Influence of age on deterioration of the remnant kidney in uninephrectomized rats.

To investigate the influence of age on the remnant kidney, unilateral nephrectomy was performed in rats at 1 day (group N-0), 2 weeks (group N-2), 4 weeks (group N-4) or 8 weeks (group N-8) of age. Serial changes in urinary protein during 48 weeks after the uninephrectomy and blood chemistries and renal histology at week 48 were compared between the groups. The increase in proteinuria was significantly greater in groups N-0, N-2 and N-4 than in group N-8 from week 32 to week 48 after the uninephrectomy. There was no significant difference in urinary protein between groups N-0, N-2 and N-4. Hypoproteinaemia and hypoalbuminaemia were also more severe in groups N-0, N-2 and N-4 than in group N-8 at week 48. A compensatory renal growth in groups N-0 and N-4 was significantly greater than that in group N-8 at week 48 after the uninephrectomy. Focal and segmental glomerular sclerosis, a characteristic finding in the uninephrectomy groups, was significantly more marked in groups N-0, N-2 and N-4 than in group N-8 at week 48. We conclude that uninephrectomy at young ages leads to increased incidence of glomerular sclerosis in rats compared with uninephrectomy in the adult.

Incidence of strokes and its prognosis in patients on maintenance hemodialysis.

The incidences of cerebral hemorrhage (CH), cerebral infarction (CI) and subarachnoid hemorrhage (SAH) were examined retrospectively in patients with chronic renal failure on maintenance hemodialysis, followed for 13 years in our 26 satellite dialysis centers. During 10,364 patient-years of experience (PYE), CH developed in 66, CI in 16, SAH in 3 and unclassified stroke in 5 cases. The incidence was 637 per 10(5) PYE for CH and 154 for CI, the former being approximately 5 times and the latter one third of the incidence of CH or CI in the general population in Japan. Forty-six percent of fatal CH cases died within 24 hours and 73% within 3 days after the onset, while 13% of CI deaths died within 24 hours and 26% within 3 days. These data suggest that factors such as the regular use of heparin as an anticoagulant in hemodialysis patients or other inherent factors in these patients may increase vulnerability to CH and decrease the probability of CI.

Effect of hypertension on the progress and prognosis of experimental focal glomerular sclerosis.

Effect of hypertension on progressive renal disease was examined in spontaneously hypertensive rats (SHR) with experimental focal glomerular sclerosis, produced by the intravenous administration of adriamycin (ADR). Serial changes of urinary protein, blood pressure and blood chemistry for 22 weeks after ADR-treatment, and renal histology at week 22, were compared between ADR-treated SHR (group ADR-HT) and ADR-treated SHR given antihypertensive drugs (group ADR-AH). Hypertension persisted in group ADR-HT, while blood pressure markedly decreased in group ADR-AH, after oral administration of antihypertensive drugs (guanethidine and hydralazine). Massive proteinuria, hypoalbuminaemia and hypercholesterolaemia were observed throughout the experiment both in group ADR-HT and in group ADR-AH. Urinary protein levels were significantly larger in the former at weeks 12 and 16. Blood urea nitrogen and serum creatinine levels increased progressively from week 16 in the ADR-treated rats. The increase was more rapid in group ADR-HT than in group ADR-AH. In group ADR-HT, 10 of 25 rats died between weeks 20 and 22, whereas all in group ADR-AH survived. Histologically, ADR-treated rats showed focal glomerular sclerosis with tubulointerstitial changes. The lesions were more extensive in group ADR-HT than in group ADR-AH. We conclude that hypertension influences the progress and prognosis of chronic progressive renal disease, as induced by adriamycin.

Adriamycin-induced nephropathy as a model of chronic progressive glomerular disease.

Serial changes in urine protein, blood chemistry, and histology of the kidney were investigated in rats for 28 weeks after injections of adriamycin (ADR). Massive proteinuria, hypoalbuminemia, and hyperlipidemia were observed at week 4 and throughout the experiment. Both BUN and serum creatinine began to increase at week 16 and reached the uremic level at week 28. Light microscopic study of the kidney demonstrated a normal appearance at week 4, vacuole formation in glomerular tuft at weeks 8 and 12, focal and segmental glomerular sclerosis at weeks 16 and 20, and extensive glomerular sclerosis with tubulointerstitial degenerations at weeks 24 and 28. Immunohistologically, IgM with a small amount of IgG and C3 appeared in the sclerosing glomeruli from week 16. Aggregated human IgG, injected intravenously at week 24, had accumulated mainly in the glomeruli. Electron microscopy revealed degenerative changes of glomerular epithelial cells with small vacuoles in the cytoplasm at week 4. Size of vacuoles increased at the later stage. In conclusion, ADR produced chronic, progressive glomerular changes in rats, which led to terminal renal failure. The segmental glomerular sclerosis and IgM-dominant glomerular deposition in these animals are similar to pathological characteristics of focal and segmental glomerular sclerosis seen clinically.

