Remote ischemic preconditioning for kidney protection.

Acutekidneyinjury (AKI) iscommonandfrequentlyassociated withsubstantialmorbidityandmortality.Elevatedserumcreatinine levels in patients after surgery are associated with poor outcomes.1,2Asmall increase inserumcreatinine inhospitalized patients is associatedwithhighermortality, longer hospitalization, andhigher cost of care.3Acute tubularnecrosis (ATN), definedasacute injury to therenal tubularepithelial cells,mayoccurfollowingsevererenal ischemiaorexposuretonephrotoxins. Preconditioning-mediated protection is a phenomenon in whichtissue,onceexposedtoaspecifictypeof insult,willbeprotected from injury during a repeated similar or sometimes dissimilar insult.4Theprotectivephenotype(preconditioning) in response to ischemia depends on a coordinated response at the genomic,molecular, cellular, and tissue levels, in whatisdescribedas“genomicreprogramming.”5Preconditioningmediatedprotectioniswelldescribedforthebrainandheart,and recentreportssuggestthat italsofunctionsforthekidneyinATN. For instance, in experimental mouse/rat models of ischemia/ reperfusion kidney injury, in which bilateral kidney pedicles (arteriesandveins)areclampedfor30to45minutes,AKIdevelopswithin24hours; invariably,kidneyfunctionrecoverswithin aweek.However, if thekidneysaresubjectedtoanequivalent insult 1or2weeksafter the initial insult,anequal increase inserum creatinine or kidney inflammationmarkers comparedwith the initial insult isnotobserved.6Resistancetorepeatedischemicepisodesaffordedby30minutesofbilateralkidneyischemiacanpersistfor12weeksafterpreconditioning,6,7whereasashorterperiod ofischemia(15minutes) ispartiallyprotectiveagainstsubsequent ischemic injury imposed8days later.Similarly, thekidneysmay displayattenuated ischemia/reperfusion injury followingnephrotoxic (eg, cisplatin) injury, andviceversa.8Amajor limitation totheclinicaluseof this ischemicpreconditioningstrategy is the need for direct access to the blood supply of the organ at risk. Recentdata suggest that ischemia inoneorgan is accompaniedwith protective changes in distant organs, a phenomenon knownas remote ischemicpreconditioning (RIPC).Application ofoneormorebrief cyclesofnonlethal ischemia/reperfusion to an organ or tissuemay protect a remote organ or tissue from a sustainedepisodeof lethal ischemia/reperfusion.Thebeneficial effectsofRIPChavebeendemonstratedindiverseorgansandtissues (lung, liver, kidney, intestine, brain, skeletal muscle) subjectedtoacuteischemia/reperfusion,9andthediscoverythatRIPC canbe inducednoninvasively by simple inflation anddeflation ofastandardbloodpressurecuffplacedona limbhas facilitated its translation into the clinical setting. ThereportbyZarbockandcolleagues inthis issueofJAMA10 examined the effects of RIPC on the rate and severity of AKI in patients undergoing cardiac surgery. In amulticenter trial, 240 patients at high risk for AKI (ClevelandClinic Foundation score ≥6)wererandomizedtoreceiveeitherRIPC(n = 120)orshamcontrol (n = 120) after inductionof anesthesia. TheRIPC involved3 cycles of 5minutes of ischemia induced by inflation of a blood pressure cuff to 200mmHgor at least 50mmgreater than systolic bloodpressure inoneupper arm, followedby5minutesof reperfusionwith the cuff deflated. The shamRIPC (control) involved3 cycles of “pseudoischemia,” consistingof 5minutesof bloodpressurecuff inflationto20mmHg,followedby5minutes of cuff deflation. All patients completed follow-up30days after surgeryand wereanalyzedaccordingto the intention-to-treatprinciple.The primary end point was the rate of AKI defined by KDIGO criteriawithinthefirst72hoursaftercardiacsurgery.11Secondaryend points included use of renal replacement therapy (RRT), duration of intensive care, occurrence ofmyocardial infarction and stroke, in-hospital and30-daymortality, andchange inAKIbiomarkers.AcutekidneyinjurywassignificantlyreducedwithRIPC (45/120; 37.5%) comparedwith control (63/120; 52.5%),withan absoluteriskreduction(ARR)of15%.FewerpatientsreceivedRRT after RIPC (7 [5.8%] vs 19 control [15.8%]; ARR, 10%) and RIPC reduced intensive care unit stay (3 vs 4 days). RIPC had no significant effect onmyocardial infarction, stroke, ormortality. Eventhoughthemechanism(s)underlyingpreconditioning remainselusive, a fewcluesabout itsnaturehaveemerged.Upregulation of inducible nitric oxide synthase and heat shock proteins7,12 as well as activation of the endoplasmic reticulum stress response13mayplaya role in the longer-termkidneyprotectionattributedto ischemicpreconditioning.Recentdatasuggestthatrecruitmentofmesenchymalstemcells iscritical forthis protection.Regenerationofproximal tubuleepitheliumafter ischemic injuryappears tobe intrinsic to thekidneyanddoesnot requiretransdifferentiationofbonemarrow–derivedstemcells.14 However, bonemarrow–derived leukocytes andcells bearingendothelialmarkers (mesenchymalcells)aredetected inthe kidney interstitium after ischemic injury.14,15 Kuo et al16 suggested that injuredkidneycells (endothelial) recruitmesenchymalstemcells throughthereleaseofpreformedvesicles(WeibelPalade bodies) packed with messenger signals that include IL-8,eotaxin3,vonWillebrandfactor,andangiopoietin2.Atrigger for the releaseof thesevesicles isuricacid, aproductofxanthine oxidase activation in the ischemic organ, through interactionwithToll-like receptors TLR2 andTLR4.Angiopoietin 2 amplifies release of Weibel-Palade bodies and plays a pivotal role in the recruitmentofmesenchymal stemcells in response touric acidandpotentiallyother“alarmsignals.”16Administration ofmesenchymal stem cells to rats protects against ischemic kidney injury, and this protection is associated with upRelated article page 2133 Opinion