Katsuya Obara

The role of macrophages in diabetic glomerulosclerosis

To elucidate the role of macrophages in diabetic glomerulosclerosis (DGS), an immunohistologic study was performed using monoclonal antibodies to common leukocyte antigen (DAKO-LC), T cells (T3), B cells (CD22), and macrophages (MAC 387, Leu-M5, and EBM-11). Kidney biopsy specimens were obtained from 28 patients with non-insulin-dependent diabetes mellitus. Cells were identified by a three-layer immunoperoxidase technique applied to cold ethanol-fixed, paraffin-embedded sections and quantitated as the number of cells per glomerular cross-sections and number of cells per square millimeter of glomerulus. The severity of the diffuse lesions in each glomerulus was graded semiquantitatively. The average grades for all the glomeruli were calculated and registered as an index of DGS for a biopsy specimen. There was no relationship between the index of DGS and the number of T or B cells. However, the number of macrophages and common leukocyte-positive cells increased significantly in the moderate stage of glomerulosclerosis compared with the mild or advanced stage. The results suggest that macrophages may transiently infiltrate during the moderate stage of diffuse DGS, contributing to irreversible structural damage.

Antihypertensive and renal-protective effects of losartan in streptozotocin diabetic rats.

Objective To assess the renal benefits of a specific angiotensin II receptor antagonist, losartan, in diabetic rats with renal impairment. Design and methods Uninephrectomized streptozotocin diabetic spontaneously hypertensive rats (SHR) were randomly assigned to receive vehicle, or to receive losartan or captopril, or both, intraperitoneally via osmotic minipumps for 8 weeks. Results Blood pressure and urinary protein excretion in the diabetic SHR increased progressively during the experimental period. Both captopril treatment and losartan treatment completely blocked the development of hypertension in diabetic SHR. Simultaneous administration of captopril and losartan did not enhance the antihypertensive effects of losartan treatment or captopril treatment. Furthermore, losartan treatment, captopril treatment and losartan + captopril treatment all significantly decreased urinary protein excretion, urinary albumin excretion and serum creatinine to the same extent. These effects were sustained for the entire experimental period and were not associated with any significant changes in body weight, urine volume, urine sugar and urinary electrolytes excretion. These results were confirmed by morphological analysis of kidneys in each group of rats. Losartan treatment, captopril treatment and losartan + captopril treatment all significantly and effectively protected against an increase in the percentage of focal glomerular sclerosis. Losartan treatment and captopril treatment both significantly attenuated the increase in heart weight: body weight ratio. The heart weight: body weight ratio in the losartan-treated group was significantly lower than in the captopril-treated group. Conclusions These results indicate that hypertension could accelerate diabetic renal impairment and that losartan has antihypertensive and renoprotective effects in this rat model. They also suggest that the antihypertensive and renoprotective effects of captopril treatment in this rat model are caused mainly by inhibition of angiotensin II production rather than stimulation of the kallikrein-kinin system or of vasodilator prostaglandins. The difference in potency between losartan treatment and captopril treatment to attenuate the increase in heart weight: body weight ratio might partly explain the existence in the heart of angiotensin-forming pathways, which are not dependent on angiotensin converting enzyme.

Angiography with Nonionic X-Ray Contrast Media in Severe Chronic Renal Failure: Renal Function and Contrast Retention

The effects of contrast media on renal function and the cortical retention of contrast media after abdominal angiography were investigated. Sixteen nondiabetic patients with predialytic chronic renal failure received either the nonionic dimeric contrast medium iodixanol or the monomeric contrast medium iohexol in a double-blind randomized study. All patients were well hydrated before, during and after angiography. Mean 99mTc-DTPA clearance was 14.0 ml/min/1.73 m2 in the iodixanol group, and 9.3 ml/min/1.73 m2 in the iohexol group at baseline. No statistically significant changes were seen after angiography. Serum creatinine increased significantly 48 and 72 h after angiography in both groups, and then normalized. Creatinine clearance was reduced only in the iohexol group, at 72-96 h. The urinary excretion of renal enzymes and of total protein did not change significantly. No patients developed oliguria or required dialysis during the 7-day observation period. Increased attenuation in the renal cortex, measured by computed tomography and probably reflecting intracellular retention of contrast medium, peaked at 24 h, and was observed in both groups during the follow-up period. Thus, although transient and minor changes in glomerular filtration rate were noted, both iodixanol and iohexol were safe for use in angiography in nondiabetic patients with severe chronic failure when the patients were well hydrated.

Effect of a Nonpeptide Vasopressin V1 Antagonist (OPC-21268) on Experimental Accelerated Focal Glomerulosclerosis

The effects of the nonpeptide orally effective vasopressin V1 receptor antagonist OPC-21268 were studied in progressive focal glomerulosclerosis (FGS) which developed in spontaneously hypercholesterolemic (SHC) rats with manifestations of hypercholesterolemia and proteinuria. Unilateral nephrectomy was performed at 7 weeks of age to accelerate spontaneous FGS. After nephrectomy, OPC-administered rats were fed chow containing 1% OPC-21268 for 9 weeks. Treatment with vasopressin V1 antagonist significantly reduced the rate of increase in the levels of triglyceride, systolic blood pressure, serum creatinine and BUN, and prevented a significant deterioration in creatinine clearance. Rats were sacrificed at 16 weeks of age. Histologically, the index of glomerular sclerosis in the OPC group showed a significant decrease compared to that in the control group (2.2 +/- 0.1 vs. 2.6 +/- 0.1, p < 0.01). Relative interstitial volume and glomerular volume in the OPC group showed a tendency to decrease compared to those in the control group. These results indicate that vasopressin plays an important role through V1 receptors in the development of glomerulosclerosis, and vasopressin V1 antagonist may prevent the progression of renal injury in glomerulosclerosis.

