Accepted Manuscript

Remote ischemic preconditioning and contrast-induced nephropathy: a systematicreview

Caroline Koch, Ségolène Chaudru, Mathieu Lederlin, Vincent Jaquinandi, AdrienKaladji, Guillaume Mahé

PII: S0890-5096(16)00034-0

DOI: 10.1016/j.avsg.2015.10.017

Reference: AVSG 2645

To appear in: Annals of Vascular Surgery

Received Date: 31 July 2015

Revised Date: 13 October 2015

Accepted Date: 15 October 2015

Please cite this article as: Koch C, Chaudru S, Lederlin M, Jaquinandi V, Kaladji A, Mahé G, Remoteischemic preconditioning and contrast-induced nephropathy: a systematic review, Annals of VascularSurgery (2016), doi: 10.1016/j.avsg.2015.10.017.

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Remote ischemic preconditioning and contrast-induced nephropathy: 1 a systematic review 2

3

4

5

Caroline Koch 1, Ségolène Chaudru 2, Mathieu Lederlin 3, Vincent Jaquinandi3, Adrien Kaladji 4, 6

Guillaume Mahé 2,3 7

1 Département d’imagerie, CHU de Rennes, F-35033 Rennes, FRANCE. 8

2 INSERM, Centre d’investigation clinique, CIC 1414, F-35033 Rennes, FRANCE. 9

3 Département d’imagerie cœur-vaisseaux,CHU de Rennes, F-35033 Rennes, FRANCE. 10

4 INSERM, LTSI, F-35033 Rennes, FRANCE. 11

Correspondence to: Guillaume MAHE, Pôle imagerie médicale et explorations fonctionnelles, 12

Hôpital Pontchaillou, 2 rue Henri Le Guilloux, Rennes, F-35033, France ; E-mail: 13

maheguillaume@yahoo.fr 14

Acknowledgements: The authors thank the University Hospital of Rennes which granted to them a 15

funding within the framework of CORECT 2014 projects. 16

17

ABSTRACT 18

Background: The use of imaging is increasing in clinical practice either for diagnosis or 19

intervention. In these aims, contrast medium is widely used. However, contrast-medium can induce 20

contrast-induced nephropathy (CIN). The incidence of CIN varies from 2% to 50% depending on 21

patient risk factors and CIN is the third cause of renal insufficiency. To date, methods such as hyper 22

hydration to prevent CIN have a low level of evidence. Remote ischemic preconditioning (RIPC), 23

which has already proved its efficiency in the cardiology field, seems to be a promising technique 24

for CIN prevention. The aim of this work was to carry out a systematic review of the literature of 25

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the randomized clinical studies on ischemic preconditioning (IPC) in the prevention of nephropathy 1

to the iodized products of contrast in man. 2

Material and methods: We conducted a systematic review of randomized clinical studies on the 3

remote ischemic preconditioning in the prevention of CIN in man. Documentary sources were 4

PubMed articles published until June 2015. Randomized clinical trials of remote ischemic 5

preconditioning in preventing CIN in human were reviewed. 6

Results: Five articles were selected for the analysis. One article studied the impact of RIPC in a 7

population at high risk of CIN whereas the four other analyzed populations at low risk of CIN (three 8

studies) and a diabetic population (one study). In all studies except the latter one, the risk of CIN 9

was based on the Mehran score that was previously published. In the high-risk population, a 10

decrease in the incidence of CIN was found in the preconditioning group compared with the control 11

group (12% against 40%; p = 0.002). Among the three other studies using the Mehran score, one 12

also demonstrated the interest of such a procedure in a sub-group of high risk patients. A second 13

one found a low incidence of CIN in the RIPC group (5/47 (10%) as compared with a control group 14

(17/47 (36%) (p= 0.003) in patients at low risk of CIN. In another low risk population, a significant 15

lower level of a biological marker (L-FABP: liver-type fatty acid-binding protein) that assesses a 16

renal impairment was found in the preconditioning group compared with the control group. 17

Conclusion: Only five studies were found in this search, which may constitute a limitation. 18

