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University Hospital of Saarland Homburg, Germany
University Hospital of Erlangen-Nurnberg Erlangen, Germany
We read with interest the article by Gleeson and Bulugahapitiya [1]. Among other intrinsic causes of contrast media nephrotoxicity, the authors suggested that contrast media causes a disruption of the physiologic balance between vasodilator and vasoconstrictor influences in the kidney as a result of the delivery of a large hyperosmotic load to the juxtaglomerular apparatus and that it leads to tubuloglomerular feedback [1]. Indeed, in the radiological literature, activation of tubuloglomerular feedback by osmotic diuresis induced by contrast media is a common hypothesis for the development of contrast nephropathy. However, in the physiological literature, it is known that the tubuloglomerular feedback mechanism is activated by an increased delivery of Cl- to the macula densa rather than by osmolality [2, 3]. In a recent study [4], it was shown that in osmotic diuresis induced by mannitol, even the early distal sodium chloride (NaCl) concentration is decreased and that this is likely to deactivate the tubuloglomerular feedback mechanism, thereby leading to afferent vasodilation. So, it seems very unlikely that activation of the tubuloglomerular feedback mechanism by osmotic diuresis contributes to the pathogenesis of contrast nephropathy [3].
The authors stated that intrarenal hypoxia is directly related either to hemodynamic changes or increased tubular energy expenditure caused by osmotic stress [1]. If osmotic diuresis increased the NaCl delivery to the loop of Henle, this could induce an increase in oxygen consumption by the tubular cells and thus contribute to necrosis of the medullary thick ascending limbs. However, reabsorption of sodium and water is reduced in the proximal tubule as well as in the loop of Henle during osmotic diuresis, and the results of a recent study [4] suggest that osmotic natriuresis depends on the inhibition of sodium and water reabsorption in the segments of the nephron that are located downstream from the distal convoluted tubule. Moreover, blocking of the Na+-K+-2Cl-cotransporter in the medullary thick ascending limb by furosemide would strongly decrease oxygen consumption [3]. However, furosemide does not prevent contrast-induced nephropathy and can even have a deleterious effect on renal function [1]. Thus, there is no evidence for an increased workload of the tubular cells due to osmotic stress induced by contrast media [3].
Future studies should perhaps direct more attention to the direct toxic effects on the tubular cells and to the changes in renal hemodynamics induced by the increase in proximal tubular pressure due to osmotic diuresis and increased viscosity by the contrast media. It was shown that the marked increase of proximal tubular pressure in osmotic diuresis was associated with a gradual decrease in renal blood flow and a moderate decrease in the glomerular filtration rate. Afferent vasodilation and an increase in renin release, probably associated with efferent vasoconstriction, seemed to counteract the fall in the glomerular filtration rate [4]. One can speculate that in patients with a reduction in the endogenous vasodilators nitric oxide and prostaglandins (e.g. high-risk patients with diabetes and renal failure), the afferent vasodilation in response to the increase in proximal tubular pressure is affected, leading to a more pronounced decrease in renal blood flow and glomerular filtration rate.
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Mater Misericordiae University Hospital Dublin, Ireland
We thank Heinrich and Uder for their letter regarding our review [1] in which they raise several interesting points in an area that is a source of much speculation and debate. It was simply not possible to address all the intricacies of the pathophysiology of contrast-induced nephropathy (CIN) in our study. We attempted to summarize the findings of as many studies in the area as possible, the vast majority of which admittedly had a radiological and not physiological basis. We represented this published data faithfully and do not feel obliged to defend it.
The truth is that the exact mechanism of the pathophysiology of CIN is still unknown. Indeed, most treatments based on the many proposed mechanisms have failed to show clinical benefit, as was outlined in our review. The only finding of clinical relevance in this field at the time of publication was that low- or isoosmolar contrast agents are less nephrotoxic than high-osmolar agents in high-risk patients. Even the widely accepted treatment with IV hydration has never been proven in large clinical trials. However, Heinrich and Uder's points are well made and their recently published study [2] adds significant weight to their arguments. Their findings in this well-designed study switch the focus onto the direct tubular toxicity of contrast media and undoubtedly go some way toward furthering our understanding of the complex pathophysiology of CIN. We welcome their correspondence and hope it will stimulate more debate and research in this area, which is in a constant state of flux. However, it should not be allowed to distract from the take-home message of our review, namely that optimization of hydration, careful assessment of risk factors (most notably preexisting renal impairment with or without concomitant diabetes), and close cooperation with referring clinicians are still the current mainstays of prevention of CIN.
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