Contrast induced nephropathy pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]

Overview

The pathophysiology of CIN is not clearly understood; however, several attempts have been made to explain the underlying mechanism. It is generally agreed that CIN is due to a combination of several influences brought on by contrast-media infusion rather than a single process. The most important mechanism thought to be involved in CIN is a reduction in renal perfusion and subsequent hypoxia. This has been attributed to several alterations in the renal microenvironment including activation of the tubuloglomerular feeback, local vasoactive metabolites including adenosine, prostaglandin, NO, and endothelin as well as increased interstitial pressure. Although sometimes considered controversial, studies have also proposed injury to renal tubular cells as another contributor both via a direct cytotoxic effect and via reactive oxygen species production.

Pathophysiology

Several mechanisms have been put forth to explain the development of nephropathy following contrast administration. Broadly, the pathophysiology can be divided into renal vascular compromise and cytotoxic tubular cell injury.

Renal Vascular Compromise and Hypoxia

Vascular Resistance

The renal vascular bed is supplied by small capillaries known as the vasa recta. While these small vessels have a diameter similar to that of other capillaries, their length is usually several times longer, creating higher vascular resistance. To offset that, viscosity needs to be maintained at its lowest demonstrated in Poiseuille’s law:

Several rat models have shown association between plasma viscosity, increased vascular resistance, and contrast-media infusion. As viscosity increases, resistance in the vasa recta can rise to cause significant renal tissue hypoperfusion . Some agents have an inherently higher viscosity leading to higher resistance while others can interact with red blood cells causing a decrease in deformability and a secondary increase in resistance.

Increased viscosity also transfers to tubular fluid which is usually low in proteins and less viscous than plasma. Some models have shown that as urine concentration occurs in the tubules, viscosity increases significantly in the renal tubules leading to an increase in renal interstitial pressure. The rising pressure further increases vasa recta hypoperfusion and also contributing to hypoxia.

Cytotoxic Effects of Contrast

Contrast Media can directly cause renal tubular injury. Another mechanism had been described by the generation of free oxygen radicals such as superoxide anions, hydrogen peroxide, hydroxyl radicals and hypochlorous acid. The endothelial dysfunction discussed above is also partly due to oxygen free-radical generation during post ischemic reperfusion as they decrease bioavailibility of nitric oxide leading to vasoconstriction. Also the oxidative and nitrosative effects mediated by these reactive species on the sulfhydrylic groups and aromatic rings of proteins, cellular membrane lipids and nucleic acids associated with the vasoconstriction. This occurs through the nitrosation of tyrosine residues of enzymes which are involved in the synthesis of medulla vasodilators, such as prostacycline synthase and nitric oxide synthase. Other causes reported to contribute in this mechanism through studies have been done on animals are the mitochondrial injury, cytochrome-c release, and plasma membrane damage. Creatinine clearence has also been seen reduced with increase in adenosine excreation on administration of low osmolality, non-ionic contrast, and with use of theophylline the fall in creatinine clearance declined.