However, remote ischemic preconditioning appears as a promising method to prevent CIN since it 19

is a non-invasive, low cost, easy, and safe method. More randomized controlled trials are needed to 20

confirm these preliminary results. 21

22

INTRODUCTION 23

Cardiovascular diseases are the second cause of mortality in France. The principal etiology is 24

atherosclerosis which generates a deposit reducing the arterial lumen and limiting the distribution of 25

nutrients to the tissues. This limitation reveals initially with effort symptoms, before rest symptoms. 26

The management of this pathology requires the realization of morphological examinations. 27

Diagnostic and/or therapeutic radiological examinations frequently require the use of iodized 28

contrast products (ICP). Combined with the performances of CT-scan, they make it possible to 29

improve the visualization of a tissue compared to its environment, thus optimizing for example the 30

detection of tumoral lesions, the analysis of vascular axes, and the realization of therapeutic 31

procedures like embolization or implantation of intravascular stents. 32

The use of ICPs is not devoid of risks. The literature reports early undesirable effects such as 33

simple vagal discomfort, angina, pulmonary edema, extravasation of the contrast products or even 34

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anaphylactic shock, and delayed adverse events, such as thyroid or renal complications. 1–3 The 1

nephropathy due to the iodized products of contrast (NIPC) constitutes one of these delayed adverse 2

effects. In the literature, there exist several definitions of NIPC.4 One of the most used definitions 3

was proposed by the European Society of Urogenital Radiology (ESUR). 5 This definition is also 4

the most accepted. NIPC is thus defined by an increase of the serum creatinine rate ≥ 0,5mg/dL or > 5

25% compared to the baseline value 48 to 72 hours after the exposure to the IPC.6 The incidence of 6

NIPC varies from 2% to 50% according to the existence or not of risk factors 7 and represents the 7

third cause of intra-hospital acute impaired renal function after the functional acute impaired renal 8

functions and the medicinal causes.8 It generates an increase in the durations and costs of 9

hospitalization in the short and long term. The work of Maïoli et al. showed that 20% of the patients 10

who developed a NIPC following a coronarography presented a renal dysfunction which persisted 11

after three months, increasing the risk of mortality at five years.9 The risk of progression towards 12

chronic renal insufficiency remains important even in the event of initial recovery.10 13

The prevention of NICP is thus a key issue to decrease the morbi-mortality and the inherent 14

costs of health more especially as there is currently no available curative treatment of NIPC. 15

16

Pathophysiological mechanisms of NICP 17

To date, the pathophysiological mechanisms implied in the NIPC are not entirely clarified.11 It 18

appears as a secondary acute renal insufficiency (ARI) due to an acute tubular necrosis (ATN). 19

NIPC would be induced at the same time by a direct renal cellular toxicity and hemodynamic 20

modifications.12 (Fig. 1). The hemodynamic modifications seem to be of three types: 1) ICPs 21

increase the production of endothelin and adenosine (vasoconstrictor agents), which decrease blood 22

flow, and thus the supply to the renal medullary leading to its hypoxemia;13 2) ICPs increase blood 23

viscosity, leading to the aggregation of red blood cells, which limits the oxygen supply to the renal 24

medullary 3) ICP increase the osmotic load at the level of the distal tubule, increasing the local 25

oxygen uptake to the detriment of the medullary one. 26

These three hemodynamic mechanisms generate an ischemia. After this episode of ischemia, a 27

phenomenon of reperfusion occurs. This reperfusion is characterized by a sudden oxygen 28

contribution, which starts a cascade of pathological events more serious than those induced by the 29

initial ischemia.10 These lesions of reperfusion are attributable to the release of toxic products 30

(oxygenated free radicals and pro-inflammatory cytokines) leading to cellular death and thus to 31

acute tubular necrosis (ATN). 32

33

Risk factors of NIPC 34

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For each individual, the occurrence of a NIPC is conditioned by the presence of several modifiable 1

and/or non-modifiable risk factors (Fig. 2). 14 Among these factors, the existence of a preexistent 2

chronic impaired renal function (creatinine clearance <60 mL/min according to Cockcroft) is the 3

principal predictive factor of the occurrence of a NIPC.15 The incidence of NICP in patients 4

presenting a preexisting deterioration of the renal function varies between 14.8 and 55.0%. 16 5

