The Impact of Hematological Indices on the Occurrence of Delayed Graft Function (DGF) of Transplanted Kidney.

BACKGROUND: to analyse the effect of haematological indices on the occurrence of Delayed Graft Function (DGF) in patients undergoing kidney transplantation and on the function of the transplanted kidney on the 7th postoperative day. METHODS: 365 recipients who underwent kidney transplantation from a donor with known brain death between 2010 and 2017 were included in this retrospective study. Information from patient medical records, donor medical records, and donation and transplantation protocols was used for analysis. Statistica 13 was used for statistical analysis. RESULTS: In the study group, DGF occurred in 144 recipients (39.45%), and Non-Graft Function (NGF) occurred in 12 recipients (3.29%). Recipients who developed DGF had a significantly higher Neutrophil/Monocyte Ratio (NMR) before renal transplantation (p = 0.048), a lower NMR value on postoperative day 1 (p < 0.001), and a difference between the values on day 1 and before surgery (p < 0.001). In addition, they had a significantly lower Lymphocyte/Monocyte Ratio (LMR) on postoperative day 1 LMR 1 (p < 0.001). It was shown that the value of the indices based on the ROC curve-NMR1 > 29.29, NMR1-0 > 22.71, and LMR1 > 1.74 (respectively: AUC = 0.624; 95% CI 0.566-0.682; and p < 0.001/AUC = 0.622; 95% CI 0.563-0.680; and p < 0.001/AUC = 0.610; 95% CI 0.550-0.670; and p < 0.001)-can be used to identify recipients with a significant probability of DGF. CONCLUSIONS: the NMR and LMR parameters on the first postoperative day and the difference between the NMR values on the first post-transplant day and the first pre-transplant day are predictive factors associated with the risk of DGF.

Contemporary Biomarkers for Renal Transplantation: A Narrative Overview.

Renal transplantation (RT) is the preferred treatment for end-stage renal disease. However, clinical challenges persist, i.e., early detection of graft dysfunction, timely identification of rejection episodes, personalization of immunosuppressive therapy, and prediction of long-term graft survival. Biomarkers have emerged as valuable tools to address these challenges and revolutionize RT patient care. Our review synthesizes the existing scientific literature to highlight promising biomarkers, their biological characteristics, and their potential roles in enhancing clinical decision-making and patient outcomes. Emerging non-invasive biomarkers seemingly provide valuable insights into the immunopathology of nephron injury and allograft rejection. Moreover, we analyzed biomarkers with intra-nephron specificities, i.e., glomerular vs. tubular (proximal vs. distal), which can localize an injury in different nephron areas. Additionally, this paper provides a comprehensive analysis of the potential clinical applications of biomarkers in the prediction, detection, differential diagnosis and assessment of post-RT non-surgical allograft complications. Lastly, we focus on the pursuit of immune tolerance biomarkers, which aims to reclassify transplant recipients based on immune risk thresholds, guide personalized immunosuppression strategies, and ultimately identify patients for whom immunosuppression may safely be reduced. Further research, validation, standardization, and prospective studies are necessary to fully harness the clinical utility of RT biomarkers and guide the development of targeted therapies.

Identification of potential necroinflammation-associated necroptosis-related biomarkers for delayed graft function and renal allograft failure: a machine learning-based exploration in the framework of predictive, preventive, and personalized medicine.

