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Clinical and Translational Research

The Effect of Remote Ischemic Postconditioning on Graft Function in Patients Undergoing Living Donor Kidney Transplantation

Kim, Won Ho1; Lee, Jong-Hwan2,4; Kim, Gaab Soo2; Sim, Hyun Yee2; Kim, Sung Joo3

Author Information
doi: 10.1097/TP.0000000000000098
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Abstract

In kidney transplantation (KT), ischemia-reperfusion injury (IRI) can occur before or during organ procurement, cold storage, and surgery. IRI during KT is a known short- and long-term prognostic factor, and it is associated with a greater risk of transplantation failure. For example, delayed graft function (DGF) is thought to be a manifestation of IRI and activation of the innate immune response (1, 2). Moreover, IRI is associated with increased risk of rejection after transplantation (2, 3) and reduced long-term graft function and survival (3–5).

As a way of reducing the adverse effects of IRI after organ transplantation, the concept of preconditioning or postconditioning has been investigated (6–9). Ischemic preconditioning, which is a short period of ischemia followed by reperfusion, can protect an organ from a subsequent severe IRI. Ischemic postconditioning is a manipulation of the early reperfusion phase to reduce IRI because this phase is known to be important in the pathogenesis of postischemic injury (8–11).

Recently, remote ischemic conditioning has been introduced. It is one of the protective strategies where brief IRI of one organ before, during, or even after target organ ischemia protects the target organ against sustained IRI (8). It was classified into remote ischemic preconditioning, perconditioning, or postconditioning (RiPoC) according to the time relationship between the conditioning and prolonged ischemia. Specifically, previous studies showed that remote ischemic conditioning protects the heart (12, 13), liver, kidneys (14), and lungs from IRI. It is noninvasive and technically much easier to use than ischemic conditioning.

Despite the mechanistic uncertainties of remote conditioning, previous studies have shown that RiPoC can reduce vascular endothelial IRI in humans (15, 16). Furthermore, recent animal studies have revealed that remote conditioning can protect kidneys from IRI (17–19). Considering the harmful effects of IRI on graft function during KT, RiPoC may improve graft function by reducing IRI. However, no clinical studies are available to test the clinical efficacy of RiPoC in living donor KT (20), although there have been clinical studies evaluating the effect of ischemic postconditioning in deceased donor KT (21) and remote ischemic preconditioning in living donor KT (22). We hypothesized that RiPoC mitigates IRI during KT and improves immediate postoperative graft function, leading to a better renal function test profile. Therefore, we evaluated whether RiPoC in living donor KT affects initial graft function, which was assessed by postoperative serum creatinine (sCr) level and the estimated glomerular filtration rate (eGFR).

RESULTS

From August 2011 to May 2012, 73 patients were assessed for eligibility. Thirteen were excluded for retransplantation (n=2), severe cardiac dysfunction (n=2), or not providing informed consent (n=9) (Fig. 1). The remaining 60 patients were randomly assigned to groups and completed the study according to the protocol. All 60 patients were included in the analysis, and all patients were treated with the protocol to which they had been randomly assigned. All 60 patients were followed for graft function for 1 year.

FIGURE 1
FIGURE 1:
Flow diagram of the study according to the CONSORT 2010 statement. RiPoC group=remote ischemic postconditioning group.

There were no differences in donor or recipient demographic and preoperative clinical factors (Table 1). The preoperative and postoperative sCr, eGFR, and their changes from preoperative sCr are shown in Table 2 and Figure 2. The time to 50% reduction of preoperative sCr was significantly shorter in the RiPoC group than in the control group [median (interquartile range) 12 (12–24) hr in the RiPoC group vs. 24 (21–36) hr in the control group, P=0.005]. The number of patients whose sCr was reduced by 50% within 12 hr was significantly greater in the RiPoC group than in the control group [n=17 (57%) in the RiPoC group vs. n=7 (23%) in the control group, P=0.008]. Similarly, the number of patients whose sCr was reduced by 50% within 24 hr was significantly greater in the RiPoC group than in the control group [n=26 (87%) in the RiPoC group vs. n=18 (60%) in the control group, P=0.020]. There were significant time-dependent changes in sCr and eGFR within each group but no differences in sCr, eGFR, and their changes from preoperative values at each time point between the two groups.

