Michiel C. Warlé

Ischemic preconditioning in the animal kidney, a systematic review and meta-analysis.

Ischemic preconditioning (IPC) is a potent renoprotective strategy which has not yet been translated successfully into clinical practice, in spite of promising results in animal studies. We performed a unique systematic review and meta-analysis of animal studies to identify factors modifying IPC efficacy in renal ischemia/reperfusion injury (IRI), in order to enhance the design of future (clinical) studies. An electronic literature search for animal studies on IPC in renal IRI yielded fifty-eight studies which met our inclusion criteria. We extracted data for serum creatinine, blood urea nitrogen and histological renal damage, as well as study quality indicators. Meta-analysis showed that IPC reduces serum creatinine (SMD 1.54 [95%CI 1.16, 1.93]), blood urea nitrogen (SMD 1.42 [95% CI 0.97, 1.87]) and histological renal damage (SMD 1.12 [95% CI 0.89, 1.35]) after IRI as compared to controls. Factors influencing IPC efficacy were the window of protection (<24 hu200a=u200aearly vs. ≥24 hu200a=u200alate) and animal species (rat vs. mouse). No difference in efficacy between local and remote IPC was observed. In conclusion, our findings show that IPC effectively reduces renal damage after IRI, with higher efficacy in the late window of protection. However, there is a large gap in study data concerning the optimal window of protection, and IPC efficacy may differ per animal species. Moreover, current clinical trials on RIPC may not be optimally designed, and our findings identify a need for further standardization of animal experiments.

Remote ischaemic preconditioning by brief hind limb ischaemia protects against renal ischaemia-reperfusion injury: the role of adenosine

BACKGROUNDnRemote ischaemic preconditioning (RIPC) is a strategy to protect a target organ against ischaemia-reperfusion injury (IRI) by inducing short-term ischaemia/reperfusion (I/R) in a remote organ. RIPC of the kidney by temporary limb occlusion would be a safe, inexpensive and noninvasive method to prevent renal damage in, e.g., transplantation and aortic surgery. We investigated whether brief hind limb occlusion can protect against renal IRI and whether this protection is adenosine dependent.nnnMETHODSnRats underwent either no RIPC, unilateral RIPC or bilateral RIPC. The preconditioning stimulus was either continuous (12/12 I/R) or fractionated (three times 4/4 I/R). After the last reperfusion period, we induced 25 ischaemia in the right kidney.nnnRESULTSnAfter 24 h of reperfusion, renal function was improved by 30-60% in both bilateral RIPC groups and in the fractionated unilateral group. Renal tubule damage and kidney injury molecule-1 expression were reduced in three of four RIPC groups. Treatment with the adenosine receptor blocker 8-(p-sulfophenyl)theophylline had no effect on fractionated or continuous RIPC.nnnCONCLUSIONSnBrief hind limb ischaemia induces protection against renal IRI, which makes this a promising strategy to prevent renal IRI in a clinical setting. Bilateral RIPC was more effective than unilateral RIPC, and this protection occurs via an adenosine-independent mechanism.

Influence of prolonged cold ischemia in renal transplantation

van der Vliet JA, Warlé MC, Cheung CLS, Teerenstra S, Hoitsma AJ. Influence of prolonged cold ischemia in renal transplantation. u2028Clin Transplant 2011: 25: E612–E616.

Humoral signalling compounds in remote ischaemic preconditioning of the kidney, a role for the opioid receptor

