Stanley M. Lee

Prevention of Diabetic Nephropathy by Diet Control in the db/db Mouse

Diabetes in the C57BL/KsJ(db/db) mouse is initially expressed as hyperinsulinemia, followed by hyperphagia, progressive obesity, and widespread pathologic abnormalities. This study was designed to evaluate the effects of metabolic control on the natural history of the diabetic nephropathy. Beginning at 1 mo of age and continuing for 12 wk, diabetic mice were subjected to controlled dietary restriction, such that their weight was maintained similar to that of age-matched, nondiabetic heterozygotes. Diet-restricted diabetics were compared with diabetics fed ad libitum and heterozygote nondiabetics. Significant lowering of fasting blood glucose, water intake, and plasma insulin was achieved by diet restriction. The diet-restricted diabetics demonstrated enhanced metabolic efficiency, consuming approximately half as much food as the nondiabetics, while maintaining a similar weight. Diabetics fed ad libitum evidenced well-defined renal lesions that included 3+ to 4+ immunoglobulin deposition in the glomerular mesangium, and generalized mesangial matrix expansion. These lesions were completely prevented in diet-restricted diabetics whose glomeruli were normal by light microscopy, and demonstrated trace to 1 + mesangial immunoglobulin deposition, features identical in all respects to the nondiabetics. These results indicate that diabetic control achieved by prevention of obesity in the db/db mouse prevents the development of diabetic nephropathy.

L-dopa in uremic patients with the restless legs syndrome

Restless legs syndrome (RLS) is a poorly understood, often distressing condition that is particularly prevalent among patients with chronic renal failure. A wide variety of medications have been used to treat RLS with variable results. In order to evaluate the efficacy of carbidopa/levodopa therapy, eight consecutive uremic patients with RLS on maintenance hemodialysis were treated with doses ranging from 25/100 to 25/250 twice daily. Six of eight patients obtained satisfactory relief which has continued for 3 months follow-up. Carbidopa-levodopa appears to be an effective opinion in management of RLS in patients with chronic rental failure.

Clodronate kinetics and dynamics

Clodronaie disodium (C12MDP) was given intravenously in doses of 3, 6, and 10 mg/kg to six men (aged 23 to 30 yr). Volume of distribution was 0.2720 ± 0.0255 l/kg (x̄ ± SD) after 3 mg/kg dose, 0.3037 ± 0.0445 l/kg after 6 mg/kg, and 0.2528 ± 0.0417 l/kg after 10 mg/kg. The elimination rate constant was 0.3787 ± 0.0546 hr−1, 0.3492 ± 0.0616 hr−1, and 0.3962 ± 0.0358 hr−1 after 3, 6, and 10 mg/kg. Corresponding total body clearances were 0.1026 ± 0.0149, 0.1049 ± 0.0159, and 0.0998 ± 0.0172 1/kg/hr. Renal clearance accounted for 73% of total body clearance; 73% of the drug was excreted unchanged in the urine in 24 hr. After Cl2MDP serum phosphate decreased approximately 13%; this was associated at the 10 mg/kg dose with a transient fall in fractional phosphate excretion. There were no significant changes in the serum concentration or fractional excretion of calcium, sodium, or uric acid. Creatinine clearance and renal concentrating ability were not altered by Cl2MDP. After short‐term administration Cl2MDP is excreted primarily by the kidney but has no significant effects on renal function.

