Mesna: a novel renoprotective antioxidant in ischaemic acute renal failure.

BACKGROUND: Reactive oxygen species (ROS) play a key role in renal ischaemia-reperfusion injury. After establishing the in vitro anti-oxidative potential of mesna, a sulfhydryl-containing compound, its effect on kidney function and morphology in a rat model of ischaemic acute renal failure (ARF) was examined. METHODS: Mesna (180 mg/kg) was administered at different time points relative to ischaemia and/or reperfusion onset. Kidney function was assessed by glomerular filtration rate (GFR) and fractional sodium excretion (FE(Na)) before a 45-min period of unilateral renal artery clamping and following 90 min of reperfusion. Mesna was administered by bolus, 30 min before the induction of ischaemia, 5 min before ischaemia, 5 min before reperfusion, and 5 min after the onset of reperfusion. RESULTS: Mesna improved function of the ischaemic kidney at each administration. When mesna was administered 5 min before the onset of reperfusion, GFR reached 90-100% of its pre ischaemic value and FE(Na) was improved by 75%. The beneficial effect of mesna was also demonstrated by light and electron microscopy. Kidneys treated with mesna 5 min before reperfusion resembled ischaemic non-reperfused kidneys and showed subtle morphological and ultrastructural changes compared with ischaemic-reperfused kidneys. Mesna had no haemodynamic effect on renal blood flow and did not induce any osmotic diuresis. CONCLUSIONS: We suggest that mesna acts as an antioxidant. Its antioxidant potential together with optimal protection achieved when administered 5 min before reperfusion, supports the conclusion that mesna scavenges ROS generated at the onset of reperfusion, thus diminishing reperfusion injury and organ damage.

Renal ischemia-reperfusion injury: contribution of nitric oxide and renal blood flow.

The contributions of nitric oxide (NO) and renal blood flow (RBF) were examined in ischemia-reperfusion injury in the rat kidney. The function of both kidneys was assessed by glomerular filtration rate (GFR), and fractional excretion of sodium (FENa), calculated before, during unilateral renal artery clamping (45 min), and following reperfusion (90 min). RBF was measured in the same model by ultrasonic flowmetry. Intrarenal NO levels were modulated by administration of S-nitroso-N-acetylpenicillamine (SNAP), L-arginine, acetylcholine, and the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). SNAP increased GFR from 0.20 +/- 0.04 ml/min in control ischemic kidney to 0.38 +/- 0.06 ml/min and reduced FENa from 19.3 +/- 3.4 to 9.5 +/- 1.8%. Similar results were observed when L-arginine was administered. Acetylcholine had no effect on GFR or FENa. RBF was fully restored within 60 min following reperfusion, with no change in the rate of recovery by L-arginine. L-NAME aggravated the ischemia-reperfusion injury, preventing full restoration of RBF, further reducing GFR and worsening FENa. In conclusion, ischemia-reperfusion injury ends in low intrarenal levels of NO. We propose that this low NO level results from damage to the endothelial receptor signal transduction process and is not due to impaired NO synthase activity or to changes in RBF.

Antioxidant enzymes activity in polymorphonuclear leukocytes in chronic renal failure.

In the present study, activity of polymorphonuclear leukocyte (PMNL) intracellular antioxidant enzymes, i.e. catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPX), was assessed in CRF patients on hemodialysis (HD), or continuous ambulatory peritoneal dialysis (CAPD) and in healthy controls. The activity of SOD and GPX was reduced in HD and in CAPD (SOD: by 34.2 and 42%, respectively, and GPX 66 vs. 42%, respectively, taking the activity in normal controls as 100%). Catalase activity, on the other hand, was significantly augmented (298 and 175%, respectively) as compared to the healthy controls. This impairment in antioxidant enzymes activity, involved in the respiratory burst and phagocytosis, may contribute to the understanding of the reduced bactericidal ability of PMNL activity found in these patients.

Effect of oxygen tension on activity of antioxidant enzymes and on renal function of the postischemic reperfused rat kidney.

The aim of the present study was to examine the effect of exposing animals to 100% oxygen instead of room air on renal function and endogenous antioxidant enzymes of the postischemic reperfused rat kidney. Superoxide dismutase (SOD), catalase and glutathione peroxidase (GPX) were determined in the homogenate of the left kidney after 45 min of ischemia, caused by clamping the left renal artery, 10 and 90 min after reperfusion while the animals breathed room air or 100% O2. The right kidney served as a control. The possible influence of trapped blood in the clamped kidney was also investigated by the use of a correction factor based on the Hb concentration in the homogenate. The results indicate that such correction is necessary as the blood adds significant antioxidant activity. The activities of all 3 enzymes after 45 min of ischemia decreased significantly in the left (ischemic) compared to the right (control) kidney, to 64% of the control levels for catalase, 58% for SOD and 49% for GPX. After 10 min of reflow, a further decrease in the activities of catalase (to 49%) and of GPX (to 29%) was found. SOD activity, however, increased to 64%. After 90 min of reperfusion, restoration toward normal levels was noticed (SOD activity increased to 70%, catalase to 76% and GPX to 58%). Breathing 100% O2 resulted in a significant decrease in all enzyme activities (to 38.6% for catalase, 45% for SOD and to 27.4% for GPX). This inactivation can be explained by increased reactive oxygen species (ROS) activity during hyperoxia.(ABSTRACT TRUNCATED AT 250 WORDS)