Delayed graft function (DGF) is one of the key post-operative challenges for a subset of kidney transplantation (KTx) patients. Graft survival is significantly lower in recipients who have experienced DGF than in those who have not. Assessing the risk of chronic graft injury, predicting graft rejection, providing personalized treatment, and improving graft survival are major strategies for predictive, preventive, and personalized medicine (PPPM/3PM) to promote the development of transplant medicine. However, since PPPM aims to accurately identify disease by integrating multiple omics, current methods to predict DGF and graft survival can still be improved. Renal ischemia/reperfusion injury (IRI) is a pathological process experienced by all KTx recipients that can result in varying occurrences of DGF, chronic rejection, and allograft failure depending on its severity. During this process, a necroinflammation-mediated necroptosis-dependent secondary wave of cell death significantly contributes to post-IRI tubular cell loss. In this article, we obtained the expression matrices and corresponding clinical data from the GEO database. Subsequently, nine differentially expressed necroinflammation-associated necroptosis-related genes (NiNRGs) were identified by correlation and differential expression analysis. The subtyping of post-KTx IRI samples relied on consensus clustering; the grouping of prognostic risks and the construction of predictive models for DGF (the area under the receiver operating characteristic curve (AUC) of the internal validation set and the external validation set were 0.730 and 0.773, respectively) and expected graft survival after a biopsy (the internal validation set's 1-year AUC: 0.770; 2-year AUC: 0.702; and 3-year AUC: 0.735) were based on the least absolute shrinkage and selection operator regression algorithms. The results of the immune infiltration analysis showed a higher infiltration abundance of myeloid immune cells, especially neutrophils, macrophages, and dendritic cells, in the cluster A subtype and prognostic high-risk groups. Therefore, in the framework of PPPM, this work provides a comprehensive exploration of the early expression landscape, related pathways, immune features, and prognostic impact of NiNRGs in post-KTx patients and assesses their capabilities as.predictors of post-KTx DGF and graft loss,targets of the vicious loop between regulated tubular cell necrosis and necroinflammation for targeted secondary and tertiary prevention, andreferences for personalized immunotherapy. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-023-00320-w.

Evaluation of the efficacy of HEMO2life®, a marine OXYgen carrier for Organ Preservation (OxyOp2) in renal transplantation: study protocol for a multicenter randomized trial.

BACKGROUND: Preventing ischemia‒reperfusion injury (IRI) is a major issue in kidney transplantation, particularly for transplant recipients receiving a kidney from extended criteria donors (ECD). The main consequence of IRI is delayed graft function (DGF). Hypoxia is one of the key factors in IRI, suggesting that the use of an oxygen carrier as an additive to preservation solution may be useful. In the OxyOp trial, we showed that the organs preserved using the oxygen carrier HEMO2life® displayed significantly less DGF. In the OxyOp2 trial, we aim to definitively test and quantify the efficacy of HEMO2life® for organ preservation in a large population of kidney grafts. METHODS: OxyOp2 is a prospective, multicenter, randomized, comparative, single-blinded, parallel-group study versus standard of care in renal transplantation. After the selection of a suitable donor according to the inclusion/exclusion criteria, both kidneys will be used in the study. Depending on the characteristics of the donor, both kidneys will be preserved either in static cold storage (standard donors) or on machine perfusion (for ECD and deceased-after-cardiac-death donors (DCD)). The kidneys resulting from one donor will be randomized: one to the standard-of-care arm (organ preserved in preservation solution routinely used according to the local practice) and the other to the active treatment arm (HEMO2life® on top of routinely used preservation solution). HEMO2life® will be used for ex vivo graft preservation at a dose of 1 g/l preservation solution. The primary outcome is the occurrence of DGF, defined as the need for renal replacement therapy during the first week after transplantation. DISCUSSION: The use of HEMO2life® in preservation solutions is a novel approach allowing, for the first time, the delivery of oxygen to organs. Improving graft survival by limiting ischemic lesions is a major public-health goal in the field of organ transplantation. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT04181710 . registered on November 29, 2019.

Pancreas transplantation with grafts obtained from donation after cardiac death or donation after brain death results in comparable outcomes.

