low susceptibility of lymphocyte-depleted recipient mice to primed spleen cells of hepatitis mice was no longer demonstrated after reconstitution with normal spleen cells. In a cell-migration study using 51Cr-labelled spleen cells, it was shown that a considerable number of infiltrating cells in the liver of recipient mice were derived from recipient mice themselves. These results seem to indicate that cell-to-cell interaction between radiosensitive precursor cells of recipient mice and liver-antigen-primed T cells from hepatitis donor mice play an essential role in the induction of liver injury in the recipient mice.

Inhibitory effects of prostaglandin E1 on T-cell mediated cytotoxicity against isolated mouse liver cells.

The effects of prostaglandin E1 on cell-mediated cytotoxicity against hepatocytes were investigated using an in vitro cytotoxic assay system. Isolated liver cells from normal C57BL/6 mice were used as the target cells, and effector cells were obtained from spleens of C57BL/6 mice in which experimental hepatitis had been induced by immunization with syngeneic liver antigens. In this assay system, spleen T cells adhering to nylon wool demonstrated a high cytotoxic activity against target liver cells. The cytotoxicity was markedly reduced by prostaglandin E1 at concentrations greater than 10(-7) M. Maximum suppressive activity was obtained when prostaglandin E1 was continuously present during the assay period. By contrast, indomethacin, a specific inhibitor of prostaglandin synthesis, enhanced the cytotoxic activity of effector cells. These data seem to indicate that exogenously added prostaglandin E1 has an inhibitory effect on cell-mediated cytotoxicity of effector spleen cells against target hepatocytes.

Suppressor system in murine interstitial nephritis. Analysis of tubular basement membrane (TBM)-specific suppressor T cells and their soluble factor in C57BL/6 mice using a syngeneic system.

We induced typical interstitial nephritis with high titers of anti-tubular basement membrane (TBM) autoantibody in genetically resistant C57BL/6 mice by treating them with sodium aurothiomalate (gold) and immunizing them with syngeneic TBM antigen. When gold was not used, the T-cell fraction of nylon wool adherent splenic cells showed prominent suppressive activity against the proliferative response of nonadherent cells to TBM antigen. However, this suppressive activity was remarkably decreased by the gold treatment. TBM antigen sensitized thymocytes, a thymocyte extract, and a spleen cell extract were transferred to C57BL/6 mice which had been immunized with TBM antigen and treated with gold. This transfer clearly depressed the induction of autoimmune interstitial nephritis in an antigen-specific manner. These results indicate that TBM antigen-specific suppressor T cells and their soluble factor may play an important role in the negative regulation of interstitial nephritis in C57BL/6 mice.