Abstract
The pathophysiological mechanism of contrast media (CM) acute renal failure (CM-ARF) is still not clearly understood, partly because of the lack of reproducible animal models and relevant diagnostic renal markers. This work describes a reproducible rat model of uranyl acetate(UrAc) -induced CM-ARF as well as evaluating other potential risk factors such as old age, different strain and 5/6 nephrectomy. The role of renal markers in the different renal models was also evaluated. In normal (control) rats typical examples of three types of CM, the ionic monomer iothalamate, non-ionic monomer iohexol and the dimer iodixanol, all induced the release of tubular enzymes (the brush border ALP, GGT and the lysosomal NAG) and also increased urinary protein excretion. Another indication of the CM-induced tubular proteinuria was the increased a1-microglobulin shown in the first 3-6 hours following CM administration. These tubule-related markers declined to baseline levels implying only transient CM tubular effects rather than any irreversible epithelial injury. There was no clear correlation between CM-induced changes in these tubule markers and renal function assessed by creatinine and GFR. These tubular markers therefore possess no diagnostic role in the initiating period leading to CM-ARF with normal animals which appear to be resistant. The rat with partially compromised renal function (e. g. old age and 5/6 nephrectomy) tolerated CM without further impairment in renal function. This indicates that CM-induced tubular effects were tolerated by the rat even in compromised renal models. It was only with UrAc-induced early degenerating and extensive tubular necrosis together with the added risk of dehydration that ARF could be induced reproducibly by CM in Wistar Albino rat. Interestingly only the low osmolar CM iodixanol and iohexol induced ARF in this model. In support of the recognised role of urinary electrolytes as functional parameters in predicting renal failure, it was also shown that both Na and K are suitable as early indicators in CM-ARF. Evaluation of endogenous proximal tubule metabolites by NMR showed the potential of these metabolites to diagnose (and possibly predict) CM-induced tubular effects. Although all three types of CM induced similar biochemical changes, formation of vacuoles in the epithelial cell of the PCT (assessed by LM and EM morphology) and iodine retention (determined by an in house X-ray fluorescence method) were most pronounced with iodixanol and iohexol. Retention of CM and vacuole formation in the cortical tubules were affected by renal function and tubular cell status (increased with UrAc-induced tubular necrosis). Therefore, increased CM retention and hence vacuole formation in renal failure could represent an early indicator of CM-ARF that requires further follow up. The cellular proliferation capacity of the rat tubular epithelia did not show any differences after administering CM. Therefore, the capacity of the proliferating rat tubular epithelium was sufficient enough to tolerate any CM-induced effect or even damage. In the isolated perfused rat kidney (IPRK) which allowed the simultaneous monitoring of biochemical markers and functional changes, a range of different CM showed an increase in the filtrate (urine) proteins and enzymes (especially ALP and GGT) which were increased before any decrease in renal perfusate flow (RPF). Thus the release of tubular markers appeared to be due to direct CM effects on the tubular epithelia rather than to CM-related decreased RPF. Increased endothelin release after CM in the IPRK system indicated that this vascular constrictor peptide (of renal origin) plays a role in inducing CM-related reduction of RPF. Renal impairment (whether induced before or after CM administration) delayed CM excretion, and hence could expose the renal vasculature to continuous high CM levels which could sustain the decrease of RPF. Therefore, CM showed dual effects on renal tubules both through direct PCT epithelial cell effects and reduced renal perfusion In summary, this study indicates that the integrity of the tubular epithelia is an important factor in the development of CM-ARF.