The relation between the volume of ICP injected and NIPC was shown in several studies.17 This 6

relation is all the more important as there exist other risk factors. Nikolsky et al.18 showed in a 7

population of diabetics that an injection of a volume < 200mL was associated with an incidence of 8

16% of NIPC vs. 48% for a volume > 600 mL. 9

10

Evaluation and minimizing of the risk of the NIPC 11

To quantify the risk of NIPC, the score of Mehran was proposed 19 (Fig. 3). This score does not 12

propose any action to be taken. It simply makes it possible to evaluate the risk to develop a NICP 13

according to the presence of risk factors. If the score is low (less than or equal to 5), the risk to 14

develop a NICP is 7.5%, whereas if the score is very high (> 16), this risk reaches 57.3%. To 15

minimize the risk of NICP, recommendations were published by the CIRTACI (Interdisciplinary 16

Committee of Research and Work on the Agents of Contrast in Imagery). For each patient, before 17

any injection of ICP, a systematic search for factors of risk must be carried out to balance the 18

awaited benefit of the injection.9 One should note that these recommendations do not directly 19

propose to use Mehran’s score and are primarily based on the clearance of creatinine. 20

If the risk of NICP is moderate and/or high (creatinine clearance ranging between 45 21

mL/min and 60 mL/min according to Cockcroft), it is recommended to privilege an examination 22

proposing a similar efficiency but not requiring the use of ICP (ultrasound or MRI, for example). If 23

CT-scan remains nevertheless the only examination susceptible to bring the necessary information 24

the indication of the imagery technique must be discussed with the referring clinician, by weighing 25

the benefit/risks balance. It will be crucial to minimize the risk by stopping the administration of 26

drugs likely to raise the risk (non-steroidal anti-inflammatory drugs and diuretic should be stopped 27

48h before the injection) and by asking the radiologist to inject the lowest possible amount of a low 28

osmolality ICP. A protocol of hyperhydration will precede and follow the injection of ICP (see 29

below). If the creatinine clearance is lower than 30 mL/min the injection of ICP is a priori not done 30

in the absence of an absolute necessity. In the event of vital urgency, the injection of ICP must 31

postpone all the steps which could delay the diagnosis. Measures against the NIPC will be then 32

applied as far as possible. 33

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Protocols of prevention of NIPC 1

In patients at risk (diabetics, moderate renal insufficiency), protocols of prevention are 2

recommended by the CIRTACI. Among those, hyperhydration and/or the administration of N-3

acetyl-cysteine (NAC) are the most used techniques. 4

Hyperhydration. CIRTACI agrees on the international recommendations (ESUR) by 5

recommending a protocol of hyper-hydratation.20 For the patients having a significant risk to 6

develop NIPC (based on a creatinine clearance ranging between 45 and 60 mL/min according to 7

Cockcroft), hyperhydration must be carried out orally with one liter “of tap water” and one liter of 8

water containing sodium and bicarbonate during the 24 hours preceding the injected scanner. The 9

same 2L hyperhydration must be prescribed for 24 hours after the CT-scan. If the patient cannot 10

drink, intravenous hyperhydration will be obtained with 100mL/h of a saline or bicarbonate solution 11

