Perioperative renal protective strategies in kidney transplantation
Nieuwenhuijs, Gertrude Johanna
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Chapter 6
Nicoline Valentina Krogstrup Gertrude J Nieuwenhuijs-Moeke* Mihai Oltean* Frank J M F Dor* Ulla Møldrup Søren Palmelund KragBo Martin Bibby Henrik Birn Bente Jespersen * equally atributed
Published as part in: Am J Transplant. 2017; 17(4):1042-9
of deceased renal transplants does not
improve early graft function. First results
from the multicenter, randomised,
controlled clinical trial CONTEXT
Introduction
Ischemia-reperfusion injury (IRI) in a renal transplant may lead to slow onset or delayed graft function (DGF).1 DGF is associated with an increased incidence of early post-transplant complications and with worse long-term outcomes such as impaired graft function and reduced graft survival following donation after brain death (DBD).1-3 DGF complicates 20-45% of DBD transplantations3, and up to 72% of donation after circulatory death (DCD) transplantations.4,5 These figures might increase with greater acceptance of extended criteria donors.
Remote ischemic conditioning (RIC) protects against IRI in a variety of experimental and clinical settings.6,7 RIC is associated with improved outcome following IRI to the heart when evaluated both by early, surrogate endpoints and by long-term, clinical outcomes, including all cause mortality.7-9 Experimental observations and small, clinical studies indicate that RIC may also protect against IRI to the kidney.10,11 RIC applied to the recipient animal in a DBD porcine renal transplantation model was associated with a greater, early glomerular filtration rate (GFR) and increased renal plasma perfusion.12 The aim of this study was to examine whether RIC applied to adult recipients of deceased donor renal transplants just prior to graft reperfusion reduces the time for recovery of graft function evaluated as the estimated time to a 50% decrease in plasma creatinine (tCr50). tCr50 has been shown to be inversely associated with estimated GFR (eGFR) one year post-transplant.13
Materials and methods Study design and participants
The study design has previously been described.14 In brief, this investigator initiated, randomised, controlled, clinical trial included adult patients with end stage renal disease receiving a renal transplant from a deceased donor. Patients were included at four European transplantation centers; Aarhus, Denmark; Gothenburg, Sweden; and Groningen and Rotterdam in the Netherlands. Patients were selected for transplantation in accordance with local allocation programmes and guidelines. At the Dutch centers recipients of both DBD and DCD donor kidneys were included. Exclusion criteria were: arteriovenous-fistula in the leg of planned RIC (contralateral to the side of graft implantation); pre-existing lower limb ischemia; other immunosuppression than standard regimen described below; and recipients of a double kidney transplantation (table 1). Informed consent was obtained by the admitting physician or by the transplant surgeon prior to surgery. Relevant ethical and data management approvals were obtained in the respective countries.14
Inclusion criteria Exclusion criteria Deceased donor kidney
transplantation candidate
AV-fistula in the leg of planned RIC (opposite to the side of graft implantation)
Aged 18 years or older Increased risk of complications from RIC due to preexisting lower limb ischemia (as determined by the investigator)
Informed consent Unable to deliver informed consent Double kidney transplant recipient Table 1. Eligibility criteria
Randomisation and masking
Randomisation, intervention, and sample collections were performed by a trained medical student, and in some cases a lab technician or the local principal investigator not involved in post-operative patient care. Participants were randomised 1:1 to RIC or sham-RIC using an online block randomisation programme, stratifi ed by center and donor type, and randomised within kidney pairs stratifi ed by operation sequence, when applicable (fi gure 1).14 An appropriately sized tourniquet was placed before surgery on the thigh contralateral to graft implantation on all participants. The tourniquet was covered with surgical drapes allowing for infl ation (or sham-infl ation) blinded to the surgeons, anesthesiologist, and the anaesthetised patient. The tourniquet infl ation was practically silent and not audible to the operation staff . Both the treating physicians and the involved statistician were blinded to the randomisation.
