Complications related to extracorporeal life support in lung transplantation: single-center analysis.

Background: Extracorporeal life support (ECLS) is not routinely used at our center during sequential single-lung transplantation (LTx), but is restricted to anticipate and overcome hemodynamic and respiratory problems occurring peri-operatively. In this retrospective descriptive cohort study, we aim to describe our single-center experience with ECLS in LTx, analyzing ECLS-related complications. Methods: All transplantations with peri-operative ECLS use [2010-2020] were retrospectively analyzed. Multi-organ and heart-lung transplantation were excluded. Demographics, support type and indications are described. Complications are categorized according to the underlying nature and type. Data are presented as median [interquartile range (IQR)]. Kaplan-Meier was used for survival analysis. Results: The overall use of ECLS was 22% (156/703 patients) with a mean age of 52 years (IQR, 36-59 years). Transplant indications in ECLS cohort were interstitial lung disease (38%; n=60), chronic obstructive pulmonary disease (COPD) (19%; n=29), cystic fibrosis (17%; n=26) and others (26%; n=41). Per indication, 94% (15/16) of pulmonary arterial hypertension patients required ECLS, whereas only 8% (29/382) of COPD patients did. In 16% (25/156) of supported patients, veno-venous extracorporeal membrane oxygenation was initiated, while 77% (120/156) required veno-arterial support, and 7% (11/156) cardiopulmonary bypass. Thirty-day mortality was 6% (9/156). Sixteen percent (25/156) of patients were bridged to transplantation on ECLS and 24% (37/156) required post-operative support. Main reasons to use ECLS were intra-operative hemodynamic instability (53%; n=82), ventilation/oxygenation problems (22%; n=34) and reperfusion edema (17%; n=26). Overall incidence of patients with at least one ECLS-related complication was 67% (n=104). Most common complications were hemothorax (25%; n=39), need for continuous renal replacement therapy (19%; n=30), and thromboembolism (14%; n=22). Conclusions: ECLS was required in 22% of LTxs, with a reported ECLS-related complication rate of 67%, of which the most common was hemothorax. Larger databases are needed to further analyze complications and develop tailored deployment strategies for ECLS-use in LTx.

Ischemia-Induced Metabolic Patterns Associate With Kidney Function During Normothermic Kidney Perfusion, a Preclinical Study.

OBJECTIVE: To investigate if ischemia alters donor kidney metabolism and whether these changes associate with organ function. SUMMARY BACKGROUND DATA: An unmet need in kidney transplantation is the ability to predict post-transplant organ function before transplantation. Key to such viability testing is a profound understanding of the organ's complex biochemistry and how ischemia, inevitable during the transplantation process, influences this. METHODS: First, metabolic changes in glucose, lactate and 20 amino acids induced by no, 1h of warm, or 22h of cold ischemia were investigated during 4h perfusion of pig kidneys with autologous whole blood (n=6/group), simulating the ischemia-reperfusion phase of transplantation. Next, we confirmed similar metabolic changes during normothermic preservation of pig (n=3/group; n=4 for cold ischemia) and discarded human kidneys (n=6) perfused with a red-blood cell based perfusate. RESULTS: At 2h of perfusion with autologous whole blood, abundances of 17/20 amino acids were significantly different between groups, reflecting the type of ischemia. Amino acid changes at 15 min and 2h of perfusion correlated with future kidney function during perfusion. Similar metabolic patterns were observed during perfusion preservation of pig and discarded human donor kidneys, suggesting an opportunity to assess kidney viability before transplantation. CONCLUSIONS: Perfusate metabolite changes during normothermic kidney perfusion represent a unique non-invasive opportunity to assess graft viability. These findings now need validation in transplant studies.

Differential Cytokine Levels during Normothermic Kidney Perfusion with Whole Blood- or Red Blood Cell-Based Perfusates-Results of a Scoping Review and Experimental Study.

