Tubulointerstitial nephritis with IgM-positive plasmacytoid large lymphocyte infiltration in a patient with primary biliary cirrhosis and Sjögren's syndrome.

We report a 38-year-old woman diagnosed with tubulointerstitial nephritis (TIN) on renal biopsy, followed by being diagnosed with primary biliary cirrhosis (PBC) and Sjögren's syndrome (SS). Immunohistochemically, the cellular infiltrates in TIN were mainly composed of small lymphocytes and IgM-positive plasmacytoid large lymphocytes. IgM-positive plasmacytoid large lymphocytes were not identical with, but colocalized with CD3- or CD20-positive lymphocytes. TIN in patients with PBC is very rare and little is known about immunohistochemical characteristics of infiltrating cells in this setting. To our knowledge, this is the first report demonstrating predominant infiltrating of IgM-positive plasmacytoid large lymphocytes in TIN due to PBC and SS.

Antagonism of p66shc by melanoma inhibitory activity.

The p66shc protein governs oxidant stress and mammalian lifespan. Here, we identify melanoma inhibitory activity (MIA), a protein secreted by melanoma cells, as a novel binding partner and antagonist of p66shc. The N-terminal collagen homology-2 (CH2) domain of p66shc binds to the Src Homology-3 (SH3)-like domain of MIA in vitro. In cells, ectopically expressed MIA and p66shc colocalize and co-precipitate. MIA also co-precipitates with the CH2 domain of p66shc in vivo. MIA expression in vivo suppresses p66shc-stimulated increase in endogenous hydrogen peroxide (H(2)O(2)), and inhibits basal and H(2)O(2)-induced phosphorylation of p66shc on serine 36 and H(2)O(2)-induced death. In human melanoma cells expressing MIA, endogenous MIA and p66shc co-precipitate. Downregulation of MIA in melanoma cells increases basal and ultraviolet radiation (UVR)-induced phosphorylation of p66shc on serine 36, augments endogenous H(2)O(2) levels, and increases their susceptibility to UVR-induced death. These findings show that MIA binds to p66shc, and suggest that this interaction antagonizes phosphorylation and function of p66shc.

Direct inhibitory effects of simvastatin on matrix accumulation in cultured murine mesangial cells.

BACKGROUND: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been demonstrated to suppress glomerular injuries in various renal diseases. These agents inhibit in vitro proliferation of several cell types, including mesangial cells. This effect indicates the ability to ameliorate mesangioproliferative lesions, independent of the improvement of hypercholesterolemia. On the other hand, it is not clear whether HMG-CoA reductase inhibitors directly regulate extracellular matrix (ECM) accumulation from mesangial cells. METHODS: In this study, to examine the in vitro effects of simvastatin, an HMG-CoA reductase inhibitor, on mRNA expressions of matrix proteins, growth factors, and matrix turnover proteins, we incubated cultured murine mesangial cells stimulated by fetal calf serum (FCS) with or without simvastatin for 24 hours, and Northern analysis was performed. RESULTS: Simvastatin showed a slightly suppressive effect on mRNA expression of type IV collagen and fibronectin and a slightly up-regulative effect on that of type I collagen, whereas mRNA expression of type III collagen was markedly up-regulated. mRNA expression of platelet-derived growth factor (PDGF)-B chain and PDGF receptor beta-subunit was suppressed, whereas that of transforming growth factor-beta (TGF-beta) was not affected by simvastatin. Concerning matrix turnover proteins, simvastatin markedly reduced mRNA expression of plsminogen activator inhibitor-1 (PAI-1) without affecting the expression of tissue-type plasminogen activator (tPA). CONCLUSION: These results suggest type-specific modulation of matrix protein production independent of TGF-beta and the suppressive effects of autocrine PDGF by administration of HMG-CoA reductase inhibitors in mesangial cells. Moreover, the beneficial effects of these agents on matrix protein accumulation may be through promoting ECM degradation derived from PAI-1 suppression.

Pulmonary angiomyolipoma recurring 26 years after nephrectomy for angiomyolipoma: benign clinical course.

Angiomyolipoma (AML), a benign renal tumor, has various clinical forms, and the nature of AML is not sufficiently understood because of few reports of long-term observation. We report a 57-year-old female without tuberous sclerosis who developed multiple pulmonary AML 26 years after a right nephrectomy for renal AML. A computed tomogram demonstrated multifocal round lesions with lipid-like density throughout both lung fields. An open lung biopsy revealed a histological diagnosis of pulmonary AML. An abdominal computed tomogram was also compatible with splenic AML. She has been in good health for 12 years since the lung biopsy over the 38 years since the nephrectomy. This case suggests that multicentric AML can recur at distant organs even after long-term silence in a patient who has a past history of renal AML.

[Chinese herbs nephropathy in the Kansai area: a warning report].

In 1993, Vanherweghem and his associates reported cases of rapidly progressive renal interstitial fibrosis in young women who were administered a slimming regimen including Chinese herbs. Subsequently, similar cases have been reported. In Japan, especially in the Kansai area, several cases of Chinese herbs nephropathy have already been reported. We experienced a patient suffering from Chinese herbs nephropathy (CHN), and further detected aristolochic acids from the Chinese herbs taken by the patient. Aristolochic acids are known to be causative agents of CHN. The danger of CHN should be noted as soon as possible and drugs containing aristolochic acids should be prohibited.