Figure 1. Randomisation algorithm
RIC or sham-RIC, (1:1) by the online block randomisation program, stratifi ed by center and donor type. When both recipients of a kidney pair are included, randomisation is also stratifi ed by operation order. RIC: remote ischemic conditioning.
Procedures
Anesthesia was based on volatile agents.14 In brief, anesthesia was induced with propofol and maintained with sevoflurane, while analgesia was based on fentanyl or remifentanil according to local protocol. Anesthesia could be modified according to individual needs as judged by the treating anesthesiologist. The transplantation procedure was performed according to standard techniques and local routines. RIC was initiated approximately 40 min prior to the time of expected graft reperfusion. RIC consisted of four cycles of 5 min occlusion by inflation of the tourniquet to 250 mmHg followed by 5 min of deflation. For sham-RIC the tourniquet remained deflated. RIC was always terminated prior to graft reperfusion, even if the cycles were not complete. Immunosuppression was based on intravenous induction with basiliximab and methylprednisolone, or oral prednisolone, and oral triple maintenance therapy with calcineurin inhibitors, mycophenolate mofetil and prednisolone.
Blood samples were drawn prior to skin incision (baseline), after RIC/sham-RIC, and 30 and 90 min after graft reperfusion. Post-transplant blood samples were taken day 1, 3 and 5. EDTA blood samples were centrifuged for 10 min at 2800G and 4°C, and stored at -80°C. Plasma neutrophil gelatinase-associated lipocalin (NGAL), myoglobin and troponin were measured at the Department of Clinical Biochemistry, Aarhus University Hospital using a particle-enhanced turbidometric immunoassay (NGAL, ®BioPorto Diagnostics A/S, Denmark) and Myoglobin STAT and Troponin T Hs STAT (Cobas 6000, Roche). A kidney graft biopsy was taken 20-30 min after reperfusion and fixed in formalin to be embedded in paraffin. After the completion of patient inclusion, serial sections from graft biopsies were stained using hematoxylin and eosin, periodic acid Schiff and masson-trichrome and scored according to Remuzzi15 by a single, dedicated renal pathologist (SPK) blinded to allocation. Plasma creatinine (P-cr) was measured at local laboratories using automated enzymatic assays standardised to isotope dilution mass spectrometry. Samples for P-cr were collected at baseline and twice daily until day 4 after transplantation, then daily until discharge and twice weekly until day 30 or, in case of temporary, post-transplant dialysis, until day 30 following the last day of dialysis. In patients not on dialysis, GFR was measured at day 5±1 as 51Cr-EDTA plasma clearance. The eGFR at 21 days post-transplant was calculated using the simplified Modification of Diet in Renal Disease (MDRD) formula without correction for race (>90% of included patients were Caucasians (figure 2).16
Outcomes
The primary outcome was the estimated time to a 50% decrease in P-cr (tCr50) as a measure of the time for kidney graft recovery.13 The observed changes in P-cr until day 30 after transplantation, or in the case of dialysis after transplantation until day 30 after last dialysis, were modelled for each patient by an exponential, logistic or a linear model. Based on this model, P-cr at reperfusion and the time (tCr50) to a 50% decrease from this value, were calculated. In patients with primary non-function (PNF, defined as permanent lack of graft non-function irrespective of cause), tCr50 could not be estimated. Secondary outcomes included: need of dialysis after transplantation, PNF, measured GFR at day 5, eGFR at day 21 post-transplant, P-NGAL17 from baseline to day 3, and the length of hospital stay. Any serious adverse events possibly related to the RIC procedure were assumed to occur within 7 days post-transplant, and were only registered during this period.
Figure 2. Timing of intervention (+/- remote ischemic conditioning), samples, measurements and follow up. mGFR: measured glomerular fi ltration rate.
