Onpi-to (TJ-8117) is a herbal medicine composed of five crude drugs (Rhei Rhizoma, Glycyrrhizae Radix, Ginseng Radix, Zingiberis Rhizoma and Aconiti Tuber). Our previous experiments have demon strated that TJ-8117 suppressed the development of glomerulosclerosis and retarded the deterioration of renal function in 5/6 nephrectomized rats. In the present study, the effects of TJ-8117 and (—) Epicatechin-3-O-gallate (ECG), which is a component of Rhei Rhizoma, on glomerular cell proliferation, extracel lular matrix accumulation and glomerular hypertrophy were investigated in 5/6 nephrectomized rats. Male Wistar rats(170-180g) were subjected to 5/6 nephrectomy, and TJ-8117 (0.32%, 0.64%) orangiotensin-converting enzyme inhibitor, captopril (CAP 0.08%) was administered daily by mixing in normal chow and ECG (2 mg, 8 mg/ 100 ml) by drinking water from the day after 5/6 nephrectomy.Following 5/6 nephrectomy, glomerular cell poliferation was increased and reached a maximum at 1 week in the untreated control rats, but was suppressed significantly at 1 and 2 weeks after treatment with TJ-8117 and at only 1 week after treatment with CAP. Extracellular matrix accumulation was detected after 1 week and increased gradually until 4 weeks in the control rats, whereas it was significantly inhibited in both the TJ-8117-and CAP treated rats. In addition, revealed that TJ-8117 significantly inhibited the increase of fibronectin, and tended to reduce type I and type IV collagen at 4 weeks. Furthermore, TJ-8117 suppressed glomerular hypertrophy at 4 weeks. Systolic blood pressure (SBP) and urinary protein excretion (UP) were higher in the control rats than shamoperated rats. TJ-8117 prevented this increase of SBP and UP at 1 week. ECG also suppressed glomerular cell proliferation and the increase of SBP and UP at 1 week after 5/6 nephrectomy. These findings suggest that ECG was one of active components of TJ-8117. These results suggest that TJ-8117 suppressed proliferating changes in glomeruli at an early stage in 5/6 nephrectomized rats, and inhibited the development of glomerulosclerosis.

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In view of the hypothesis that suppression of energy demand may prevent ischemic cell damage, it seemed possible that suppression of ATP utilization during ischemic might ameliorate the severity of renal failure following kidney preservation. To test this possibility, a short-term in situ kidney preservation model was prepared in dogs. Euro-Collins solution containing 10^-5 M ouabain (O-EC) was used as the preservation solution. The kidney was preserved with cold O-EC for two hours and reperfused with auto blood. As the control, the kidney was treated with Euro-Collins solution (EC) alone. Three hours after reperfusion, recovery of creatinine clearance was 47.4±8.0 % in the control and 71.6±14.0 % in the O-EC group (p<0.02). The increase in urinary excretion of N-acetyl-β-D-glucosaminidase was significantly lower in the O-EC group. It was 21.3±4.5 nU/gr renal weight for three hours after reperfusion in the control group and 7.2±1.5 nU/gr renal weight in the O-EC group (p <0.05). Fractional excretion of sodium three hours after reperfusion was 1.42±0.44 % and 5.51±0.63 % in the control and O-EC groups (p < 0.002), respectively. There were no significant differences in renal blood flow, urine volume and urine osmolality between the two groups. These results suggest that ouabain-containing EC was effective in protecting the kidney, especially renal proximal tubular cell, against ischemic damage.

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There have been many reports indicating that Escherichia coli from pyelonephritis may exhibit several specific phenotypes. The purpose of the present study was to examine the effects of various toxins from Escherichia coli on cultured renal cell growth. α-hemolysin suppressed growth of Mardin Darby canine kidney (MDCK) cells in a dose dependent manner. A low dose of O-antigen suppressed MDCK cell growth, while a high dose of the antigen increased the cell growth slightly. K:1-antigen had no effect on MDCK cell growth. Mesangial cell growth was not affected by α-hemolysin. A significant increase in mesangial cell growth was recongized by the O-or K:1-antigen. From these results it can be speculated that α-hemolysin from Escherichia coli may play a leading role, and O- or K-antigen may play a supporting role in the pathogenesis of pyelonephritis.

