Masato Kimura

Roles of reactive oxygen species and antioxidant enzymes in murine daunomycin-induced nephropathy

We evaluated the roles of reactive oxygen species and intrinsic antioxidant enzymes in the development of daunomycin (DM)-induced nephropathy in mice. A single dose of DM (20 mg/kg intravenously) induced proteinuria by day 7 and the nephrotic syndrome by day 14 in DM-sensitive strain (A/J) but not in DM-resistant strain (C57BL/6J) (B6). Renal cortical lipid peroxide levels in the A/J mice significantly increased at days 2, 4, and 7 after DM injection, whereas no increase was observed in the B6 mice. The resistance to DM in B6 mice was associated with higher activities in renal cortical superoxide dismutase and glutathione peroxidase. The administration of superoxide dismutase or of dimethylthiourea significantly suppressed the DM-induced proteinuria in the A/J mice. Four days of superoxide dismutase or dimethylthiourea administration suppressed the proteinuria. These findings suggested that murine DM-nephropathy appeared to be mediated by reactive oxygen species and that intrinsic antioxidant enzyme activities may play an important role in the susceptibility to DM-induced nephropathy in mice.

Improvement of proteinuria in a case of hepatitis B-associated glomerulonephritis after treatment with interferon

Disappearance of proteinuria was observed in a patient with hepatitis B-associated chronic glomerulonephritis after treatment with leukocyte interferon. The decrease of proteinuria was preceded by the disappearance of both deoxyribonucleic acid polymerase activity and hepatitis B e antigen from the patients sera.

Renal involvement in mixed connective tissue disease. Report of 5 cases.

5 cases with the compatible serological criteria of mixed connective tissue disease described earlier are presented. In 1 of them with a moderate degree of proteinuria, the renal biopsy disclosed membranous nephritis. However, despite the absence of overt clinical renal disease in the other 4 cases, biopsies disclosed membranous nephritis in 1 and mild mesangial proliferative glomerulonephritis in the remaining 3 cases. In the follow-up of these 4 cases, 2 subsequently developed abnormal urinalysis. Electron microscopic examinations demonstrated electron-dense deposits in glomeruli, and 4 of these patients also had microtubular structures in the endothelial cytoplasm. Contrarily to the original concept, our findings suggest that mixed connective tissue disease also induces immune complex disease.

Interstrain Differences in Murine Daunomycin-Induced Nephrosis

Examining 8 inbred murine strains [A/J, BALB/c, SM/J, C3H/J, SWR/J, C57BL/6J (B6), DBA-2, B10D2/old (B10D2/o)] for urinary albumin excretion after a single daunomycin (DM) injection (20 mg/kg), we found strain specificity in susceptibility to DM nephrosis. This specificity did not relate to the serum disappearance rate of this drug. A/J and BALB/c were highly susceptible to the nephrosis while C57BL/6J, DBA-2 and B10D2/o were completely resistant to it. Chronological observation revealed that A/J mice had significant proteinuria at 2 weeks after injection, and it persisted for the remaining 4 weeks of this experiment, while C57BL/6J showed no increase over the experimental period. Using segregants obtained from an A/J and B6 backcross, it has been shown that susceptibility is inherited as an autosomal recessive trait and involves approximately three genes. Neither a C5 deficiency, H-2 type nor coat color gene (c-locus) was related to this susceptibility. This strain difference in nephrotoxicity would be a promising way to investigate its subcellular mechanism.

Bucillamine (a new therapeutic agent for rheumatoid arthritis) induced nephrotic syndrome: a report of two cases and review of the literature

SummaryTwo cases of nephrotic syndrome during bucillamine treatment were encountered in 1989 in our hospital; both patients had suffered from rheumatoid arthritis for 2 years. They had received 200 mg bucillamine orally per day for 3–4 months before the onset of the nephrotic syndrome. Discontinuation of bucillamine led to complete remission of the nephrotic syndrome within 1 year. Bucillamine is a new therapeutic agent for rheumatoid arthritis developed in 1982 in Japan. Since 1985, 14 cases of nephrotic syndrome, including the two cases reported here have been reported. We review these cases and discuss the pathogenesis.

Acute aortic thrombosis associated with spinal cord infarction in nephrotic syndrome.

SummaryAcute aortic thrombosis associated with spinal cord infarction in a 47-year-old man with nephrotic syndrome is described. He was admitted to our hospital presenting with the nephrotic syndrome. Renal biopsy revealed mild mesangial proliferative glomerulonephritis. The urinary protein excretion rate transiently decreased after the start of treatment with prednisolone, but it increased again and was followed by the development of the signs and symptoms of spinal cord infarction, which was diagnosed by magnetic resonance signal abnormalities, and then symptoms of ischemia in the lower limbs. Digital subtraction angiography revealed an obstruction at the bifurcation of the abdominal aorta. Emergency thrombectomy was performed, and the arterial blood flow was reestablished. Laboratory data on the fibrinocoagulation system showed a hypercoagulable state. In this case, fibrinocoagulation abnormalities due to the nephrotic syndrome led to the hypercoagulable state, and dehydration might have triggered the thrombotic complication.