12 hours before and 12 hours after the injection of the product of contrast. After the examination, 12

the creatinine level will be controlled after 48h and 72h, as well as the potassium rate, to judge if an 13

acute renal insufficiency occurred. 14

Despite recommendations, this protocol of hyperhydration is not employed in a consensual 15

way and is sometimes difficult to set up, in particular in units like emergency departments where 16

many patients present, with a short care.21Moreover, because of the too high risk of cardiac 17

decompensation, some patients cannot receive this preventive hyperhydration. 18

Administration of N-acetyl cysteine. N-acetyl cysteine (NAC) (Mucomyst®) is another therapeutic 19

proposed these last years to prevent NIPC due to an injection of ICP. It is an antioxidant, generally 20

used in pneumology to fluid bronchial secretions. A randomized study showed that in patients at 21

high-risk of NIPC (creatinine clearance <50 mL/min), the addition of NAC (2 x 600 mg/d orally 22

during two days) in addition to a protocol of hyperhydration with sodium chloride, was associated 23

with an incidence of NIPC as low as 2% versus 12% in control patients treated by hydration only 24

without NAC.22 In spite of its low costs, its facility of accessibility in hospitals and of use, there is 25

little evidence supporting the use of NAC. A recent randomized study including a large number of 26

patients at risk of NIPC based on the Mehran’ score did not show any benefit of NAC at the dose of 27

1200mg twice a day for four days.23 At time, the use of this molecule is left with the choice of the 28

physician. 29

Other protocols of prevention proposed in the prevention of NIPC. From its action of purification, 30

the impact of dialysis after the injection of ICP was studied in the prevention of NIPC. A 31

randomized study reported that one session of hemodialysis carried out immediately after the 32

injection of ICP does not bring any effectiveness on the prevention of the NIPC.24 Finally, when 33

looking at the vasoconstriction intervening in the pathophysiological mechanisms of NIPC, 34

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vasodilating agents were proposed such as the selective agonists of the dopamine receptors, 1

calcium antagonists and E1 prostaglandin. However they did not show any benefit compared to 2

hyperhydration only.25 More recently, studies looked into a new procedure of prevention of 3

nephropathy called ischemic preconditioning. 4

5

What is ischemic preconditioning? 6

According to a pathophysiological concept, repeated short duration ischemia in an organ induces a 7

“resistance” to a later prolonged ischemia. This is a physiological adaptive mechanism of protection 8

of tissues faced to hypoperfusion, which has therapeutic potential when ischemia-reperfusion is 9

induced in a targeted way. In 1982, this mechanism called ischemic preconditioning (Isch-PreC) 10

was highlighted for the first time on canine models in myocardial infarction.26 In experiments, short 11

periods of ischemia intersected with periods of reperfusion were applied to dogs by using a balloon 12

to occlude a coronary artery.27 This allowed the prevention of necrotic myocardial territories. These 13

results opened prospects on a possible use of this method of preconditioning for myocardial 14

protection in the man. 15

Thus, in 1993 the first study in patients showed that upstream from a coronary bypass, the 16

realization of two series of short arterial clamping confers a myocardial protection by slowing down 17

the reduction of the level of ATP, which reflects myocardial ischemia.28 This mechanism of Isch-18

PreC not only showed its effectiveness at the local tissue level (directly on a given coronary artery), 19

but also proved to be efficient on remote organs, with the idea of “remote ischemic 20

preconditioning”. An action of local ischemia-reperfusion, while releasing mediators systemically, 21

makes it possible to protect for a given period of time remote organs exposed to a prolonged 22

ischemia. This method was proposed in the prevention of NIPC. This work made a systematic 23

review of the literature relating to Isch-PreC in the prevention of the NIPC. 24

25

Isch-PreC studies 26

The process of identification and selection of the studies is presented on Fig. 4. A search was 27

carried out on Pubmed® by using the following keywords: “remote ischemic preconditioning” OR 28

“remote preconditioning” OR “remote ischemic preconditioning” AND “kidney” AND “contrast” 29

AND “randomized”. Only the randomized clinical trials involving ischemic remote ischemic 30

preconditioning in the prevention of the NIPC in the man were selected for this review. Ten 31

references were initially identified by the PubMed® database. On the basis of reading of the titles 32

and summaries, four articles were excluded (one study protocol, two meta-analyses, one letter to the 33

editor). At this stage, six articles thus were subjected to a comprehensive reading. One article was 34

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excluded because of the absence of use of iodized products of contrast. Five studies were then 1

accepted for this systematic review relating to the prevention of NIPC by Isch-PreC. Table I 2

presents the five studies selected, the target population, the Isch-PreC protocol and the techniques 3

used for disease prevention as well as the principal results of each technique. 4

