Kohei Uriu

Renal hemodynamics in Otsuka Long-Evans Tokushima fatty rat, a model rat of spontaneous non-insulin-dependent diabetes mellitus with obesity

Renal hemodynamic features in obese non-insulin-dependent diabetic rats remain unknown. We investigated renal hemodynamic and morphologic changes in Otsuka Long-Evans Tokushima Fatty (OLETF) rats at the age of 5 and 10 months compared with age-matched lean nondiabetic control rats (LETO). OLETF rats showed obesity compared with age-matched LETO rats. Hyperglycemia was mild in 5-month-old OLETF rats and moderate in 10-month-old OLETF rats. The absolute value for glomerular filtration rate (GFR) was significantly higher in OLETF rats than in age-matched LETO rats at the age of 5 and 10 months. Ten-month-old OLETF rats had significantly higher absolute values for renal plasma flow (RPF) than age-matched LETO rats but not 5-month-old OLETF rats. Stepwise multiple regression analysis revealed that body weight was a powerful determinant of GFR and RPF. When factored for body weight, no difference in GFR was demonstrated between 5-month-old OLETF and LETO rats, whereas 10-month-old OLETF rats still had significantly higher GFR and RPF than age-matched LETO rats. Renal hypertrophy was demonstrated in both 5- and 10-month-old OLETF rats even when factored for body weight. Glomerular volume was significantly increased in 10-month-old OLETF rats, but the ratio of glomerular volume to body weight was not different among the groups. Both absolute value for glomerular capillary length free from mesangial area and the value factored for glomerular area were significantly longer in OLETF rats than in age-matched LETO rats. Mesangial matrix expansion was remarkable in 10-month-old OLETF rats, and the glomerular sclerosis index was significantly higher in 10-month-old OLETF rats than in age-matched LETO rats. Stepwise multiple regression analysis revealed that body weight, hemoglobin A1c, and hypertriglyceridemia were powerful determinants for kidney weight and glomerular volume. These data suggest that renal hyperfiltration and hypertrophy observed in 10-month-old OLETF rats are related to diabetic metabolic disorders and that obesity-related conditions may be involved in the renal hemodynamic and morphologic features in OLETF rats.

Clinical significance of urinary enzymes in diabetic nephropathy

Urinary enzyme activities (N-acetyl-beta-D-glucosaminidase [NAG], alkaline phosphatase [ALP], leucine aminopeptidase [LAP], gamma-glutamyl transpeptidase [gamma-GTP]) were investigated to determine their clinical significance in diabetic nephropathy. There were correlations among ALP, LAP, and gamma-GTP, though no correlation existed between NAG and the other three enzymes. Activities of NAG isozymes (both A and B) were higher than in normal controls. It has been reported that NAG isozyme A might be associated with glomerular diseases, and isozyme B might be associated with proximal tubular damage. The results of our study suggest that NAG reflects lysosomal dysfunction of both glomerular and proximal tubular epithelial cells, which may be caused by poor glycemic control, and that ALP, LAP, and gamma-GTP reflect brush border damage of proximal tubules, which may be caused by diabetic nephropathy.

The characteristics of renal hemodynamics in diabetic spontaneously hypertensive rats in comparison with diabetic Wistar-Kyoto rats

Diabetic Sprague-Dawley (SD) rats are known to exhibit renal hyperfiltration and hyperperfusion accompanied by renal hypertrophy. We examined whether such characteristics of renal hemodynamics in diabetic SD rats are also observed in diabetic spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. SHR and WKY rats were divided into four groups: D-S, diabetic SHR; N-S, nondiabetic SHR; D-W, diabetic WKY rats; and N-W, nondiabetic WKY rats. Streptozotocin (STZ), 90 mg, was intraperitoneally injected to induce diabetes. Renal blood flow (RBF) and glomerular filtration rate (GFR) were measured by a clearance method with paraaminohypurate and insulin, respectively, 7-12 days after diabetes induction. In D-S and D-W, there was no increase in the kidney weight and RBF, in spite of significant increases in GFR and fasting blood sugar levels. These results indicate that, in both WKY and SHR, diabetes does not always produce renal hypertrophy and does not result in an increase in RBF.

