Human urine can be concentrated up to four times higher than that of the plasma. Urine concentrating mechanism has attracted for a long time. However, studies in the field are now picking up momentum due to recent breakthrough discoveries using molecular biology techniques. Vasopressin-regulated water channel in the apical membrane of the collecting duct and water channel in the basolateral side of the membrane were cloned. Osmolality dependent chloride channel in the thin ascending limb of Henle was also cloned. In addition, vasopressin-regulated urea transporter was found in the collecting duct. These newly discovered channels and transporter should be playing important physiological roles in urine concentrating mechanism. Furthermore, recent findings on osmolytes and their transporters also add to the list of urine concentrating mechanisms.

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Atrial natriuretic peptide (ANP) is degraded by neutral metalloendopeptidase (EC 3.4.24.11) (NEP), and the kidney is the major site of ANP clearance. The regional distribution of NEP in rat kidney was investigated by an enzymatic method and by in vitro autoradiography. The activity of NEP, measured with an enzymatic fluorimetric method employing N-dansy 1-D-alanyl-glycy1 -L-4-nitrophenylalany 1-glycine as a synthetic substrate, was 18 times higher in the outer stripe and 8 times higher in the inner cortex than in the outer cortex. Low concentrations of NEP were found in the outer cortex, in the inner stripe and in the inner medulla. NEP activity in rat kidney was inhibited by specific NEP inhibitors (phosphoramidon, thiorphan, SCH39370, SCH47896 and SCH 48446) at micromolar concentrations. SCH 47896 is a phenolic derivative of SCH39370 which can be radioiodinated with ¹²⁵I. SCH48446 is a di-iodo analog of SCH47896. Thus, [¹²⁵I] SCH47896 retains the full enzymatic inhibitory activity and full biological potency to bind to the active site of NEP. Autoradiographs using [¹²⁵I] SCH47896 demonstrated maximal binding to regions of the outer stripe of the outer medulla and to the inner cortex, which was consistent with binding to the deep proximal tubules. These bindings were displaced in a dose-dependent manner by NEP inhibitors. Enalaprilat did not displace [¹²⁵I] SCH47896 binding. EDTA inhibited these bindings by 90%. The present result suggests that degradation of ANP by NEP occurs mainly in the deep proximal tubules, and that the proximal convoluted tubule in the outer cortex is not a major site of location of NEP. These properties enable [¹²⁵I] SCH47896 to be used as a radioligand for in vitro autoradiography. Using these methods, investigation of the regulation of NEP under different physiological and pathophysiological conditions is possible.

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Acute renal failure induced by the administration of gentamicin (GM) was studied enzymochemically in comparison with that in rats with tubular disorder resulting from postischemic reperfusion. Renal ischemia was caused by clamping the renal artery for 30 minutes to create complete ischemia and reflow. The activities of renal tissue glutathione peroxidase (GSH-PX) and the values to the renal contents of glutathione (GSH) and malondialdehyde (MDA) were measured in each sample. In order to confirm whether GSH plays an important role in the intrinsic anti-oxidant system in this model, buthionine sulfoximine (BSO), which is a γ-glutamylcysteine synthetase inhibitor, was administered in traperitoneally to decrease the renal GSH content before the procedure in renal ischemia. On the other hand, the GM-induced ARF model was made by injection with GM 100mg/kg during a period of 5 days. In the GM group, a significant increase in MDA and a reduction in the sphigomyelin (SPH)/phosphatidylcholine (PC) ratio and inactivation of PLA2 were observed. In the kidney tissue obtained 15 min. after reperfusion, the renal content of MDA was elevated markedly in the BSO-preadministered group. A reduction of SPH/PC ratio was also observed in the reperfusion model. PAL2 hydrolyzes the acyl group at the 2-position containing much of the highly unsaturated fatty acids that are easily oxidized. Further, PLA2 is considered to act directly on one of PC or phosphatidylinositol. Phospholipidosis thesaur uses, noted in acute renal failure induced by GM, is considered to be caused by reduced liberation of lysosomal intramembranous phospholipid into the cytoplasm and accelerated