Statistical analyses
For sample size calculation a 30% decrease in tCr50 was considered clinically signifi cant. Based on the magnitude and variation in tCr50 in a cohort of 62 DBD renal transplant recipients from Aarhus.14, the assumption that each donor contributes with two kidneys randomised within the pair to RIC and sham-RIC, and using a signifi cance level of 0.05 and a power of 0.80, it was calculated that 100 donors were needed to detect a clinically signifi cant decrease in tCr50 based on a paired t-test. As not all included kidneys were expected to be paired, the total number of recipients to be included was increased from 200 to 220.14
Per-protocol comparative analyses were performed. A repeated measurement analysis of variance was used for analysing tCr50, mGFR day 5, eGFR day 21, P-NGAL, P-troponin and P-myoglobin: A linear mixed regression eff ects model was used to compare log transformed outcomes between the intervention groups, with intervention and center as fi xed eff ects, and donor as random eff ect. The primary outcome analysis of tCr50 included all recipients except PNF, and in a subanalysis the outcome was adjusted for cold ischemia time. An analysis of DBD and DCD recipients was performed separately. Data is shown as means with SDs, n (%), or medians with interquartile ranges (IQR). Groups were compared with Student t-test, or Wilcoxon two-sample rank sum test if data were not normally distributed. χ2 test or Fisher’s exact test were used for categorical outcomes. P < 0.05 was considered statistically signifi cant.
Data was analysed in Stata/IC 12.1 for Mac (Copyright 1985-2011 StataCorp LP) and R 3.2.0 (R Development Core Team, 2015).
The study was registered at www.clinicaltrials.gov: NCT01395719. A data monitoring committee was not required as the intervention was performed using approved medical equipment.
Results
The CONSORT guidelines were followed in reporting this RCT.
Between June 12, 2011, and December 28, 2014, 225 patients were included. Patients included in Aarhus (n=132) were identified by consecutive screening of all recipients of deceased renal transplants from June 12, 2011, to December 18, 2014. In the other participating centers (Gothenburg, n=46; Groningen, n=25, and Rotterdam, n=22), patients were not assessed consecutively due to other concomitant studies. In total, 305 patients were assessed in the four centers and a total of 202 DBD and 23 DCD transplant recipients were included. Three participants were withdrawn at the time of, or just after transplantation (no data registered) and were excluded from the following per-protocol analyses. One patient was withdrawn due to a missing signed consent, one was not transplanted due to extensive atherosclerosis identified during surgery, and one patient randomised to sham-RIC was withdrawn due to a serious adverse event caused by uninterrupted inflation of the cuff caused by a malfunctioning machine. The remaining 222 patients received the allocated intervention (RIC n=109 and sham-RIC n=113) and data was analysed accordingly (Figure 3: CONSORT diagram).
The baseline characteristics of the recipients and donors, as well as HLA-mismatches, ischemia time, surgery time, and baseline histology were well matched with no significant differences between the intervention groups (Table 2). The full, 4 cycle conditioning stimulus was applied to 94% of the RIC group while the remaining received only 3 cycles. The median time between completion of RIC and reperfusion of the graft was 38 min (IQR 19-54 min).
Five patients in the RIC group and six in the sham-RIC experienced PNF (Table 3). This included two early transplant nephrectomies in the sham-RIC group, one due tohyperacute/acute humoral rejection and one due to renal vein thrombosis. Thus, tCr50 was estimated in 104 patients in the RIC and 107 patients in the sham-RIC group. This was performed after completion of the inclusion and before unblinding the randomisation. In ten patients, P-cr values could not be described by an exponential, logistical or linear curve, or the decline in P-cr was insufficient to calculate tCr50 despite clear evidence of graft function.
In these patients further modelling was performed to describe the post-transplant P-cr changes and estimate a tCr50, either by log transforming time (two patients), ignoring the initial dialysis period (five patients), neglecting an increase in P-cr 12 days post-transplant (one patient), or by a combination of two models (two patients).No significant difference was observed in the primary analysis of tCr50 comparing the RIC group and the sham-RIC group (median tCr50 of 122 hours, 95%-CI 98-151, n=104; versus 112 hours, 95%-CI 91-139, n=107, P=0.58). No significant effect on treatment outcome was observed when adjusting for cold ischemia time (P=0.57) or recipient gender (P=0.59), and no difference in outcome was found between males and females (P=0.14).