Glomerulocystic kidneys. Report of an adult case.

Glomerulocystic kidney characterized by dilatation of Bowman's space occurs primarily in infants and children. We treated a normally developed 29-year-old Japanese man for hypertension and renal failure, who had been well up to 6 months before admission. Extrarenal malformations were not determined. A biopsy of both kidneys was done at the time of interdialysis, and the histology revealed diffuse glomerular cystic lesions. Electron-dense deposits were also observed in the mesangial area. Radiological studies of the kidneys showed numerous minute cysts in the cortical area, a normal architecture of the arterial trees, and negative evidence of urinary tract obstruction. This may be the first documentation of glomerulocystic kidney in an adult, without extrarenal anomalies.

Effect of blood pressure on the progress of renal deterioration in rats with renal mass reduction.

The effect of hypertension on the progress of renal deterioration with renal mass reduction was investigated in spontaneously hypertensive rats. Nephrectomies of five sixths, two thirds, and one third were performed. The antihypertensives guanethidine and hydralazine were given to half of the rats. Increase in urinary protein excretion and decreases in serum total protein and albumin were greater in rats with a larger nephrectomy. With the same extent of nephrectomy, these changes were severe in the group of rats with untreated hypertension, as compared with findings in rats given the antihypertensive drugs (AHD). Similar changes were obtained in BUN and creatinine levels. Only the animals with a five-sixths nephrectomy and hypertension became uremic. Glomerulosclerosis in five-sixths nephrectomized rats with hypertension was present in 71% of the glomeruli, whereas it was reduced to 34% in rats treated with AHD. The diameter of normal-appearing glomeruli increased significantly in rats with a large nephrectomy, but did not differ between the groups given or not given AHD. Medical thickening of the arterial walls, which increased with the reduction of renal mass, was significantly greater in five-sixths nephrectomized rats with hypertension than in those treated with AHD. These results indicate that a hyperdynamic state of the glomeruli, that is, a prominent urinary protein excretion and compensatory glomerular hypertrophy, may play a causative role in the progress of glomerulosclerosis in rats with extreme renal mass reduction. The hypertensive state may aggravate these renal dysfunctions.

Pharmacokinetics of a new angiotensin I converting enzyme inhibitor (alacepril) after oral dosing in fasting or fed states.

The plasma concentration and urinary excretion of a newly developed angiotensin I converting enzyme inhibitor, alacepril (which is converted to captopril after absorption), were investigated in seven normal healthy subjects. Fifty milligrams of the drug was administered orally either in the fasting or in the fed state. In the fasting state, the time of maximal plasma concentration (tmax) was 1 hour for free captopril, 1.7 hours for protein-conjugated captopril, and 1.6 hours for total captopril. The biologic t1/2 of free, protein-conjugated, and total captopril was 1.9, 4.2, and 5 hours, respectively. In the fed state, neither tmax nor t1/2 changed, except that the tmax of free captopril was prolonged to 1.9 hours (P less than 0.01). Cumulative urinary excretion of free captopril at 8 hours was 35% of the drug administered in the fasting state and that of total captopril at 24 hours was 59%. These data did not differ significantly from those obtained after food intake. The biologic t1/2 of free captopril after alacepril dosing was longer than in previous studies of captopril per se. Because biologic or clinical effects have not been studied, it should be left conjectural whether alacepril is a longer-acting angiotensin I converting enzyme inhibitor. A prolonged effect of the drug can be expected by its administration after a meal.

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 Bowman's 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.

Necrotizing vascular lesions in spontaneously hypertensive rats with nephrotic syndrome: hypercoagulability as a contributory factor.

Heymann nephritis was induced in rats with spontaneous hypertension (group HN), and renal lesions were investigated at the twentieth and thirty-sixth week. An identical group given antihypertensive drugs (group HN-AH), an identical group given anticoagulant drugs (group HN-AC), and a nonimmunized control group of spontaneously hypertensive rats (controls) were also examined. Massive proteinuria, hypoalbuminemia, and hyperlipidemia were present in groups with induced Heymann nephritis (HN, HN-AH, and HN-AC). Coagulation studies demonstrated a shortening of prothrombin time, an increase in serum fibrinogen and thrombocytes, and a reduction of antithrombin III in the groups HN and HN-AH. Necrotizing lesions were observed only in group HN and without further elevation in blood pressure. Intravascular thrombosis was prominent at the twentieth week, and marked fibrinoid necrosis appeared at the thirty-sixth week. These vascular lesions were not observed in the HN-AH, HN-AC, and control groups. Thus, a state of hypercoagulability in addition to high blood pressure probably contributes to the genesis of necrotizing vascular lesions in spontaneously hypertensive rats with nephritis.