Introduction: Pancreas organ shortages and long recipient waitlist times are critical components that limit recipients from receiving a pancreas transplant. Over the last decade, our center has been using donation after cardiac death (DCD) donors as an adjunct to donation after brain death (DBD) donors to expand the organ pool. The aim of this study was to compare recipient and graft survival between DCD and DBD recipients. Methods: A retrospective single center propensity matched analysis (2011-2020) of 32 DCD vs 96 DBD pancreas transplants was performed. Results: 8-year recipient survival was similar between DCD and DBD groups (87.4% vs 92.7%, p=0.35) as was simultaneous kidney and pancreas transplant (SPK) 8-year kidney (88.9 vs 96.9%, p=0.219) and pancreas graft survival (77.4% vs 86.7%, p=0.344). There was no difference in vascular thrombosis rate between DCD and DBD pancreas grafts (3.1% vs 7.3%, p=0.73). DCD kidneys had a higher rate of DGF vs DBD kidneys (28.1% vs 6.3%, p=0.004), without any significant difference in long term kidney failure (12.5% vs 8.3%, p=0.5). Discussion: Recipients of DCD grafts demonstrate equivalent long-term patient and graft survival compared to DBD recipients for pancreas transplantation. Increased utilization of well selected DCD donors is a safe strategy to increase the donor pool.

Extracellular Vesicles From Kidney Allografts Express miR-218-5p and Alter Th17/Treg Ratios.

Delayed graft function (DGF) in kidney transplantation is associated with ischemic injury and carries long term functional and immunological risks. Extracellular vesicles (EV) released from allografts may signal a degree of ischemic stress, and are thought to play an important role in the development of anti-donor immunity. Here, we show that kidney perfusate-derived extracellular vesicles (KP-EV) express donor-specific human leukocyte antigen. KP-EV from kidneys that experience DGF increase the T-helper 17 (Th17) to T-regulatory (Treg) ratio in third party peripheral blood mononuclear cells to a greater degree than those from kidneys with immediate function. We report miR-218-5p upregulation in KP-EV of kidney transplant recipients with DGF. Levels of miR-218-5p in KP-EV inversely correlated with recipient eGFR at multiple time points following transplantation. Additionally, the degree of increase in Th17/Treg ratio by KP-EV positively correlated with miR-218-5p expression in KP-EV samples. Taken together, these data provide evidence that KP-EV may contribute to modulating immune responses in transplant recipients. This could lead to novel intervention strategies to inhibit DGF in order to improve graft function and survival.

Histological evaluation of ischemic alterations in donors after cardiac death: A useful tool to predict post-transplant renal function.

Kidneys retrieved from donors after cardiac death (DCD) pose significant challenges from a clinical and technical point of view, undergoing a variable degree of ischemia-reperfusion injury. At present, the utilization of kidneys is assessed according to the Karpinski score, which does not take into account the ischemic insult and does not predict the functional recovery of the organ once transplanted. Therefore, the correlation between biopsy results and post-transplant graft function is still debated. In this study we examined kidney biopsies from DCD donors; we calculated the Karpinski score and subsequently identified and quantified the ischemic lesions in the glomerular, interstitial, and tubular compartments. These same lesions were quantified in kidney biopsies from donors after brain death (DBD) in a case-control analysis. The collected data were correlated with the clinical data of the donors and the post-transplant follow-up. Proximal tubule alterations are crucial in ischemia-reperfusion damage, showing precise histological alterations, which are more frequent in DCD than in DBD donors and are statistically correlated with functional recovery of the organ. Quantification of ischemic tubular lesions in biopsies of kidneys from DCD donors is a useful tool for predicting post-transplant renal function and a valid parameter for assessing the quality of the graft.

The value of cystatin C in predicting perioperative and long-term prognosis of renal transplantation.