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Although the inhibition of nitric oxide (NO) synthesis is known to induce systemic hypertension, the underlying mechanisms mediating this type of hypertension are incompletely understood. In the present study we investigated the influence of sodium intake on the pressor effect of long-term administration of the NO synthesis inhibitor, N^G-nitro-L-arginine methyl ester (L-NAME, 16 mg/dl in drinking fluid for 8 weeks), in conscious Sprague-Dawley rats. Urinary excretion rates of catecholamine during NO synthesis inhibition were also examined. Long-term administration of L-NAME produced a sustained elevation in tailcuff pressure without altering urine flow, or sodium excretion rate. L NAME-induced hypertension was accompanied by a decreased urinary excretion of the stable NO metabolites, NO₂^- and NO₃^-, and was aggravated when rats drank 0.9% saline in place of tap water. Thus, inhibition of NO synthesis resulted in a rightward shift of the pressure natriuresis relationship and a significant decrease in the slope of this relationship. Urinary excretion of epinephrine and norepinephrine, but not that of dopamine, in L-NAME-treated rats significantly increased within the first week of the study when compared with those observed in control rats. A natriuretic index of the sympathetic nervous system, the ratio of dopamine to norepinephrine excretion, was significantly less in L-NAME-treated rats than in control rats. After 8-week treatment with L-NAME, renal morphologic evaluation revealed significant narrowing and obliteration of the arterioles. L-arginine (2 g/dl in drinking fluid) completely reversed the elevation of blood pressure as well as the decrease in urinary NO₂^- and NO ₃^- excretion and the increased urinary excretion of catecholamines associated with L-NAME treatment after 3 weeks of concomitant administration. These results suggest that the inhibition of chronic NO synthesis produces sodiumsensitive hypertension and that changes in sympathetic nerve activity may, at least in part, contribute to the sodium sensitivity in this type of hypertension.

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Studies were performed to investigate whether prior cisplatin-induced acute renal failure affords resistance to a second challenge with cisplatin in Sprague-Dawley rats. Both the increase in serum creatinine and tubular damage following a challenge with cisplatin (5 mg/kg, i. p.) were significantly less rats which had received cisplatin (3 mg/kg, i. p.) 14 days prior to the rechallenge compared with the previously untreated animals. Attenuation of nephrotoxicity was more obvious in the histological index than in the increase in serum creatinine, and increase in serum creatinine concentration did not correlate with tubular necrosis. There were fewer tubular cells that expressed proliferating cell nuclear antigen in previously treated kidneys, suggesting that the enhanced regeneration of tubular cells plays a minor role the decrease of tubular damage in kidneys recovering from prior acute renal failure. These findings suggest that rats recovering from previous acute renal failure are resistant to a second insult with cisplatin and that the attenuation of nephrotoxicity is more prominent in histological damage than in functional disturbance.

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We have investigated associations between HLA-DQβ and TCRCβ gene polymorphisms and IgA nephropathy in Japanese children. DNA from 33 cases of IgA nephropathy, 29 cases of nephrotic syndrome and 29 cases of healthy volunteers were analyzed by Southern blotting using HLA-DQβ and TCRCβ probes. A 2kb (Taq I) polymorphic band that hybridized to the DQβ probe was predominant in patients of IgA nephropathy (p<0.05) compared to the controls. The 10kb (Bgl II) polymorphic band of TCRCβ was also predomi nantly present (but not significantly) in the DNA of these patients. Proteinuria in IgA nephropathy patients was found to be associated with this 10kb TCR polymorphism. We conclude that the HLA-DQβ and TCR genes make major contributions to the genetic patho genesis of IgA nephropathy in Japanese children.