Figure 3. Consort diagram
When stratified by DBD and DCD a significant effect of donor type on tCr50 was observed as expected (P=0.01), but this did not change the outcome of the treatment (P=0.56). The estimated median tCr50 in DBD transplants only, adjusting for center and donor, was 112 hours (95%-CI 89-141, n=94) versus 102 hours (95%-CI 82-128, n=97), P=0.57; while DCD transplants had a median tCr50 of 285 hours, 95%-CI 200-406, n=10; versus 269 hours, 95%-CI 189-384, n=10, P=0.83, in the RIC and sham-RIC group respectively. A Student’s t test on log transformed tCr50 on all patients resulted in an estimated median tCr50 of 123 hours CI 99-154, n=104) and 113 hours (95%-CI 91-142, n=107) in the RIC and sham-RIC group respectively, P=0.59. An analysis of tCr50 in the recipients with paired kidneys only did not show any significant difference between groups, P=0.73 (estimated median tCr50 of 120 hours (95%-CI 86-166, n=50) versus 111 hours (95%-CI 80-154, n=50) in the RIC and sham-RIC group). An intention to treat analysis of the primary endpoint including the patient that had a malfunctioning cuff, resulted in median tCr50 of 122 hours, 95%-CI 98-151, n=104 in the RIC group, versus 113 hours, 95%-95%-CI 92-140, n=108 in the sham-RIC group,
133
P=0.61. Finally, there was no significant difference between the groups in the outcome of tCr50 (DBD and DCD combined) if patients with tCr50 > 30 days or the ten patients, in which tCr50 could only be estimated with additional modelling, were excluded (P=0.46 and P=0.81, respectively). No significant differences were observed between RIC and sham-RIC treated patients in the number of patients receiving dialysis within the first week after transplantation (36/109 versus 40/113 patients, P=0.71); or in eGFR at day 21 post-transplant (39 ml/min/1.73m2 (95%-CI 36-43, n=97) in the RIC group, versus 39 ml/min/1.73m2 (95%-CI 36-42, n=106) in the sham-RIC group, P=0.59). No significant differences were observed between groups regarding the time until the last performed post transplant dialysis or the duration of hospital stay (Table 3).
Table 2. Baseline Characteristics.
Data given as mean (SD), n (%), or median (IQR)
RIC (n=109) Sham-RIC (n=113) Recipient Gender Male 65 (60%) 69 (61%) Age (years) 58.1 (49.5-65.0) 61.4 (49.4-66.6) Dialysis mode Preemptive HD PD HD + PD 17 (16%) 66 (61%) 24 (22%) 2 (1.8%) 23 (20%) 64 (57%) 25 (22%) 1 (0.9%) Number of transplant First Retransplantation 95 (87%) 14 (13%) 98 (87%) 15 (13%) Original renal disease
Glomerulopathy ADPKD Diabetes mellitus (DM) Vascular/hypertension Reflux/obstructive Other Unknown 26 (24%) 24 (22%) 13 (12%) 12 (11%) 4 (3.7%) 10 (9%) 20 (18%) 25 (22%) 20 (18%) 13 (12%) 12 (11%) 3 (2.7%) 14 (12%) 26 (23%) Comorbidity DM Hypertension 18 (17%) 96 (88%) 104 (92%) 25 (22%) Total HLA-A, B, DR mismatches
0 1-2 3-4 5-6 6 (5.5%) 17 (16%) 70 (64%) 16 (15%) 6 (5.3%) 24 (21%) 58 (51%) 25 (22%) Immunosuppresion at discharge Tacrolimus Mycophenolate mofetil Corticosteroids Cyclosporine None (graft loss)
