Contrast-induced nephropathy (CIN) is an acute, iatrogenic kidney injury triggered by the intravascular administration of iodinated contrast agents. Defined as a 25 % rise or an absolute 0.5 mg/dl (44 μmol/L) increase in serum creatinine within 72 h of contrast exposure, in the absence of an alternative explanation [1], CIN is an important clinical problem following angiography and percutaneous intervention. It represents the third most common cause of hospital-acquired acute renal failure [2, 3] and is associated with significant mortality and morbidity, with up to 19 % of those suffering CIN developing persistent renal impairment months after contrast media exposure [4]. With the incidence of renal replacement therapy estimated at 0.2 % [5], the attendant healthcare costs associated with CIN are substantial [5]. Moderate to severe chronic renal impairment (estimated glomerular filtration (eGFR) <60 ml/min or a creatinine of >120 mmol/L; National Kidney Foundation chronic kidney disease (CKD) stages 3 and 4 [6]) is regarded as the most important risk factor in the development of CIN [7], but other risk factors such as diabetes, reduced left ventricular systolic function, advancing age, concomitant use of nephrotoxic drugs, large contrast agent volumes, intraprocedural hypotension and either high or low haematocrits (dehydration/anaemia) are also well recognised [8]. Due to the association between renal and cardiovascular disease, patients with CIN risk factors are common within the cohort of patients requiring an angiographic intervention and, despite the introduction of a number of prophylactic measures, the incidence of CIN remains unacceptably high. In the CARE study, the incidence of CIN despite optimal medical therapy remained between 10 and 15 % [9]. The notion of optimal medical care in this patient cohort remains hotly contested. There are a number of national and international guidelines and all recommend avoidance of nephrotoxic drugs, adequate pre-hydration and the use of low- or iso-osmolar contrast agents. The augmentation of pre-hydration with antioxidants or alkalinizers such as N-acetyl cysteine and sodium bicarbonate, respectively, remain hotly contested, but recent meta-analyses appear to suggest a small advantage towards bicarbonate pre-hydration over N-acetylcysteine [10]. Given a lack of clarity regarding the most efficacious intervention against CIN, a large, multicentre randomised control study has started recruiting (target 8,680 patients, the prevention of serious adverse events following angiography (PRESERVE) trial [11]), the results of which will hopefully help to clarify optimal preparation of patients at risk of CIN. Similarly, there is debate over which contrast media is the least injurious to the at-risk kidney. The landmark comparison trial between iso-osmolar iodixanol and the low-osmolar iohexol contrast media by Chalmers and Jackson in 1999, which demonstrated a modest superiority for iodixanol, has been a powerful influence on subsequent contrast media decision-making, although more recent meta-analyses seem to suggest parity of risk between iso-osmolar and the majority of low-osmolar contrast media [12‐16]. The lack of clear evidence of one intervention over another appears to suggest one thing: the lack of a single successful intervention to prevent CIN. There is, therefore, a clear clinical need for an effective intervention that can reduce the incidence of CIN following angiographic and other iodinated contrast requiring procedures.

While the pathophysiology of contrast-induced renal injury remains the subject of on-going basic research, one of the principal mechanisms for acute contrast nephropathy is thought to be vaso-constrictive renal hypoxic injury and release of reactive oxygen species (ROS) [17]. Such an injury is likely to be mediated by cell-death signalling of the type found in many other organ systems typified by lethal reperfusion injury [18]—and as such may be amenable to interventions such as ischaemic preconditioning (see review [19]). Interestingly, the potential of remote ischaemic conditioning was highlighted in a retrospective study by Whittaker and Przyklenk [20], and more recently three prospective trials have been published to support the supposition of remote renoprotection. In the first, Er et al. demonstrated in a small (n = 50/group) proof-of-concept trial that remote ischaemic conditioning (RIC), consisting of 4 cycles of 5 min ischaemia/5 min reperfusion of the upper limb by inflation/deflation of a blood pressure cuff prior to contrast exposure, was effective in significantly reducing the rate of CIN from 40 % in controls to 12 % [21]. The second, Deftereos et al. recruited 225 non-ST elevation myocardial infarction (NSTEMI) patients to receive either sham or an ischaemic conditioning stimulus consisting of 4, 30 s ischaemia/30 s reperfusion cycles by inflation/deflation of an intracoronary balloon following intervention upon the culprit lesion; consistent with upper limb RIC, they demonstrated that intracoronary RIC reduced the rate of CIN from 29.5 % in control to 12.4 % [22]. The third, Igarashi et al. [23], using an identical conditioning regime to that used by Er et al. and, utilising a novel bio-marker, urinary liver-type fatty acid-binding protein (L-FABP) as a primary endpoint, demonstrated a significant reduction of CIN from 26.9 to 7.7 % in the remote ischaemic preconditioned group. Although a small trial (n = 20 per group), there was an attempt to uncover the mechanism of contrast media renal injury, with the demonstration of attenuated oxidative stress as measured by derivatives of reactive oxidative metabolite (D-ROM) levels and reduced asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase following remote ischaemic preconditioning. These data are encouraging, but there is a need for further evidence before routine medical practice can be altered. These previous proof-of-concept trials have been small and relatively limited in scope, concentrating primarily upon the incidence of acute kidney injury and have not looked at the longer-term sequelae of that renal injury in terms of persistent renal damage. As noted above, CIN is not a purely transient phenomenon; it frequently has long-term serious sequelae with persistent kidney damage evident in a fifth of those with an acute biochemical manifestation of CIN [4]. The effect of remote ischaemic conditioning against contrast-induced nephropathy (ERICCIN) trial is therefore designed to evaluate RIC against CIN in elective angiography/PCI, and to ascertain the longer-term efficacy in terms of prevention of persistent renal injury at 3 months determined by serum creatinine/estimate glomerular filtration rate and development of proteinuria, a known consequence of CIN [24] and a portent for increasing cardiovascular risk and all-cause mortality [25].