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In patients with diabetic renal failure, attention must be paid to the prevention of atherosclerosis as well as the preservation of renal function. Insulin resistance is one of the important risk factors of atherosclerosis and the involvement of tumor necrosis factor -α (TNF-α) has been shown in the patho genesis of insulin resistance in some diseases. A lowprotein diet (LPD) is recommended for patients with advanced renal disease, but a large proportion of the total caloric intake is supplied from carbohydrates and fat in LPD. Therefore, we designed a study to determine : (1) the effect of TNF-α on insulin sensitivity, and (2) the effect of LPD on the TNF-α response and the risk factors of atherosclerosis, such as insulin sensitivity and lipid metabolism, in patients with diabetic renal failure. Insulin sensitivity was measured by an euglycemic hyperinsulinemic clamp technique and serum TNF-α level and in vitro release of TNF-α from peripheral blood mononuclear cells (PBMCs) was measured in patients with diabetic renal failure. A significant negative correlation was observed between lipopolysaccharide-stimulated TNFα release from PBMCs and insulin sensitivity (r= -0.58, p<0.05) . Secondly, risk factors of atherosclerosis were measured before and two weeks after the introduction of LPD in patients with diabetic renal failure. LPD did not have any significant effect on insulin sensitivity, the production of TNF-α by PBMCs, lipid metabolism and glucose metabolism. These results indicate that : (1) TNF-α derived from PBMCs might affect insulin sensitivity in patients with diabetic renal failure, and (2) LPD does not have any significant effect on the risk factors of atherosclerosis.

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The effects of obesity on target organ injuries and cardiovascular risk factors were examined in hypertensive subjects. The subjects were 22 obese (OB-HT) and 54 nonobese (NO-HT) men with never treated essential hypertension, and 37 obese (OB-NT) and 50 nonobese (NO-NT) normotensive men. In these 4 groups with the average age of about 50 years, we evaluated serum lipids, glucose tolerance, and hypertensive organ injuries in the heart, kidney, and optic fundus. Although the fasting blood glucose levels were similar in the 4 groups, the area under the blood glucose curve after 75g glucose ingestion (NO NT 15.6, OB-NT 17.5, NO HT 15.8, OB-HT l7.6 × 10³ mg/dl ⋅ min ; p<0.02) and the fast serum insulin level (NO-NT 7.3, OB-NT 10.1, NO HT 7.7, OB-HT 12.2 mU/l ; p<0.001) were increased in obese men. In OB-HT, serum HDL-cholesterol was decreased (- 11%, p <0.05) and triglycerides were increased (+58%, p <0.01) comparing with NO-NT. The incidence of electrocardiographic left ventricular hypertrophy was not significantly different among the 4 groups, however, urinary albumin excretion was increased in OB-HT (NO NT 3.0, OB-NT 3.4, NO-HT 3.6, OB-HT 4.3 mg/g creatinine ; p<0.05) and sclerotic lesions of the retinal arteries were observed even in normotensive OB-NT. These data suggest that obesity unfavorably alters lipid and glucose metabolism, and acilitates organ injuries such as arteriosclerosis and renal dysfunction in hypertensive subjects.

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We report a 63-year-old male patient with purpura nephritis, which appeared 7 days after extracor poreal shock wave lithotripsy (ESWL). He was referred to our clinic because of a petechial rash on both lower extremities, pretibial edema and massive proteinuria. Urinalysis showed proteinuria and hematuria and some hyaline casts. A 24 hour urine sample contained 5.0 g of protein. Renal function on admission was decreased : serum creatinine was 1.5 mg/dl and creatinine clearance, 21 ml/min. Immunoserological tests demonstrated an increase in serum IgA (424.3 mg/dl). A skin biopsy revealed leukocytoclastic vasculitis. A renal biopsy showed endocapillary proliferation in a diffuse, but segmental fashion. However, no crescent formation was seen. Immunofluorescence microscopy disclosed mesangial staining for IgA and C3. Electron microscopy demonstrated severe injury to endothelial and epithelial cells : detachment of endothelial and epithelial cells, foot process effacement and macrophage infiltration. Electron dense deposits were observed in the subendothelial and paramesangial areas. Because renal function was deteriorating rapidly, methylprednisolone pulse therapy and immunosuppressive treatment were implemented. Treatment was effective and the patient's renal function and proteinuria improved remarkably. The electron microscopic findings in this case of purpura nephritis seemed to be more severe than usual, suggesting that ESWL may aggravate glomerular damage.

