Short periods of limb blood flow obstruction to reduce kidney injury

What is the issue?

The kidney is highly sensitive to shortage in blood flow and thus oxygen supply. This may cause irreversible kidney injury leading to haemodialysis or death. Kidney injury does not only relate to the temporary lack of oxygen supply, but is also due to the re-saturation of blood flow. At this stage, toxic products are released and initiate a reaction of the body causing further cellular damage within the kidney, the so called ‘ischaemia-reperfusion injury’. A lack of oxygen supply to the kidney injury may have many different causes, for example blood pressure changes that may occur during major surgery.

What did we do?

Our hypothesis is that short harmless periods (5 minutes) of blood flow obstruction to an organ can reduce injury in this particular organ (local ischaemic preconditioning), but can also reduce injury in other organs at a distance (remote ischaemic preconditioning). A blood flow obstruction can easily and safely be achieved in a limb by inflating blood pressure cuff around the upper arm or leg. The mechanism of this remote ischaemic preconditioning is not precisely known, it is assumed that a protective signal from the remote organ to the kidney is transferred through the blood stream or nervous system.

In this analysis our primary goal is to investigate whether remote ischaemic preconditioning is safe and effective in reducing kidney injury in patients undergoing a (surgical) procedure in which kidney injury may occur. Kidney injury after kidney transplantation may have a different underlying pathophysiology and therefore these studies are not taken into account. The impact of remote ischaemic preconditioning on the need for dialysis, hospital stay and mortality will be assessed.

What did we find?

We performed a search off all available literature on 8 August 2016 to find all randomised controlled studies. 28 studies including 6851 patients were included in this analysis. Five studies included children undergoing cardiac surgery. Adult studies included patients undergoing major vascular surgery (three studies), cardiac surgery (nine studies), coronary bypass surgery (10 studies) and partial kidney resection (one study). The overall quality of the studies was acceptable.

Twenty studies were funded without economical interest. One study was funded from a source with commercial interest. The other seven studies did not report funding.

Remote ischaemic preconditioning performed with a blood pressure cuff appears to be safe as only two of 15 studies reported adverse effects (6/1999 in the remote ischaemic preconditioning group and 1/1994 in the control group). However remote ischaemic preconditioning by vascular clamping may cause vascular complications. Kidney injury in patients undergoing (surgical) procedures in which kidney injury may occur, was not reduced by remote Ischaemic preconditioning measured at day one, two or three after surgery. The need for dialysis, hospital stay and death were not reduced by remote ischaemic preconditioning.

Conclusion

Although remote ischaemic preconditioning by cuff inflation is safe, available data do not confirm the efficacy of remote ischaemic preconditioning in reducing kidney injury.

Authors' conclusions: 

Remote ischaemic preconditioning by cuff inflation appears to be a safe method, and probably leads to little or no difference in serum creatinine, adverse effects, need for dialysis, length of hospital stay, death and in the incidence of acute kidney injury. Overall we had moderate-high certainty evidence however the available data does not confirm the efficacy of remote ischaemic preconditioning in reducing renal ischaemia reperfusion injury in patients undergoing major cardiac and vascular surgery in which renal ischaemia reperfusion injury may occur.

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Background: 

Ischaemia reperfusion injury can lead to kidney dysfunction or failure. Ischaemic preconditioning is a short period of deprivation of blood supply to particular organs or tissue, followed by a period of reperfusion. It has the potential to protect kidneys from ischaemia reperfusion injury.

Objectives: 

This review aimed to look at the benefits and harms of local and remote ischaemic preconditioning to reduce ischaemia and reperfusion injury among people with renal ischaemia reperfusion injury.

Search strategy: 

We searched Cochrane Kidney and Transplant's Specialised Register to 5 August 2016 through contact with the Information Specialist using search terms relevant to this review.

Selection criteria: 

We included all randomised controlled trials measuring kidney function and the role of ischaemic preconditioning in patients undergoing a surgical intervention that induces kidney injury. Kidney transplantation studies were excluded.

Data collection and analysis: 

Studies were assessed for eligibility and quality; data were extracted by two independent authors. We collected basic study characteristics: type of surgery, remote ischaemic preconditioning protocol, type of anaesthesia. We collected primary outcome measurements: serum creatinine and adverse effects to remote ischaemic preconditioning and secondary outcome measurements: acute kidney injury, need for dialysis, neutrophil gelatinase-associated lipocalin, hospital stay and mortality. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes.

Main results: 

We included 28 studies which randomised a total of 6851 patients. Risk of bias assessment indicated unclear to low risk of bias for most studies. For consistency regarding the direction of effects, continuous outcomes with negative values, and dichotomous outcomes with values less than one favour remote ischaemic preconditioning. Based on high quality evidence, remote ischaemic preconditioning made little or no difference to the reduction of serum creatinine levels at postoperative days one (14 studies, 1022 participants: MD -0.02 mg/dL, 95% CI -0.05 to 0.02; I2 = 21%), two (9 studies, 770 participants: MD -0.04 mg/dL, 95% CI -0.09 to 0.02; I2 = 31%), and three (6 studies, 417 participants: MD -0.05 mg/dL, 95% CI -0.19 to 0.10; I2 = 68%) compared to control.

Serious adverse events occurred in four patients receiving remote ischaemic preconditioning by iliac clamping. It is uncertain whether remote ischaemic preconditioning by cuff inflation leads to increased adverse effects compared to control because the certainty of the evidence is low (15 studies, 3993 participants: RR 3.47, 95% CI 0.55 to 21.76; I2 = 0%); only two of 15 studies reported any adverse effects (6/1999 in the remote ischaemic preconditioning group and 1/1994 in the control group), the remaining 13 studies stated no adverse effects were observed in either group.

Compared to control, remote ischaemic preconditioning made little or no difference to the need for dialysis (13 studies, 2417 participants: RR 0.85, 95% CI 0.37 to 1.94; I2 = 60%; moderate quality evidence), length of hospital stay (8 studies, 920 participants: MD 0.17 days, 95% CI -0.46 to 0.80; I2 = 49%, high quality evidence), or all-cause mortality (24 studies, 4931 participants: RR 0.86, 95% CI 0.54 to 1.37; I2 = 0%, high quality evidence).

Remote ischaemic preconditioning may have slightly improved the incidence of acute kidney injury using either the AKIN (8 studies, 2364 participants: RR 0.76, 95% CI 0.57 to 1.00; I2 = 61%, high quality evidence) or RIFLE criteria (3 studies, 1586 participants: RR 0.91, 95% CI 0.75 to 1.12; I2 = 0%, moderate quality evidence).

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