Ischemic Preconditioning Limits Contrast-Induced Kidney Damage

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In patients at high risk of nephropathy, remote conditioning before angiography dramatically cuts rates of acute kidney injury. The results, from a small-single-center study, are promising enough to merit confirmation in a larger trial, researchers assert in a paper published online June 26, 2012, ahead of print in Circulation.

The double-blind sham-controlled RenPro-I-Trial (Renal Protection-I-Trial), randomized 100 patients with impaired renal function who were undergoing elective angiography to standard care with (n = 50) or without ischemic preconditioning (n = 50). Using standard upper-arm blood pressure cuffs, Fikret Er, MD, of the University of Cologne (Cologne, Germany), and colleagues gave patients assigned to preconditioning 4 cycles of 5-minute inflation to 50 mm Hg above systolic blood pressure followed by 5-minute deflation. In controls, the cuff was inflated to diastolic pressure levels then deflated to 10 mm Hg.

Preconditioning/control therapy began immediately before angiography, with fewer than 45 minutes between last inflation and the procedure. There were no major adverse events.

Clear Short-term Effect

Contrast-induced nephropathy, the primary endpoint, was defined as an increase of serum creatinine (sCr) of at least 25% and/or at least 0.5 mg/dL above baseline at 48 hours after exposure.

Risk of nephropathy was substantially lower in the preconditioning group (OR 0.21; 95% CI 0.07-0.57). Surrogate measures for acute kidney injury including urinary neutrophil gelatinase-associated lipocalin (NGAL) and serum cystatin C also were positive (table 1).

Table 1. Effect of Remote Conditioning: 48-Hour Outcomes

At 6-week follow-up, death and hemodialysis rates were similar for both groups, but controls had a higher rate of rehospitalization (36% vs. 14% with preconditioning; P = 0.016).

“Our hypothesis that [ischemic preconditioning] may be nephroprotective was largely based on earlier reports showing the beneficial action of [the treatment] in several clinical settings,” Dr. Er and colleagues note. Many mechanisms for remote conditioning have been proposed, they say, highlighting the theory that the “remote organ releases humoral factors such as adenosine or bradykinin into the systemic circulation” that are subsequently protective in other regions.

The RenPro-II-Trial will now test whether ischemic preconditioning has extended effects on cardiovascular mortality and morbidity, the paper reports.

Guarded Excitement

In an editorial accompanying the paper, Joseph V. Bonventre, MD, PhD, of Brigham and Women’s Hospital (Boston, MA), highlights the long history of preconditioning, pointing out that the relationship between prior exposure to renal injury and subsequent renal protection was reported a full century ago.

Today, ischemic preconditioning via a limb is a reasonably safe, clinically feasible, and inexpensive therapeutic approach, Dr. Bonventre adds. In particular, the “study results are very interesting since the protective effects of remote preconditioning suggest an intervention that could be relatively easily applied in routine medical practice.”

Hitinder S. Gurm, MD, of the University of Michigan Cardiovascular Center (Ann Arbor, MI), agreed that the study offers “provocative” results.

“I am cautiously optimistic that this may be a useful strategy, since there appears to be a beneficial signal as assessed by other markers such as NGAL and cystatin C,” he told TCTMD in an e-mail communication. “The field of [contrast-induced nephropathy] research is littered with promising therapies that were dramatically effective when tested in small studies and then failed when tested in larger, adequately powered studies. I would congratulate the authors for exploring this strategy and look forward to the results of a larger confirmatory study.”

In a telephone interview with TCTMD, Richard Solomon, MD, of the University of Vermont (Burlington, VT), also seemed simultaneously enthusiastic and cautious.

Preconditioning “has been around for a long time,” he stressed, noting that his own experience with the technique has been less promising. “Our [center’s] data suggested it wasn’t doing that much [for patients undergoing cardiac surgery], so we stopped doing it a couple of years ago.”

The current study, though “certainly very positive,” is small, Dr. Solomon noted. “It’s something that clearly needs confirmation and for other people to take a shot at to see if they can reproduce this result.”

Dr. Solomon emphasized that many single-center studies do not pan out, particularly in the field of contrast-induced nephropathy. Results for N-acetylcysteine and sodium bicarbonate were initially encouraging but “both of those therapies remain unproven at this point despite multicenter trials,” which have shown mixed findings.

That being said, “most patients tolerate this pretty well. The actual technique is very similar to what we do for testing endothelial function,” he noted.

The “really important piece” is whether acute injury has lasting effects, Dr. Solomon commented. “It’s not clear whether that initial episode of [kidney injury] causes those downstream adverse events or not. It may be that the people who get [acute kidney injury] are sicker people so when more things happen to them 6 months later, it’s because they were sicker to begin with. The [damage] is simply a marker.”

Study Details

All patients had sCr > 1.4 mg/dL and/or eGFR < 60 mL/min/1.73 m². Baseline characteristics were similar between the 2 groups. Angiography was performed using iohexol, a nonionic low-osmolar contrast medium. Due to higher use of PCI, patients in the preconditioning group received larger contrast volumes compared with controls (124 ± 44 mL vs. 103 ± 41 mL).

 

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Sources:
1. Er F, Nia AM, Dopp H, et al. Ischemic preconditioning for prevention of contrast-medium-induced nephropathy: Randomized pilot RenPro-Trial (Renal Protection Trial). Circulation. 2012;Epub ahead of print.

2. Bonventre JV. Limb ischemia protects against contrast-induced nephropathy. Circulation. 2012;Epub ahead of print.

 

 

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• Remote Conditioning in Ambulance Increases Myocardial Salvage After AMI

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