TABLE 1
TABLE 1:
Summary of kidney transplantation donor and recipient characteristics in the remote ischemic postconditioning (RiPoC) group and the control group
TABLE 2
TABLE 2:
Comparison of decrease of serum creatinine (sCr) and estimated glomerular filtration rate (eGFR) after surgery between the remote ischemic postconditioning (RiPoC) group and the control group
FIGURE 2
FIGURE 2:
Postoperative levels in creatinine and eGFR in remote ischemic postconditioning and control groups. Numbers are the hours after surgery. RiPoC=remote ischemic postconditioning, eGFR=estimated glomerular filtration rate.

Urine output on postoperative day 1 was significantly higher in the RiPoC group than in the control group [mean (SD) 7912 (3093) mL in RiPoC vs. 6416 (2046) mL in the control, P=0.030], but there were no differences in urine output thereafter. In addition, there was no difference in mean urine output during the first postoperative week between groups [5079 (4589–5667) ml in RiPoC vs. 5348 (4372–6522) ml in the control, P=0.11]. Also, urine creatinine and creatinine clearance, which was calculated using urine creatinine, were not different between the two groups at any time point.

In Table 3, postoperative graft function, postoperative clinical outcome, and hospital stay are compared. There were no differences in hospital stay, the incidence of graft dysfunction, or the postoperative complication rate between groups. In addition, there was no tacrolimus or cyclosporine toxicity in our study sample, which was confirmed by biopsy or Doppler ultrasonography.

TABLE 3
TABLE 3:
Comparison of graft function, postoperative transplantation-related complications, and hospital stay between the remote ischemic postconditioning (RiPoC) group and the control group

DISCUSSION

In the present study, we demonstrated the effect of RiPoC on immediate postoperative graft function in patients undergoing living donor KT. Although there have been clinical studies of applying ischemic postconditioning in deceased donor KT (21) or remote ischemic preconditioning in living donor KT (22), no clinical efficacy on early renal function was demonstrated. Compared with the control group, we found that sCr levels were reduced more quickly and more patients’ sCr levels were reduced by 50% within 12 or 24 hr after surgery in the RiPoC group than in the control group. These results are supported by our finding that urine output during the first 24 postoperative hours was significantly greater in the RiPoC group than in the control group. However, the mean sCr and eGFR values at each time point were not different between groups. Additionally, graft function, the postoperative complication rate, and hospital stay were not different between groups.

In renal transplantation, no particular method has been reported to improve graft function or survival except for immunosuppressive therapy (23, 24) and ischemic preconditioning or postconditioning (25, 26). Acute kidney injury often occurs with KT and frequently progresses to the clinical diagnosis of DGF. Poor kidney function during the first postoperative week is detrimental to the longevity of the allograft (27), and DGF can be compounded by acute rejection and chronic allograft nephropathy. To avoid apoptosis and subsequent DGF, ischemic preconditioning has been studied extensively. In a recent study with an animal DGF model, recipient pretreatment with inhaled carbon monoxide (CO) was explored for its ability to avert apoptosis (28), and the allografts showed relative benefit when transplanted into a recipient who received CO. In addition to ischemic preconditioning, ischemic postconditioning has been demonstrated to attenuate renal IRI as well (25, 26).

Remote ischemic preconditioning by hind limb ischemia has been shown to protect against renal IRI and to prevent renal damage in animal studies (29). Remote ischemic preconditioning seems to be a safe, inexpensive, noninvasive, and user-friendly technique to prevent renal damage. Although many animal studies have evaluated the relationship between this method and circulating dendritic cell counts (30) or adenosine levels (29, 31, 32), the exact mechanism is still unknown. However, remote ischemic preconditioning may not be beneficial in KT, as the kidney graft is removed from the donor as soon as it experiences ischemia. Furthermore, in deceased donor KT, remote ischemic preconditioning is difficult to perform because the donor kidney may be removed at a different institution.