This study aimed to evaluate the value of cystatin C (Cys C) in predicting the perioperative and long-term prognosis of renal transplantation (RT). The clinical data of 198 RT recipients were collected. Blood samples were obtained daily until 7 d after transplantation and then discharge day to determine the serum levels of Cys C. The receiver-operating characteristic (ROC) analysis and the area under the curve (AUC) were used to determine the diagnostic accuracy of Cys C for delayed graft function (DGF). The presence of shrunken pore syndrome (SPS) with a cystatin C-based estimate of glomerular filtration rate less than 70% of a creatinine-based estimate, was also evaluated as a prognostic factor for the development of DGF. The serum Cys C levels of patients with DGF were higher than those of the non-DGF group. Cys C showed a higher AUC (0.928) in the ROC analysis than did sCr (0.862). Compared to the non-SPS group, there were more patients diagnosed with SPS in the DGF group (p < .05). The follow-up data showed that patients diagnosed with SPS had higher levels of sCr and Cys C compared to other patients, suggesting a poor long-term prognosis. Our findings suggest that Cys C is a sensitive indicator of renal function during the perioperative period. Cys C at a concentration of 4.9 mg/L had the highest sum of sensitivity and specificity for prediction of DGF, with a sensitivity of 0.889 and a specificity of 0.8. SPS is associated with the development of DGF and the poor long-term prognosis of RT.

A novel genomic model for predicting the likelihood of delayed graft function in DCD kidney transplantation.

BACKGROUND: The high incidence of delayed graft function (DGF) following kidney transplantation with donation after cardiac death allografts (DCD-KT) poses great challenges to transplant clinicians. This study aimed to explore the DGF-related biomarkers and establish a genomic model for DGF prediction specific to DCD KT. METHODS: By data mining a public dataset (GSE43974), the key DGF-related genes in DCD kidney biopsies taken after short-time reperfusion (45-60 min) were identified by differential expression analysis and a LASSO-penalized logistic regression model. Their coefficients for modeling were calculated by multivariate logistic regression. Receiver operating characteristic curves and a nomogram were generated to evaluate its predictive ability for DGF occurrence. Gene set enrichment analysis (GSEA) was performed to explore biological pathways underlying DGF in DCD KT. RESULTS: Five key DGF-related genes (CHST3, GOLPH3, ZBED5, AKR1C4, and ERRFI1) were first identified, all of which displayed good discrimination for DGF occurrence after DCD KT (all P<0.05). A five-mRNA-based risk score was further established and showed excellent predictive ability (AUC =0.9708, P<0.0001), which was obviously higher than that of the five genes alone. Eight DGF-related biological pathways in DCD kidneys, such as "arachidonic acid metabolism", "lysosome", "proximal tubule bicarbonate reclamation", "glutathione metabolism", were identified by GSEA (all P<0.05). Moreover, a convenient and visual nomogram based on the genomic risk score was also constructed and displayed high accuracy for DGF prediction specific to DCD KT. CONCLUSIONS: The novel genomic model may effectively predict the likelihood of DGF immediately after DCD KT or even prior to transplantation in the context of normothermic machine perfusion in the future.

Recipient Obesity and Kidney Transplant Outcomes: A Mate-Kidney Analysis.

RATIONALE & OBJECTIVE: The impact of extreme recipient obesity on long-term kidney transplant outcomes has been controversial. This study sought to evaluate the association of various levels of recipient obesity on kidney transplantation outcomes by comparing mate-kidney recipient pairs to address possible confounding effects of donor characteristics on posttransplant outcomes. STUDY DESIGN: Nationwide observational cohort study using mate-kidney models. SETTING & PARTICIPANTS: In analysis based on the Organ Procurement and Transplant Network/United Network of Organ Sharing database, 44,560 adult recipients of first-time deceased-donor kidney transplants from 2001 through 2016 were paired by donor. PREDICTORS: Recipient body mass index (BMI) categorized as 18-25 (n = 12,446), >25-30 (n = 15,477), >30-35 (n = 11,144; obese), and >35 (n = 5,493; extreme obesity) kg/m2. OUTCOMES: Outcomes included patient survival, graft survival, death-censored graft survival, delayed graft function (DGF), and hospital length of stay. ANALYTICAL APPROACH: Conditional logistic regression and stratified proportional hazards models were used to compare outcomes as odds ratios and hazard ratios (HRs), adjusted for recipient and transplant factors, using recipients with a BMI >35 kg/m2 as a reference. RESULTS: At a median follow-up of 3.9 years, adjusted odds ratios for DGF were 0.42 (95% CI, 0.36-0.48), 0.55 (95% CI, 0.48-0.62), and 0.73 (95% CI, 0.64-0.83) for BMI 18-25, >25-30, and >30-35 kg/m2, respectively (P < 0.001 for all). Death-censored graft failure was less frequent for BMI ≤25 and >25-30 kg/m2 (HRs of 0.66 [95% CI, 0.59-0.74] and 0.79 [95% CI, 0.70-0.88], respectively; P < 0.001 for both), but not for BMI >30-35 kg/m2 (HR, 0.91 [95% CI, 0.81-1.02]; P = 0.09). Length of stay and patient survival did not differ by recipient BMI. LIMITATIONS: Observational study with limited detail regarding potential confounders. CONCLUSIONS: Despite an increased risk of DGF likely unrelated to donor organ quality, long-term transplant outcomes among recipients with a BMI >35 kg/m2 are similar to those among recipients with a BMI >30-35 kg/m2, supporting a flexible approach to kidney transplantation candidacy in candidates with extreme obesity.