Cardiovascular and renal protective effects of losartan in spontaneously hypertensive rats with diabetes mellitus.

1. Cardiovascular and renal benefits of a specific angiotensin II (AII) receptor antagonist, losartan (LOS), were assessed in diabetic rats with renal impairment.

Membranous nephropathy complicating adenolymphoma of the parotid (Warthin's tumour).

Membranous nephropathy has been described in association with many malignancies including various lymphomas. However, it has not been previously described as a complication of benign solid adenolymphoma of the parotid, also called Warthins tumour. We describe a patient who presented with an adenolymphoma of the parotid, and developed a severe nephrotic syndrome due to membranous nephropathy 6 months after the parotid swelling. The nephrotic syndrome resolved following parotidectomy and a short course of immunosuppression with prednisolone and cyclophosphamide. The possible pathophysiologic mechanisms are discussed.

Significance of lymphocyte fatty acid changes in chronic renal failure

In the present study we describe fatty acid fluctuations in peripheral blood lymphocytes of patients with chronic renal failure who were undergoing maintenance hemodialysis. The decreased concentrations of linoleic acid and arachidonic acid and the increase in stearic acid are discussed in relation to the lymphocyte immune response and lymphocyte membrane enzymic systems in the disease.

Administration of Triton WR 1339 aggravates chronic aminonucleoside nephrosis.

Katsuya Obara, MD, Second Department of Internal Medicine, Tohoku University, School of Medicine, 1-1 Seiryo-cho, Aobaku, Sendai 980 (Japan) TR or Saline mini obtained before the initial AN administration and on days 10, 24, 42, 54, 66, 78 and 90. TC and TG levels were also assayed before and 1, 2 and 4 days after the initial TR injection. Renal tissues were removed for histology on day 90. Coronal sections were stained with periodic acid-Schiff, and more than 150 glom-eruli from each specimen were examined. Dear Sir, It has recently been suggested that abnormalities in lipid metabolism may play an important role in the pathogenesis of focal glom-erulosclerosis (FGS) [1]. Previous studies [2^‡] have shown that diet-induced hyperlipidemia aggravates various experimental FGS. On the other hand, it is known that Triton WR 1339 (TR), a nonionic detergent, produces hyperlipidemia when injected intravenously into experimental animals [5]. Therefore, we have examined by using the chronic aminonucleoside model whether TR-induced hyperlipidemia also aggravates FGS. Ten-week-old male Sprague-Dawley rats were first uninephrectomized and then injected with puromycin aminonucleoside (AN; 10 mg/day/kg body weight s.c.) for 4 days, and after a 10day interval, again with AN (now 5 mg) for 4 days. Twelve days after the last AN injection, TR at a dose of 250 mg/kg body weight dissolved in 0.9% saline or saline alone was intravenously injected, and the injection was subsequently repeated every 4 days for 2 months (fig. 1). Urine was collected over a 24-hour period. During the urine collection, rats were deprived of food, but had free access to water. Blood was obtained from the tail veins of rats subjected to light ether anesthesia at the end of the 24-hour period. Urinary protein and fasting serum total cholesterol (TC) and triglyceride (TG) levels were

Combination of vasopressin and angiotensin inhibition in experimental focal glomerulosclerosis

Summary: This study was designed to investigate the role of vasopressin and angiotensin II in the pathogenesis of focal glomerulosclerosis (FGS). A non‐peptide vasopressin VI antagonist (OPC‐21268) and an angiotensin converting enzyme inhibitor (ACE‐I) were administered either alone or in combination for 15 weeks to FGS, spontaneously hypercholesterolaemic rats. Treatment with the V1 antagonist (1% OPC‐21268) suppressed the rise in systolic blood pressure (SBP), serum triglyceride (TG), blood urea nitrogen (BUN) and serum creatinine (S‐Cr) levels, but not the elevations of urinary protein excretion (UPE) or serum total cholesterol (TC) levels. Morphologically, V1 antagonist significantly prevented an increase in the index of glomerular sclerosis (IS) and relative interstitial volume (RIV). In the low dose/high dose of V1 antagonist supplementation, the administration of 0.2% OPC‐21268 failed to suppress any increase in the SBP and TG levels, but significantly preserved renal function and attenuated renal lesions. In the combination study, rats were divided into four groups: (i) V1 antagonist (1% OPC‐21268); (ii) ACEI (imidapril, 5 mg/kg/per day); (iii) both treated groups; and (iv) an untreated control group. Angiotensin‐converting enzyme inhibitor significantly suppressed increases in SBP, UPE, TC, BUN, and S‐Cr levels compared with V1 antagonist. the combination therapy significantly enhanced these effects. Both agents significantly reduced IS and RIV, and combination therapy further reduced these levels. the results indicated that vasopressin, as well as angiotensin II, via the V1 receptor cause hypertension and renal injury in FGS rats. Vi antagonist and ACE‐I have antihypertensive and renoprotective effects in this FGS model, and enhanced their beneficial effects when used as combination therapy.

Sex Chromosomes Do Not Influence Renal Injury in Borderline Hypertensive Rats

The present study was undertaken to investigate whether the development of proteinuria in the borderline hypertensive rat (BHR) is influenced by the Y chromosome and to determine if the onset of prote