Considering the limitations of remote ischemic preconditioning in KT, RiPoC can be an appealing alternative. Recently, Kadkhodaee et al. (17) reported the first evaluation of the protective effect of remote perconditioning and postconditioning on ischemia/reperfusion-induced renal injury in rats. After 24 hr of reperfusion, both remote ischemic perconditioning or postconditioning significantly improved renal function and prevented the ischemia/reperfusion-induced increase in plasma creatinine. With these results, we expected to reveal clinical efficacy and therapeutic potential of RiPoC in KT recipients. However, previous human studies failed to demonstrate the efficacy of ischemic conditioning strategies on renal function or incidence of DGF in kidney transplantation (21, 22). Various clinical factors including immunosuppressive drug, duration of ischemia, comorbidity, comedication, anesthesia regimen, type of organ preservation, and age seem to affect IRI and response to ischemic conditioning (33, 34). These factors may be the reason why it is difficult to prove the efficacy of ischemic conditioning in human transplantation setting.

In accordance with the previously reported benefit of RiPoC, we found modest efficacy of RiPoC on graft function. The quick reduction in sCr level in the RiPoC group during the immediate postoperative period seems to be due to a RiPoC effect via reduced IRI in the kidney graft. However, postoperative sCr and eGFR values were not different between groups. Our inability to demonstrate differences in graft function in terms of sCr and eGFR between groups, aside from the rate of sCr decrease, may be a result of our small sample size and the good graft function in most patients (35). Indeed, it would be very difficult to demonstrate a difference in renal function between two groups of recipients when both have good graft function. Therefore, a large number of patients would be required to show an improved graft function effect with RiPoC in living donor KT. Otherwise, it might be easier to show the efficacy of RiPoC in recipients of deceased donor KT that are prone to DGF, or the effect may be revealed in patients with less robust initial graft function.

For the evaluation of graft function, we used a creatinine-based approximation of GFR. However, problems with creatinine (varying muscle mass, recent meat ingestion, etc.) have led to the exploration of alternative methods for GFR estimation. One of these alternatives is Cystatin-C, which is a better predictor of early graft function after KT than sCr (36). Other biomarkers for renal injury, such as neutrophil gelatinase-associated lipocalin and interleukin-18, have been developed and extensively studied (37, 38). However, because the initial serum biomarkers in the recipient may come from a donor kidney, the biomarkers may not accurately reflect the initial graft function in the recipient’s body.

In remote ischemic conditioning, the mechanism of the transfer of protection from one limb to the target organ is not certain, but some mediators are believed to play a role. The mediators, such as adenosine, bradykinin, or opioids, are released from the preconditioned organ or tissue and are transported to the target organ through the circulation (8, 20, 31, 32). Activation of the mediators by triggers results in the opening of the adenosine triphosphate (ATP)-dependent mitochondrial potassium channel and the inhibition of mitochondrial permeability transition pores, which reduces the amount of reactive oxygen species (8, 20, 39). Although the triggers and end effectors are the same for both preconditioning and postconditioning, the mediators are thought to be different. These mediators include protein kinase C, mitogen-activated protein kinase, heat shock factor 1, and nuclear factor κ B for ischemic preconditioning and the reperfusion injury salvage kinase pathway for ischemic postconditioning (20).

Although the optimal schedule is unknown, there have been many studies evaluating the efficacy of remote conditioning with different regimens. We chose to use a regimen consisting of three 5-min cycles of ischemic postconditioning according to the previous clinical studies (40, 41), and a cuff pressure of 300 mmHg was chosen based on the high blood pressures of our study sample. In addition, we chose to use the upper limb according to the previous clinical studies (16, 40–42), whereas previous animal studies mostly used the lower limb (13, 17, 19, 29, 30).

