Evaluation of outcomes in renal transplantation with hypothermic machine perfusion for the preservation of kidneys from expanded criteria donors

In 2012, an expert working group from the French Transplant Health Authority recommended the use of hypothermic machine perfusion (HMP) to improve kidney preservation and transplant outcomes from expanded criteria donors, deceased after brain death. This study compares HMP and cold storage (CS) effects on delayed graft function (DGF) and transplant outcomes. We identified 4,316 kidney transplants from expanded criteria donors (2011‐2014) in France through the French Transplant Registry. DGF occurrence was analyzed with a logistic regression, excluding preemptive transplants. One‐year graft failure was analyzed with a Cox regression. A subpopulation of 66 paired kidneys was identified: one preserved by HMP and the other by CS from the same donor. Kidneys preserved by HMP (801) vs CS (3515) were associated with more frequent recipient comorbidities and older donors and recipients. HMP had a protective effect against DGF (24% in HMP group and 38% in CS group, OR = 0.49 [0.40‐0.60]). Results were similar in the paired kidneys (OR = 0.23 [0.04‐0.57]). HMP use decreased risk for 1‐year graft failure (HR = 0.77 [0.60‐0.99]). Initial hospital stays were shorter in the HMP group (P < 0.001). Our results confirm the reduction in DGF occurrence among expanded criteria donors kidneys preserved by HMP.     

Impact of machine perfusion after long static cold storage on delayed graft function incidence and duration and time to hospital discharge

Delayed graft function (DGF) is very high in our center (70%‐80%), and we usually receive a kidney for transplant after more than 22 hours of static cold ischemia time (CIT). Also, there is an inadequate care of the donors, contributing to a high rate of DGF. We decided to test whether machine perfusion (MP) after a CIT improved the outcome of our transplant patients. We analyzed the incidence of DGF, its duration, and the length of hospital stay (LOS) in patients who received a kidney preserved with MP after a CIT (hybrid perfusion—HP). We included 54 deceased donors kidneys preserved with HP transplanted from Feb/13 to Jul/14, and compared them to 101 kidney transplants preserved by static cold storage (CS) from Nov/08 to May/12. The median pumping time was 11 hours. DGF incidence was 61.1% vs 79.2% (P = .02), median DGF duration was 5 vs 11 days (P < .001), and median LOS was 13 vs 18 days (P < .011), for the HP compared to CS group. The observed reduction of DGF with machine perfusion did not occur in donors over 50 years old. In the multivariate analysis, risk factors for DGF, adjusted for CIT, were donor age (OR, 1.04; P = .005) and the absence of use of MP (OR, 1.54; P = .051). In conclusion, the use of HP contributed to faster recovery of renal function and to a shorter length of hospital stay.     

Pediatric deceased donor kidney transplant outcomes under the Kidney Allocation System

The Kidney Allocation System (KAS) has resulted in fewer pediatric kidneys being allocated to pediatric deceased donor kidney transplant (pDDKT) recipients. This had prompted concerns that post‐pDDKT outcomes may worsen. To study this, we used SRTR data to compare the outcomes of 953 pre‐KAS pDDKT (age <18 years) recipients (December 4, 2012–December 3, 2014) with the outcomes of 934 post‐KAS pDDKT recipients (December 4, 2014–December 3, 2016). We analyzed mortality and graft loss by using Cox regression, delayed graft function (DGF) by using logistic regression, and length of stay (LOS) by using negative binomial regression. Post‐KAS recipients had longer pretransplant dialysis times (median 1.26 vs 1.07 years, P = .02) and were more often cPRA 100% (2.0% vs 0.1%, P = .001). Post‐KAS recipients had less graft loss than pre‐KAS recipients (hazard ratio [HR]: _0.350.54_0.83, P = .005) but no statistically significant differences in mortality (HR: _0.290.72_1.83, P = .5), DGF (odds ratio: _0.931.32_1.93, P = .2), and LOS (LOS ratio: _0.961.06_1.19, P = .4). After adjusting for donor–recipient characteristics, there were no statistically significant post‐KAS differences in mortality (adjusted HR: _0.371.04_2.92, P = .9), DGF (adjusted odds ratio: _0.941.41_2.13, P = .1), or LOS (adjusted LOS ratio: _0.931.04_1.16, P = .5). However, post‐KAS pDDKT recipients still had less graft loss (adjusted HR: _0.380.59_0.91, P = .02). KAS has had a mixed effect on short‐term posttransplant outcomes for pDDKT recipients, although our results are limited by only 2 years of posttransplant follow‐up.     