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A case of systemic lupus erythematosus (SLE) associated with minimal change nephrotic syndrome (MCNS) in a 25-year-old female is described. The patient suddenly manifested butterfly rash and proteinuria was first pointed out on. On admission, her skin biopsy indicated SLE. Subse quently, she developed nephrotic syndrome. Urinalysis showed heavy proteinuria (4.1 g/day), with no other abnormalities in the urinary sediment. Immunological examination revealed positive antinuclear antibody at a titer of 1 : 80 with a speckled pattern. Anti-ssDNA and anti-SS-A antibodies were positive, but other antibodies were negative. Serum complement (CH50) was within the normal rangc (30.5 U/ml). The renal biopsy showed no apparent cellular proliferation or increase of extracellular matrices in glomeruli by light microscopy. Slight deposition of IgG, IgM, C3 and C1 q was focally seen in the mesangium and capillary wall by immunofluorescence. Electron microscopic examination revealed small and scattered dense deposits in the mesangium, subepithelium and subendothelium, associated with diffuse fusion of the foot processes of epithelial cells along the glomerular basement membrane. According to the WHO classification, the histological features were compatible with those of lupus nephritis (LN), class I b. The patient was treated with PREDNISOLONE, Mizorbine and Dilazep, resulting in the disappealance of proteinuria and a normal serum level of total protein. The association of LN and MCNS is very rare. We also investigated the relationship between the intensity of proteinuria and histological types of 53 cases with LN examined in our laboratory. The cases with heavy proteinuria were mostly classified as WHO Class IV and Class V. We report here a case of LN associated with MCNS and also review the literatures.

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We present a case of IgA nephropathy (IgAGN) which developed rapidly progressive glomerulone phritis and showed marked clinical improvement with treatment. The patient was a 7-year-old boy who initially presented with acute nephritic syndrome with hypocomplementemia. Although the renal function improved with normalization of the serum complement level, it deteriorated again progressively. The first renal biopsy revealed cellular crescents in about 70 percent of 43 glomeruli. Immunofluorescent microscopy demonstrated deposits of IgA, C₃ and IgG in the mesangium ; they were also deposited along the glomerular capillary walls. He was treated with plasma exchange associated with hemodialysis and methylprednisolone pulse therapy, followed by oral administration of prednisolone, cyclophosphamide and warfarin. Renal function recovered to the normal range about two months after the initiation of treatment. The second biopsy demonstrated a marked decrease in histological activity. In this case, transient hypocomplementemia at onset may indicate that acute glomerulonephritis caused exacerbation of clinically silent IgAGN. Agressive therapy may be effective in patients with rapidly progressive IgAGN if treated at an early stage.

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Selective transcatheter embolization using an interlocking detachable coil (IDC) or detachable balloon was performed in three patients with renal artery aneurysms. All aneurysms were of the saccular type, located on segmental branches of the renal artery. After the embolization procedures, the levels of LDH, GOT, WBC and the body temperature were transitionally elevated in all patients. Complete occlusion of the aneurysms were achieved in all cases. Good clinical results were achieved in two of these patients without any renal dysfunction. However, local infarction of ipsilateral renal parenchyma occurredin one patient immediately after the embolization and a Tc-99m-DMSA renal scintigraphy study suggested renal dysfunction after infarction, and the level of serum renin activity was slightly elevated. Selective transcatheter embolization may constitute an acceptable therapeutic approach for renal artery aneurysms because beside avoiding surgery, it has a low risk of complications.

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