BACKGROUNDnRenal ischaemia-reperfusion injury (IRI) is a common clinical problem associated with significant mortality and morbidity. One strategy to reduce this damage is remote ischaemic preconditioning (RIPC), in which brief ischaemia of a limb protects the kidney against a prolonged ischaemic insult. The mechanism of renal RIPC has not yet been elucidated. Here, we address the gap in our understanding of renal RIPC signalling, using a rat model of renal IRI and RIPC by brief hind limb ischaemia.nnnMETHODSnRats were treated with either no RIPC, RIPC+vehicle or RIPC+ an inhibitor or antagonist of one of the following candidate signalling molecules: noradrenalin, cannabinoids, glucocorticoids, inducible nitric oxide synthase, calcitonin gene-related peptide, ganglion-mediated signalling, haem oxygenase and free radicals. Subsequently, the animals underwent 25 min of renal ischaemia and 2 days of reperfusion, after which renal function and damage were assessed.nnnRESULTSnRIPC by three 4 min cycles of hind limb ischaemia effectively reduced renal IRI. Pre-treatment with the opioid receptor antagonist naloxone completely blocked this protective effect, when compared with animals treated with RIPC+vehicle; serum creatinine and urea increased (307.8±43.7 versus 169.5±16.7 µmol/L and 42.2±4.9 versus 27.6±2.2 mmol/L, respectively), as did the renal histological damage (score 4.2±0.7 versus 2.8±0.5) and expression of kidney injury molecule-1 (KIM-1; relative-fold increase in mRNA expression 164±18 versus 304±33). All other antagonists were without effect.nnnCONCLUSIONSnRenal RIPC by brief hind limb ischaemia may be the result of endorphin release from the hind limb. The importance of opioid signalling in renal RIPC provides vital clues for its successful translation to the clinical setting.

Ischaemic preconditioning for the reduction of renal ischaemia reperfusion injury

BACKGROUNDnIschaemia 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.nnnOBJECTIVESnThis 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.nnnSEARCH METHODSnWe searched Cochrane Kidney and Transplants Specialised Register to 5 August 2016 through contact with the Information Specialist using search terms relevant to this review.nnnSELECTION CRITERIAnWe 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.nnnDATA COLLECTION AND ANALYSISnStudies 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.nnnMAIN RESULTSnWe 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).nnnAUTHORS CONCLUSIONSnRemote 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.

Remote ischemic preconditioning to reduce contrast-induced nephropathy: study protocol for a randomized controlled trial

BackgroundDespite the increasing use of pre- and posthydration protocols and low-osmolar instead of high-osmolar iodine-containing contrast media, the incidence of contrast-induced nephropathy (CIN) is still significant. There is evidence that contrast media cause ischemia-reperfusion injury of the medulla. Remote ischemic preconditioning (RIPC) is a non-invasive, safe, and low-cost method to reduce ischemia-reperfusion injury.MethodsThe RIPCIN study is a multicenter, single-blinded, randomized controlled trial in which 76 patients at risk of CIN will receive standard hydration combined with RIPC or hydration with sham preconditioning. RIPC will be applied by four cycles of 5xa0min ischemia and 5xa0min reperfusion of the forearm by inflating a blood pressure cuff at 50xa0mmHg above the actual systolic pressure. The primary outcome measure will be the change in serum creatinine from baseline to 48 to 72xa0h after contrast administration.DiscussionA recent pilot study reported that RIPC reduced the incidence of CIN after coronary angioplasty. The unusual high incidence of CIN in this study is of concern and limits its generalizability. Therefore, we propose a randomized controlled trial to study whether RIPC reduces contrast-induced kidney injury in patients at risk for CIN according to the Dutch guidelines.Trial registrationCurrent Controlled Trials ISRCTN76496973

Local and remote ischemic postconditionings have synergistic protective effects on renal ischemia-reperfusion injury.

I n the current era of meticulous surgical technique and modern immunosuppressive therapy, ischemiareperfusion injury (IRI) is one of the major determinants of early and longterm allograft function after kidney transplantation (1, 2). In an experimental model of renal IRI, we showed that remote ischemic preconditioning using the hind limb as the remote organ is effective in reducing IRI (3). Kadkhodaee et al. (4) recently reported that remote ischemic perconditioning and remote ischemic postconditioning (RIPostC) also significantly reduce renal IRI in a comparable model. Here, we report the first data on the combined effect of local IPostC (LIPostC) and RIPostC on renal IRI. Male Sprague-Dawley rats weighing approximately 300 g were randomized into five groups before surgery. All animals underwent nephrectomy of the left kidney. Five sham-operated animals served as a baseline control (sham). All other animals were subjected to 25 min of renal ischemia (by clamping the renal artery and vein of the right kidney) with 48 hr of reperfusion. Eight animals underwent renal IRI only (no IPostC). In nine animals, three cycles of RIPostC by brief hind limb ischemia were induced directly after clamp release, by inflating small blood pressure cuffs around both proximal thighs for 5 min, followed by 5 min of reperfusion (RIPostC). Successful hind limb occlusion (loss of pulse and strong decrease of saturation) was confirmed by means of a pulse oximeter clip placed on the foot. In another nine animals, LIPostC was induced by six cycles of 8 sec of ischemia, followed by 8 sec of reperfusion (LIPostC). Seven

