Use of Remote Ischaemic Preconditioning in the Prevention of Contrast Induced Nephropathy
Condition: Remote Ischaemic Preconditioning; Contrast Induced Nephropathy
MeSH terms: Kidney Diseases; Ischemia
Study type: Interventional

Summary: 
      With an increasingly ageing population the incidence of peripheral arterial disease (PAD) is
      rising. With approximately one quarter of all PAD patients ultimately progressing to Critical
      Limb Ischaemia (CLI), increased demands are being placed on vascular imaging to accurately
      assess stenotic lesions. Early infrainguinal lesions (i.e. TASC A & B) can be treated with
      angioplasty+/- stenting and accurate assessment relies on the imaging gold standard of
      angiography.

      Patients with PAD often have concomitant co morbidities such as diabetes and chronic renal
      impairment placing them at increased risk of developing contrast induced nephropathy (CIN)
      when exposed to iodinated contrast media. High risk individuals with decreased eGFR <60ml/min
      have a risk of between 20-30% of developing CIN. They have increased morbidity and mortality
      risks with a greater need for dialysis and prolonged in patient hospital stays. Ideally, the
      investigators should be searching for ways to decrease the incidence of CIN. Animal studies
      and more recently pilot human trials have shown that subjecting a remote vascular bed to a
      brief ischaemic stress, followed by a period of reperfusion; in what has been termed remote
      ischemic preconditioning (RIPC), may confer a protective benefit against the development of
      CIN. This study aims to determine if RIPC can protect against CIN in patients undergoing
      elective peripheral angiography for infrainguinal disease.
    

Detailed description: 
      Peripheral arterial disease (PAD) affects between 3-10% of the population with prevalence
      rates rising with age to 15-20% in patients over 70 [1]. Worldwide incidence rates are
      rising, with the trend likely to persist with rising obesity and diabetes levels. Increasing
      numbers of affected patients require angiography as either a diagnostic or a therapeutic
      modality to improve peripheral blood flow and relieve the symptoms of CLI. The use of
      iodinated contrast medium during either diagnostic or therapeutic procedures can lead to
      contrast induced nephropathy (CIN) by direct toxic effects on renal tubular cells or by the
      induction of renal ischemia. Contrast induced nephropathy is a leading cause of hospital
      acquired acute kidney injury (AKI) and is defined as an acute deterioration in renal function
      as defined by the relative increase in serum creatinine levels >=25% or by a factor
      >=0.5mg/dl above baseline within 48 hours of administration of iv contrast in absence of
      other causes of renal dysfunction [2],[3]. While the incidence of CIN in the general
      population is only 2%, it rises in high risk patients to as high as 20-30% [4],[5]. Important
      risk factors for the development of CIN include pre-existing impaired renal function,
      diabetes mellitus, hypertension, increased age and congestive cardiac failure [5]. Depending
      on the risks present varying percentages of patients will proceed to require temporary or
      permanent dialysis, with inherently higher morbidity and mortality rates [5],[6],[7]. The
      identification and appropriate management of these patients to prevent CIN is important to
      decrease the associated accompanying morbidity and mortality in this patient cohort. Remote
      ischaemic preconditioning (RIPC) has been shown to confer benefit in both animal studies and
      in patients undergoing coronary angiography.

      A large cohort study of 5787 patients with advanced PAD found that both moderate and severe
      renal insufficiency were associated with increased odds of death. The 1 year mortality risk
      was noted to be higher in patients with severe renal insufficiency (GFR<30ml/min per 1.73m2)
      (OR: 2.97 95%CI: 2.39-3.69) and they also tended to have a higher risk of presenting with
      tissue damage (ischemic ulceration or gangrene) compared with individuals having normal renal
      function (OR: 2.21; 95% CI: 0.64-2.98) [8].

      Zaraca et al. in a recent systematic review reported on incidence of CIN of 9.2% in patients
      undergoing vascular surgery [9]. Identifiable risk factors included age >70yrs, high contrast
      volume, pre exisiting renal disease and the use of antihypertensive medication.

      Ischaemic preconditioning is an endogenous mammalian mechanism whereby a brief period of
      ischaemia and reperfusion confers resistance to subsequent prolonged ischaemic insults. First
      observed in the canine heart, subsequent investigators noted that brief ischaemia in remote
      organs e.g. skeletal muscle induced protection in key central organs e.g. the heart. This
      remote ischaemic preconditioning (RIPC) does not require direct interference with the target
      organs' blood supply. It can be induced using blood pressure cuffs to produce brief episodes
      of upper limb ischaemia and reperfusion. It confers protection upon numerous organs
      simultaneously. RIPC reduces myocardial injury following aortic aneurysm repair, cardiac
      surgery and angioplasty. It also reduces adverse ischaemic events up to six months following
      percutaneous coronary intervention, implying some medium-term effect.

      To date ischaemic conditioning has been applied primarily to the heart however animal studies
      have shown pre conditioning to offer renal protection [11],[12]. Although direct application
      of renal ischaemia is impractical, remote ischaemic conditioning applied prior to or during
      angiography procedures may offer protection to the kidneys against CIN. Whittaker and
      Przyklenk in 2011 explored this concept retrospectively using data from patients who had
      undergone emergency angioplasty for ST elevation myocardial infarction [13]. The original
      trial was a RCT which examined the protective effect of postconditioning on myocardial
      ischemia [14]. The authors retrospectively examined if study patients treated with multiple
      coronary balloon inflations had better renal function than patients not exposed to this
      remote conditioning. They concluded that patients in the conditioning group received 25% more
      contrast volume than the control group and showed no decline in renal function as
      demonstrated by examination of glomerular filtration rate at day 3 post procedure in
      comparison to the control group which saw a significant decline in renal function. Fikret et
      al in 2012 in the Renal Protection Trial demonstrated a protective benefit with RIPC from the
      development of CIN in high risk patients undergoing elective coronary angiography [15]. The
      need for contrast-based procedures is rising, especially in vascular surgery with increasing
      numbers of patients undergoing endovascular procedures, as is the incidence of post-contrast
      renal failure, which has a reported mortality of 34% [16]. The potential use of RIPC
      therefore to reduce the risk of kidney damage demands s further investigation in patients
      with advanced peripheral arterial disease who are at an increased risk of developing CIN.
    

Intervention name(s): RIPC
Intervention type(s): Other
Intervention description(s): IV hydration prior to procedure dependent on classification of risk as per eGFR + RIPC
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: remote ischemic preconditioning