Design of the studies. The five studies were prospective and randomized with an experimental 5

group (with Isch-PreC) and a control group (without Isch-PreC or with sham-Isch-PreC). Four of 6

them were simple blind studies. 7

Population. While being based on the Mehran’s score, three studies evaluated the impact of Isch-8

PreC in subjects with a low to moderate risk of developing NIPC (mean score = 6), 29-31 and one 9

study related to high risk patients (mean score = 13). 32 The study of Savaj et al. was based on a 10

population of diabetics, in whom the Mehran’s score was not calculated. Each of those studies 11

included at least 30 people in each group. 12

Pre-existing prevention. In each study, before the injection of IPC, the patients were submitted to a 13

protocol of intravenous hyperhydration. This protocol was carried out with the infusion of a 0.9% 14

sodium chloride aqueous solute at a rate of 1mL/kg/h or 3-4 mL/kg/h. Hyperhydration was done 15

before and after the injection of the product of contrast, and only the durations of treatment differed 16

slightly. In the study by Er et al. the patients also received an oral administration of 600 mg of NAC 17

twice a day, the day preceding and the very same day of the IPC injection.32 18

Protocol of remote ischemic preconditioning (RIPC). All the selected studies were randomized 19

studies with a control group (without intervention 29.33 or with an intervention known as “sham” 30-20 32) and a group having Isch-PreC. According to the studies, the Isch-PreC procedure (always 21

realized using a standard blood pressure cuff positioned at the level of the arm) differed; in three of 22

them, it consisted of four repetitions of a cycle including five min of inflation and five min of 23

deflation. In two studies it consisted of three cycles of five min. It should be noted that the 24

Yamanaka et al. study used an automated blood pressure cuff.31 The pressure applied by the cuff 25

varied between the studies. The cuff was inflated with a fixed pressure (200 mmHg) in three studies 26

whereas it was inflated with the systolic pressure of each patient plus 50 mmHg in two studies. In 27

each study, the deflation of the cuff was complete. 28

According to the studies the sham procedure differed. In two of them a pressure equal to 29

diastolic blood pressure minus ten was maintained during the phase of inflation, 30,32 but the cuff 30

was not inflated in two other studies. One of the studies did not report any data on the procedure 31

used in the control group.33 The time between the Isch-PreC procedure and the injection of IPC 32

(with a low osmolality in each study) varied between 45min and 2h according to the studies. 33

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Criteria of judgment. All the studies defined the principal criterion of judgment as the occurrence 1

of a NIPC. To define NIPC, four studies used creatinine as a serum marker, and one used a urinary 2

biological marker, the Liver-type Fatty Acid-Binding Protein (L-FABP). This is a sensitive and 3

specific marker, and the increase of its level is correlated with the occurrence of renal insufficiency, 4

with an early peak of increase after 24h.34 Among the four studies which were based on the kinetics 5

of creatinine, three of them used the same definition for the occurrence of NIPC. 5 NIPC was 6

defined by an increase of the serum level of creatinine ≥ 0.5mg/dL or > 25% compared to the 7

baseline value 48 to 72 hours after the exposure to the IPC. The study of Savaj et al. was based on 8

the definition of KDIGO where NIPC was defined by an increase of the serum level of creatinine ≥ 9

0.3mg/dL or > 30% compared to the baseline value 24 hours after the exposure to the IPC.33 It 10

should be noted that three studies analyzed clinical data remotely of the procedure as secondary 11

criteria of judgment, such as the occurrence of a re-hospitalization, the need for a session of 12

hemodialysis, a death at six weeks, or the occurrence of a cardiac or cerebral major adverse effect at 13

30 days. 14

Principal results. Significant differences between the two groups sham Isch-PreC and Isch-PreC 15

are reported regarding the occurrence of NIPC. In the study of Er et al., 26 patients developed 16

NIPC: 6/50 (12%) in the RIPC group and 20/50 (40%) in the control group, (p=0.002) while 17