Improved short-term outcomes of kidney transplants in controlled donation after the circulatory determination of death with the use of normothermic regional perfusion.

Normothermic regional perfusion (NRP) allows the in situ perfusion of organs with oxygenated blood in donation after the circulatory determination of death (DCDD). We aimed at evaluating the impact of NRP on the short-term outcomes of kidney transplants in controlled DCDD (cDCDD). This is a multicenter, nationwide, retrospective study comparing cDCDD kidneys obtained with NRP versus the standard rapid recovery (RR) technique. During 2012-2018, 2302 cDCDD adult kidney transplants were performed in Spain using NRP (n = 865) or RR (n = 1437). The study groups differed in donor and recipient age, warm, and cold ischemic time and use of ex situ machine perfusion. Transplants in the NRP group were more frequently performed in high-volume centers (≥90 transplants/year). Through matching by propensity score, two cohorts with a total of 770 patients were obtained. After the matching, no statistically significant differences were observed between the groups in terms of primary nonfunction (p = .261) and mortality at 1 year (p =  .111). However, the RR of kidneys was associated with a significantly increased odds of delayed graft function (OR 1.97 [95% CI 1.43-2.72]; p < .001) and 1-year graft loss (OR 1.77 [95% CI 1.01-3.17]; p = .034). In conclusion, compared with RR, NRP appears to improve the short-term outcomes of cDCDD kidney transplants.

Effect of delayed graft function on longer-term outcomes after kidney transplantation from donation after circulatory death donors in the United Kingdom: A national cohort study.

Kidneys from donation after circulatory death (DCD) donors are utilized variably worldwide, in part due to high rates of delayed graft function (DGF) and putative associations with adverse longer-term outcomes. We aimed to determine whether the presence of DGF and its duration were associated with poor longer-term outcomes after kidney transplantation from DCD donors. Using the UK transplant registry, we identified 4714 kidney-only transplants from controlled DCD donors to adult recipients between 2006 and 2016; 2832 recipients (60·1%) had immediate graft function and 1882 (39·9%) had DGF. Of the 1847 recipients with DGF duration recorded, 926 (50·1%) had DGF < 7 days, 576 (31·2%) had DGF 7-14 days, and 345 (18·7%) had DGF >14 days. After risk adjustment, the presence of DGF was not associated with inferior long-term graft or patient survivals. However, DGF duration of >14 days was associated with an increased risk of death-censored graft failure (hazard ratio 1·7, p = ·001) and recipient death (hazard ratio 1·8, p < ·001) compared to grafts with immediate function. This study suggests that shorter periods of DGF have no adverse influence on graft or patient survival after DCD donor kidney transplantation and that DGF >14 days is a novel early biomarker for significantly worse longer-term outcomes.

The predictive value of urinary kidney injury molecular-1 for long-term graft function in kidney transplant patients: a prospective study.

