Fumio Ishimoto

Clinical Characterization of Drug-Induced Allergic Nephritis

To elucidate the clinical characterization of drug-induced allergic nephritis (DIAN), we analyzed the cases attending our department. We now report on the 14 cases of DIAN due to administration of penicillin in 2 cases, cephem antibiotics in 6 cases, nonsteroidal anti-inflammatory drugs in 4 cases and new quinolone anticidal drugs in 2 cases. With 1 exception, all these cases reached the stage of acute renal failure after taking these drugs for 2-13 days, followed by characteristic allergic symptoms such as fever, skin eruptions and serum IgE elevation in 5 of the 14 cases. A lymphocyte stimulation test (LST) with the suspected drugs proved to be positive in 10 of the 12 cases examined, and the uptake of 67Ga in the kidneys was extremely positive in all 6 cases examined, reflecting the natural course of this disease. Furthermore, there were some cases where 67Ga accumulated in the kidneys in spite of the negative result of LST examination. In all of these cases, a needle or open renal biopsy was performed, and acute tubulointerstitial nephritis (AIN) was diagnosed. Almost all cases were treated with glucocorticoid for AIN or dialysis for acute uremic symptoms several times. However, 4 of the 14 cases could not return to normal condition in spite of these forms of treatment. We would therefore like to suggest that LST and 67Ga scintigram are useful diagnostic tools for DIAN as an alternative to renal biopsy.

A Case of Renal Amyloidosis Associated with Hepatic Adenoma: The Pathogenetic Role of Tumor Necrosis Factor-α

We report a case of a 35-year-old man with secondary amyloidosis chiefly involving the kidney and heart. The patient showed severe proteinuria and ischemic heart damage and had hepatic adenoma at the age of 33. Biopsy specimens from the kidney, heart, stomach and rectum showed extensive deposition of amyloid. After the surgical resection of a 300-gram hepatic adenoma, highly elevated c-reactive protein (CRP) levels decreased and the serum amyloid A (SAA) level was completely normalized. Normal liver cells were immunostained with rabbit anti-SAA antibody, but the cells in adenoma tissue and kidney were not. Electron microscopic examination revealed extracellular deposition of amyloid fibrils in the hepatic adenoma and kidney tissue. The concentration of tumor necrosis factor-alpha (TNF-alpha) (312 pg/mg tissue protein) was 7-fold higher in adenoma tissue than in normal liver tissue. Moreover, SAA (2.8 ng/mg tissue protein) was 2-fold higher in normal liver tissue than in adenoma tissue. Since TNF-alpha has been known to induce SAA production in target cells, the present results suggest that the hepatic adenoma produced TNF-alpha, which then caused mainly secondary amyloidosis in the kidney and heart. Currently, 2 years after surgical resection, urinary excretion of protein has been markedly reduced (from 3.5 to 0.8 g/day) and renal and cardiac functions are normal without specific medical treatment.

A Case of Pheochromocytoma of the Urinary Bladder in a Long-Term Hemodialysis Patient

The development is reported of a pheochromocytoma of the urinary bladder in a 33-year-old patient with systemic lupus erythematosus who had undergone long-term hemodialysis. A hypertensive episode followed by defecation was demonstrated by the monitoring of blood pressure with a portable automated sphygmomanometer without elevation of plasma catecholamines. The tumor was surgically removed and normalization of the patients blood pressure followed. Thus, monitoring of blood pressure for 24 h proved useful for the diagnosis of pheochromocytoma and, in particular, of paroxysmal hypertension.