Menting et al. did not report any difference between the two groups except in a sub-group of 11 18

high-risk patients (Mehran’s score ≥11) in which they observed a lower prevalence of NIPC in the 19

RIPC group vs sham RIPC (p=0.048). 30,32 In the study of Yamanaka et al., 22 patients developed 20

NIPC: 5/47 (10%) in the RIPC group and 17/47 (36%) in the control group (p= 0.003). 31 In the 21

Savaj study, six patients developed NIPC: 1/48 in the Isch-PreC group and 5/48 in the control group 22

(p=0.13). The difference of creatinine level between the two groups before and after the procedure 23

was significant (p=0.04) 33. In the study of Igarashi et al., the percentage of change of the level of L-24

FABP was significantly higher in the control group (159 ± 34.1 vs. 41.3 ± 15.6%, p = 0.003). The 25

prevalence of NIPC based on the modification of the level of L-FABP was 26.9% (n=8) in the 26

control group, and 7.7% (n=2) in the Isch-PreC group (p = 0.038). 29 In the Er et al. study, the 27

clinical data evaluated as secondary criteria were gathered as a composite criterion.32 A significant 28

difference (p=0,018) was observed between the two groups, including a significant difference in re-29

hospitalization (p=0.016). Twenty-five patients were re-hospitalized: 18 in the control group and 30

seven in the Isch-PreC group. In the study of Menting et al., no re-hospitalization and no 31

hemodialysis were observed in the groups over the six weeks. Two deaths occurred in the control 32

group vs. none in the Isch-PreC group (p = 0.49). 30 Yamanaka et al. did not report a significant 33

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difference between the two groups on a composite criterion gathering the cardiac and cerebral 1

attacks at 30 days (p=0.07)31. 2

3

DISCUSSION 4

This review highlights that the literature on the data regarding Isch-PreC to prevent NIPC is limited 5

even though it should be a major concern taking into account the great number of scanner 6

examinations involving the injection of contrast agents in the field of vascular surgery and the 7

morbi-mortality allotted to NIPC. The protective effect of Isch-PreC was already largely shown on 8

other organs. Isch-PreC decreases the perioperative myocardial damage of cardiac surgery in adult35 9

and pediatric patients 36. It also decreases the myocardial and renal damage during endovascular 10

procedures or surgical interventions for abdominal aortic aneurisms.37,38 The current literature 11

shows that Isch-PreC decreases NIPC in the patients at high-risk of NIPC. It also indicates that 12

results are more contrasted in lower risk patients. Several assumptions can be made. First, the power 13

of the studies of Igarashi et al. and Menting et al. was too low. The total number of patients was 60 14

(30 in each group) in the study of Igarashi et al. and 76 (38 in each group) in the study of Menting 15

et al. vs. 100 (50 in each group) for the study of Er et al.. Secondly, the benefit of this protective 16

treatment could be smaller for the patients at a lower risk based on Mehran’s score. Isch-PreC 17

protocols with a fixed pressure (200 mmHg) or adapted to the systolic blood pressure of the patient 18

(+ 50 mmHg) do not appear to significantly modify the results in the various studies. 19

In addition to the effect of this technique on the incidence of NIPC and the reduction of the 20

renal damage, Er et al. also highlighted a significant reduction in morbi-mortality at six weeks 21

(death, re-hospitalization, dialysis), which showed that the impact of this technique is not only 22

biological (NIPC) but also clinical.32 Nevertheless, a longer follow-up conducted on more patients 23

would be interesting. 24

Another interesting point is that none of these studies reported adverse effects, which 25

showed the harmlessness of the procedure. This result is in agreement with the literature which 26

studied the effect of Isch-PreC on other organs. However, the evaluation of the tolerance of the 27

patients during the Isch-PreC procedure was not reported in these five studies. Several questions 28

remain posed. First of all, the choice of the marker of NPCI can be questioned. If the literature 29

relies on the evolution of creatinine over 48 to 72 hours to define the NIPC, the use of other markers 30

could be discussed, in particular L-FABP, used by Igarashi et al., cystatin C, or NGAL which were 31

considered as more sensitive, more specific and present an earlier rise kinetics compared with 32

creatinine. 39 Moreover, 50% of the renal function can be damaged before a rise in creatinine.40 The 33