Changes in offer and acceptance patterns for pediatric kidney transplant candidates under the new Kidney Allocation System

Stakeholders have expressed concerns regarding decreased deceased donor kidney transplant (DDKT) rates for pediatric candidates under the Kidney Allocation System (KAS). To better understand what might be driving this, we studied Scientific Registry of Transplant Recipients kidney offer data for 3642 pediatric (age <18 years) kidney‐only transplant candidates between December 31, 2012 to December 3, 2014 (pre‐KAS) and December 4, 2014 to January 6, 2017 (post‐KAS). We used negative binomial regression and multilevel logistic regression to compare offer and acceptance rates pre‐ and post‐KAS. We stratified by donor age (<18, 18‐34, and 35+ years) and KDPI (<35% and ≥35%) to reflect differing allocation prioritization pre‐KAS and post‐KAS. As might be expected from prioritization changes, post‐KAS candidates were less likely to receive offers for donors 18‐34 years old with KDPI ≥ 35% (adjusted incidence rate ratio [aIRR]: _0.180.21_0.25, P < .001), and more likely to receive offers for donors 18‐34 years old and KDPI < 35% (aIRR: _1.121.20_1.29, P < .001). However, offer acceptance practices also changed post‐KAS: kidneys from donors 18‐34 years old and KDPI < 35% were 23% less likely to be accepted post‐KAS (adjusted odds ratio: _0.610.77_0.98, P = .03). Using kidneys from donors 18‐34 years old with KDPI < 35% post‐KAS to the same extent they were used pre‐KAS might be an effective strategy to mitigate any decrease in DDKT rates for pediatric candidates.     

The landscape of international living kidney donation in the United States

In the United States, kidney donation from international (noncitizen/nonresident) living kidney donors (LKDs) is permitted; however, given the heterogeneity of healthcare systems, concerns remain regarding the international LKD practice and recipient outcomes. We studied a US cohort of 102 315 LKD transplants from 2000‐2016, including 2088 international LKDs, as reported to the Organ Procurement and Transplantation Network. International LKDs were more tightly clustered among a small number of centers than domestic LKDs (Gini coefficient 0.76 vs 0.58, P < .001). Compared with domestic LKDs, international LKDs were more often young, male, Hispanic or Asian, and biologically related to their recipient (P < .001). Policy‐compliant donor follow‐up was substantially lower for international LKDs at 6, 12, and 24 months postnephrectomy (2015 cohort: 45%, 33%, 36% vs 76%, 71%, 70% for domestic LKDs, P < .001). Among international LKDs, Hispanic (aOR = _0.230.36_0.56, P < .001) and biologically related (aOR = _0.390.59_0.89, P < .01) donors were more compliant in donor follow‐up than white and unrelated donors. Recipients of international living donor kidney transplant (LDKT) had similar graft failure (aHR = _0.780.89_1.02, P = .1) but lower mortality (aHR = _0.530.62_0.72, P < .001) compared with the recipients of domestic LDKT after adjusting for recipient, transplant, and donor factors. International LKDs may provide an alternative opportunity for living donation. However, efforts to improve international LKD follow‐up and engagement are warranted.     

Temporal trends in utilization and outcomes of steatotic donor livers in the United States

Steatotic donor livers (SDLs) (macrosteatosis ≥30%) represent a possible donor pool expansion, but are frequently discarded due to a historical association with mortality and graft loss. However, changes in recipient/donor demographics, allocation policy, and clinical protocols might have altered utilization and outcomes of SDLs. We used Scientific Registry of Transplant Recipients data from 2005 to 2017 and adjusted multilevel regression to quantify temporal trends in discard rates (logistic) and posttransplant outcomes (Cox) of SDLs, accounting for Organ Procurement Organization–level variation. Of 4346 recovered SDLs, 58.0% were discarded in 2005, versus only 43.1% in 2017 (P < .001). SDLs were always substantially more likely discarded versus non‐SDLs, although this difference decreased over time (adjusted odds ratio in 2005‐2007:_13.1515.28_17.74; 2008‐2011:_11.7713.41_15.29; 2012‐2014:_9.8711.37_13.10; 2015‐2017:_7.798.89_10.15, P < .001 for all). Conversely, posttransplant outcomes of recipients of SDLs improved over time: recipients of SDLs from 2012 to 2017 had 46% lower risk of mortality (adjusted hazard ratio [aHR]: _0.430.54_0.68, P < .001) and 47% lower risk of graft loss (aHR: _0.420.53_0.67, P < .001) compared to 2005 to 2011. In fact, in 2012 to 2017, recipients of SDLs had equivalent mortality (aHR: _0.901.04_1.21, P = .6) and graft loss (aHR: _0.901.04_1.20, P = .6) to recipients of non‐SDLs. Increasing utilization of SDLs might be a reasonable strategy to expand the donor pool.     

