Yukinori Oh

Germanium dioxide-induced nephropathy: a new type of renal disease.

Chronic renal failure developed in 5 patients who were taking germanium dioxide (GeO2)-containing compounds. Renal functional deterioration was slow but progressive and dialysis treatment was necessitated temporarily in 2 patients. After the discontinuation of GeO2, the impaired renal function tended to improve but remained abnormal for an observation period of 10-40 months. The lack of proteinuria and hematuria was characterized as the clinical manifestations. Renal biopsy specimens revealed the tubular epithelial cell degeneration containing hematoxylin-positive fine granules on light microscopy, and electron-dense inclusions in the swollen mitochondria on electron microscopy. These findings localized mainly in distal segment of the tubules. In the rats given GeO2 orally for 10 weeks, similar histological lesions were evident, as manifested by marked weight loss, anemia, azotemia, and negative proteinuria. In the rats given carboxyethylgermanium sesquioxide, these changes were not observed and Ge concentration of kidney was significantly lower than in the rats given GeO2. The present study indicates that chronic GeO2 intake causes progressive renal dysfunction characterized by the degeneration of distal tubules.

Cerebral hemorrhage in patients on maintenance hemodialysis. CT analysis of 25 cases

Site of hematoma and clinical outcome in cerebral hemorrhage were analyzed in 25 maintenance hemodialysis (HD) patients and compared with those in 27 non-HD patients. Ganglionic-thalamic hemorrhage was found in 56% of HD and 74% of non-HD patients, lobar hemorrhage in 36% and 11%, respectively. Size of hematoma, expressed as a ratio (%) of hematoma area to entire brain on CT slice, was 6.5 +/- 4.2% (mean +/- SD) in HD, being significantly larger than that of 4.7 +/- 3.5% in non-HD patients (p less than 0.05). Mortality rate was 60% in HD patients, nearly twice as much as the 33% in non-HD patients. The hematomas were significantly larger in the death cases (8.4 +/- 3.7%) than the survivors on HD (3.6 +/- 3.1%, p less than 0.005). Likewise, the fatal cases in the non-HD group had bigger hematomas (6.9 +/- 4.3%) than the non-fatal ones (3.6 +/- 2.4%, p less than 0.05). Intraventricular hemorrhage (IVH) was found in 40% of HD and 44% of non-HD patients. Hematomas were significantly larger in HD patients with IVH (9.3 +/- 3.3%) than in those without IVH (4.6 +/- 3.7, p less than 0.005). Ninety percent of the HD patients with IVH but only 42% of non-HD patients died of hemorrhage. Hypertension was equally seen in HD (76%) and non-HD patients (74%). It is concluded that in HD patients cerebral hemorrhage is more severe in terms of hematoma size, association of IVH and clinical outcome. Chronic systemic heparinization might be responsible to the severity in HD patients.

Dose dependency of germanium-dioxide-induced nephrotoxicity in rats.

The dose dependency of germanium dioxide(GeO2)-induced nephrotoxicity was investigated experimentally in rat groups orally treated with high (150 mg/kg/day), moderate (75 mg/kg/day), or low (37.5 mg/kg/day) doses of GeO2, and in an untreated group. Renal dysfunction, indicated by the increase of blood urea nitrogen and the decrease of creatinine clearance, and systemic toxicity by weight loss, anemia, and hypoproteinemia were more apparent in rats treated with higher dose of GeO2. Urinalysis including daily urinary protein excretion did not reveal any abnormalities in any of the groups. Urinary excretion and renal-tissue content of Ge were significantly elevated in the group of the higher dose of GeO2. Light microscopically, vacuolar degeneration and depositions of granules positive for periodic acid-Schiff in distal tubules were predominant in the higher-dose group of GeO2. The present study demonstrates that GeO2-induced nephrotoxicity develops dose dependently.

