Differential diagnosis of diabetes insipidus has been discussed in this paper in terms of pathophysiologicalaspects. Three points are emphasized: (1) we should include dipsogenic DI. as one form of diabetes insipidus; (2) the water deprivation test is inconclusive in approximately 25% of patients, where the main difficulty is to distinguish between partial neurogenic D.I. and dipsogenic D.I.; and (3) this difficulty cannot be solved by a single determination of plasma vasopressin. Pathophysiology of inherited neurogenic DI. and nephrogenic D.I. are also discussed.

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Genetic analysis of systemic lupus erythematosus (SLE) in several lupus-prone mice has revealed that multiple, unlinked genes are required for the expression of various autoimmune manifestations, and that several, quite distinct genetic backgrounds are compatible with this disease. Although the nature of these genetic components has not been fully defined, it is becoming clear that certain genes such as the major histocompatibility complex class II genes and the genes regulating apoptosis apparently play a major role in the development of autoimmune responses characteristic in SLE. Analysis of the nephritogenic potential of monoclonal autoantibodies underlines the importance of qualitative features of autoantibodies in the pathogenesis of lupus nephritis. Strikingly, "wire-loop" glomerular lesions characteristic in human lupus nephritis can be induced by the direct localization of murine IgG3 antibodies with cryoglobulin activity without the involvement of immune complex formation. The remarkable correlation of IgG3 production with the development and acceleration of murine lupus nephritis, in association with enhanced activation of the Ti-il subset which can lead to an increase in lgG3 production, is highly significant. The production process of more pathogenic autoantibodies appears to be genetically regulated. Further identification of the genetic defects present in lupus-pronemice, but lacking in mice with non-autoimmune backgrounds, is of paramount importance for the understanding of the immunopathogenetic mechanism of lupus nephritis and for the development of new therapeutic approaches for SLE.

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Recent research has indicated the role of reactive oxygen species (ROS) in experimental nephritis. We examined the role of ROS and the effect of probucol, an anti-hyperlipidemic drug with antioxidant activity, on adriamycin (ADR)-induced nephrosis in the rat. Fourteen days after single intravenous injection of ADR (7.5 mg/kg b.w.), a nephrotic state was observed. Compared with the normal control values, the total kidney glutathione content was lower on day 5, but significantly higher on day 14 in the ADR-injected rats. Feeding ADR-injected rats with food containing 1% probucol was effective in reducing urinary protein excretion. Serum lipid peroxide level and kidney total glutathione content, both of which increased on day 14 in the ADR-injected rats, were also decreased significantly by concomitant probucol treatment. During long-term observation period of 18 weeks, probucol treatment relieved both urinary protein excretion and the progression of renal impairment. These protective effects of probucol suggest a role of ROS in the induction and progression of ADR nephrosis.

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Accumulating evidence suggests that platelet-activating factor (PAF) may play a role in renal pathophysiology. Therefore, in order to investigate this notion further, the effects of PAF on cell growth and tyrosine phosphorylation were analyzed in cultured rat mesangial cells. PAF was found to enhance a time and concentration-dependent increase in phosphotyrosine in several proteins and stimulate ³H-thymidine incorporation. Tyrosine phosphorylation was also enhanced by PAF in protein kinase C (PKC) depeleted cells, whereas a tyrosine kinase inhibitor, genistein, inhibited tyrosine phosphorylation of these proteins at the concentration of 1 μg/ml. PAF stimulated ³H-thymidine incorporation at concentrations below 10^-6M, but exerted progressive inhibition at concentrations above 10^-6M. Pre-treatment with phorbol 12-myristate 13-acetate (PMA) did not affect PAF-enhanced incorporation at lower concentrations of PAF, and reversed the inhibitory effects of PAF at higher concentrations. Finally, genistein pre-treatment completely inhibited PAF-induced cell growth at the concentration of 1 μg/ml. Both tyrosine phosphorylation and ³H-thymidine incorporation induced by PAF were completely inhibited by pre-treatment with the PAF-receptor antagonist, CV-6209, at the concentration of 10^-5M. These results suggest that PAF enhancement of tyrosine phosphorylation occurred in a PKC-independent manner and that a tyrosine kinase was associated with PAF-induced tyrosine phosphorylation. Moreover, they indicate that the phosphoinositide hydrolysis-PKC pathway is not essential for PAF-induced cell proliferation, and that PKC activation may play an inhibitory rather than a stimulatory role in mitogenesis in response to PAF. Our results indicate that the tyrosine phosphorylation pathway induced by PAF may participate critically in downstream mitogenic signaling through the PAF receptor.