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main difficulties with these other markers are the cost and the availability of some of their dosage 1

and the absence of consensual defined values. 2

The timeline of Isch-PreC is also discussed. Igarashi et al. carried out the procedure two 3

hours before the coronarography, whereas in the studies of Er et al. and Menting et al. it was carried 4

out 45 minutes before the injection.30,32 How much time before the injection should Isch-PreC be 5

done? The effect of Isch-PreC seems to have a duration extending in time up to 24h, which could 6

facilitate its application without implying the obligation of its realization in the hour preceding the 7

injection, which could facilitate the diffusion of the procedure. 8

Another important point is that in all these studies the patients were hyperhydrated. Thus, 9

was the effect observed only due to RIPC or was it related to a synergistic effect between 10

hyperhydration and Isch-PreC? Did the addition of NAC in the Er study play a role? Moreover, can 11

Isch-PreC be as interesting for diagnostic imaging examinations requiring less products of contrast 12

than coronarography (angio-CT for example)? The last point which is probably the most important 13

one is: which patients will benefit from this procedure? Is this simply those which are strongly 14

exposed to the risk of developing RIPC or all the patients if it is considered that each injection is 15

finally noxious on markers of the renal function as the work of Igarashi suggested? 29 16

In conclusion, an injection of IPC should never be taken lightly, especially as the 17

examinations of imagery tend to be standardized in the cardiovascular field. Remote Isch-PreC thus 18

appears a very interesting prospect to prevent the nephropathies induced by the products for 19

contrast, because of its non-invasiveness, its low cost, its facility of use and the absence of adverse 20

effect reported in the literature. 21

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17

18

Legend of figures 19

Fig. 1. Pathophysiologic mechanisms involved in contrast induced nephropathy. 20

Fig. 2. Risk factors to develop a contrast induced nephropathy. 21

Fig. 3. Mehran’s score of risk. 22

Fig. 4. Selection process of the studies selected for the systematic review. 23

24

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Target

population Procedure

Additional

prophylaxis

Criterion of judgement for

NICP Prevalence of NICP

Igarashi

et al.

(2013)

Patients at

moderate risk of NICP Mean

Mehran’s score = 6

RICP group (n=30) : 2h before injection

Control group (n=30): no prophylaxis

Hyperhydration 4h before and 12 h

after the injection of contrast product

L-FABP (urinary biological marker).

L-FABP >17.4 µg/g Cr in the 24h following the injection of contrast product or increasing >25% from the baseline value

confirms NICP.

RICP group: 7.7% (2/30)

Control group: 26.9% (8/30) P = 0.038

Er et al.

(2012)

Patients at high risk of

NICP Mean

Mehran’s score = 13

RICP group (n=50) : 45min before injection

Sham-RICP group (n=50) : 45min before injection

Hyperhydration 12h before and 12h after

the injection of contrast product +

NAC the day before and the day of

injection

Creatinine (serum marker).

An increase ≥ 25% or ≥ 0.5mg/dL between T0 and T0+48h confirms

NICP.

To: value before the injection of iodized contrast product.

RICP group: 12% (6/50) Sham-RICP group: 40% (20/50)

P = 0.002

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Menting

et al.

(2015)

Patients with a low to

moderate risk of NICP

Men Mehran’s

score = 6

RICP group (n=38) : 45min before the injection

Sham-RICP group (n=38) : 45min before the injection

Hyperhydration 12h before and 12h or 4h before and 4h after the injection of contrast product

Creatinine (serum marker).

An increase ≥ 25% or ≥ 0.5mg/dL between T0 and T0+48h-72h

diagnoses NICP.

To: value before the injection of iodized contrast product.

RICP group: 6% (2/36) Sham-RICP group: 6% (2/36)

P = 1.0

With a high risk subgroup of patients (Mehran’s score≥11)

RICP group: 55% (6/11)

Sham-RICP group: 45% (5/11) P = 0.048

Savaj et

al.