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In order to clarify the abnormalities of the coagulation and fibrinolysis system in patients with various renal diseases, we produced a new monoclonal antibody for FDP (fibrin/fibrinogen degradation product) D-dimer (D-D E72). We also established a new highly sensitive method of enzyme-linked immunosorbent assay (ELISA) for urinary FDP D-dimer using this monoclonal antibody. The urine from 110, patients with various renal diseases was investigated for the FDP D-dimer. The results are summarized as follows: 1) Urinary FDP D- dimer in normal subjects was 0.69±0.60 ng/ml. 2) The level of urinary FDP D-dimer in patients with primary nephrotic syndrome and in patients with chronic renal failure was significantly higher than that of normal subjects, whereas the urinary FDP D-dimer levels in patients with diabetes mellitus were higher than those of normal subjects. 3) In the CGN and NS groups there was a tendency for an increase in the level of urinary FDP D-dimer in more active forms of the disease. 4) A significant correlation between urinary FDP D-dimer and urinary protein in the CGN and NS groups was demonstrated. 5) In all of the renal diseases investigated in this study, the ratio of urinary FDP D-dimer to total FDP was less than 4%

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One hundred kidneys from 100 non-selected autopsy cases without any overt renal disease were examined by immunofluorescence to reveal the incidences and features of cases with clinically latent glomerular IgA deposits. Glomerular IgA deposits were found in 10 cases (10.0%), consisting of 4 with liver cirrhosis and 6 with other diseases. IgA deposition was observed in 4 of 13 cirrhotic patients (30.8%), 3 of 15 patients with gastrointestinal carcinoma (20.0%), one of 11 patients with cardiovascular disease (9.1%), one of 3 patients with fulminant hepatitis (33.3%), and one of 21 patients with broncho-pulmonary disease (4.8%). Light microscopy showed minor glomerular abnormalities in all non-cirrhotic cases with IgA deposits except in one case. By contrast, variable significant glomerular lesions were found in the cirrhotic cases with IgA deposits, for example mesangial proliferation and circumferential mesangial inter-position. Excluding 13 cases with liver cirrhosis, the results of urinalysis at the time of admission were available for the study in 55 of 87 cases. Forty-four of 55 cases showed normal urinalysis. Glomerular IgA deposition was found in 4 cases(9.1%) of 44 with normal urinalysis. It may be said that IgA deposition without clinical evidence of nephro pathy occurred even in a normal population with an incidence of about 10%.

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The most reliable factors predicting a long-term prognosis in individual progressive IgA nephropathy patients were evaluated. Ninety-eight cases who showed moderate to severe histological alterations (total score of 7 or more) and were continuously followed up for 10 years or more from the first biopsy were the subjects of this study. During the follow-up period of 10 years, 52 of the 98 cases went into hemodialysis treatment (HD). All 24 cases who had a higher total score of 17 or more, or severe renal dysfunction of less than 60 ml/min in their initial Ccr values went into HD. The remaining 74 cases who showed both a total score below 16 and initial Ccr values of 60 ml/min or more were divided into two groups in their clinical courses: 28 (group I) of the 74 cases went into HD and the other 46 (group II) did not. The degree of initial proteinuria was significantly different between groups I and II, but the degree of individual proteinuria was in a similar range from 0.5 to 2.5g/day in most cases of both groups. Therefore, in order to clarify a more precise factor associated with the individual prognosis, the % duration of massive proteinuria (% DP) was calculated in individual cases. The % DP was more significantly different between groups I and II (82, 6±26.1 vs 19.6±27.3%, p<0.01). Moreover, all cases but one in group I showed 30% or more in % DP and 35 of 46 cases in group II showed 30% or less. Multivariable analysis using a logistic model of factors associated with prognosis indicating HD revealed that % DP was the highest relative risk factor rather than histologic severity, initial Ccr values, initial proteinuria and persistent hypertension. These results indicate that the most valuable factor determining a long- term individual prognosis is persistent massive proteinuria in progres sive IgA nephropathy.

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Effect of heparin and low-molecular-weight heparin (LMWH) were evaluated on 15 patients with proliferative glomerulonephritis with various degrees of sclerosing legion. Five cases were subcutaneously administered with 7000 to 11000 units of heparin for 4 weeks. Ten cases were administered with 60 unit/kg of LMWH by drip infusion for 4 weeks. Eleven cases were treated with prednisolone and all cases were treated with anti-platelet agent as well. Urinary protein excretion reduced from 3.0±1.8 to 1.8±0.6g/day in the heparin-treated group and from 2.4±1.9 to 1.8±1.4g/day in the LMWH-treated group, respectively. There were no remarkable changes in the renal functions of both groups. In one case, both heparin and LMWH brought about reduction of proteinuria. Therefore, LMWH reduced urinary protein excretion by the same mechanism as heparin. The LMWH has an advantage over heparin in that the former has less risk of causing bleeding. We conclude that heparin and LMWH reduce proteinuria in some patients with proliferative glomerulonephritis. The LMWH is beneficial in the treatment of proliferative glomerulonephritis with a sclerosing lesion.