Effect of Acute Thromboxane A2 Inhibition on the Renal Hemodynamics in a Spontaneously Non–Insulin-Dependent Diabetic Rat, Otsuka Long-Evans Tokushima Fatty Rat

Thromboxane (TX) A2 plays important roles on renal injuries in streptozotocin (STZ)-induced diabetic rats, whereas its role on the renal injuries in non-insulin-dependent diabetic (NIDDM) rats remains unknown. We evaluated the effects of an intravenous infusion of TXA2 synthetase inhibitor (OKY-046, 6 mg/kg/h) on the clearances on inulin and para-aminohippurate (Cin, C(PAH)) in a spontaneously NIDDM rats, Otsuka Long-Evans Tokushima Fatty (OLETF) rats (n = 8), and Long-Evans Tokushima Otsuka (LETO) rats (n = 7), served as control rats, at the age of 40-44 weeks. OLETF rats showed obesity, moderate hyperglycemia, and hyperinsulinemia. Urinary excretion of TXB2 was slightly higher and the ratio of TXB2 to 6-keto prostaglandin F1alpha (6-kPG) was significantly higher in OLETF rats (TXB2/6-kPG: 0.22 +/- 0.04 versus 0.12 +/- 0.02, P < 0.05). Both Cin and C(PAH) were significantly higher in OLETF rats than in LETO rats (Cin: 1.1 +/- 0.1 versus 0.7 +/- 0.1 mL/min/100 g BW, C(PAH): 3.1 +/- 0.2 versus 2.3 +/- 0.3 mL/min/100gBW, P < 0.01). OKY-046 did not restore Cin and C(PAH) in OLETF rats although it significantly decreased urinary excretion of TXB2, and thus ameliorated TXB2/6-kPG in OLETF rats. These data suggested that TXA2 was not involved in the renal hyperfiltration in OLETF rats at the age of 40-44 weeks, and that TXA2 might contribute to renal injuries in OLETF rats through mechanisms other than hemodynamic injury.

Acute effect of calcium blocker on renal hemodynamics in diabetic spontaneously hypertensive rat.

This study was done to examine the acute effect of a calcium channel blocker on renal hemodynamics in the diabetic spontaneously hypertensive rat (SHR). Streptozotocin was used to induce diabetes, and barnidipine (B) was used as a calcium blocker. Renal blood flow (RBF) and glomerular filtration rate (GFR) were measured by a clearance method with paraaminohypurate (PAH) and inulin, respectively. Rats were divided into two groups: nondiabetic SHR, N-SHR; diabetic SHR, DM-SHR. B increased RBF in N-SHR (7.44 +/- 1.99 versus 8.50 +/- 1.97 mL/min/g.kw) while there was no change in DM-SHR. B reduced renovascular resistance (RVR) in DM-SHR and N-SHR. B increased GFR in N-SHR (1.15 +/- 0.24 versus 1.34 +/- 0.25 mL/min/g.kw), in spite of no changes in DM-SHR. B did not modify filtration fraction (FF) in both groups. These results indicate (1) in SHR, B exerts beneficial effects on hypertensive renal damage by reducing mean arterial pressure (MAP), RVR, RBF, and GFR; (2) in diabetic SHR, B is less effective in restoring renal hyperfiltration in spite of reducing RVR.

