Experimental gentamicin nephrotoxicity: effect of streptozotocin-induced diabetes

To determine the effect of diabetes mellitus on gentamicin nephrotoxicity we treated male F344 rats with streptozotocin 22 mg/kg (DM rats). DM rats were compared to controls (C) and nondiabetic rats ingesting the osmotic diuretic isosorbide administered to simulate glycosuric diuresis (C/I). Base-line C/I renal function and histology did not differ from C. However, in DM rats base-line inulin clearance (CIN) was 20% lower, and renal cortical slice uptake of p-aminohippurate was reduced compared to C and C/I. DM rats also had foci of renal tubular epithelial dysplasia not seen in C or C/I. Gentamicin was administered at 40 mg/kg-day to C and C/I and 32 mg/kg-day to DM rats to adjust for base-line CIN. Acute tubular necrosis, associated with depression of CIN and renal cortical p-aminohippurate and N-methylnicotinamide uptake, developed in all three groups. There were no differences between C and C/I. However, the degree of acute tubular necrosis and dysfunction was less in DM rats than C and C/I. Renal cortical gentamicin accumulation was also slower in DM than either C or C/I, and changes in renal cortical gentamicin over time followed a different pattern in DM rats. These results indicate that 1) attenuation of gentamicin injury in DM rats may be related to reduced accumulation of gentamicin by the renal cortex, 2) this reduced accumulation may be due to subtle baseline tubular injury mediated by streptozotocin or the diabetic state, and 3) osmotic diuresis does not account for attenuation of renal injury in DM.     

Urinary transforming growth factor-beta excretion in patients with hypertension,type 2 diabetes,and elevated albumin excretion rate: effects of angiotensin receptor blockade and sodium restriction

OBJECTIVE: Transforming growth factor-beta (TGF-beta) is a prosclerotic growth factor implicated in the pathogenesis of diabetic nephropathy. In addition to high glucose, other factors implicated in renal fibrosis and increased TGF-beta synthesis include angiotensin II and high dietary sodium intake. The aim of this study was to examine the effect of angiotensin receptor blockade (ARB) and dietary sodium restriction on the plasma concentration and urinary excretion of TGF-beta in hypertensive patients with type 2 diabetes and elevated albumin excretion rate (AER). RESEARCH DESIGN AND METHODS: Twenty-one subjects with hypertension and AER between 10 and 200 microg/min were randomized to receive either 50 mg losartan daily (n = 11) or placebo (n = 10). Drug therapy was given in two 4-week phases, separated by a 4-week washout period. In the last 2 weeks of each phase, patients were assigned to regular- or low-sodium diets in random order. Parameters measured at week 0 and 4 of each phase included plasma TGF-beta concentration, TGF-beta urinary excretion, AER, clinic mean arterial blood pressure, and urinary sodium excretion. RESULTS: Plasma TGF-beta was unaffected by losartan treatment or sodium intake. In the losartan group, urinary TGF-beta excretion decreased by 23.2% (-39.2 and 13.6) [median (interquartile range)] and 38.5% (-46.8 and -6.1) in the regular- and low-sodium phases, respectively (P < 0.05 for drug effect). In the placebo group, median changes of 0.0% (-12.1 and 44.4) and 0.0% (-29.2 and 110.7) occurred in the regular- and low-sodium phases, respectively. Sodium restriction did not affect urinary TGF-beta excretion in either losartan- or placebo-treated patients (P = 0.54 for overall dietary effect), and there was no evidence of interaction between drug and diet (P = 0.29). CONCLUSIONS: In hypertensive type 2 diabetic patients with elevated AER, the ARB losartan, but not sodium restriction, reduced urinary TGF-beta excretion. These data suggest that the renoprotective effects of losartan in patients with type 2 diabetes and nephropathy may include a reduction in renal TGF-beta production.     

Effect of Propofol With and Without EDTA on Haemodynamics and Calcium and Magnesium Homeostasis During and After Cardiac Surgery

Objective: To determine the effect of the addition of disodium edetate (EDTA) to propofol on haemodynamics, ionised calcium and magnesium serum concentrations, and adverse events during cardiac surgery. Design: Double-blind, randomised, multicenter trial. Setting: Operating room and intensive care unit of 5 academic health centres. Patients: A total of 102 evaluable patients, aged 34 to 85 years, undergoing first-time, elective coronary artery bypass graft surgery. Interventions: Comparison of propofol with EDTA and propofol without EDTA, each in conjunction with the opioid sufentanil, for intraoperative anaesthesia and postoperative sedation. Measurements and Results: There were no significant differences at any time between the two formulations in any clinical chemistry measurements, including ionised calcium, ionised magnesium, total calcium, parathyroid hormone, blood urea nitrogen, creatinine, sodium, potassium, and phosphate. During bypass, the mean concentration of ionised calcium decreased to below the normal range, but the decrease was similar in both groups (propofol with EDTA, 0.98 ± 0.07 mmol/L [N = 51]; propofol, 0.99 ± 0.10 mmol/L [N = 51]; p = NS). Calcium concentration returned to normal after rewarming. Mean ionised magnesium concentrations remained within normal limits in both groups. Similarly, there were no clinically meaningful differences between treatments with respect to haemodynamic variables, efficacy variables, or incidence of adverse events. Conclusions: The inclusion of EDTA in the current formulation of propofol appears to have no significant effects on calcium and magnesium profiles, renal function, haemodynamic variables, or other indicators of safety and efficacy during intraoperative anaesthesia and postoperative sedation in patients undergoing cardiac surgery.