Limb ischemia protects against contrast-induced nephropathy.

Contrast-induced acute kidney injury (CI-AKI), or nephropathy (CIN), is frequently diagnosed in the setting of coronary angiography. The incidence varies in the literature partly related to the differences in diagnostic criteria used for CIN. In a recently published article in Circulation, Maioli et al1 used a definition of an increase of 0.5 mg/dL over baseline serum creatinine within 3 days of the administration of contrast medium and found an incidence of 12.1% among 1490 patients who had a baseline estimated creatinine clearance of 60 mL/min. It has become increasingly recognized that even mild forms of AKI are associated with adverse shortand long-term outcomes, including onset or progression of chronic kidney disease and more rapid progression to end-stage kidney disease.2,3 Patients with CIN have an increase in short-term and long-term mortality after adjustments for other comorbidities, whether the renal dysfunction is acute or chronic.4 Although it has been concluded by many that the development of CIN may identify other comorbidities that are more responsible for the adverse outcomes, there are increasing data from randomized trials that CIN may directly contribute to the increased risk of cardiovascular and renal adverse outcomes.5 In the previously mentioned study by Maioli et al,1 the authors reported that persistent renal dysfunction, defined as a relative decrease of creatinine clearance of 25% from baseline at 3 months after coronary angiography, occurred in 18.6% of CIN patients.1 These patients with persistent renal dysfunction had a higher incidence of death at 5 years when compared with those whose renal functional impairment was transient or those who did not develop CIN. In another study, the adjusted odds ratio of sustained decline in kidney function 3 months after coronary angiography was 4-fold in patients who had mild AKI ( 0.3 mg/L or 50% to 99% increase in serum creatinine) and 17-fold for those with moderate or severe AKI ( 100% increase in creatinine).6 Experimental models in animals provide pathophysiological explanations for how the effects of acute injury can lead to chronic inflammation, vascular rarefaction, tubular cell atrophy, interstitial fibrosis, and glomerulosclerosis.7–9 It is therefore very important to avoid the kidney injury associated with contrast administration. Er et al,10 in this issue of Circulation, report that remote ischemic preconditioning protects the kidneys against CIN. Preconditioning represents an activation by the organism of intrinsic defense mechanisms to cope with pathological conditions. Ischemic preconditioning is the phenomenon whereby a prior ischemic insult renders the organ resistant to a subsequent ischemic insult. Renal protection afforded by prior renal injury was described exactly one century ago, in 1912, by Suzuki who noted that the kidney became resistant to uranium nephrotoxicity if the animal had previously been exposed to a sublethal dose of uranium.11 In referring to the work of Suzuki, Aschoff12 attributed the resistance to uranium toxicity to a resistance of the renal epithelium and proposed this to be a defense mechanism of the kidney. There have been a number of studies over the years demonstrating that preconditioning with a number of renal toxicants led to protection against injury associated with a second exposure to the same toxicant or to another nephrotoxicant.13 It is not, however, a universal finding that toxins confer resistance to subsequent insults.14 Zager and colleagues15 performed experiments evaluating the effects of prior exposure of the kidney to ischemia on subsequent susceptibility to ischemic injury in rats a short time later. Our laboratory created a mouse model in which prior exposure to ischemia protects against a second ischemic insult imposed 8 or 15 days later.16 Unilateral ischemia was also protective against a subsequent ischemic insult to that kidney, revealing that systemic uremia was not necessary for protection. Unilateral ischemia, however, did not protect the contralateral kidney against ischemic injury 6 or 8 days later. In a subsequent study we found that protection afforded by 30 minutes of ischemic preconditioning (inducing severe functional and histological damage) lasted for at least up to 12 weeks.17 Some of the cellular processes and signaling mechanisms proposed to explain preconditioning in the kidney and other organs are listed in the Table. Although it is possible in humans that preconditioning can be carried out directly on the kidney (eg, by inducing ischemia before allograft placement or transiently obstructing the native kidney before a procedure which will result in ischemia18), it is nevertheless more clinically tractable to develop methods in patients in which preconditioning can be induced pharmacologically or by minimally invasive remote ischemic preconditioning protocols. Remote ischemic preconditioning is a therapeutic strategy by which protection can be afforded in one vascular bed by ischemia to another vascular bed in the same organ or a different organ. In 1993 The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Renal Division, Brigham and Women’s Hospital & Harvard Medical School, Boston, MA. The article by Er et al10 that is the subject of this editorial was published in the July 17 issue of Circulation. Correspondence to Joseph V. Bonventre, MD, PhD, Renal Division, Brigham and Women’s Hospital, Harvard Institutes of Medicine, Room 576, Boston, MA 02115. E-mail [email protected] (Circulation. 2012;126:384-387.) © 2012 American Heart Association, Inc.