The effect of alpha-glucosidase inhibition on intestinal disaccharidase activity in normal and diabetic mice

Abstract Acarbose is a potent alpha-glycosidase inhibitor which decreases postprandial hyperglycemia when administered with a carbohydrate-containing meal. The genetically diabetic mouse C57 BLKsJ db/db represents a model of type II, noninsulin dependent diabetes mellitus. Characteristic features of this animal include hyperglycemia, hyperinsulinemia, hyperphagia, and the development of obesity and widespread pathologic abnormalities. To evaluate the effects of Acarbose on intestinal disaccharidase activity, groups of normal and diabetic mice were given Acarbose as a drug-food mixture in doses of 20 (A-20) and 40 (A-40) mg 100 g food. Sucrase activity was measured in intestinal homogenates and on the mucosal surface of proximal, middle, and distal segments of jejunoileum. In normal mice, sucrase activity was significantly increased in mid- and distal-intestinal segments following 2 wk of Acarbose in both A-20 and A-40 groups. No changes were noted following 5 and 10 days of drug treatment. Acarbose did not influence body weight, food:water intake or fasting blood glucose. When compared to normal mice, untreated diabetics had significantly more protein, DNA, and sucrase activity throughout the small intestine. Following 10 wk of Acarbose administration, both A-20 and A-40 groups showed increased sucrase activity in intestinal homogenates of distal segments. Surface mucosal sucrase activity however was slightly decreased in proximal intestinal segments as a result of drug therapy, with no changes in middle and distal segments. Acarbose did not influence body weight, food intake or fasting blood glucose, but water consumption and glucosuria were significantly decreased. Experimental diabetes mellitus is associated with significant alterations in enzyme activity and protein content of the brush border membrane of the small intestine. Acarbose administration influences both sucrase activity and distribution in normal and diabetic mice. The mechanisms responsible for these changes and their potential clinical importance remain to be determined.

The effect of chronic alpha-glycosidase inhibition on diabetic nephropathy in the db/db mouse

Acarbose, a complex oligosaccharide, is a potent competitive inhibitor of sucrase and decreases postprandial hyperglycemia when administered with food. To evaluate its potential for metabolic control and prevention of diabetic nephropathy, groups of gentically diabetic mice (C57 BLKsJ db/db) were treated with Acarbose for 10 wk. Control mice received normal chow and experimental groups were given Acarbose prepared as a drug-food mixture in doses of 10, 20, and 40 mg/100 g of food. Acarbose did not influence fasting blood glucose, food intake, or the normal development of obesity in the mice. Urinary glucose excretion and glycosylated hemoglobin was significantly reduced in animals receiving high-dose Acarbose (40 mg/100 g food). Immunopathologic examination of the kidneys showed a dose-dependent decrease in glomerular mesangial immunoglobulin deposition. By light microscopy, glomerular mesangial thickening was significantly reduced in the group receiving high-dose Acarbose (40 mg/100 g food). To the extent that Acarbose improves metabolic control in the db/db mouse, chronic treatment with this agent produces a dose-dependent amelioration of diabetic nephropathy. Alphaglycosidase inhibition may be a useful adjunctive therapy for blood glucose control in diabetes mellitus.

Early immunopathologic events in experimental diabetic nephropathy: a study in db/db mice.

Abstract The natural history of the nephropathy in the diabetic mouse ( db db ) was examined during the first 5 months of life. Age-matched nondiabetic heterozygotes ( DB db ) served as controls. At 1 month of age, diabetic animals were recognized by the appearance of early obesity. Weight gain in the diabetics followed a Gompertz growth curve, which peaked at 4–5 months. Nonfasting blood glucose levels were not significantly different between controls (155 ± 3) and diabetics (169 ± 18) at 1 month, but older diabetics were overtly hyperglycemic. Immunofluorescent microscopy of the diabetic kidney at 1 month showed significant immunoglobulin deposition in the glomerular mesangium as compared to controls. IgM was the most prominent immunoglobin followed by IgG and IgA. Initially focal and segmental, the distribution of fluorescent staining became more diffuse with advancing age, whereas the intensity demonstrated only a modest increase. Diabetics differed significantly from controls at all time periods and with each immunoglobulin stain. Five-month-old diabetics exhibited linear albumin staining on glomerular and tubular basement membranes. Light microscopy revealed focal and segmental mesangial matrix expansion in diabetics at 2 and 3 months, becoming more diffuse in older animals. In this animal model of diabetes mellitus, immunopathologic evidence of glomerulopathy is apparent at the onset of the diabetic state, in the absence of severe hyperglycemia. This observation suggests a subtle alteration in glomerular mesangial function, a factor which may be of importance in the development of progressive glomerulosclerosis.

