Kenichi Motomura

Worsening of anemia by angiotensin converting enzyme inhibitors and its prevention by antiestrogenic steroid in chronic hemodialysis patients.

The effects of angiotensin converting enzyme (ACE) inhibitors and their combined use with an antiestrogenic steroid on erythropoiesis were investigated in patients on chronic hemodialysis (CHD). Hematocrit was decreased by 10% or more in 6 of 12 patients who received either captopril or enalapril for 2–6 months. Erythropoietin (Epo) and angiotensin II (AH) were significantly reduced in these patients. When treatment with mepitiostane was combined with ACE inhibitor, anemia was significantly improved but without evidence of changes in circulating Epo concentrations or indices of renin-angiotensin activity. The reduction of AN and Epo formation by ACE inhibitors seems to play an important role in the worsening of anemia in patients on CHD; addition of an antiestrogenic steroid should be considered.

High Incidence of Glomerular Sclerosis in Rats Subjected to Uninephrectomy at Young Age

To examine the effect of age on a compensatory renal growth, adaptive renal hemodynamics and renal histology in solitary kidney, unilateral nephrectomy was performed in young rats at 4 weeks of age (group 4-UN) or in adult rats at 10 weeks of age (group 10-UN). Urinary protein was measured every 4 weeks until the 48th week. Serial changes in kidney weight, glomerular filtration rate (GFR), renal plasma flow (RPF) and renal histology were investigated at weeks 4, 8, 24 and 48 after the uninephrectomy. Increase in proteinuria was significantly greater in group 4-Un than in group 10-UN from weeks 32-48 after uninephrectomy. The remnant kidney showed a compensatory enlargement which was more marked in group 4-UN than in group 10-UN at weeks 24 and 48. GFR or RPF in group 4-UN was significantly greater than that in group 10-UN at weeks 4, 8, and 24. Focal and segmental glomerular sclerosis was evident at week 24 or later in the uninephrectomized rats, being more severe in group 4-UN than in group 10-UN at week 48. We conclude that uninephrectomy in young rats leads to augmented compensatory renal growth and glomerular hyperperfusion, resulting in extensive glomerular sclerosis compared to that in adult rats.

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.

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 t½ of free, protein‐conjugated, and total captopril was 1.9, 4.2, and 5 hours, respectively. In the fed state, neither tn, nor t½ changed, except that the tmax of free captopril was prolonged to 1.9 hours (P < 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 t½ 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.

Effect of Phosphate Binders on the Course of Chronic Renal Failure in Rats with Focal Glomerular Sclerosis

To investigate the effect of phosphate binders on the progress of renal functional deterioration, aluminium hydroxide (AL) or calcium carbonate (CA) was administered to adriamycin (ADR)-induced progressive renal failure model rats. Urinary protein excretion was reduced in ADR rats treated with AL (ADR-AL group) or CA (ADR-CA group), compared to those without the treatment (ADR group). Urinary phosphate excretion, serum phosphate concentration, and calcium-phosphate product were significantly lower in the ADR-AL and ADR-CA groups than in the ADR group. At week 34, increased serum creatinine, glomerular sclerosis and tubulointerstitial alterations, being marked in the ADR group, were ameliorated in the ADR-AL and ADR-CA groups. However, there was no significant difference in body weight and serum total protein among the three groups. We conclude that AL and CA could both prevent chronic progressive renal deterioration in focal glomerular sclerosis induced by ADR, and preserve the nutritional condition.

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.

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.