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Intercellular adhesion molecule-1 (ICAM-1) is expressed on the surface of various types of cells, including lymphocytes, monocytes and vascular endothelial cells. Recently, ICAM-1 was reported to be shed from the cell membranes and released into circulation. The soluble ICAM-1 (sICAM-1) level has been reported to be increased in patients with certain inflammatory diseases. It is well known that the functions of leukocytes including neutrophils, lymphocytes and monocytes are impaired in patients with chronic hemodialysis. In this study, we evaluated the effect of hemodialysis (HD) on the lymphocytes and monocytes by periodically measuring the serum concentration of sICAM-1 during HD. Pre-HD sICAM-1 levels in chronic hemodialysis patients were significantly increased as compared with healthy subjects. Two hundred and forty minutes after the start of HD, sICAM-1 levels were significantly higher than the pre-HD levels. The sICAM-1 levels at the venous side of the dialyzer were significantly increased compared with the levels at the arterial side. There was no significant difference between the sICAM-1 levels of the patients under hemodialysis with the regenerated cellulose membrane and those with the polymethylmethacrylate membrane. These results suggest that ICAM-1 is shed from the surface of mononuclear cells (lymphocytes and monocytes) and released into circulation stimulated by hemodialysis membranes. Chronic hemodialysis may impair the function of mononuclear cells by inducing the shedding of ICAM-1.

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This study included 25 patients receiving hemodialysis (HD) but in whom diabetes mellitus was not the primary disease (HD-non DM group), 25 patients receiving hemodialysis with diabetes mellitus as the primary disease (HD-DM group), and 50 patients with diabetes mellitus who had not yet been treated with hemodialysis (DM group). The following markers of myocardial injury were measured in these patients: troponin T (TnT), creatine kinase (CK), myoglobin (Mb), and myosin light chain-1 (MLC-1). No significant correlation was found between myocardial TnT and Cr in any study group. The Mb and MLC-1 values in patients receiving HD were markedly higher than normal regardless of the primary disease involvement, while myocardial TnT was found to be only slightly abnormal . These results suggest that myocardial TnT may be a more useful marker of myocardial injury in HD patients than the markers in current use. In the present investigation, myocardial TnT was the only marker that was higher in the HD-DM group than in the HD-non DM group. This suggests the possibility that the HD-DM group included more patients with arteriosclerotic lesions, such as myocardial injury .

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Clinical effects of an anti-platelet drug (dilazep dihydrochloride) in the microalbuminuric stage of diabetic nephropathy were investigated in a multi-center study. Thirty-seven patients with at the microalbuminuric stage of diabetic nephropathy were examined in the present study. They were administered 300 mg/day of dilazep dihydrochloride (Comelian(R)-Kowa) orally for 6 months. Mean values of albuminuria after the administration of dilazep dihydrochloride were significantly decreased compared with the pre-administration values. Urinary NAG activity was improved after this treatment in the microalbuminuric stage of diabetic nephropathy. Furthermore, impairment of renal function was not observed at that stage. It appears that administration of dilazep dihydrochloride from the early stage of diabetic nephropathy may be useful for the improvement of albuminuria and prevention of renal dysfunction.

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We evaluated the diagnostic utility of urinary transferrin (Tf) in patients with diabetic nephropathy by comparing the diagnostic findings with those of clinical stage and renal biopsy specimens. According to the rate of urinary albumin excretion, a total of 60 patients with non-insulin-dependent diabetes mellitus were separated into normoalbuminuria (<28.8 mg/day), microalbuminuria (28.8-288 mg/day), and overt proteinuria (>288 mg/day). They were also divided into 5 groups, D₀, D_I, D_II, D_III and D_IV according to the severity of glomerular diffuse lesions using Gellman's criteria. Thirty-eight non-diabetic volunteers were used as controls. Using 24-hour urine specimens, Tf was measured by latex-immuno-turbidimetry. Urinary concentrations of albumin, α₁-microglobulin, β₂-microglobulin and N-acetyl-β-D-glucosaminidase (NAG) were also evaluated. Urinary Tf was significantly increased in the diabetic patients relative to the non-diabetic controls. The incidence of microtransferrinuria (440 4, 400 μg/day) was 33.3% in normoalbuminuria, 63.2% in microalbuminuria, and 18.2% in overt proteinuria. The incidence of overt transferrinuria (>4, 400 μg/day) was 0%, 36.8% and 81.8%, respectively. Among the diabetic patients, urinary Tf showed a significant increase with respect to the progress of glomerular diffuse lesions. The glomerular diffuse lesions of 10 normoalbuminuric cases with microtransferrinuria were graded as D_I in 8 cases, D_II in 1 case, and D_III in 1 case. There was a significant correlation between the urinary excretion of Tf and that of albumin, α₁-microglobulin or NAG. The findings indicate that urinary Tf may be useful in detecting diabetic nephropathy at an early stage.

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A 15-year-old boy with proteinuria and hematuria is reviewed in this study. He was first found to have urinary abnormalities at the age of 13 years, and his renal function was exacerbated for a short duration. Renal biopsy was performed to make a histological diagnosis and to establish adequate therapy. Light microscopy showed marked tubulointerstitial inflammation with granulomatous changes, and electron microscopy revealed that numerous osmiophilic inclusions were present in podocytes, mesangial cells, and endothelial cells of the glomeruli and in epithelial cells of the tubules . The α-galactosidase activity of lymphocytes from the patient was measured, and the results of this assay indicated that the patient's lymphocytes had a low level of α-galactosidase activity . Therefore, the patient was diagnosed as having Fabry's disease with renal dysfunction. This study demonstrated that the onset age of renal insufficiency in Fabry's disease may be earlier than that described previously, and that when granulomatous interstitial nephritis is developed, renal function may deteriorate progressively .

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