Outcome of Kidney Allografts in Recipients With a Femoral Arteriovenous Fistula: Report of Two Cases

Two patients, who were on hemodialysis over a femoral arteriovenous fistula, were transplanted in our center. Despite adequate blood pressure, perfusion of the renal allograft remained poor after completion of the vascular anastomoses. Ligation of the femoral arteriovenous fistula (1.6 L/min) led to adequate perfusion. Initial graft function was good. Although it remains unclear whether ischemia of a renal allograft is caused by venous hypertension or vascular steal due to a femoral arteriovenous fistula, it might be necessary to ligate a femoral arteriovenous fistula to obtain adequate graft perfusion.

Ruptured Iliac Artery Aneurysm Presenting as Acute Right Heart Failure and Cardiac Arrest

Aortocaval fistula due to aneurysmal degradation can result in obscure clinical signs but with life-threatening sequelae. Our patient presented with multiple cardiac arrests because of sudden right heart decompensation after a ruptured iliac aneurysm into the adjacent iliac vein. He fully recovered after emergency open surgical repair. High awareness with subtle clinical signs is of great importance.

Double J is Superior to Externally Draining Ureteric Stent in Enhancing Recovery After Living Donor Kidney Transplantation

Introduction Prophylactic ureteral stenting in kidney transplantation has been proven to reduce urological complications, such as urine leakage and ureteral obstruction. However, there is no consensus on the optimal stent design. We aimed to compare the influence of double-J (or JJ) catheters and externally draining ureteric stents on the early recovery after living donor kidney transplantation. Materials and Methods Between April 2016 and October 2017 a prospective cohort study was performed in 80 recipients of living donor kidney transplants at the Radboud University Medical Center Nijmegen. The patients were divided in two cohorts, the first cohort received an externally draining ureteric stent (splint), in accordance with the standard protocol at the Radboud UMC. The second cohort received a JJ catheter to stent the ureterovesical anastomosis. The splint was removed after 5 days, followed by removal of the Foley catheter 2 days later. In patients treated with the JJ catheter, the Foley catheter was removed after 5 days and the JJ catheter after 2 to 3 weeks at the outpatient clinic by cystoscopy. Early recovery after surgery was daily monitored until patients were discharged. The primary outcome measure was the Quality of Recovery-40 (QoR-40) score. The Quality of Recovery-40 is a validated patient-rated questionnaire with a maximum score of 200, measuring 5 dimensions of recovery after surgery including comfort, emotions, physical independence, pain, and patient support. Secondary outcomes were components of pain scores, achievement of discharge criteria, length of hospital stay, and complications. Results The mean QoR-40 scores on postoperative day 5 of the recipients with JJ catheter and splint were 190.3 (SD 8.0) and 185.0 (SD 13.9) respectively, p 0.02. The course of the QoR-40 scores during the first 5 days is depicted in Figure 1. Furthermore, when compared to patients with a splint, patients with a double J stent reached the discharge criteria earlier, and consequently their length of hospital stay was significantly shortened with 1 or 2 days. Daily pain scores were comparable between both groups, except for slightly raised pain scores in the double J group on postoperative days 1 and 2. Early urological complications were similar between the two groups. Figure. No caption available. Discussion In accordance to the validated QoR-40 questionnaire, the difference of 6.3 on postoperative day 5 is a clinically relevant improvement in postoperative recovery, as result of the JJ catheter. This is also supported by the fact that patients with a JJ catheter could be discharged earlier without making concessions to postoperative complication rates. The increased pain scores in the JJ catheter group on the first postoperative days can be explained by earlier mobilization. Conclusion Double J stenting improves the early postoperative recovery after living donor kidney transplantation, when compared to externally draining ureteric stents.