Impact of the kidney allocation system on young pediatric recipients

The kidney allocation system (KAS) altered pediatric candidate prioritization. We determined KAS's impact on pediatric kidney recipients by examining delayed graft function (DGF) rates from 2010 to 2016. A propensity score‐matched pediatric recipients pre‐ and post‐KAS. A semiparametric decomposition analysis estimated the contributions of KAS‐related changes in donor characteristics and dialysis time on DGF rate. The unadjusted odds of DGF were 69% higher post‐KAS for young (<10 years at listing) recipients (N = 1153, P = .02) but were not significantly increased for older pediatric (10‐17 years at listing) recipients (N = 2624, P = .48). Post‐KAS, young recipients received significantly fewer pediatric (<18 years) donor kidneys (21% vs 32%, P < .01) and had longer median pretransplant dialysis time (603 vs 435 days, P < .01). After propensity score matching, post‐KAS status increased the odds of DGF in young recipients 71% (OR 1.71, 95% CI 1.01‐2.46). In decomposition analysis, 24% of the higher DGF rate post‐KAS was attributable to donor characteristics and 19% to increased recipient dialysis time. In a confirmatory survival analysis, DGF was associated with a 2.2 times higher risk of graft failure (aHR2.28, 95% CI 1.46‐3.54). In conclusion, KAS may lead to worse graft survival outcomes in children. Allocation changes should be considered.     

Transplanting kidneys from donation after cardiac death donors with acute kidney injury

Donation after cardiac death (DCD) and acute kidney injury (AKI) donors have historically been considered independent risk factors for delayed graft function (DGF), allograft failure, and inferior outcomes. With growing experience, updated analyses have shown good outcomes. There continues to be limited data, however, on outcomes specific to DCD donors who have AKI. Primary outcomes for this study were post–kidney transplant patient and allograft survival comparing two donor groups: DCD AKIN stage 2‐3 and DBD AKIN stage 2‐3. In comparing these groups, there were no short‐ or long‐term differences in patient (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.54‐1.93, P = .83) or allograft survival (HR 1.47, 95% CI 0.64‐2.97, P = .32). In multivariate models, the DCD/DBD status had no significant impact on the estimated GFR (eGFR) at 1 (P = .38), 2 (P = .60), and 3 years (P = .52). DGF (57.9% vs 67.9%, P = .09), rejection (12.1% vs 13.9%, P = .12), and progression of interstitial fibrosis/tubular atrophy (IFTA) on protocol biopsy (P = .16) were similar between the two groups. With careful selection, good outcomes can be achieved utilizing severe AKI DCD kidneys. Historic concerns regarding primary nonfunction, DGF resulting in interstitial fibrosis and rejection, and inferior outcomes were not observed. Given the ongoing organ shortage, increased effort should be undertaken to further utilize these donors.     

Mitochondrial membrane potential and delayed graft function following kidney transplantation

Delayed graft function (DGF) complicates 20%‐40% of deceased‐donor kidney transplants and is associated with increased length of stay and subsequent allograft failure. Accurate prediction of DGF risk for a particular allograft could influence organ allocation, patient counseling, and postoperative planning. Mitochondrial dysfunction, a reported surrogate of tissue health in ischemia‐perfusion injury, might also be a surrogate for tissue health after organ transplantation. To understand the potential of mitochondrial membrane potential (MMP) in clinical decision‐making, we analyzed whether lower MMP, a measure of mitochondrial dysfunction, was associated with DGF. In a prospective, single‐center proof‐of‐concept study, we measured pretransplant MMP in 28 deceased donor kidneys and analyzed the association between MMP and DGF. We used hybrid registry‐augmented regression to adjust for donor and recipient characteristics, minimizing overfitting by leveraging Scientific Registry of Transplant Recipients data. The range of MMP levels was 964‐28 333 units. Low‐MMP kidneys (MMP<4000) were more likely from female donors (75% vs 10%, P = .002) and donation after cardiac death donors (75% vs 12%, P = .004). For every 10% decrease in MMP levels, there were 38% higher odds of DGF (adjusted odds ratio = _1.081.38_1.78, P = .01). In summary, MMP might be a promising pretransplant surrogate for tissue health in kidney transplantation and, after further validation, could improve clinical decision‐making through its independent association with DGF.     

