Toffa, Samuel Edwin Kao; (1994) Reperfusion injury following hypothermic renal preservation: Evidence of early oxidative damage in the rabbit kidney. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Rabbit kidney preservation for 72h by methods used clinically followed by ex vivo normothermic reperfusion produced functional changes associated with injury to vascular and urinary systems. Protein leaked into these spaces and solute reabsorption was disrupted, although energy substrate production persisted. Experiments tested the hypothesis that reactive oxygen species produced following kidney reoxygenation caused reperfusion damage, and that injury was dependent upon biochemical changes which provided a transition metal catalyst (iron) during ischaemic preservation. Fresh and preserved kidneys were reperfused normoxically or hypoxically in the presence of salicylate which produced characteristic hydroxyl radical (●OH) dependent metabolites during early reperfusion, particularly in preserved kidneys reperfused normoxically. In the absence of ●OH scavenging by salicylate, LDH release into the renal vasculature was elevated by normoxic reperfusion and there was evidence of oxygen-dependent injury to proximal tubules, however lipid peroxidation was unaltered. Groups of kidneys were given a cold re-flush (CRF) following preservation to remove putative pathological metabolites before normothermic reperfusion. Urinary and vascular spaces were cleared, and kidneys showed less tissue damage upon reperfusion than non-CRF controls, characterized by decreased enzyme release from cytosolic (LDH) compartments and tubule cell membranes (r-GT). After storage and CRF kidneys were reperfused either hypoxically or normoxically to determine whether tissue damage upon reperfusion was oxygen- dependent. LDH release into the vasculature at the onset of reperfusion was elevated by normoxia. The anti-malarial drug chloroquine was added to the preservation solution to prevent intracellular acidification during kidney storage. Chloroquine improved some functional parameters in 48h preserved kidneys compared with untreated controls. For example release of the intralysosomal enzyme N- acetyl-β-D-glucosaminidase into vascular and urinary spaces was decreased and urinary tubule and glomerular integrity was better maintained. Studies of the distribution of an iron chelator, desferrioxamine (DFX) showed urinary clearance rates equal to glomerular filtration rate, and no accumulation in kidney tissues. DFX administered in storage and reperfusion solutions decreased ●OH production during early reperfusion, suggesting a role for iron in the synthesis of these species. DFX did not appear to prevent tissue damage.

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