98 (90%) 105 (96%) 101 (93%) 7 (6.4%) 4 (3.7%) 106 (94%) 111 (98%) 109 (96%) 5 (4.4%) 2 (1.8%) Donor Gender Male 60 (55%) 61 (54%) Age (years) 58 (52-66) 58 (52-65) Paired kidneys Single kidneys 50 (46%) 59 (54%) 50 (44%) 63 (56%) DBD DCD 98 (90%) 11 (10%) 102 (90%) 11 (10%) Cause of death, DBD (n=98) Cerebrovascular insult Cerebral anoxia Trauma
Benign cerebral neoplasm
64 (65%) 22 (22%) 11 (11%) 1 (1.0%) 70 (69%) 20 (20%) 12 (12%) 0 Cause of death, DCD (n=11) Cerebrovascular insult Cardiac disease Trauma Status asthmaticus Other 3 3 1 2 2 3 4 4 0 0 Preservation solutions Custodiol UW Other 77 (71%) 27 (25%) 5 (4.6%) 75 (66%) 35 (31%) 3 (2.7%)
RIC (n=109) Sham-RIC (n=113) P tCr50, estimated median (95%-CI), hours Difference (RIC/sham-RIC) n=104 122 (98-151) n=107 112 (91-139) 9% (-19-45%) 0.58 Dialysis* 36/109 (33%) 40/113 (35%) 0.71 PNF 5/109 (4.6%) 6/113 (5.3%) 1.00
Time from transplantation to last dialysis < 7 d ≥ 7 d Median (Days) 15/109 (14%) 16/109 (15%) 7 (4-14) 20/113 (18%) 14/113 (12%) 6 (3-10) 0.40 0.28 eGFR at 21 days, median
(95%-CI), ml/min/1.73m2 Difference (RIC/sham-RIC) n=97 39 (36-43) N=106 39 (36-42) 0% (-11-13%) 0.59
Length of hospital stay (days) 9 (7.5-14) 10 (7-13.5) 0.90
RIC (n=109) Sham-RIC (n=113) Recipient Gender Male 65 (60%) 69 (61%) Age (years) 58.1 (49.5-65.0) 61.4 (49.4-66.6) Dialysis mode Preemptive HD PD HD + PD 17 (16%) 66 (61%) 24 (22%) 2 (1.8%) 23 (20%) 64 (57%) 25 (22%) 1 (0.9%) Number of transplant First Retransplantation 95 (87%) 14 (13%) 98 (87%) 15 (13%) Original renal disease
Glomerulopathy ADPKD Diabetes mellitus (DM) Vascular/hypertension Reflux/obstructive Other Unknown 26 (24%) 24 (22%) 13 (12%) 12 (11%) 4 (3.7%) 10 (9%) 20 (18%) 25 (22%) 20 (18%) 13 (12%) 12 (11%) 3 (2.7%) 14 (12%) 26 (23%) Comorbidity DM Hypertension 18 (17%) 96 (88%) 104 (92%) 25 (22%) Total HLA-A, B, DR mismatches
0 1-2 3-4 5-6 6 (5.5%) 17 (16%) 70 (64%) 16 (15%) 6 (5.3%) 24 (21%) 58 (51%) 25 (22%) Immunosuppresion at discharge Tacrolimus Mycophenolate mofetil Corticosteroids Cyclosporine None (graft loss)
98 (90%) 105 (96%) 101 (93%) 7 (6.4%) 4 (3.7%) 106 (94%) 111 (98%) 109 (96%) 5 (4.4%) 2 (1.8%) Donor Gender Male 60 (55%) 61 (54%) Age (years) 58 (52-66) 58 (52-65) Paired kidneys Single kidneys 50 (46%) 59 (54%) 50 (44%) 63 (56%) DBD DCD 98 (90%) 11 (10%) 102 (90%) 11 (10%) Cause of death, DBD (n=98) Cerebrovascular insult Cerebral anoxia Trauma
Benign cerebral neoplasm
64 (65%) 22 (22%) 11 (11%) 1 (1.0%) 70 (69%) 20 (20%) 12 (12%) 0 Cause of death, DCD (n=11) Cerebrovascular insult Cardiac disease Trauma Status asthmaticus Other 3 3 1 2 2 3 4 4 0 0 Preservation solutions Custodiol UW Other 77 (71%) 27 (25%) 5 (4.6%) 75 (66%) 35 (31%) 3 (2.7%) Warm ischemia time DCD donor (min)
Missing data 20 (15-21) 0 14 (13-18) 1
Cold ischemia time (hours), DBD+DCD
n > 24h 3 (2.8%) 13.3 (4.0) 13.6 (4.8) 4 (3.5%)
HD – hemodialysis, PD – peritoneal dialysis, ADPKD – autosomal dominant polycystic kidney disease, HLA – human leukocyte antigen, DBD – donation after brain death, DCD – donation after circulatory death. Remuzzi scores on biopsies taken 30 min after reperfusion of the graft (baseline-biopsy). + Score if including only biopsies with minimum 6 or 10 glomeruli in the analysis. *Biopsies were either not performed (n=22) or insufficient (n=15). Table 3. Renal outcome and length of hospital stay.