BACKGROUND: Monitoring allograft function during the early stages is crucial, and therefore requires biomarkers more sensitive than serum creatinine (Scr). Kidney injury molecular-1 (KIM-1) is a potent biomarker; however, disparities exist in the literature concerning its predictive value in allograft function. Therefore, this study aimed to evaluate its predictive value for the long-term prognosis of kidney transplantation patients. METHODS: A prospective study with a cohort comprising 160 patients scheduled for kidney transplantation was conducted to evaluate the predictive power of urinary KIM-1 (uKIM-1) and other renal ischemia-reperfusion biomarkers including urinary L-type fatty acid binding protein (uL-FABP), urinary N-acetyl-ß-D glucosaminidase (uNAG), and urinary neutrophil gelatinase-related lipoprotein (uNGAL) for allograft prognosis. RESULTS: One hundred and forty kidney recipients who were admitted to our hospital between September 2014 and December 2017 with a median follow-up of 30.3 months were included. Thirty-seven recipients had functional delayed graft function (fDGF) in the first week post transplantation, and 42 recipients had progressed to allograft dysfunction [estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2] by the end of the study, while nine recipients deteriorated into allograft loss (defined by the initiation of dialysis). The levels of uKIM-1 in the fDGF group were higher than those in the immediate graft function (IGF) recipients (P<0.05) at 0 hour post transplantation [5.885 (4.420-7.913) vs. 4.605 (3.417-5.653) ng/mmol], and on the first day post transplantation [5.569 (4.181-6.722) vs. 4.002 (3.222-6.488) ng/mmol]. The levels of uL-FABP in the fDGF group were also higher than those in the IGF group at 0 hour post transplantation (89.818±39.332 vs. 69.187±37.926 µg/mmol) and on the third day post transplantation [77.835 (60.368-100.678) vs. 66.841 (28.815-89.783) µg/mmol]. Multivariate Cox regression analysis demonstrated that recipients with higher uKIM-1 levels on the first day post transplantation had a 23.5% increase in the risk of developing fDGF and a 27.3% increase in the risk of prolonged renal allograft dysfunction. CONCLUSIONS: uKIM-1 on the first day post transplantation can predict short-term graft function and is a potent biomarker for the long-term prognosis of graft function.

Risk factors and outcomes for delayed kidney graft function in simultaneous heart and kidney transplant recipients: A UNOS/OPTN database analysis.

There are no prior studies assessing the risk factors and outcomes for kidney delayed graft function (K-DGF) in simultaneous heart and kidney (SHK) transplant recipients. Using the OPTN/UNOS database, we sought to identify risk factors associated with the development of K-DGF in this unique population, as well as outcomes associated with K-DGF. A total of 1161 SHK transplanted between 1998 and 2018 were included in the analysis, of which 311 (27%) were in the K-DGF (+) group and 850 in the K-DGF (-) group. In the multivariable analysis, history of pretransplant dialysis (OR: 3.95; 95% CI: 2.94 to 5.29; p < .001) was significantly associated with the development of K-DGF, as was donor death from cerebrovascular accident and longer cold ischemia time of either organ. SHK recipients with K-DGF had increased mortality (HR: 1.99; 95% CI: 1.52 to 2.60; p < .001) and death censored kidney graft failure (HR: 3.51; 95% CI: 2.29 to 5.36; p < .001) in the multivariable analysis. Similar outcomes were obtained when limiting our study to 2008-2018. Similar to kidney-only recipients, K-DGF in SHK recipients is associated with worse outcomes. Careful matching of recipients and donors, as well as peri-operative management, may help reduce the risk of K-DGF and the associated detrimental effects.

Delayed graft function and acute rejection following HLA-incompatible living donor kidney transplantation.