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To investigate some of the problems associated with pregnancy and delivery in lupus nephritis, 13 pregnancies in 7 patients with inactive lupus nephritis and 5 pregnancies in one patient with primary antiphospholipid syndrome (PAPS) were compared with 36 pregnancies in 22 patients with primary nephrotic syndrome (NS). Furthermore, a follow-up survey during 0-8 years was made with 12 babies born to mothers with lupus nephritis. Some pregnancies during lupus nephritis were accompanied by disease exacerbation and worsen ing of renal function. There was a higher incidence of babies born with a low birth weight, and the incidences of fetal loss or premature birth and toxemia were higher in lupus nephritis than in NS. The number of babies with a low birth weight was significantly higher in patients with pregnancy-induced hypertension or skin lesion due to lupus erythematosus. The presence of antibodies against SSA/R_o in the mother was associated with the occurrence of congenital heart block. Birth weight of babies born to mothers with lupus nephritis was low, but there were no statistical differences in the growth of babies after 6 months of age compared with babies born to normal women.

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Cerebrovascular accident (CVA) is an important predictor of survival in patients with chronic renal failure (CRF). Although serum lipoprotein (a) [Lp(a)] is an independent risk factor for atherosclerosis in the general population and Lp(a) levels are increased in patients with CRF, the relationship between increased Lp(a) and CVA has not been clarified in patients with CRF. We therefore determined the association between serum Lp(a) levels and the risk of CVA in a retrospective study of 105 patients with CRF. Lp (a) was measured by ELISA in 31 patients with CVA and 74 patients without CVA. The median Lp(a) concentration of the patients with CVA was significantly higher than that of patients without CVA (38 vs 23 mg/dl: p<0.001). Logistic regression analysis determined that elevated serum Lp (a) concentration (relative risk ratio: 1.041, p<0.005), hypertension (relative risk ratio: 9.747, p<0.05) and smoking (relative risk ratio: 4.554, p<0.05) were risk factors for CVA. In contrast, serum total cholesterol, triglycerides, high density lipoprotein cholesterol, low density lipoprotein cholesterol, gender, underlying condition of renal disease and duration of hemodialysis were not associated with an increased risk of CVA. These results suggest that Lp(a) is a risk factor for clinical events attributable to CVA in patients with CRF.

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Helicobacter pylori (Hp) infection is thought to play an important role in for the pathogenesis of atrophic gastritis and even gastric carcinoma. The ratio of Pepsinogen I/II(PI/II)also shows good correlation with atrophic gastritis and gastric ulcer. Since many hemodialysis (HD) and renal transplantation patients suffer from gastrointestinal problems, we investigated the importance of Hp infection and PI/II in these patients. Serum Hp IgG was measured by EIA. Pepsinogen titer was measured with antipepsinogen antibody-bearing beads and anti-pepsinogen antibody. Hp positive HD patients accounted for 50.7% of the subjects. Of the renal transplantation patients, 23.5%were positive with lower values than the HD patients. The value of PI/II in all patients with a high Hp positive titer also was low (under 3).In conclusion, serum IgG antibody to Hp and PI/II exhibit good correlation and both are useful for the diagnosis of atrophic gastritis in chronic renal failure.

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Crow-Fukase syndrome is a rare multiorgan disorder. Although renal disorders, such as proteinuria, and renal impairment, have been observed in half the cases of this syndrome, there have been few reports describing the renal lesions. We report here a case of this syndrome associated with menbranoproliferative glomerulonephritis. A 43-year-old woman was referred to our hospital because of hyperglycemia. She had also been suffering from hyperpigmentation, hepatosplenomegaly, lymphadenopathy, polyneuropathy and endocrine dysfunction, including diabetes mellitus and amenorrhea. Serum electrophoresis showed M protein and immunoelectrophoresis revealed IgA (A). Bone marrow aspiration showed a slight increase in the number of plasma cells. Urine protein was 30 mg/dl, BUN was 17 mg/ dl and creatinine 0.8mg/dl. Light microscopic examinations showed enlargement of glome ruli with proliferation of mesangial cells and matrix, a lobular pattern of the glomeruli and thickening of the glomerular basement membrane and associated double contour. Electron microscopic examinations showed thickened capillary walls, associated mesangial interposi tion and subendothelial dense deposits. Moreover, fine granular deposits of IgM, C3, and fibrinogen along the basement membrane were observed on immunofluorescent studies.