Data are estimated median (95%-CI), n (%), or median (IQR). tCr50 and eGFR analysed adjusted for center and donor (paired or single kidney)
*Within one week after transplantation, including PNF. PNF – primary non-function: Permanent lack of graft Chapter 6
In addition, no significant differences were found between groups in P-NGAL (Fig. 4), P-troponin or P-myoglobin (data not shown). In patients not on dialysis mGFR day 5 was conducted in two centers in a total of 91 patients. In these patients, median mGFR was 27 ml/min/1.73m2 (95%-CI 23-31, n=45) in the RIC group, versus 34 ml/min/1.73m2 (95%-CI 29-40, n=46) in the sham-RIC group, P=0.03.
Figure 4. Plasma NGAL in renal transplant recipients with RIC or sham-RIC.
No significant differences were found between the groups at the different time points (p>0.34 for all) and in the change over time (p=0.57). Estimated median and 95% confidence intervals are shown.
Discussion
This large renal transplantation study including patients with a high risk of DGF, shows that RIC performed during the transplant surgery to the recipients of deceased donor kidneys, does not improve the time to graft recovery. No significant differences were identified either in the primary outcome of estimated time to a 50% decrease in plasma creatinine or in the number of patients requiring dialysis within one week post-transplant. In accordance, neither the incidence of PNF, eGFR at day 21 post-transplant or P-NGAL was significantly different following RIC when compared to the control group. We did observe a difference in mGFR day 5 in favour of sham-RIC, but GFR was measured only in 91 patients, and eGFR at 21 days was exactly the same in the two groups. The two groups were similar with regard to recipient and donor characteristics, HLA-mismatches, cold and warm ischemia time, surgery time, and baseline histology. The primary endpoint in our study is novel in renal transplantation. We developed this endpoint as a way of describing early graft function for a number of reasons.13 Dialysis first week is the most widely used index of DGF, but with a known incidence of 25-30% in DBD transplantation it would require a very large study in order to detect a clinical significant difference between groups. In addition, we wanted the primary endpoint to be applicable to as many transplant outcomes as possible, and be a continuous variable to gain strength. tCr50 describes the various transplant
outcomes except PNF, as one numeric variable rather than different categorical variables, and covers the spectrum from immediate over slow to delayed graft function. As all P-cr based methods used to evaluate kidney function, precautions must be taken for tCr50. However, the risk of misclassification may be reduced by modelling the P-cr changes occurring over a longer time period rather than looking at a single time-point18, or day-to-day changes as represented by “functional DGF” defined as the absence of a minimum 10% decline of P-cr over 3 consecutive days within the first transplant week.19 The latter DGF index could point to DGF in a patient with immediate function with no further decline during the third postoperative day. A number of mostly small studies have evaluated the effect of RIC in renal transplantation. A study including 24 paired renal transplants from young DCD donors applying recipient RIC by clamping the external iliac artery in three cycles of 5 min showed a significant reduction in post-transplant serum creatinine levels until day 14 in the RIC group.20 The analyses did not consider a lower baseline serum creatinine in the RIC group, and no difference in serum creatinine was observed 30 days after transplantation. A randomised controlled study applying a RIC protocol similar to the one used in this study in 40 recipients of living donor transplants and comparing to 40 controls showed no significant effect on eGFR at 1 and 3 months post-transplantation or in the incidence of DGF.21 However, as DGF is infrequent (incidence <5%) in living donor renal transplantation, a positive effect may have been missed in this small study. A small trial reported in a letter to the editor included 60 recipients of living donor transplants and applied RIC on either the leg of the donor (n=20), the recipient (n=20), or none (n=20). The study showed no differences between the groups in DGF, urine volume, or plasma and urinary biomarkers.22 The open-label, one-arm