The use of N-terminal pro-B type natriuretic peptide in a pre-operative setting to predict left ventricular systolic dysfunction on echocardiogram.

Heart failure is a major risk factor for adverse postoperative events following non-cardiac surgery. The use of transthoracic echocardiogram as a pre-operative investigation to assess cardiac dysfunction has limitations in this setting. The N-Terminal fragment of B-Type natriuretic peptide (NT proBNP) has been used in screening for heart failure. We have investigated the use of NT proBNP as a screening tool for left ventricular systolic dysfunction to reduce the requirement for pre-operative echocardiograms. Ninety-eight pre-operative non-cardiac surgical patients scheduled to undergo echocardiography were assessed clinically and with an NT proBNP measurement. Echocardiogram was used to define two groups of patients depending on the presence or absence of abnormal left ventricular function and the NT proBNP level was compared between the groups using non-parametric and receiver-operator-characteristic (ROC) curve analysis. In terms of pre-operative screening, a NT proBNP of <38.2 pmol x l(-1) had a 100% negative predictive value in predicting patients with normal left ventricular systolic function and would have prevented the requirement for echocardiogram in 43% of pre-operative patients. NT proBNP was superior to electrocardiological and clinical criteria for detection of a normal echocardiogram. This may have significant impact in the pre-operative assessment of patients undergoing non-cardiac surgery.

Cyclosporin A-induced nephrotoxicity in the rat: relationship to increased plasma renin activity.

Cyclosporin A (CsA; 50, 100 or 150 mg/kg) was administered by gavage, daily for 4 days, to groups of normotensive rats. An additional group of animals received the drug vehicle. CsA-induced nephrotoxicity, characterized by reduced glomerular filtration rate (GFR) and urinary sodium flow, enzymuria and proximal tubular cell damage was accompanied by elevated plasma renin activity (PRA). These changes were dose-related at 50 and 100 mg/kg CsA, but were not increased by administration of 150 mg/kg. Circulating trough drug levels were related to dosage. Four days after CsA withdrawal in animals given 50 mg/kg, there was reduced nephrotoxicity and PRA had returned to normal, even though circulating CsA levels had not diminished. Rats given 100 and 150 mg/kg, however, showed no reduction in nephrotoxicity or in PRA. Hyperglycaemia was evident at 4 days in animals given 100 and 150 mg/kg CsA and persisted 4 days after drug withdrawal. There were no accompanying abnormalities in islet cell structure. Continuous administration of CsA (50 mg/kg) to rats for 14 days caused elevated PRA on day 4 but a return to normal levels by day 7. In contrast, significant GFR impairment was evident by day 7 whilst enzymuria was significantly increased from day 4 onwards. CsA nephrotoxicity in the rat is clearly associated with activation of the renin-angiotensin-aldosterone system. Possible mechanisms leading to increased renin release are discussed.

The influence of enalapril or spironolactone on experimental cyclosporin nephrotoxicity.

Adult Sprague-Dawley rats treated daily for 14 days with 50 mg/kg cyclosporin A (CsA) exhibited nephrotoxicity, characterized by reduced glomerular filtration rate, decreased urinary sodium and potassium flow, tubular enzymuria and proximal tubular structural damage. Elevations in plasma renin activity (PRA) were observed on day 4, but returned to normal within 7 days. Co-treatment of animals for the 14 day period with enalapril (8 mg/kg/day), a potent inhibitor of angiotensin converting enzyme (ACE), or spironolactone (25 mg/kg/day), the distal tubular antagonist of aldosterone, reduced the nephrotoxicity, although PRA remained elevated. Neither enalapril nor spironolactone affected circulating CsA levels. These data suggest that the action of aldosterone on the distal tubule may be important in the pathogenesis of CsA nephrotoxicity.

The predictive value of enzymuria in cyclosporin A-induced renal toxicity in the rat.

The acute nephrotoxic properties of cyclosporin A (CsA) were investigated in normotensive, adult male Sprague-Dawley rats. Animals received either 50 or 100 mg CsA/kg by gastric intubation for 7 days. Within 24 h, significant increases in urinary N-acetyl-beta-D-glucosaminidase (NAG) and gamma-glutamyl transpeptidase (gamma GT) activity were observed at both doses of CsA. Renal function abnormalities, however, were not apparent until 2 days (100 mg/kg) or 7 days (50 mg/kg). Progressive increases in enzymuria were evident in both groups between 1 and 4 days, at which later time proximal straight tubular cell damage was first observed. The data obtained using this model clearly demonstrate that enzymuria provides a sensitive index of acute CsA-induced renal cell damage and that enzymuria precedes detectable renal functional and structural abnormalities.