A 41-year-old woman with protein S deficiency and diffuse proliferative lupus nephritis: is protein S deficiency associated with a hyperinflammatory response?

A 41-year-old woman with complete protein S (PS) deficiency who developed diffuse proliferative lupus nephritis is reported. She was referred to our hospital with nephrotic syndrome and thrombocytopenia. Her medical history included colorectostomy and amputation of the extremities because of repeated thrombotic episodes during her teens without any evidence of systemic lupus erythematosus. The diagnosis of PS deficiency was made from the patient's clinical course, undetectable serum PS in either the active or inactive form, normal protein C activity, and no evidence of the antiphospholipid syndrome. However, there was no definitive family history. A depressed level of complements and a positive antinuclear acid antibody suggested a diagnosis of systemic lupus erythematosus. The patient had a rapidly progressive course and died of disseminated intravascular coagulation. An autopsy showed generalized thrombotic lesions and diffuse proliferative lupus nephritis on both ordinal light and immunoperoxidase microscopy. Our observations suggest that PS-deficient patients may have a hyperinflammatory response.

Coagulation process proceeds on cultured human mesangial cells via expression of factor V.

BACKGROUND: In a previous clinicopathological study, we observed mesangial factor V expression accompanied by the intact form of cross-linked fibrin deposition in the active type of IgA nephropathy. The conversion of prothrombin to thrombin by factor Xa is potently accelerated more than 104-fold by the presence of factor V, which is a membrane-bound cofactor. Another membrane-bound cofactor, tissue factor, is known to play an initiating role in the coagulation cascade and to be synthesized in mesangial cells (MCs) by the stimulation of tumor necrosis factor-alpha (TNF-alpha). However, the synthesis of factor V, which plays on the terminating stage of prothrombin activation, has not been reported previously in MCs by in vitro study. Our current study tested the coagulation process via expression of factor V by the stimulation of proinflammatory cytokine, TNF-alpha, in cultured human MCs. METHODS: To evaluate factor V protein expression, immunoperoxidase staining with densitometric evaluation and Western blot analysis were conducted after stimulation of TNF-alpha. To test factor V activity, stimulated MCs were incubated in combination with factor Xa, prothrombin, fibrinogen and factor XIII, and fibrin production on MCs was assessed after immunoperoxidase staining on the cell surface. In a blocking test using an antibody against factor V, suppression of fibrin production was evaluated to clarify the role of factor V activity. For the evaluation of factor V mRNA expression in cultured human MCs, in situ hybridization and Northern blot analysis were performed. RESULTS: Factor V protein expression in MCs after TNF-alpha stimulation increased both time- and dose-dependently. As a marker of factor V activity with exogenous factor Xa, fibrin production on TNF-alpha-stimulated MCs was increased in a time-dependent manner and was inhibited by the addition of anti-factor V antibody. Factor V mRNA was identified in MCs by in situ hybridization and showed an increase after stimulation with TNF-alpha on Northern blot analysis. CONCLUSIONS: Our data suggest that the coagulation process proceeds on MCs as the result of increased expression of endogenous factor V activity on its cell surface in cooperation with exogenous factor Xa.

Atrial natriuretic peptide as a preload depressor in acute renal failure secondary to congestive heart failure.

The present study was undertaken to verify the hypothesis that infusion of atrial natriuretic peptide (ANP) might lower preload and be beneficial in the treatment of pulmonary congestion even without a diuresis in patients with acute renal failure (ARF) secondary to severe congestive heart failure (CHF). We studied 22 patients with ARF secondary to CHF. The mean age of the patients (14 men and 8 women) was 72 years (range 36 to 85 years). Seven of the patients had dilated cardiomyopathy, ten had ischemic heart disease, and five had valvular heart disease. ANP was infused intravenously and the following data before and 1 hour after the start of ANP infusion were recorded; urinary output, systemic blood pressure (SBP), pulmonary blood pressure (PBP), right atrial pressure (RAP), cardiac index (CI), heart rate (HR), and arterial blood oxygen partial pressure. Diastolic PBP were employed as pulmonary capillary wedge pressure. Urinary output did not change. Mean SBP decreased from 92 to 85 mmHg (p < 0.05), and mean PBP decreased from 34 to 28 mmHg (p < 0.01). Mean RAP decreased from 11 to 9 mmHg (p < 0.01) and diastolic PBP decreased from 25 to 19 mmHg (p < 0.01). HR did not change significantly and CI increased 2.4 to 2.5 mi/min/m2 (p < 0.05). Arterial blood oxygen partial pressure increased significantly from 71 to 82 mmHg (p < 0.05). In conclusion, ANP decreased preload and improved arterial blood oxygen partial pressure, though diuretic response to ANP is attenuated in ARF secondary to CHE. Infusion of ANP will be very beneficial in cases in which dyspnea and pulmonary edema due to elevation of preload are the principal clinical problems.