The present study has several limitations. First, the present study was not powered to detect statistical differences in incidence of DGF, long-term graft survival or hospital stay. Short-term effects of RiPoC including initial changes of sCr, need for dialysis and hospital stay are important. However, the long-term effect of RiPoC should also be evaluated in further studies by measuring GFR in the steady state with a more exact method, which could be accomplished by measuring clearance of 51Cr-EDTA (43). Second, sevoflurane or desflurane were used as the principal anesthetic agents during the surgeries. Volatile anesthetics were reported to have protective effects against renal IRI and the use of these inhalational agents in the present study might have decreased IRI during KT (44, 45). Hence, the protective effect of the inhalational agents may have attenuated the protective effect caused by RiPoC in the present study. Third, we did not measure serum biomarkers of kidney injury as mentioned previously. Fourth, there were more female donors than male donors enrolled in the control group of this study. As female subjects are known to be more resistant to ischemia than male subjects (46), this donor sex difference may have affected the results of this study. However, as the immediate graft function favored the RiPoC group, this confounder does not explain the results. Finally, the primary outcome variable of this study was simple observation of creatinine and eGFR, which could be influenced by fluid administration or postoperative serum calcineurin inhibitor level (47, 48).

In conclusion, our clinical trial for RiPoC in living donor KT recipients demonstrated the efficacy of RiPoC on immediate postoperative graft function. Postoperative sCr decreased faster, and more patients’ sCr was reduced by 50% within 24 hr after surgery in the RiPoC group. However, we failed to show any difference in graft function or clinical outcomes thereafter. Considering that most recipients in this study had immediate and good graft function, the clinical efficacy of RiPoC may not have been fully revealed. Further studies with deceased donor KT or studies powered to detect a smaller difference in graft function are needed.

MATERIALS AND METHODS

The institutional review board of our institution (2011-03-047) approved this single-center, prospective, double-blinded, randomized controlled trial, and all patients provided informed consent. This study was registered at www.clinicaltrial.gov (NCT01363687).

Enrollment and Randomization

Patients scheduled for elective living donor KT were evaluated for eligibility. The indication for transplantation was end-stage renal failure on dialysis. Patients with retransplantation, peripheral ischemic vascular disease that involved the upper limb, and severe cardiac dysfunction (NYHA class III-IV) were excluded from this study.

Patients were randomly assigned to either the RiPoC group or the control group in a 1:1 allocation ratio according to the randomized assignment number generated by an internet-based computer program (www.randomizer.org). Professor J. Lee enrolled participants and Professor W. Kim assigned patients to their respective study groups according to the random number generated. Professor G.S. Kim received the sealed envelope containing the patient assignment, entered the operating room during reperfusion, and directed to perform RiPoC or not. The attending surgeon, patients, and anesthesiologist, who mainly managed the patient during KT, did not know the group assignment. A resident independent from the study dealt with the automated cuff inflator machine. The outcome assessor was blinded to group assignments.

Surgical Procedures and Anesthesia

Kidney transplantation was performed using the standard operative technique in the iliac fossa. An end-to-end arterial anastomosis to the internal iliac artery and an end-to-side venous anastomosis onto the external iliac vein were performed. Custodiol solution (histidine-tryptophan buffer, HTK) was the storage medium for the grafts. Perioperative immunosuppression was induced with methylprednisolone 500 mg (Solumedrol, Pfizer, Ballerup, Denmark) along with basiliximab 20 mg I.V. (Simulect, Novartis Pharma B.V., Arnhem, Netherlands) or anti-thymocyte globulin 1.5 mg/kg I.V. (ATGAM, Upjohn, Kalamazoo, MI, USA).

A blood pressure cuff for remote ischemic postconditioning was prepared on an upper arm free of arteriovenous fistula. After anesthesia induction and endotracheal intubation, all patients were mechanically ventilated. A continuous inhalation anesthesia was maintained along with continuous remifentanil infusion. Normal saline was administered to manage intravascular volume with a goal of maintaining a central venous pressure (CVP) of more than 5 mmHg from the start of surgery until the clamping of the donor renal vessels and maintaining CVP of more than 10 mmHg from the clamping of the renal vessels until the end of renal vascular anastomosis (49). Mannitol 1 g/kg was administered before graft reperfusion. Dopamine was infused to elevate the systolic blood pressure to more than 120 mmHg during the surgery.

