Hideho Gomi

SERUM URIC ACID AND RENAL PROGNOSIS IN PATIENTS WITH IGA NEPHROPATHY

Background/Aims: This study was designed to elucidate the clinical significance of serum uric acid (SUA) and the relationship between hyperuricemia and renal prognosis in IgA nepropathy. Methods: The correlation between SUA and other clinical parameters were examined in 748 IgA nephropathy patients (432 males and 316 females). Among these patients, 226 (144 males and 82 females) who were followed for more than 5 years were examined for the relationship between hyperuricemia and renal prognosis. Results: In IgA nephropathy, SUA correlated negatively with creatinine clearance (Ccr), and positively with urinary protein and tubulointerstitial damage. SUA was higher in patients with hypertension or diffuse proliferative glomerulonephritis. Hyperuricemia was a risk factor for renal prognosis, both in terms of serum creatinine (p = 0.0025) and Ccr (p = 0.0057). In 56 patients with normal Ccr at renal biopsy, the change of Ccr after more than 8 years was –22.3 ± 20.8% in 13 patients with hyperuricemia, compared with +2.6 ± 39.4% in 43 patients without hyperuricemia (p = 0.0238). Hyperuricemia was related independently to deterioration of Ccr (p = 0.0461). Conclusion: Hyperuricemia in IgA nephropathy is derived from both glomerular and tubulointerstitial damage, and correlated with hypertension. Hyperuricemia is a risk factor for renal prognosis in IgA nephropathy.

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.

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.

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.

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.

Significance of serum lipase in patients undergoing hemodialysis

Serum levels of lipase (Lp) during the end of the dialysis showed a significant increase after the administration of heparin in hemodialysis patients. However, serum Lp levels were not increased after the administration of the anti-coagulant nafamostat mesylate in hemodialysis patients. Serum levels of Lp were significantly correlated with serum levels of lipoprotein lipase (LPL), hepatic triglyceride lipase (H-TGL) and nonesterified fatty acid (NEFA) 20 min after the administration of heparin during maintenance hemodialysis. Lp activity did not appear with the NEFA ligand for determining the NEFA activity. Inhibitors of LPL and H-TGL reduced the measured Lp activity in vitro. The main mechanism of elevated measured serum Lp activity in hemodialysis patients was determined to be cross-reactivity with LPL or H-TGL. Furthermore, measurement of Lp may be a method for determining optimal coagulation time in patients with hemodialysis.

A case of chronic renal failure followed by cold agglutinin due to Mycoplasma pneumoniae infection.

Toshiaki Shibasaki, MD, Second Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 NishiShinbashi, Minato-ku, Tokyo 105 (Japan) Dear Sir, It is well known that cold agglutinin may be induced by the effect of autoimmune mechanisms [1, 2], and then hemoglobinuria and skin pain caused by disorders of the peripheral capillaries but in frequently hemolytic anemia are observed associated with cold sensitization [3]. There are three kinds of antigens against agglutinin such as I, i and Pr located on the surface of erythrocytes [4, 5], and hemolysis is induced by the activation of binding to the complement. Cold agglutinin might be formed in various diseases [6, 7] such as idiopathic, malignant lymphoma, neoplasms, and infections [8, 9] mainly such as Mycoplasma pneumoniae, cytomegalovirus and Epstein-Barr virus. The presence of warm agglutinin antibody in the patient with chronic renal failure (CRF) has been reported earlier. However, this is the first case of the cold agglutinin associated with M. pneumoniae infection appearing in a patient with CRF derived from membranoprolifera-tive glomerulonephritis (MPGN). A 31-year-old male had been treated for MPGN at another hospital since June 1979. When he came to our department in July 1987, he only had CRF with the following data: daily urinary excretion of protein was 7–10 g and the serum creatinine was 4.8 mg/dl. In January 1988, he complained of a sore throat, general malaise, cough, fever (37–38 °C) and the exacerbation of azotemia, and so he was admitted for further examinations. On admission, he had a body temperature of 37.1 °C, blood pressure of 164/90 mm Hg, and the presence of a heart murmur and moist rales in his chest were observed. Regarding, laboratory data, there existed marked anemia such as RBC 140 × lOVmm3, hemoglobin 5.5 g/dl and hematocrit 15.3%, but haptoglobin 112 mg/dl, serum Fe 80 μg/dl, and sugar water and Ham tests were within normal limits. Daily excretion of proteinuria was 15.8 g and serum total protein was decreased to 5.6 g/dl. Marked metabolic acidosis was observed including pH 7.30 and HCOi 14.3 mmol/l, and marked renal dysfunction shown as blood urea nitrogen 78 mg/dl and serum creatinine 12.3 mg/dl. For serological and immunological data, the titer of cold agglutinin showed 2,048 × at a temperature of 15 °C in vitro and Coombs tests were positive. The serum titer against various infections was only