Mizoribine reduces urinary protein excretion in rats given puromycin aminonucleoside

Mizoribine (MZR), a purine nucleoside antibiotic, is an effective immunosuppressive agent that prevents rejection reactions after kidney transplantation in humans. The present study was performed to examine the effect of MZR on nephrosis produced in rats given puromycin aminonucleoside (PAN). Urinary protein excretion in rats injected with PAN and MZR (PAN + MZR rats) was shown to be reduced significantly in comparison with rats given only PAN (PAN rats). Although mild hypoproteinemia persisted during the experimental period in PAN + MZR rats, no loss of body weight or state of malnutrition was observed. The reduction of serum IgG and C3 was reversed by administration of MZR. Polyethyleinamine (PEI) staining of renal sections showed increased numbers of anionic sites in PAN + MZR rats in comparison with PAN rats, suggesting that MZR improved the permselectivity of the glomerular basement membrane (GBM). Moreover, the production of thromboxane B2 (TxB2) was significantly inhibited in PAN + MZR rats compared with PAN rats. No serious adverse effects of MZR were observed after a large dose of the agent. It is possible that restoration of the charge barrier of the GBM damaged by PAN, or reduction of TxB2 production by the glomeruli may underlie the reduction of protein excretion induced by administration of MZR.

Effect of Sairei-to on gentamicin nephrotoxicity in rats

The effect of Sairei-to, an oriental traditional medicine, against gentamicin nephrotoxicity was examined in gentamicin nephrotoxicity rat models. Gentamicin nephrotoxicity was induced by s. c. injection of gentamicin (100 mg/kg/day, for 3 days) in male Sprague-Dawley rats. Renal functions of two rat groups were compared, one eating rat chow containing 2.5% Sairei-to, the other eating normal rat chow. Sairei-to administration reduced the increase of urinary N-acetyl-β-D-glucosaminidase (NAG) and protein excretion, and decreased creatinine clearance induced by gentamicin. Gentamicin increased renal cortical malondialdehyde (MDA) concentration in normal diet group but not in the Sairei-to diet group. The renal cortical gentamicin concentration was not different between the two groups. In conclusion, Sairei-to shows reno-protective action against gentamicin nephrotoxicity, possibly through its anti-oxidant action.

Effect of polyaspartic acid on CdCl2-induced nephrotoxicity in the rat

We produced an animal model of CdCl2 nephrotoxicity in rats, and treated them with polyaspartic acid (PAA) to prevent renal damage. Male Sprague-Dawley (SD) rats (190–200 g) were used to induce proximal renal tubular damage by daily injection of CdCl2 3.0 mg/1,000 g body wt for 2 wk. CdCl2-exposed SD rats exhibited significant increases in urine volume, urinary excretion ofN-acetyl-β-D-glucosaminidase (NAG), alanine aminopeptidase (AAP), and fractional excretion of sodium (FENa) and a decrease in the percentage of tubular reabsorption of phosphate (%TRP). Of these indicators of proximal tubular function, AAP and %TRP are more sensitive than NAG or FENa. No glycosuria or aminoaciduria, however, were observed. PAA markedly improved these indicators of proximal tubular function. Daily urinary protein excretion and creatinine clearance, on the other hand, did not change after administration of PAA. Cd concentrations in the cortex were 3 times higher than in the medulla, however, there were no differences between Cd-treated rats and PAA-treated rats. Our animal model is an excellent one for determining the effect of cadmium on renal proximal tubule damage. PAA appears to be useful in the treatment of CdCl2 nephrotoxicity.

Effect of pentoxifylline on CdCl2-induced nephrotoxicity in the rat.

We developed a rat model of cadmium (Cd)-induced nephrotoxicity and tried to prevent renal damage by treating the animals with pentoxifylline (PTX). Sprague-Dawley (SD) rats given CdCl2 3.0 mg/kg sc, daily for 2 wk showed evidences of renal proximal tubular damage, including significant increases in urine volume, urinary excretion ofN-acetyl-β-D-glucosaminidase (NAG), alanine aminopeptidase (AAP), and fractional excretion of sodium (FENa), and a decrease in the percentage of tubular reabsorption of phosphate (%TRP). PTX significantly improved the urinary excretion of NAG and %TRP. Urine volume was increased threefold in the CdCl2-treated rats and fivefold in the Cd+PTX-treated rats, respectively, as compared with saline-treated control. Total protein, AAP, and creatinine clearance, showed no change after PTX administration. Concentration of Cd in the renal cortex was three times higher than that in the renal medulla, but there were no differences in concentration between the Cd-treated rats and the Cd+PTX-treated rats. Our animal model was useful in studying the renal tubular damage produced by cadmium. PTX appears useful for improving the nephrotoxicity of Cd.