Postoperative immunosuppressive regimens included tacrolimus with mycophenolate mefotil or cyclosporine with mycophenolate mefotil. Calcineurin inhibitors were started as soon as the serum creatinine was under 3.3 mg/dL and at least 5 days after transplantation, and patient blood concentration was monitored daily during the first two weeks and weekly thereafter.

Study Intervention

In the RiPoC group, RiPoC was performed in recipients immediately after reperfusion of the transplanted kidney. RiPoC consisted of three 5-min cycles of upper limb ischemia, which were performed by using an the automated pneumatic cuff inflator placed on the upper limb without the arteriovenous fistula. The cuff-inflator inflated to 300 mmHg with an intervening 5 min of reperfusion during which time the cuff was deflated. In the control group, patients had a deflated cuff placed on the upper limb for 30 min.

Data Collection

Blood sampling was performed via peripheral venous puncture. The measurement time points were 2 hr before the induction of anesthesia, 2 hr after the end of surgery, and at 12-hr intervals from 12 to 96 hr after the end of surgery. At each time point, sCr and eGFR were measured. Standard kidney function tests were performed at 12-hr intervals, and eGFR was calculated with the two formulas listed below. Creatinine clearance was also calculated using the urine creatinine and sCr values.

  • [1] eGFR (mL/min/1.73 m2)=175 [sCr (mg/dL)]−1.154*Age-0.203*(0.742 if female)*(1.212 if African American)
  • [2] Creatinine clearance (mL/min)=Urine creatinine (mg/dL)*flow rate (mL/min)/sCr (mg/dL)

Urine output and urine creatinine were measured at 1-day intervals from postoperative day 1 to postoperative day 7. Events such as acute rejection of the transplanted kidney, DGF, and length of total and postoperative hospital stay were compared. DGF was defined as graft dysfunction requiring patients to receive postoperative hemodialysis within 1 week of transplantation (3, 5). DGF was also defined as graft dysfunction when the time required for the kidney to achieve creatinine clearance of more than 10 mL/min/1.73 m2, a value determined empirically as the threshold for minimum graft function, was more than 24 hr after transplantation (50). Immediate and slow graft function were defined as sCr reduction at posttransplantation day 7 by more than and less than 70% of preoperative value, respectively. The following variables were measured and compared between groups: time to 50% reduction of postoperative sCr, number of patients with 50% reduction in sCr within 12, 24, and 36 hr, number of patients whose sCr was normalized within 48, 72, and 96 hr, and the sCr and eGFR levels at the 1-year follow-up.

Sample Size

Sample size was calculated on the basis of the postoperative creatinine value. This study was designed as a superiority trial according to the data from a pilot study. We tested the hypothesis that the creatinine value 3 days after transplantation would be different between the RiPoC and control groups. To ensure that the sample sizes of the ischemic postconditioning and control groups would support a valid comparison, a power analysis was performed (α=0.05, β=0.20), indicating that at least 30 patients per group should be randomized. For this calculation, we used the standard deviation of creatinine values at 3 days after transplantation (0.65) obtained from a pilot study and assumed that a creatinine difference of 0.5 mg/dL between groups would be significant.

Statistical Analysis

All data were analyzed using SPSS version 20.0 (SPSS Inc., Chicago, IL, USA). Normality of the data distribution was checked with a Kolmogorov-Smirnov test. Demographics were compared using an unpaired t test or Mann-Whitney test for continuous variables according to their normality, and a Chi-square test or Fisher’s exact test for categorical variables according to their expected counts. The outcome variables were compared within each group using a repeated measures analysis of variance. An unpaired t test or Mann-Whitney test was used to compare outcome variables or the magnitude of change from the preoperative value at individual time points between the two groups. A Bonferroni correction was performed to reduce the false positive results by repetitive comparison. A P<0.05 was considered statistically significant.

ACKNOWLEDGMENT

The authors thank the biostatistics team at Samsung Bioresearch Institute for the valuable assistance in statistical analysis.

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Keywords:

Kidney transplantation; Ischemic postconditioning; Creatinine; Delayed graft function; Reperfusion injury

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