Hypothermic Machine Perfusion Versus Static Cold Storage in Deceased Donor Kidney Transplantation: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials

Static cold storage (SCS) and hypothermic machine perfusion (HMP) are two primary options for renal allograft preservation. Compared with SCS, HMP decreased the incidence of delayed graft function (DGF) and protected graft function. However, more evidence is still needed to prove the advantages of the HMP. In this study, the outcomes of kidney grafts from the two preservation methods were compared by conducting a systematic review and meta‐analysis. Randomized controlled trials (RCTs) comparing the effect of hypothermic machine perfusion and static cold storage in deceased donor kidney transplantation were identified through searches of the MEDLINE, EMBASE, and Cochrane databases between January 1, 1980 and December 30, 2017. The primary endpoints were delayed graft function and graft survival. Secondary endpoints included primary non‐function (PNF), graft renal function, duration of DGF, acute rejection, postoperative hospital stay and patient survival. Summary effects were calculated as risk ratio (RR) with 95% confidence interval (CI) or mean difference (MD) with 95% confidence intervals (CI). A total of 13 RCTs were included, including 2048 kidney transplant recipients. The results indicated that compared with SCS, HMP decreased the incidence of DGF (RR 0.78, 95% CI 0.69–0.87, P < 0.0001), and improved the graft survival at 3 years (RR 1.06, 95% CI 1.02–1.11, P = 0.009). There was no significant difference in other endpoints. HMP might be a more desirable method of preservation for kidney grafts. The long‐term outcomes of kidney allografts stored by hypothermic machine perfusion still need to be further investigated.     

DCD donor hemodynamics as predictor of outcome after kidney transplantation

Insufficient hemodynamics during agonal phase—ie, the period between withdrawal of life‐sustaining treatment and circulatory arrest—in Maastricht category III circulatory‐death donors (DCD) potentially exacerbate ischemia/reperfusion injury. We included 409 Dutch adult recipients of DCD donor kidneys transplanted between 2006 and 2014. Peripheral oxygen saturation (SpO2‐with pulse oximetry at the fingertip) and systolic blood pressure (SBP‐with arterial catheter) were measured during agonal phase, and were dichotomized into minutes of SpO2 > 60% or SpO2 < 60%, and minutes of SBP > 80 mmHg or SBP < 80 mmHg. Outcome measures were and primary non‐function (PNF), delayed graft function (DGF), and three‐year graft survival. Primary non‐function (PNF) rate was 6.6%, delayed graft function (DGF) rate was 67%, and graft survival at three years was 76%. Longer periods of agonal phase (median 16 min [IQR 11‐23]) contributed significantly to an increased risk of DGF (P = .012), but not to PNF (P = .071) and graft failure (P = .528). Multiple logistic regression analysis showed that an increase from 7 to 20 minutes in period of SBP < 80 mmHg was associated with 2.19 times the odds (95% CI 1.08‐4.46, P = .030) for DGF. In conclusion, duration of agonal phase is associated with early transplant outcome. SBP < 80 mmHg during agonal phase shows a better discrimination for transplant outcome than SpO2 < 60% does.     

