Remote ischemic preconditioning to reduce contrast-induced nephropathy.

Iodine-containing contrast media are often used for diagnostic and therapeutic
procedures. The number of procedures in which contrast meda are used is
currently in the Netherlands approximately 1 million per year. It is expected
that this number will rise considerablly in the near future. Despite the
increasing use of low-osmolar instead of high-osmolar iodine-containing
contrast media, the incidence of acute kidney injury due to contrast media is
still significant. This so called contrast-induced nephropathy (CIN) is defined
as a rise > 25% in serum creatinine within 72 hours after contrast
administration without an alternative cause of kidney injury. CIN is associated
with considerable morbidity and mortality.

Recently a CBO guideline on the use of iodine-containing contrast media is
developed. All patienst who receive iodine-containing contrast should be
screened for risk factors of CIN and also renal function should be measured
(estimated glomerular filtration rate, based upon the MDRD formula). High risk
patients should receive infusion with saline 8-20 hours prior to contrast
administration. Furthermore, 48-72 hours after contrast administration, renal
function should be checked. Despite this treatment of high-risk patients the
incidence of CIN is still 2-5% in this population.

Although the precise mechanims of CIN has not yet been elucidated, ischemia of
the medulla seems to play an important role. The outer layer of the medulla is
a high oxygen consuming area at a relatively far distance from the vasa recta
(blood supply of the medulla). Contrast-induced vasoconstriction of the vasa
recta attributes signifcantly to ischemia-reperfusion injury of the medulla
which causes CIN. Furthermore, iodine-containing contrast media also have
direct toxic effects on the tubular cells of the kidney, causing mitochondrial
dysfunction and apoptosis.

Ischemic preconditioning is a phenomenon that was first discovered in 1986 by
Murrey et al. Short ischemia of the myocardium reduces ischemia-repefusion
injury due to a prolonged ischemic stimulus of the myocardium. Later, Pryzklenk
et al. described that the protective effects of ischemic preconditioning also
occurs if a short ischemic stimulus is applied to an organ at distance of the
organ undergoing prolonged ischemia. Remote Ischemic PreConditioning (RIPC)
with an extremity as remote organ is non-invasive, safe, low-cost and easy to
implement into clinical practice. In great lines it is assumed that a humoral
and/or neurogenic signal from the remote organ is transferred to the organ
undergoing prolonged ischemia. In our experimental model of renal
ischemia-reperfusion injury with hind limbs as remote organ, it appeared that
the opiate-receptor plays a pivitol role in RIPC. Other possible humoral
mediators are e.g. bradykinin, endocannabinoids and nitric oxide. In the target
organ a intracellular signalling is initiated within seconds to minutes which
reduces the mitochondrial permeability and this protects the cell for several
hours against oxidative stress.

Recent preclinical research from our group showed that remote ischemic
preconditioning using a hind limb as remote organ significantly reduces
ischemia-reperfusion injury of the kidney. A recent retrospective cohort study
by Whittaker et al. showed that multiple balloon inflations during coronary
angioplasty (as remote stimulus) might reduce contrast-induced nephropathy.
Furthermore, a recent randomized pilot study reported that in high-risk
patients undergoing elective coronary angiography RIPC reduced CIN. However in
this study a group of patients was included with a very high prevelance of CIN
(40%). To question arises whether RIPC could also protect against
contrast-induced kidney injury in a cohort of patients in which the prevelance
of CIN is lower (approximately 5%). For this reason a study will be performed
in which patients are included undergoing a diagnostic and/or therapeutic
intervention with intravascular contrast at the departments of Surgery
(division of Vascular- and Transplant Surgery) and Interventional Radiology of
the Radboud University Nijmegen Medical Center.

To demonstrate that remote ischemic preconditioning reduces contrast-induced
nephropathy in patients ar high-rish of CIN (according CBO guidelines) next to
the use of pre- and posthydration.

It concerns a single-center (RUNMC), blinded and randomized study. Inclusion
will occur after informed consent by the treating physician of the department
of Surgery. 76 sealed envelopes will be used to randomly divide consecutive
patients with a 1:1 ratio between the control (sham preconditioning) and
experimental (ischemic preconditioning) group.

After informed consent, the researcher checks the scheduled time of the
diagnostic and/or therapeutic procedure with iodine-containing contrast at the
department of (interventional) radiology. The researcher is present at the
angiography- or operation room or the CT-preparation room to perform the sham
preconditioning or ischemic preconditioning procedure. RIPC will be applied by
4 cycles of 5 minutes inflation and 5 minutes deflation of a standard
bloodpressure cuff around the upper arm at a pressure of the actual systolic
bloodpressure plus 50 mmHg. Sham preconditioning will be applied in a similar
fashion as the RIPC stimulus, but the blood pressure cuff is inflated to the
actual diastolic blood pressure. The researcher carefully keeps the
inflationpressure unvisible for both the patient and the (interventional)
radiologist. The collection of patientcharacteristics, renal function data and
the storage of urine samples will also be done by the researcher (not blinded).

Burden:
Patients are asked to fill in one questionnaire (10-15 minutes). Two additional
blood samples are taken during the insertion or removal of the needle for
infusion of the pré- and posthydration solution. The third blood sample at day
2 should be taken according to the CBO guideline and is therefore part of the
standard treatment. The collection of two urine samples will occur one day
prior to and after contrast administration. If a patient develops CIN (>25%
rise in serum creatinine), the patient will be offered to pay a visit to the
contrast outpatient clinic of the department of Nephrology (RUNMC) to check
whether or not additional measures should be taken.

Risk:
A RIPC stimulus by short, repeated insufflations of a blood pressure cuff
around the upper arm is generally considered as a safe technique. To our
knowledge complications has not been described so far.