The protective effect of nitrendipine on gentamicin acute renal failure in rats.

Aminoglycoside nephrotoxicity was produced in two groups of Fischer rats by intraperitoneal injection of gentamicin, 40 mg/kg/day for 2 weeks. Beginning 3 days prior to, and continuing throughout the 2-week treatment period, one of the groups (control) received the inert vehicle, polyethylene glycol, while the experimental group was given nitrendipine, a calcium channel blocker, in a dose of 25 mg/kg/day by gavage. Both groups received food and water ad libitum. Gentamicin with vehicle caused a marked decrease in inulin clearance (4.9 ml/min/kg) and paraaminohippurate (PAH) extraction (26%), and extensive renal tubular necrosis. In comparison, the nitrendipine-treated rats had a significantly increased clearance (9.8 ml/min/kg) and PAH extraction (48%), and less histopathologic damage. Renal tissue content of gentamicin was not influenced by nitrendipine after 4 days of dosing. Nitrendipine, a diisopyridine derived calcium channel blocker, offers significant functional and histologic protection against aminoglycoside nephrotoxicity in Fischer rats. Its mode of action in this regard is unknown.

Continuous Arteriovenous Hemodiariltration: An Aggressive Approach to the Management of Acute Renal Failure

Continuous arteriovenous hemodiafiltration (CAVHD) offers a modified therapeutic approach to the patient with acute renal failure. The system employs a hollow-fiber dialyzer, whose perfusion is dependent on the patients BP. Peritoneal dialysis solution is infused through the dialysate ports in a direction countercurrent to blood flow at a rate of 500 to 1,500 mL/h. Five complex patients with acute renal failure were treated with CAVHD for periods ranging from two to 40 days. Urea clearances approached 37 Lld, and in stable patients, the BUN was maintained at 40 to 60 mg/dL and serum creatinine 1.4 to 4.0 mg/dL. Ultrafiltration up to 1 Llh could be obtained without difficulty. CAVHD is a safe and technically simple procedure that is particularly suitable for hemodynamically unstable patients with ongoing needs for fluid removal.

Exertional Heat Stroke and Acute Renal Failure in a Young Woman

Strenuous exercise leading to heat stroke is known to cause rhabdomyolysis and acute renal failure in men, but there are no reports of this environmental illness in otherwise healthy women. We report the first case of heat and exercise induced acute renal failure in a young nonacclimated adult female following intense exertion in the Grand Canyon. This individual displayed the typical clinical features of exertional heat stroke including hyperpyrexia, CNS disturbance, rhabdomyolysis, oligoanuric acute renal failure, and disseminated intravascular coagulopathy. The pathophysiology is discussed as well as sexual differences in response to heat and exercise. The specific factors that may have predisposed this young woman to heat stroke from exertion are identified.

Inhibition of compensatory renal growth by indomethacin

Renal prostaglandins may be important in the modulation of compensatory renal growth. Reductions in renal mass are associated with increased synthesis of these substances by the remaining kidney, and inhibition of prostaglandin synthesis diminishes renal function in partially nephrectomized animals and in patients with reduced functioning renal mass. We examined the effects of uninephrectomy and treatment with indomethacin on renal prostaglandin E2 and 6-keto prostaglandin F1 alpha concentrations in adult male Sprague Dawley rats. The renal content of these prostaglandins was significantly increased in the remaining kidney two days following uninephrectomy (p less than 0.01). Treatment with 5 mg/kg/day of indomethacin over this period abolished the compensatory increase in renal prostaglandin synthesis and significantly attenuated compensatory increases in renal mass, protein and RNA concentrations (p less than 0.05). No alterations in kidney weight, protein or RNA concentrations were found in intact animals treated with the same dose of indomethacin. These findings suggest renal prostaglandins may participate in the biological events leading to compensatory renal growth.