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We report a case of hypocomplementemic urticarial vasculitis syndrome (HUVS) with membranous glomerulopathy in a 62-year-old man who had a 2-month history of secondary iritis. He was transferred to our hospital because of uncontrollable edema and respiratory dysfunction. Physical examination revealed anasarca, pulmonary edema, hypertension and urticaria-like eruption on his arms. Urinalysis, blood chemistry and serological studies showed massive proteinuria (10.5g/day) with numerous granular casts, hypoalbuminemia (1.5g/dl), renal dysfunction (creatinine; 1.6mg/dl, BUN; 86mg/dl), hypercholesterolemia (total cholesterol; 455mg/dl), positive results for antinuclear factor, microsome test, thyroid test, lupus anticoaglant, antithyroglobulin test and rheumatoid factor, but LE cell or doublestrand anti DNA antibody was negative. Serum complement levels were persistently low as CH50 of 13 U/ml and Clq of 6.0 μg/dl. The patient serum precipitated with normal human Clq by immunodiffusion analysis, indicating the presence of anti-Clq antibody. Renal biopsy revealed membranous glomerulopathy with promiment fine granular deposition of Clq along the glomerular basement membrane by immunofluorescent study and subepithelial dense deposit by electron microscopy. Corticosteroid treatment was ineffective for hypocomplem-entemia and nephrotic syndrome. Acute subendocardial infarction occurred on the 25th hospital day and he died of acute respiratory distress syndrome on the 45th hospital day. Autopsy revealed leucocytoclastic vasculitis in the alveolar wall. HUVS was confirmed by clinical symptoms, such as iritis and urticaria-like eruption, serum anti-Clq antibody, the absence of any specific autoantibody for systemic lupus erythematosus (SLE) and leucocytoclastic vasculitis in the alveolar wall. HUVS is an autoimmune disease which is differentiated from SLE by the presence of anti-Clq autoantibody. Renal involvement leading to nephrotic syndrome or functional impairment is reported to be rare. In the present case the main clinical features were due to glomerulopathy and the calssic HUVS manifestations were modest. However, it is suggested that the serological abnormalities related to HUVS might participate in the pathogenesis of renal injury.

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We report a case of sporadic acute type A hepatitis associated with acute renal failure, due to mesangioproliferative glomerulonephritis and interstitial nephritis. A 42 year-old-man was admitted to Mitsui Memorial Hospital because of jaundice and oliguria with fever in February, 1989. His serum creatinine was 12.2 mg/dl, BUN 87 mg/dl, GOT 57 U/l and GPT 358 U/l. The serum IgM antibody to hepatitis A virus was positive, which indicated recent infection with hepatitis A virus. Hemodialysis and steroidal therapy were started, and the patient's acute renal failure and liver dysfunction ameliorated within one month. Light microscopic examinations showed an increased number of mesangial cells and an increased amount of mesangial matrix, and also showed inflammatory cell invasion in the interstitium. Electron microscopic examinations showed proliferation of mesangial cells and matrix, and a dense deposit along the basement membrane. On immunofluoressent studies, fine granular deposits of IgA and clq were observed in the mesangium.

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We report a case of hypereosinophilia which was associated with the onset of anginal attacks. A 64-year-old man progressed to end-stage renal failure due to diabetic nephropathy, and was treated with continuous ambulatory peritoneal dialysis (CAPD). He had no past history of angina pectoris nor hypereosinophilia. Three weeks after the initiation of CAPD, the eosinophil count in peripheral blood increased (up to 4093/mm³). Two weeks later, hesuffered from an anterior chest pain attack, and angina pectoris was diagnosed. As a result of treatment with isosorbide dinitrate and prednisolone, hypereosinophilia disappeared rapidly and repeated episodes of anginal attacks also disappeared. After an interval of 3 months, however, hypereosinophilia (up to 15190/mm³) and anginal attacks recurred. He underwent coronary angiography, in which no stenotic change was observed. The administration of prednisolone was effective in the trcatment of these episodes. Although a close relationship between hypereosinophilia and anginal attack has been reported, it has not been known in CAPD patients as described here. Attention should be paid to these relationships in CAPD patients, because hypereosinophilia is frequently observed in maintenance peritoneal dialysis patients.

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