Renal Resistance Trend During Hypothermic Machine Perfusion Is More Predictive of Postoperative Outcome Than Biopsy Score: Preliminary Experience in 35 Consecutive Kidney Transplantations

Hypothermic machine perfusion (HPM) grants a better postoperative outcome in transplantation of organs procured from extended criteria donors (ECDs) and donors after cardiac death (DCD). So far, the only available parameter for outcome prediction concerning those organs is pretransplant biopsy score. The aim of this study is to evaluate whether renal resistance (RR) trend during HPM may be used as a predictive marker for post‐transplantation outcome. From December 2015 to present, HMP has been systematically applied to all organs from ECDs and DCD. All grafts underwent pretransplantation biopsy evaluation using Karpinski's histological score. Only organs that reached RR value ≤1.0 within 3 hours of perfusion were transplanted. Single kidney transplantation (SKT) or double kidney transplantation (DKT) were performed according to biopsy score results. Sixty‐five HMPs were performed (58 from ECDs and 7 from DCD/ECMO donors). Fifteen kidneys were insufficiently reconditioned (RR > 1) and were therefore discarded. Forty‐nine kidneys were transplanted, divided between 21 SKT and 14 DKT. Overall primary nonfunction (PNF) and delayed graft function (DGF) rate were 2.9 and 17.1%, respectively. DGF were more common in kidneys from DCD (67 vs. 7%; P = 0.004). Biopsy score did not correlate with PNF/DGF rate (P = 0.870) and postoperative creatinine trend (P = 0.796). Recipients of kidneys that reached RR ≤ 1.0 within 1 hour of HMP had a lower PNF/DGF rate (11 vs. 44%; P = 0.033) and faster serum creatinine decrease (POD10 creatinine: 1.79 mg/dL vs. 4.33 mg/dL; P = 0.019). RR trend is more predictive of post‐transplantation outcome than biopsy score. Hence, RR trend should be taken into account in the pretransplantation evaluation of the organs.     

Utilization of high donor sequence number grafts in cardiac transplantation

Donor sequence number (DSN) represents the number of candidates to whom a graft was offered and declined prior to acceptance for transplantation. We sought to investigate the outcomes of patients receiving high DSN grafts. Consecutive isolated adult cardiac transplantations performed at a single‐center were reviewed. Recipients were grouped into standard (≤75th percentile) DSN and high (>75th percentile) DSN. A previously validated donor risk index was used to quantify the risk associated with donor grafts, and recipient outcomes were assessed. Overall, 254 patients were included: 194 standard DSN (range 1‐79) and 60 high DSN (range 82‐1723). High DSN grafts were harvested at greater distance (P < .001) with increased ischemia time (P < .001), resulting in a modest increase in donor risk index (1 point median difference, P = .014). High DSN recipients were less frequently listed as UNOS status 1A (P < .001). Despite a nonsignificant trend toward increased in‐hospital/30‐day mortality in high DSN recipients, there were no differences in primary graft dysfunction or 1‐year survival (high DSN 89% vs standard DSN 88%, P = .82). After adjustment for risk factors, high DSN was not associated with increased 1‐year mortality (hazard ratio 1.18, 95%‐CI 0.54‐2.58, P = .68).     

Financial impact of delayed graft function in kidney transplantation

Increased utilization of suboptimal organs in response to organ shortage has resulted in increased incidence of delayed graft function (DGF) after transplantation. Although presumed increased costs associated with DGF are a deterrent to the utilization of these organs, the financial burden of DGF has not been established. We used the Premier Healthcare Database to conduct a retrospective analysis of healthcare resource utilization and costs in kidney transplant patients (n = 12 097) between 1/1/2014 and 12/31/2018. We compared cost and hospital resource utilization for transplants in high-volume (n = 8715) vs low-volume hospitals (n = 3382), DGF (n = 3087) vs non-DGF (n = 9010), and recipients receiving 1 dialysis (n = 1485) vs multiple dialysis (n = 1602). High-volume hospitals costs were lower than low-volume hospitals ($103 946 vs $123 571, P < .0001). DGF was associated with approximately $18 000 (10%) increase in mean costs ($130 492 vs $112 598, P < .0001), 6 additional days of hospitalization (14.7 vs 8.7, P < .0001), and 2 additional ICU days (4.3 vs 2.1, P < .0001). Multiple dialysis sessions were associated with an additional $10 000 compared to those with only 1. In conclusion, DGF is associated with increased costs and length of stay for index kidney transplant hospitalizations and payment schemes taking this into account may reduce clinicians’ reluctance to utilize less-than-ideal kidneys.     