The ideal composition of the perfusate for normothermic kidney perfusion is unknown, though the perfusate commonly used to perfuse human kidneys contains leukocyte-depleted packed red blood cells (RBC), as this is believed to prevent excessive inflammation. We performed a systematic search identifying 19 articles reporting on cytokine levels during normothermic pig or human kidney perfusion. Cytokine levels varied widely across the reported studies. No direct comparisons of perfusate cytokines during perfusion with RBC or whole blood were performed, and no data on how these levels are influenced by ischemia are available. Therefore, we compared perfusate IL-6, IL-1ß, TNF-α, TGF-ß, IL-10, IL-8, and CCL2 levels during 4 h normothermic pig kidney perfusion with a whole blood- or RBC-based perfusate. Kidneys were exposed to either 1 h of warm or 22 h of cold ischemia. We found no evidence of different perfusate cytokine or gene expression levels in whole blood or RBC perfusions. There was no clear evidence to suggest that cytokine concentrations differ between ischemically injured kidneys and controls. In conclusion, pro-inflammatory and anti-inflammatory cytokines and chemokines are detectable in the perfusate and urine of kidneys undergoing normothermic perfusion. It is unclear how cytokine levels change in different ischemic conditions and whether the use of a leukocyte filter plays a role.

Unraveling metabolism during kidney perfusion using tracer studies: a systematic review.

BACKGROUND: Understanding kidney metabolism during perfusion is vital to further develop the technology as a preservation, viability assessment, and resuscitation platform. We reviewed the evidence on the use of labeled metabolites (tracers) to understand "on-pump" kidney behavior. METHODS: PubMed, Embase, Web of Science, and Cochrane databases were systematically searched for studies evaluating metabolism of (non)radioactively labeled endogenous compounds during kidney perfusion. RESULTS: Of 5899 articles, 30 were included. All were animal studies [rat (70%), dog (13%), pig (10%), rabbit (7%)] perfusing but not transplanting kidneys. Perfusion took place at hypothermic (4-12°C) (20%), normothermic (35-40°C) (77%), or undefined temperatures (3%). Hypothermic perfusion used albumin or a clinical kidney preservation solution, mostly in the presence of oxygen. Normothermic perfusion was mostly performed with oxygenated crystalloids often containing glucose and amino acids with unclear partial oxygen tensions. Active metabolism of carbohydrate, amino acid, lipids, and large molecules was shown in hypothermic and normothermic perfusion. Production of macromolecules, such as prostaglandin, thromboxane, and vitamin D, takes place during normothermic perfusion. No experiments compared differences in metabolic activity between hypothermic and normothermic perfusion. One conference abstract showed increased anaerobic metabolism in kidneys donated after circulatory death by adding labeled glucose to hypothermically perfused human kidneys. CONCLUSIONS: Tracer studies during kidney perfusion contribute to unraveling kidney metabolic behavior in pre-clinical models. Whether findings are truly translational needs further investigation in large animal models of human kidneys. Furthermore, it is essential to better understand how ischemia changes this metabolic behavior.

Renal Normothermic Machine Perfusion: The Road Toward Clinical Implementation of a Promising Pretransplant Organ Assessment Tool.

The increased utilization of high-risk renal grafts for transplantation requires optimization of pretransplant organ assessment strategies. Current decision-making methods to accept an organ for transplantation lack overall predictive power and always contain an element of subjectivity. Normothermic machine perfusion (NMP) creates near-physiological conditions, which might facilitate a more objective assessment of organ quality before transplantation. NMP is rapidly gaining popularity, with various transplant centers developing their own NMP protocols and renal viability criteria. However, to date, no validated sets of on-pump viability markers exist nor are there unified NMP protocols. This review provides a critical overview of the fundamentals of current renal NMP protocols and proposes a framework to approach further development of ex vivo organ evaluation. We also comment on the potential logistical implications of routine clinical use of NMP, which is a more complex procedure compared with static cold storage or even hypothermic machine perfusion.

A systematic review and meta-analyses of regional perfusion in donation after circulatory death solid organ transplantation.

In donation after circulatory death (DCD), (thoraco)abdominal regional perfusion (RP) restores circulation to a region of the body following death declaration. We systematically reviewed outcomes of solid organ transplantation after RP by searching PubMed, Embase, and Cochrane libraries. Eighty-eight articles reporting on outcomes of liver, kidney, pancreas, heart, and lung transplants or donor/organ utilization were identified. Meta-analyses were conducted when possible. Methodological quality was assessed using National Institutes of Health (NIH)-scoring tools. Case reports (13/88), case series (44/88), retrospective cohort studies (35/88), retrospective matched cohort studies (5/88), and case-control studies (2/88) were identified, with overall fair quality. As blood viscosity and rheology change below 20 °C, studies were grouped as hypothermic (HRP, ≤20 °C) or normothermic (NRP, >20 °C) regional perfusion. Data demonstrate that RP is a safe alternative to in situ cold preservation (ISP) in uncontrolled and controlled DCDs. The scarce HRP data are from before 2005. NRP appears to reduce post-transplant complications, especially biliary complications in controlled DCD livers, compared with ISP. Comparisons for kidney and pancreas with ISP are needed but there is no evidence that NRP is detrimental. Additional data on NRP in thoracic organs are needed. Whether RP increases donor or organ utilization needs further research.