An Experimental Study on Selective Elimination of β2-Microglobulin Using Immunoadsorption Method in Patients with Chronic Renal Failure

We studied selective elimination of beta 2-microglobulin (beta 2-m) from plasma of patients with chronic renal failure (CRF) by using immunoadsorption method. Anti-human beta 2-m antibody of rabbit IgG was coated with cellulose beads, which were filled into a small-column. One gm of cellulose beads contains 5.0 mg of the protein of antibody. Five to 7 ml of plasma samples with 40 to 70 mg/l of beta 2-m were passed through the column at 1.0 ml/10 min and each effluent was then collected by 1.0 ml consecutively. Before and after passing through the column, beta 2-m and other plasma proteins were measured. Plasma beta 2-m concentrations in all the effluent fractions after passing through the column were greatly reduced to 1/100. But no other plasma protein components than beta 2-m varied in concentration. Neither Immune complex (IC) nor rabbit IgG was detected in any effluent fraction. These results indicate that selective and effective elimination of beta 2-m from plasma in patients with CRF was possible by using our method. In addition, since neither IC nor rabbit IgG was detected in the effluent, this method was considered to be clinically applicable.

THE INFLUENCE OF AGING ON RENAL RESPONSE TO CADMIUM IN SYRIAN HAMSTERS

To determine the renal effects of cadmium (Cd) in older animals, we administered subcutaneously a single dose of cadmium, 3.0 mg/kg/BW, to Syrian hamsters aged 16 wk (“young”) and 60 wk (“old”). Marked morphologic changes in the kidney and renal dysfunction were observed, especially in the older animals. The concentration of MDA in the renal cortex was significantly increased only in young hamsters treated with cadmium. Concentrations of glutathione (GSH) in the renal cortex were increased in the old hamsters on d 6. Increased levels of renal MDA after cadmium treatment may induce the production of GSH in the kidney thus preventing renal damage. Aging can increase the susceptibility to the renal effects of cadmium.

EFFECTS OF A HEPATO-PROTECTIVE AGENT AND A HEPATO-SECRETING CHELATOR ON CADMIUM-INDUCED NEPHROTOXICITY IN SYRIAN HAMSTERS

Cadmium (Cd)-induced nephropathy in male Syrian hamsters was treated with D/L-penicillamine (D/L-p) or neomynophagen C (NMC). The subcutaneous injection of CdCl2, 3 mg/kg, three times a week led to marked renal damage, ie., increased proteinuria and the excretion of urinary N-acetyl-β-D-glucosaminidase (NAG) as compared with the saline-injected controls. Cd-treated hamsters that were injected intraperitoneally with D/L-p, 0.1 mg/kg, five times a week, showed less renal damage, including a reduction in urinary protein from 3.60±0.42 to 1.77±0.7 mg/d. NMC-treated hamsters showed a reduced excretion of NAG (from 1.47±0.34 to 0.91±0.68 u/d). The concentration of Cd in renal cortical tissue was reduced slightly (from 2.78±0.08 to 2.34±0.3 mg/g.prot) by NMC treatment, but not by D/L-p. The elevated malondialdehyde (MDA) in renal cortical tissue was unaffected by administering D/L-p or NMC. The concentration of glutathione (GSH) in the renal cortex was not elevated after administering Cd, but the ratio of the reduced to the oxidized GSH was elevated. The Cd induced liver dysfunction, as compared with untreated controls. The dysfunction was improved slightly by NMC administration, but not by that of D/L-p. Changes in renal morphology induced by Cd involving marked degeneration and necrosis of tubules as shown by light microscopy, were unaffected by treatment with D/L-p or NMC.We thus demonstrated the efficacy of D/L-p or NMC in treating the nephropathy induced by Cd in hamsters. The mechanism of therapeutic effect is not known.