Outcomes of kidney transplant from deceased donors with acute kidney injury and prolonged cold ischemia time – a retrospective cohort study

While deceased donor renal transplants (DDRT) from donors with either acute kidney injury (AKI) or long cold ischemia time (CIT) are associated with increased risk of delayed graft function (DGF), recipients of these kidneys have good patient and allograft survival. There are limited data on whether kidneys with both AKI and long CIT have outcomes similar to kidneys with only one of these insults. Using data from the Scientific Registry of Transplant Recipients, we analyzed transplant outcomes in patients (2005–2015) receiving kidneys with AKI (terminal creatinine ≥2.0 mg/dl) and CIT 24–30 h (n = 1289), 30–36 h (n = 734), and >36 h (n = 614), using kidneys with AKI and CIT <24 h (n = 5434) as a reference. DGF was more common with increasing CIT up to 36 h, then decreased slightly (41.2% vs. 46.8% vs. 52.5% vs. 50.2%, P < 0.001). Death‐censored graft survival (DCGS) at 3 years was better with CIT <24 h compared with other groups (92.5% vs. 90.8% vs. 92% vs. 89.2%, P = 0.018). On multivariable analysis, donor creatinine was predictive of DCGS, whereas only CIT >36 h was predictive of DCGS (aHR 1.27, P = 0.03). Recipients transplanted with kidneys with both AKI and long CIT have excellent intermediate‐term outcomes.     

Better graft outcomes from offspring donor kidneys among living donor kidney transplant recipients in the United States

A recent study reported that kidney transplant recipients of offspring living donors had higher graft loss and mortality. This seemed counterintuitive, given the excellent HLA matching and younger age of offspring donors; we were concerned about residual confounding and other study design issues. We used Scientific Registry of Transplant Recipients data 2001‐2016 to evaluate death‐censored graft failure (DCGF) and mortality for recipients of offspring versus nonoffspring living donor kidneys, using Cox regression models with interaction terms. Recipients of offspring kidneys had lower DCGF than recipients of nonoffspring kidneys (15‐year cumulative incidence 21.2% vs 26.1%, P < .001). This association remained after adjustment for recipient and transplant factors (adjusted hazard ratio [aHR] = _0.730.77_0.82, P < .001), and was attenuated among African American donors (aHR _0.770.85_0.95; interaction: P = .01) and female recipients (aHR _0.770.84_0.91, P < .001). Although offspring kidney recipients had higher mortality (15‐year mortality 56.4% vs 37.2%, P < .001), this largely disappeared with adjustment for recipient age alone (aHR = _1.021.06_1.10, P = .002) and was nonsignificant after further adjustment for other recipient characteristics (aHR = _0.930.97_1.01, P = .1). Kidneys from offspring donors provided lower graft failure and comparable mortality. An otherwise eligible donor should not be dismissed because they are the offspring of the recipient, and we encourage continued individualized counseling for potential donors.     

Kidney transplant from uncontrolled donation after circulatory death donors maintained by nECMO has long‐term outcomes comparable to standard criteria donation after brain death

Uncontrolled donation after circulatory death (uDCD) increases organ availability for kidney transplant (KT) with short‐term outcomes similar to those obtained from donation after brain death (DBD) donors. However, heterogeneous results in the long term have been reported. We compared 10‐year outcomes between 237 KT recipients from uDCD donors maintained by normothermic extracorporeal membrane oxygenation (nECMO) and 237 patients undergoing KT from standard criteria DBD donors during the same period at our institution. We further analyzed risk factors for death‐censored graft survival in the uDCD group. Delayed graft function (DGF) was more common in the uDCD group (73.4% vs 46.4%; P < .01), although glomerular filtration rates at the end of follow‐up were similar in the 2 groups. uDCD and DBD groups had similar rates for 10‐year death‐censored graft (82.1% vs 80.4%; P = .623) and recipient survival (86.2% vs 87.6%; P = .454). Donor age >50 years was associated with graft loss in the uDCD group (hazard ratio: 1.91; P = .058), whereas the occurrence of DGF showed no significant effect. uDCD KT under nECMO support resulted in similar graft function and long‐term outcomes compared with KT from standard criteria DBD donors. Increased donor age could negatively affect graft survival after uDCD donation.     