Ultrastructure of Tubular Epithelial Cells in Response to Microembolism-Induced Chronic Ischemic Injury in Rats

Background: Loss of polarization of proximal tubular epithelial cells (PTECs) with detachment is known as an early response of PTEC to acute ischemia during acute tubular necrosis. However, the early morphologic changes of PTECs to chronic ischemic injury are not clear. We previously reported that rat renal microembolism induced chronic tubulointerstitial ischemia and extensive proximal tubular atrophy. Among atrophic tubules, some tubules showed a peculiar pattern mixed with intact and atrophic epithelial cells, which was thought to be the earliest feature leading to atrophic tubules. Methods: Chronic ischemic injury was induced by the left renal perfusion of microspheres after removal of the right kidney in rats. The ultrastructual changes, especially focusing on the process of tubular atrophy, are examined by electron microscopy after 4, 8 and 12 weeks. Results: Early changes in PTECs showed slight simplification or dedifferentiation such as loss or diminution of basolateral infolding and microvilli. Moderately simplified PTECs were partially detached from the tubular basement membrane (TBM) with matrix production in the detached spaces but maintained cell-cell contacts between PTECs. In the advanced stage, severely simplified PTECs showed complete detachment from TBM and more atrophic features characterized by cobblestone appearance with a uniform attachment between cells. In concert with these PTEC changes, accumulation of interstitial fibroblast-like cells (FLCs) with collagenous matrices could be found first in the interstitial spaces and later in the spaces where PTECs detached from TBM. Conclusion: Our results suggest that microembolism-induced chronic ischemic injury induces PTEC dedifferentiation and detachment from TBM with matrix production in concert with FLC activation, resulting in tubulointerstitial damage characterized by tubular atrophy and renal fibrosis.

Ureteral obstruction reverses glomerular proliferation in immune complex glomerulonephritis

We investigated an effect of ureteral obstruction on a progressive immune complex glomerulonephritis in murine lupus erythematosus. Unilateral ureteral obstruction for 8 days significantly decreased the expanded glomerular mesangial area, as measured by computer-assisted morphometry (4.44 +/- 0.33 x 10(-4) mm2 to 3.60 +/- 0.34 x 10(-4) mm2, P < .05), and reduced the staining for IgG, C3, and extracellular matrix components, whereas the nephritis was exacerbated in the contralateral non-obstructed kidney. The renal concentration of prostaglandin E2 (PGE2) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) in the obstructed kidneys 8 days after obstruction significantly exceeded that of kidneys in sham-operated controls (344.2 +/- 83.9 pg/mg tissue protein vs 50.0 +/- 27.5 pg/mg tissue protein, P < .01; 71.9 +/- 11.4 pg/mg tissue protein vs 9.5 +/- 2.3 pg/mg tissue protein, P < .01), whereas thromboxane B2 (TxB2) levels were similar in the two groups (33.9 +/- 4.5 pg/mg tissue protein vs 31.3 +/- 2.6 pg/mg tissue protein). Next, an experiment was performed to evaluate the role of renal eicosanoids in the amelioration in the immune complex glomerulonephritis after ureteral obstruction. Treatment with the cyclooxygenase inhibitor indomethacin abolished the decrease in mesangial area induced by ureteral obstruction (7.7% +/- 6.9%). CV-4151, a thromboxane synthetase inhibitor, had no effect on the decrease in mesangial area (-25.8% +/- 6.8%, P < .05). We conclude that unilateral ureteral obstruction quickly decreased the mesangial expansion in immune complex glomerulonephritis, and vasodilatory eicosanoids such as PGE2 and PGI2 at least partly contribute to the amelioration of glomerular histology.

Renal Handling of Salt and Water in the Early Stage of Obstructive Jaundice in Rabbits

Renal handling of salt and water in the early stage of obstructive jaundice was studied in rabbits 10 days after the ligation of the common bile duct (BDL). Sham-operated (SO) animals served as controls. No sodium retention was found in BDL rabbits, despite reduced renal perfusion and elevated plasma aldosterone level. A redistribution of intrarenal blood flow was not found. The filtration fraction did not change. A saline load resulted in decreases in arterial hematocrit and total serum proteins, and increases in urine output, urinary sodium excretion and osmolal clearance. Blood pressure, glomerular filtration rate (GFR), RPF, the filtration fraction and the intrarenal flow distribution were not significantly affected by the saline load. No significant difference was found in the natriuretic response to the saline load between the BDL and SO groups. After 60 h of water deprivation, there was no significant difference in urine-to-plasma osmolality ratios or renal tissue fluid osmolality between the BDL and SO animals. The findings indicate that renal handling of salt and water was well maintained in the early phase of obstructive jaundice in rabbits. The data also suggest the critical role of the redistribution of intrarenal blood flow rather than of GFR or aldosterone in determining sodium retention in obstructive jaundice.