Endothelial dysfunction in the outer medullary vasa recta as a key to contrast media-induced nephropathy.

THE ROLE OF THE ENDOTHELIUM in the adverse reaction of blood vessels to contrast media imaging agents, and in particular the sensitivity of the kidney, has been a subject of interest dating back to 1964 (2). The renal vasculature seems particularly sensitive to the influence of endothelium-derived nitric oxide vasodilation (7) and its buffering of endogenous vasoconstrictors. Thus the possible interaction between contrast agents and renal vascular resistance has become a subject of intense interest, in particular regarding the possible role of endothelial dysfunction in contrast media-induced nephropathy. Several particular points regarding contrast agent toxicity have been established. First, all contrast media are cytotoxic (5), and virtually all cells may be subject to this cytotoxicity to some extent. This may be compounded by the nature of the specific contrast media, such as its ionic strength, osmolality, or viscosity (4). Contrast media have been reported to induce necrosis and apoptosis in renal tubular cells (3), and disrupt nitric oxide-mediated vasodilation without altering anatomic integrity in systemic and renal cortical endothelia (9). These detrimental interactions may be particularly important in the kidney due to the particularly increased sensitivity of the renal endothelium in maintaining renal perfusion (7) and the fact that the content of the renal tubules and postglomerular juxtamedullary capillaries (vasa recta) becomes more concentrated as they descend into the medulla (4), strengthening the potential toxicity of the contrast media. While medullary blood flow accounts for only 20% of total renal blood flow, perfusion of this anatomic region is critical for the concentrating mechanisms of the kidney, as well as regulated sodium reabsorption and its potential involvement in sodium-induced hypertension. The outer medullary vasa recta are particularly suited for regulating medullary perfusion as they are simple vessels composed of an endothelial lining surrounded by constrictor pericytes. The deep medullary vasa recta become little more than an endothelial sleeve which is unlikely to regulate perfusion, although it may play a role in endothelium-mediated selective permeability of the deep vessel. Cao et al. (1) have documented that endothelium-derived nitric oxide is a critical vasodilatory regulator of descending vasa recta perfusion, which acts in juxtaposition to the constrictor action of endogenous superoxide. Nitric oxide synthase inhibition reduces (total kidney) renal blood flow some 35%, with coupled decreases in glomerular filtration rate (GFR) and increased renal vascular resistance, and these changes have been shown to be directly linked to the endogenous levels of the renin-angiotensin system (1). Because the medullary vasa recta are in series and downstream from the afferent and efferent resistance vessels, changes in vascular resistance may be even more amplified in the medulla if endothelial integrity is compromised. The importance of this topic is underlined by the disproportionately high number of review articles addressing the subject. With all of these potential problems pointing to an exaggerated vulnerability of the medullary circulation to compromised endothelial function, in an issue of the American Journal of Physiology-Renal Physiology Sendeski et al. (6) from the Berlin group (which includes some of the major contributors to this field) have provided a series of integrated protocols that demonstrate just how important the outer medullary vasa recta endothelium is in contrast media-induced acute kidney injury. First, they tested the perfusion of both viable human and rat isolated, perfused renal medullary descending vasa recta and found that exposure to contrast media resulted in significant pericyte-mediated vasoconstriction to a luminal diameter smaller than that of a red blood cell. They found that angio