Rapidly Progressive Renal Deterioration in Partially Nephrectomized Rats with Experimental Membranous Nephropathy

The effects of nephron loss on the clinical and histological picture of experimental membranous nephropathy were examined for 18 weeks in five-sixths nephrectomized rats with Heymann nephritis (HN-5/6N group). Heymann nephritis-induced rats without nephrectomy (HN group), normal rats with 5/6 nephrectomy (5/6N group) and normal rats without nephrectomy (control group) were also examined for comparison. A rapidly progressive increase in urinary protein, BUN and serum creatinine was observed after renal ablation in the HN-5/6N group. Light microscopic study revealed global or segmental sclerosis in most of the glomeruli, crescent formation in some of the glomeruli and marked tubulointerstitial changes. Electron microscopic study demonstrated vacuolation and necrosis of podocytes, detachment of podocytes from the glomerular basement membrane (GBM) and fibrin exudation into Bowmans space. Proteinuria was also marked but renal function was not impaired in the HN group. In the 5/6N group, proteinuria was mild and elevation in BUN and serum creatinine was apparent but not progressive. There were no differences in the depositions of IgG, C3 and electron-dense materials on GBM between the HN-5/6N group and the HN group. In conclusion, renal mass reduction associated with high flow and pressure to the remnant glomeruli could lead to extensive glomerular sclerosis and to a deterioration in renal function, in the case of pre-existing nephritic lesions.

Hydrocephalus Associated with Malignant Hypertension and Renal Failure

Masakazu Washio, MD, 2nd Department of Internal Medicine, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812 (Japan) Dear Sir, It has been reported that autopsy findings of patients who died of malignant hypertension (MHT) demonstrated increased brain weight, flattened gyri, and compressed ventricles [1]. Hypertensive encephalopathy sometimes develops during the course of renal diseases [1]. It is often difficult to decide upon the relative significance of uremia and hypertension per se in the genesis of symptoms of MHT associated with uremia [2]. The presented patient had hydrocephalus which was associated with MTH and renal failure and cured by antihyperten-sive therapy and dialysis treatment. A 25-year-old male with a history of glomerulonephritis was admitted to the Fukuoka Red Cross Hospital on June 21, 1988, because of MHT, renal failure, and unconsciousness. On June 13, 1988, he noticed headache. On the next day, he developed blurred vision. On June 19, he was admitted to another hospital because of severe headache, nausea, and vomiting. The blood pressure was 244/178 mm Hg. On June 20, he became delirious. Computed tomography (CT) scanning of his brain showed no hemorrhage but flattened gyri and dilated ventricles (fig. 1A-C). Blood chemistry showed elevations in blood urea nitrogen and creatinine (101 and 13.6 mg/dl, respectively). On June 21, he became somnolent and was transferred to our institution. On admission he was drowsy. The blood pressure was 248/130 mm Hg. Ophthalmological investigation showed round pupils and retinal hemorrhage and papilledema bilaterally. Chest and abdomen were normal. The tendon reñexes of the extremities were symmetrical, and no abnormal reflexes were found. The white blood cell count was 16,800/mm3, hemoglobin 12.2 g/dl, blood urea nitrogen 129 mg/dl, and creatinine 15 mg/dl. Peritoneal dialysis was started on June 21, the day of admission to our institution. With 10 mg of nifedipine four times daily and peritoneal dialysis, the blood pressure fell, and the disturbance of consciousness improved; the patient became alert on the 3rd hospital day. On the 4th hospital day, nifedipine was decreased from 10 mg four times daily to 10 mg twice daily and 100 mg of atenolol was added. Following atenolol treatment, the blood pressure remained at 140–170/70–

Effect of vitamin C supplementation on renal oxalate deposits in five-sixths nephrectomized rats

We have previously reported that hyperoxalemia can be aggravated by vitamin C supplementation in regular hemodialysis patients. The present study was undertaken to examine the validity of this observation in an experimental setting. Fifty five-sixths nephrectomized rats were divided into two groups: 30 rats were allowed free access to water containing 8 mg/ml of vitamin C (100-160 mg/100 g/24 h) and the remainder given tap water without vitamin C. The serum creatinine increased and the Hct decreased gradually; however, there was no difference between the two groups. Plasma vitamin C, oxalate and urinary oxalate levels were higher in the vitamin -treated group than the nontreated rats. Histological examination revealed glomerular and interstitial fibrosis and round cell infiltration as well as tubular cyst formation. Oxalate deposits in renal tubules were found only in vitamin C-treated rats with advanced renal failure. Nontreated animals with equally advanced renal impairment showed no oxalate deposits. These results confirm our previous clinical findings that vitamin C supplementation aggravates the secondary oxalosis of chronic renal failure.