Comparison of the renal effects of different angiotensin-converting enzyme inhibitors in patients with chronic renal diseases

AbstractBackground. Angiotensin-converting enzyme inhibitors (ACE-Is) are important agents for preserving renal function in patients with renal diseases. However, the choice of which ACE-I to employ for the treatment of renal disease has not yet been clarified. This study compared the renal effects of enalapril with those of five other ACE-Is in patients with chronic renal diseases. Methods. One hundred and twenty-eight patients with various renal diseases were randomly assigned to six groups according to the ACE-I used: group 1, alacepril (75 mg/day; n = 20); group 2, captopril (37.5 mg/day; n = 19); group 3, cilazapril (1.0 mg/day; n = 23); group 4, delapril (30 mg/day; n = 22); group 5, enalapril (5.0 mg/day; n = 20); and group 6, temocapril (2.0 mg/day; n = 24). Doses of the ACE-I adjusted-converting to the renal function showed similar effects in decreasing blood pressure. Each ACE-I was administered to the patients for 4 months, with monthly examinations. Twenty-four patients dropped out, for various reasons; therefore, results for 104 patients were finally analyzed (group 1, n = 16; group 2, n = 11; group 3, n = 22; group 4, n = 21; group 5, n = 12; group 6, n = 22). Results. There were no differences in absolute or percent changes in mean arterial pressure (MAP), plasma aldosterone (ALDO), the urinary excretion of protein (U-P) and albumin (U-ALB), 24-h creatinine clearance (24-h Ccr), plasma renin activity (PRA), and serum potassium (K) between enalapril and the other ACE-Is, although significant decreases from baseline values in MAP, ALDO, U-P, U-ALB, and 24-h Ccr, and increases in PRA and serum K from baseline values were observed after the administration of enalapril and the other ACE-Is. Conclusions. These results indicated that the renal effects of enalapril were similar to those of the other ACE-Is tested, and suggested, therefore, that any one of the class of ACE-Is could be chosen with the choice being dependent on that considered to lead to best compliance for the patient. The beneficial effects of the class of ACE-Is in patients with renal disease would be expected to be similar.

Clinical Profiles and Outcomes of End-Stage Renal Failure Patients with Late Initiation of Renal Replacement Therapy Based on Uremic Symptoms under Intensive Renoprotective Therapies

Aim: This study describes the clinical profiles and outcomes of renal failure patients with late initiation of renal replacement therapies (RRT) based on uremic symptoms under intensive treatment prior to the start of RRT (IT). Methods: Thirteen patients (male 10, female 3) with end-stage renal disease who preferred to wait for the initiation of RRT until uremic symptoms appeared regardless of serum creatinine (s-Cr) and 24-hour creatinine clearance (24-hour Ccr) were chosen. All patients received IT including a low-protein diet, antihypertensive drugs including enalapril, erythropoietin and others to prevent and manage uremic states until the initiation of RRT. Clinical findings at the initiation of RRT and the outcomes after the start of RRT were examined. Results: RRT was initiated 23.6 ± 16.9 months after IT without any complication in all patients when mild uremic symptoms appeared. Uremic symptoms, blood pressure, serum albumin, potassium, calcium and urinary Cr excretion were well controlled except inorganic phosphate, hemoglobin and cardiac size. 24-hour Ccr and s-Cr were 3.4 ± 0.7 ml/min and 17.4 ± 3.8 mg/dl at initiation of RRT. The outcomes of all the patients were all well during chronic RRT. Conclusion: Intensive treatment prior to the start of RRT can diminish uremic symptoms and complications so that RRT might be initiated safely and with fewer problems, even in the face of lower 24-hour Ccr and markedly higher s-Cr.