The effect of IGL-1 preservation solution on outcome after kidney transplantation: A retrospective single-center analysis.

Institut Georges Lopez-1 (IGL-1) solution is increasingly used for kidney preservation, although little information on outcomes is available. Outcomes of all deceased donor kidneys preserved by IGL-1, University of Wisconsin solution (UW), or histidine-tryptophan-ketoglutarate (HTK) and transplanted in our center (2000-2018) were analyzed. Multivariable analysis for delayed graft function (DGF), functional DGF, estimated glomerular filtration rate (eGFR, CKD-EPI equation), proteinuria, acute rejection, death-censored graft loss, and patient survival were performed. A double robust approach, consisting of propensity score weighting and correction for confounders, minimized the risk of bias. In total, 1943 transplants were included: 234 with IGL-1, 1046 with UW, and 663 with HTK. As IGL-1 was only introduced in 2014, a prespecified sensitivity analysis of 917 kidneys (2010-2018) was performed using the same statistical approach. After weighting, IGL-1 retained a higher proportion of kidneys donated after circulatory death (DCD). IGL-1 was not independently associated with any of the outcomes when compared to UW or HTK. Sensitivity analysis between 2010 and 2018 showed similar results. In this retrospective analysis, using robust methodology to reduce the risk of bias, IGL-1 preservation results in equal outcomes compared to UW or HTK, despite more DCD transplants in the IGL-1 group.

IGL-1 preservation solution in kidney and pancreas transplantation: A systematic review.

We aimed to systematically review published data on the effectiveness of Institut Georges Lopez-1 (IGL-1) as a preservation solution for kidney and pancreas grafts. A systematic literature search of PubMed, Embase, Web of Science, and the Cochrane Library databases was performed. Human studies evaluating the effects of IGL-1 preservation solution in kidney and/or pancreas transplantation were included. Outcome data on kidney and pancreas graft function were extracted. Of 1513 unique articles identified via the search strategy, four articles could be included in the systematic review. Of these, two retrospective studies reported on the outcome of IGL-1 compared to University of Wisconsin (UW) solution in kidney transplantation. These show kidneys preserved in IGL-1 had improved early function (2 weeks post-transplant) compared to UW. Follow-up was limited to 1 year and showed similar graft and patient survival rates when reported. Two case series described acceptable early outcomes (up to 1 month) of simultaneous kidney pancreas transplantation after storage in IGL-1. As only four clinical papers were identified, we widened our search to include four eligible large animal studies. Three compared IGL-1 with UW in pig kidney transplant models with inconclusive or mildly positive results. One pig pancreas transplant study suggested better early outcome with IGL-1 compared to UW. Too few published data are available to allow any firm conclusions to be drawn on the effectiveness of IGL-1 as a preservation solution of kidney and pancreas grafts. The limited available data show satisfactory early outcomes though no medium to long-term outcomes have been described. Further well-designed clinical studies are needed.

Kidney Perfusion as an Organ Quality Assessment Tool-Are We Counting Our Chickens Before They Have Hatched?

The final decision to accept an organ for transplantation remains a subjective one. With "poor organ quality" commonly cited as a major reason for kidney discard, accurate, objective, and reliable quality assessment is essential. In an era of increasingly higher-risk deceased donor kidneys, the catch is to accept those where the risk-benefit scale will tip in the right direction. Currently available assessment tools, such as risk-scores predicting outcome and zero-time biopsy, perform unsatisfactory, and assessment options during static cold storage are limited. Kidney perfusion technologies are finding their way into clinical practice, and they bring a new opportunity to assess kidney graft viability and quality, both in hypothermic and normothermic conditions. We give an overview of the current understanding of kidney viability assessment during ex situ kidney perfusion. A pragmatic framework to approach viability assessment is proposed as an interplay of three different compartments: the nephron, the vascular compartment, and the immune compartment. Although many interesting ways to assess kidney injury and function during perfusion have been proposed, none have reached the stage where they can reliably predict posttransplant outcome. Larger well-designed studies and validation cohorts are needed to provide better guidance.