Prostaglandin-Based Renal Protection Against Contrast-Induced Acute Kidney Injury

Abstract

It has been known for 3 decades that the kidneys rely considerably on a group of prostaglandins that are locally produced in both a constitutive and inducible fashion, primarily in the medulla, to regulate renal blood flow and a variety of functions in tubular cells that occupy that region of the kidney. Arachidonic acid released from phospholipids is converted by cyclooxygenase (COX-1 constitutively, COX-2 inducibly) in the kidney to PGI2, PGE2, PGF2, PGD2, and thromboxane A2. PGE2 and PGF2 are produced predominantly but not exclusively in the renal medulla, whereas degradative enzymes are present in both the cortex and medulla. Prostaglandins enter the tubular lumen by facilitated transport and are partially reabsorbed from the urine in the distal nephron, with urinary levels reflecting renal synthesis. In response to ischemia, vasoconstriction, norepinephrine, or angiotensin II, the kidney increases prostaglandin synthesis to modulate renal vascular resistance with a predominance of PGI2 and PGE2, which are vasodilatory, in contrast to PGF2 and thromboxane, which are vasoconstricting. 1 These actions may be more pronounced in patients with diabetes mellitus because both the endothelial isoform of nitric oxide synthase and the COX-1 and COX-2 enzymes lose their normal regulation in the outer medulla of diabetic rats. 2,3 In addition to these effects in diabetic patients, prostanoids appear to offset the vasoconstrictive effects of iodinated contrast agents. For example, Agmon and coworkers4 examined the effects of vasodilatory prostaglandins on outer medullary blood flow in a rat model of contrast nephropathy and demonstrated that the inhibition of prostanoid production more than doubled the number of necrotic tubules in the outer medulla. Prasad and colleagues 5 measured rat medullary blood flow in real time and demonstrated that prostanoids exert more vasodilatory effects than nitric oxide. These findings illustrate the importance of the prostanoids in maintaining outer medullary blood flow to the kidney. Moreover, these observations provide a physiological basis for the common recommendation that patients discontinue nonsteroidal antiinflammatory agents, which work above and beyond aspirin, before contrast exposure to impair constitutive (COX-1) and inducible (COX-2) production of prostaglandins. Article see p 1793