Novel delivery of cellular therapy to reduce ischemia reperfusion injury in kidney transplantation

Ex vivo normothermic machine perfusion (NMP) of donor kidneys prior to transplantation provides a platform for direct delivery of cellular therapeutics to optimize organ quality prior to transplantation. Multipotent Adult Progenitor Cells (MAPC^®) possess potent immunomodulatory properties that could minimize ischemia reperfusion injury. We investigated the potential capability of MAPC cells in kidney NMP. Pairs (5) of human kidneys, from the same donor, were simultaneously perfused for 7 hours. Kidneys were randomly allocated to receive MAPC treatment or control. Serial samples of perfusate, urine, and tissue biopsies were taken for comparison. MAPC-treated kidneys demonstrated improved urine output (P = .009), decreased expression of injury biomarker NGAL (P = .012), improved microvascular perfusion on contrast-enhanced ultrasound (cortex P = .019, medulla P = .001), downregulation of interleukin (IL)-1β (P = .050), and upregulation of IL-10 (P < .047) and Indolamine-2, 3-dioxygenase (P = .050). A chemotaxis model demonstrated decreased neutrophil recruitment when stimulated with perfusate from MAPC-treated kidneys (P < .001). Immunofluorescence revealed prelabeled MAPC cells in the perivascular space of kidneys during NMP. We report the first successful delivery of cellular therapy to a human kidney during NMP. Kidneys treated with MAPC cells demonstrate improvement in clinically relevant parameters and injury biomarkers. This novel method of cell therapy delivery provides an exciting opportunity to recondition organs prior to transplantation.     

The impact of postreperfusion syndrome during liver transplantation using livers with significant macrosteatosis

The impact of postreperfusion syndrome (PRS) during liver transplantation (LT) using donor livers with significant macrosteatosis is largely unknown. Clinical outcomes of all patients undergoing LT with donor livers with moderate macrosteatosis (30%‐60%) (N = 96) between 2000 and 2017 were compared to propensity score matched cohorts of patients undergoing LT with donor livers with mild macrosteatosis (10%‐29%) (N = 96) and no steatosis (N = 96). Cardiac arrest at the time of reperfusion was seen in eight (8.3%) of the patients in the moderate macrosteatosis group compared to one (1.0%) of the patients in the mild macrosteatosis group (P = .02) and zero (0%) of the patients in the no steatosis group (P = .004). Patients in the moderate macrosteatosis group had a higher rate of PRS (37.5% vs 18.8%; P = .004), early allograft dysfunction (EAD) (76.4% vs 25.8%; P < .001), renal dysfunction requiring continuous renal replacement therapy following transplant (18.8% vs 8.3%; P = .03) and return to the OR within 30 days (24.0% vs 7.3%; P = .002), than the no steatosis group. Both long‐term patient (P = .30 and P = .08) and graft survival (P = .15 and P = .12) were not statistically when comparing the moderate macrosteatosis group to the mild macrosteatosis and no steatosis groups. Recipients of LT using livers with moderate macrosteatosis are at a significant increased risk of PRS. If patients are able to overcome the initial increased perioperative risk of using these donor livers, long‐term graft survival does not appear to be different than matched recipients receiving grafts with no steatosis.     

Synthetic hemoglobin‐based oxygen carriers are an acceptable alternative for packed red blood cells in normothermic kidney perfusion

Normothermic machine perfusion presents a novel platform for pretransplant assessment and reconditioning of kidney grafts. Maintaining the metabolic activity of a preserved graft at physiologic levels requires an adequate oxygen supply, typically delivered by crystalloid solutions supplemented with red blood cells. In this study, we explored the feasibility of using a synthetic hemoglobin‐based oxygen carrier (HBOC) in human kidney normothermic perfusion. Fourteen discarded human kidneys were perfused for 6 hours at a mean temperature of 37°C using a pressure‐controlled system. Kidneys were perfused with a perfusion solution supplemented with either HBOC (n = 7) or packed red blood cells (PRBC) (n = 7) to increase oxygen‐carrying capacity. Renal artery resistance, oxygen extraction, metabolic activity, energy stores, and histological features were evaluated. Throughout perfusion, kidneys from both groups exhibited comparable behavior regarding vascular flow (P = .66), oxygen consumption (P = .88), and reconstitution of tissue adenosine triphosphate (P = .057). Lactic acid levels were significantly higher in kidneys perfused with PRBC (P = .007). Histological findings were comparable between groups, and there was no evidence of histological damage caused by the HBOC. This feasibility experiment demonstrates that a HBOC solution can offer a logistically more convenient off‐the‐shelf alternative to PRBC in normothermic machine perfusion of human kidneys.