Incompatible living donor kidney transplant recipients (ILDKTr) have pre-existing donor-specific antibody (DSA) that, despite desensitization, may persist or reappear with resulting consequences, including delayed graft function (DGF) and acute rejection (AR). To quantify the risk of DGF and AR in ILDKT and downstream effects, we compared 1406 ILDKTr to 17 542 compatible LDKT recipients (CLDKTr) using a 25-center cohort with novel SRTR linkage. We characterized DSA strength as positive Luminex, negative flow crossmatch (PLNF); positive flow, negative cytotoxic crossmatch (PFNC); or positive cytotoxic crossmatch (PCC). DGF occurred in 3.1% of CLDKT, 3.5% of PLNF, 5.7% of PFNC, and 7.6% of PCC recipients, which translated to higher DGF for PCC recipients (aOR = 1.03 1.682.72 ). However, the impact of DGF on mortality and DCGF risk was no higher for ILDKT than CLDKT (p interaction > .1). AR developed in 8.4% of CLDKT, 18.2% of PLNF, 21.3% of PFNC, and 21.7% of PCC recipients, which translated to higher AR (aOR PLNF = 1.45 2.093.02 ; PFNC = 1.67 2.403.46 ; PCC = 1.48 2.243.37 ). Although the impact of AR on mortality was no higher for ILDKT than CLDKT (p interaction = .1), its impact on DCGF risk was less consequential for ILDKT (aHR = 1.34 1.621.95 ) than CLDKT (aHR = 1.96 2.292.67 ) (p interaction = .004). Providers should consider these risks during preoperative counseling, and strategies to mitigate them should be considered.

Viability assessment and utilization of declined donor kidneys with rhabdomyolysis using ex vivo normothermic perfusion without preimplantation biopsy.

The role of ex vivo normothermic perfusion (EVNP) in both organ viability assessment and reconditioning is increasingly being demonstrated. We report the use of this emerging technology to facilitate the transplantation of a pair of donor kidneys with severe acute kidney injury (AKI) secondary to rhabdomyolysis. Donor creatinine was 10.18 mg/dl with protein (30 mg/dl) present in urinalysis. Both kidneys were declined by all other transplantation units and subsequently accepted by our unit. The first kidney was perfused with red cell-based perfusate at 37°C for 75 min, mean renal blood flow was 110 ml/min/100 g and produced 85 ml of urine. Having demonstrated favorable macroscopic appearance and urine output, the kidney was transplanted into a 61-year-old peritoneal dialysis dependent without complication. Given the reassuring information from the first kidney provided by EVNP, the second kidney was not perfused with EVNP and was directly implanted to a 64-year-old patient. The first kidney achieved primary function and the second functioned well after delayed graft function. Recipient eGFR have stabilized at 88.5 and 55.3, respectively (ml/min/1.73 m2 ), at 2 months posttransplant.

Cytokine absorption during human kidney perfusion reduces delayed graft function-associated inflammatory gene signature.

Transplantation is the optimal treatment for most patients with end-stage kidney disease but organ shortage is a major challenge. Normothermic machine perfusion (NMP) has been used to recondition marginal organs; however, mechanisms by which NMP might benefit organs are not well understood. Using pairs of human kidneys obtained from the same donor, we compared the effect of NMP with that of cold storage on the global kidney transcriptome. We found that cold storage led to a global reduction in gene expression, including inflammatory pathway genes and those required for energy generation processes, such as oxidative phosphorylation (OXPHOS). In contrast, during NMP, there was marked upregulation OXPHOS genes, but also of a number of immune and inflammatory pathway genes. Using biopsies from kidneys undergoing NMP that were subsequently transplanted, we found that higher inflammatory gene expression occurred in organs with prolonged delayed graft function (DGF). Therefore, we used a hemoadsorber (HA) to remove pro-inflammatory cytokines. This attenuated inflammatory gene expression increased OXPHOS pathway genes and had potentially clinically important effects in reducing the expression of a DGF-associated gene signature. Together, our data suggest that adsorption of pro-inflammatory mediators from the perfusate represents a potential intervention which may improve organ viability.

Effect of preservation solutions for static cold storage on kidney transplantation outcomes: A National Registry Study.