PINK study did not identify any positive effect of local ischemic postconditioning in 20 recipients of kidneys from DCD.23 The large multicenter REPAIR study investigated RIC in living donor renal transplantation, exploring the effects of both the early and late phase RIC protection.24 Including a total of 406 donor-recipient pairs randomised in 4 groups, both donor and recipient received RIC by a tourniquet on the upper arm either at 24 h pre-transplant, immediately prior to surgery, at both time points, or none. This study demonstrated no significant differences in one year mGFR between the groups. They described a trend towards a slightly higher GFR in the group receiving RIC just prior to surgery (iohexol GFR ml/minute/1.73 m2 of 58.3 vs. 55.9, P=0.13) – thus in the group with a similar RIC timing as in our study. Previous studies have identified a cardioprotective effect of regional RIC using both short-term surrogate markers and long-term clinical outcomes, including all cause mortality.7-9 There is additional experimental evidence of renal protection by RIC from experimental6 as well as non-transplant, clinical studies.10 However, a number of factors might attenuate the protective effect of RIC in renal transplantation such as various drugs and comorbidities, including diabetes mellitus (DM).25,26 In the current study only 17% in the RIC group had DM. The uremic condition of the recipient before transplantation may also influence the response to RIC as it affects the innate and adaptive immune system resulting in a state of chronic inflammation.27 However, moderate chronic kidney disease does not appear to modify the protective effect of RIC.28,29 The transplantation setting itself is complex and completely different from e.g. myocardial ischemia and cardiac surgery procedures, in particular in relation to the complex immunological response and the required immunosuppression. The inflammatory state in the brain death donor30, and the warm and cold ischemic periods from organ retrieval
to implantation of the graft31, may expose the kidney to injury that can not be attenuated by RIC applied in the recipient before reperfusion. We used a RIC protocol that has proven effective when applied to the arm of patients with myocardial infarction.8 The optimal RIC protocol for different clinical settings still needs to be established, in terms of timing, duration, and location of the conditioning stimulus. It might be an advantage to apply RIC prior to the ischemic insult32, which in the case of transplantation from deceased donors will have to be on the donor. The RIPNOD study applying RIC on DBD donors may answer this question.33 The events leading to donor death might also hold an element of ischemic conditioning per se, for instance in the case of cardiac arrest with subsequent hypoxic injury. Cause of donor death in our study was evenly distributed between the two groups. Our study has several strengths: It was adequately powered as a poof of principle study and double blinded. The multicenter setting ensured that the study population reflected the general renal transplant population, and only a few patients were excluded. This may also represent a limitation though, if only certain subgroups of recipients would benefit from RIC. It is possible that the effect of RIC differs between recipients of kidneys from DBD and DCD, which the study is insufficiently powered to detect, and the final number of DCD recipients was small. Furthermore, the number of paired kidneys was lower than expected in the power calculation. However, as no trend was observed in the outcome, it is unlikely that increasing the number of pairs would have let to a difference in the interpretation. Finally, we cannot exclude that confounding factors, such as the use of volatile anesthetics with potential preconditioning effects, may influence the effect of RIC; however, as the anesthetic procedure applied in the study is standard at many centers, the finding is indeed relevant to clinical practice. In conclusion, RIC applied to recipients of renal transplants from deceased donors did not improve the time to early kidney graft function recovery, dialysis requirements, or eGFR at 21 days. Additional studies are required to identify whether RIC applied to the dead donor rather than the recipient may prove effective in preventing DGF.
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