Effects of acute reduction in blood pressure on the renal function of rats with diseased kidneys

We studied the effect of an acute reduction in blood pressure, induced by diltiazem, on the renal hemodynamics of spontaneously hypertensive rats (SHR) with focal glomerular sclerosis, as induced by adriamycin (ADR). Renal plasma flow (RPF) and glomerular filtration rate (GRF) were determined before (first period) and during (second period) intravenous infusion of diltiazem in SHR 4-6 weeks after ADR treatment (group 1), 14-20 weeks after treatment (group 2), and in controls without treatment (group 3). Rats in group 1 had a normal renal function (RPF and GFR) in the first period, which was not significantly different from control rats (group 3). Rats in group 2 showed a reduced renal function, reflected by the lower levels of RPF and GFR, compared with groups 1 and 3. Mean blood pressure decreased equally in the 3 groups by about 50 mm Hg after the infusion of diltiazem. During the second period, 13.4 or 12.4% increase in RPF and a 29.0 or 23.2% elevation of GFR were evident in groups 1 or 3, respectively. In contrast, a 32.0% reduction of RPF was observed in group 2, accompanied by a 25.7% decline of GFR. A reduction in renal function (percent change of RPF or GFR) significantly correlated with the severity of renal dysfunction (RPF or GFR in the first period) in group 2. Thus, the renal function of rats with diseased kidneys is sensitive to an acute reduction in blood pressure by diltiazem, and the sensitivity depends on the degree of renal deterioration.

Autologous Immune Complex Nephritis in Streptozotocin-Induced Diabetic Rats

In order to investigate the influence of diabetes mellitus on immune complex-mediated nephritis , we produced Heymann nephritis in streptozotocin-induced diabetic rats (DM-HN group) in which the clinical course for 24 weeks and histological changes were examined. Nondiabetic rats with Heymann nephritis (HN group) and diabetic rats (DM group) were also examined as controls. The degree of proteinuria, hypoproteinemia, hyperlipidemia and anemia were more pronounced and the mortality rate was higher in the DM-HN group than in the HN group or in the DM group. Histologically, larger and more subepithelial or intramembranous electron-dense deposits as well as a more markedly thickened glomerular basement membrane (GBM) were observed in the DM-HN group than in the HN group. In conclusion, the nephrotic manifestations and histological changes in the GBM in Heymann nephritis were augmented by the association with diabetes mellitus.

THREE-YEAR OUTCOME AFTER URINARY DIVERSIONS IN PATIENTS WITH OBSTRUCTIVE UROPATHY

Obstructive uropathy accounts for less than 5% of all instances of acute renal failure [1] and the causes are genitourinary tract malignancies, benign prostatic hypertrophy, urolithiasis, or retroperitoneal mass, and it is more common in the elderly [2–4]. The clinical courses progressing to an established renal failure are known to be either rapid or insidious, depending on the duration to the completion of the bilateral urinary tract obstruction. Urinary diversions such as nephrostomy or retrograde ureteral catheterizations are effective and the renal function usually recovers with a marked diuresis [5, 6]. The mortality rate is reported to be 50% at 3 months or 90% at 1 year in cases of malignancy-induced obstructive uropathy [7, 8].

Beneficial Effect of Aluminum Hydroxide on Progress of Adriamycin-Induced Nephropathy in Rats

To investigate the effect of phosphate binder on adriamycin (ADR)-induced nephropathy, serial changes in renal histology and renal hemodynamics were compared between ADR rats treated with aluminum hydroxide (ADR-AH group) and those without AH (ADR group) for 24 weeks. Urinary protein excretion was less marked in the ADR-AH group than in the ADR group. Serum creatinine in the ADR group increased progressively from week 20, while in the ADR-AH group the increase was less. There were no significant differences in glomerular filtration rate or renal plasma flow between the both groups until week 12 but these parameters decreased to the significantly lower levels at week 24 in the ADR group. Vacuolative degeneration in glomerular epithelium, which was determined as an initial renal lesion, was more marked in the ADR group compared to the ADR-AH group. Glomerular sclerosis and tubulointerstitial changes developed progressively in the ADR group at the later stages. These changes were lessened in the ADR-AH group. In conclusion, AH prevents the progress in ADR-induced nephropathy. The beneficial effects appeared as the preservation of glomerular epithelial cells.