(2014)

Diabetic patients

Mean

Mehran’s score non-available

RICP group (n=48) : 15 min before the injection

Control group (n=48) : No prophylaxis

Hyperhydration before the injection of contrast product

Creatinine (serum marker).

An increase ≥ 30% or ≥ 0.3mg/dL between T0 and T0+24h

diagnoses NICP.

To: value before the injection of iodized contrast product.

RICP group: 2.1% (1/48)

Control group: 10.4% (5/48) P = 0.13

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Table I. Characteristics of the selected studies

Yamana-

ka et al.

(2014)

Patients with a low to

moderate risk of NICP

Mean

Mehran’s score = 7.6

RICP group (n=47) : 45min before the injection

Sham-RICP group (n=38) : 45min before the injection

Hyperhydration before and 24h athe injection of contrast

product

Creatinine (serum marker).

Increase ≥ 25% or ≥ 0.5mg/dL between T0 and T0+48h-72h

diagnoses NICP.

To: value before the injection of iodized contrast product.

RICP group: 10% (5/47) Sham-RICP group: 36% (17/47)

P = 0.003

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Endothelin Adenosine

↘ Blood flow

(vasoconstriction)

Blood viscosity Aggregates

Red blood cells

↘ Oxygen supply

Renal distal tubular cells

solute load ↗ Oxygen uptake

Dir

ect

ce

llu

lar

toxi

city

Renal

medulla

hypoxia

Contrast induced nephropathy

He

mo

dy

na

mic

mo

dif

ica

tio

ns

Inje

ctio

n o

f io

diz

ed

co

ntr

ast

pro

du

cts

Augmentation

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AIIRA: angiotensin II receptor antagonists; CEI ; angiotensin conversion enzyme inhibitors; ICP:

iodized contrast products; NSAI: non-steroidal anti-inflammatory drugs.

Non-modifiable risk factors Modifiable risk factors

Age > 65 years Injected volume of ICP

Diabetes Type of ICP (osmolality)

Chronic renal insufficiency Route of ICP administration Congestive heart failure Concomitant medication (NSAI,CEI,AIIRA) Anemia Hypotension Dehydration

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* Systolic arterial pressure

** eGFR : Estimated Glomerular Filtration Rate = 186 x (Serum creatinine)-1.154 x (Age)-0.203 x (0.742 in women) x

(1.210 if African American)

Total score ≤ 5: low risk to develop a nephropathy with iodized contrast products.

Total score between 6 and 10: moderate risk to develop a nephropathy with iodized contrast products.

Total score between 11 and 16: high risk to develop a nephropathy with iodized contrast products.

Total score ≥16: very high risk to develop a nephropathy with iodized contrast products.

Yes No Hypotension (SAP* <80 mm Hg during at least one hour and

requiring inotropic drugs) 5 points 0 point

Counter-pulsation balloon in the 24 hours preceding the

injection of contrast products 5 points 0 point

Heart failure (class III or IV New York Heart Association

dyspnea and/or history of pulmonary edema) 5 points 0 point

Age >75 years 4 points 0 point Anemia (hematocrit < 39% in men and < 36% in women) 3 points 0 point Diabetes 3 points 0 point Volume of contrast product 1 for each 100 cc

3 0 point

Serum creatinine > 1.5mg/dL or eGFR < 60 mL/min/1.73m²**

4 points or

2 pour 40 -60 mL/min/1.73m2

4 pour 20-40 mL/min/1.73m2

6 pour < 20 mL/min/1.73m2

0 point

Total score

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References identified from the MEDLINE database (n=10)

"remote ischemic preconditioning" OR "remote preconditioning" OR "remote ischemic

preconditioning" AND "kidney" AND "contrast" AND "randomized"

References kept for a comprehensive reading (n=6)

4 non randomized clinical trials excluded: - 1 letter to the editor - 2 meta-analyses - 1 study protocol

References kept for systematic review (n=5)

1 reference excluded because no iodized contrast

product was injected

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