Measurement of urinary albumin using newly developed enzyme immunoassay in the rat

AbstractBackground. Since it is well known that microalbuminuria predicts the late development of diabetic nephropathy, the measurement of urinary albumin (Ualb) is important in human diabetic nephropathy. Ualb also increases in diabetic rats and the measurement of Ualb in the rat is important to determine diabetic nephropathy. Many methods have been developed for measuring human Ualb. However, there are few methods for rat Ualb assay. Since specific antialbumin antibody for rat should be used, the aim of this study was to basically evaluate a new enzyme immunoassay for determining Ualb in rats. Methods. 24-h urine samples from male Sprague-Dawley (SD) rats and diabetic spontaneously hypertensive rats (SHR) were collected and measured. Results. (1) Assay sensitivity was 16 ng/ml. (2) The urinary pH and presence of coexistent substances such as bovine serum albumin, glucose, urea, bilirubin, and hemoglobin, did not influence the Ualb measurement. (3) No changes were observed in Ualb after 28-day storage at 4°C, −20°C, or −80°C. (4) The coefficient of variation between 2.2 and 8.2% was 3.3 ± 0.9%. (5) The entire assay, including sample preparation, reagent addition, incubation, and end-point determination, can be completed within 90 min. (6) Ualb increased in SHR induced by streptozotocin compared with findings in non-diabetic SHR. Conclusions. These data demonstrated that this method for the measurement of rat Ualb, is rapid, accurate, and sensitive, and it should also be helpful in the field of research in experimental diabetic nephropathy.

Shor- and long-term effect of a calcium channel blocker, barnidipine, on renal hemodynamics in spontaneously hypertensive, diabetic rats

BackgroundThe purpose of this study was to examine the short- and long-term effects of the calcium channel blocker, barnidipine, on renal hemodynamics and urinary albumin excretion in spontaneously hypertensive rats with streptozotocin-induced diabetes.MethodsDiabetic and nondiabetic spontaneously hypertensive rats and nonhypertensive rats were treated with barnidipine or placebo (vehicle). In the short-term experiment, barnidipine was given as a single bolus injection (3 μg/kg); in the long-term experiment, barnidipine was administered orally (15 mg/kg per day) for 16 to 20 weeks.ResultsRenal hyperfiltration was observed in both hypertensive and nonhypertensive rats at 1 to 2 weeks after induction of diabetes, without changes in renal blood flow. Although short-term administration of barnidipine significantly decreased mean arterial pressure and renal vascular resistance, barnidipine did not affect renal blood flow or glomerular filtration rate in hypertensive, diabetic rats. At 16 to 20 weeks after induction of diabetes, renal hyperfiltration and increased urinary albumin excretion were still observed in hypertensive rats given placebo, compared to values for hypertensive nondiabetic rats given placebo. Long-term administration of barnidipine to hypertensive, diabetic rats suppressed the increase in both glomerular filtration rate and urinary albumin excretion, and reduced systolic blood pressure without any change in renal blood flow, renal vascular resistance, or filtration fraction.ConclusionsThese results indicate that in hypertensive, diabetic rats short-term administration of barnidipine, despite reducing renal vascular resistance, is less effective than long-term administration in restoring normal renal filtration, although long-term administration may normalize renal filtration and reduce urinary albumin excretion.

Acute renal failure prior to the onset of hepatic encephalopathy in fulminant hepatitis

Summary: We investigated the clinical characteristics of eight patients with fulminant hepatitis who developed acute renal failure (ARF). They were divided into two groups according to the time point when ARF occurred in the course of the disease: (i) group 1 (n=4), ARF occurred prior to the onset of hepatic encephalopathy; and (ii) group 2 (n=4), ARF occurred after the onset of hepatic encephalopathy. All cases in group 1 had an acute type of fulminant hepatitis, whereas a subacute type was present in the patients in group 2. All cases in group 1 and two cases in group 2 were given non‐steroidal antiinflammatory drugs before the onset of ARF. Urinary findings and/or renal biopsy findings suggested that acute tubular necrosis was the cause of ARF in group 1. Three patients in group 1 and none in group 2 recovered from both ARF and fulminant hepatitis. Although it is well‐known that a patient with fulminant hepatic failure complicated by ARF has a poor prognosis, our findings suggest that ARF that occurs prior to the onset of hepatic encephalopathy in acute type of viral fulminant hepatitis is not a determinant of the poor prognosis, and that the prognosis will be improved by intensive care.