This study aimed to evaluate how 5 preservation solutions for static cold storage affected kidney transplant outcomes. It included all first single kidney transplants during 2010-2014 from donations after brain death in the French national transplant registry, excluding preemptive transplants and transplants of kidneys preserved with a hypothermic perfusion machine. The effects of each preservation solution on delayed graft function (DGF) and 1-year transplant failure were evaluated with hierarchical multivariable logistic regression models. The study finally included 7640 transplanted kidneys: 3473 (45.5%) preserved with Institut Georges Lopez-1 solution (IGL-1), 773 (10.1%) with University of Wisconsin solution, 731 (9.6%) with Solution de Conservation des Organes et Tissus (SCOT, organ and tissue preservation solution), 2215 (29.0%) with Celsior, and 448 (5.9%) with histidine-tryptophan-ketoglutarate. Primary nonfunction rates did not differ by solution. After adjustment for donor, recipient, and transplant characteristics, the DGF risk was significantly lower with IGL-1 than with all other solutions (odds ratio [OR] 0.55, 95% confidence interval [CI] 0.48-0.64). Conversely, SCOT was associated with a DGF risk significantly higher than the other solutions (OR 2.69, 95% CI 2.21-3.27) and triple that of IGL-1 (OR 3.37, 95% CI 2.72-4.16). One year after transplantation, the transplant failure rate did not differ significantly by preservation solution. The difference between the groups for 1-year mean creatinine clearance was not clinically relevant.

Microvasculature partial endothelial mesenchymal transition in early posttransplant biopsy with acute tubular necrosis identifies poor recovery renal allografts.

Acute tubular necrosis (ATN), a frequent histopathological feature in the early post-renal transplant biopsy, affects long-term graft function. Appropriate markers to identify patients at risk of no or incomplete recovery after delayed graft function are lacking. In this study, we first included 41 renal transplant patients whose biopsy for cause during the first month after transplantation showed ATN lesions. Using partial microvasculature endothelial (fascin, vimentin) and tubular epithelial (vimentin) to mesenchymal transition markers, detected by immunohistochemistry, we found a significant association between partial endothelial to mesenchymal transition and poor graft function recovery (Spearman's rho = -0.55, P = .0005). Transforming growth factor-ß1 was strongly expressed in these phenotypic changed endothelial cells. Extent of ATN was also correlated with short- and long-term graft dysfunction. However, the association of extensive ATN with long-term graft dysfunction (24 months posttransplant) was observed only in patients with partial endothelial to mesenchymal transition marker expression in their grafts (Spearman's rho = -0.64, P = .003), but not in those without. The association of partial endothelial to mesenchymal transition with worse renal graft outcome was confirmed on 34 other early biopsies with ATN from a second transplant center. Our results suggest that endothelial cell activation at the early phase of renal transplantation plays a detrimental role.

First-in-human use of a marine oxygen carrier (M101) for organ preservation: A safety and proof-of-principle study.

The medical device M101 is an extracellular hemoglobin featuring high oxygen-carrying capabilities. Preclinical studies demonstrated its safety as an additive to organ preservation solutions and its beneficial effect on ischemia/reperfusion injuries. OXYgen carrier for Organ Preservation (OXYOP) is a multicenter open-label study evaluating for the first time the safety of M101 added (1 g/L) to the preservation solution of one of two kidneys from the same donor. All adverse events (AEs) were analyzed by an independent data and safety monitoring board. Among the 58 donors, 38% were extended criteria donors. Grafts were preserved in cold storage (64%) or machine perfusion (36%) with a mean cold ischemia time (CIT) of 740 minutes. At 3 months, 490 AEs (41 serious) were reported, including two graft losses and two acute rejections (3.4%). No immunological, allergic, or prothrombotic effects were reported. Preimplantation and 3-month biopsies did not show thrombosis or altered microcirculation. Secondary efficacy end points showed less delayed graft function (DGF) and better renal function in the M101 group than in the contralateral kidneys. In the subgroup of grafts preserved in cold storage, Kaplan-Meier survival and Cox regression analysis showed beneficial effects on DGF independent of CIT (P = .048). This study confirms that M101 is safe and shows promising efficacy data.