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Background: New diagnostic criteria have recently been established to classify small-for-size syndrome (SFSS) after living donor liver transplantation into 3 groups based on severity. This study aimed to evaluate the clinical impact of grade A SFSS and identify the mortality risk., Methods: We collected data from 406 patients diagnosed with grade A SFSS after living donor liver transplantation. Grade A SFSS is characterized by total bilirubin >5 mg/dL on postoperative day (POD) 7 or total bilirubin >5 mg/dL or ascites >1 L/d on POD 14. After propensity score matching, 193 patients were categorized into the up-trend group, down-trend group, and ascites group, with 43 patients (22.3%) in the up-trend group (total bilirubin on POD 7 < POD 14), 107 patients (55.4%) in the down-trend group (total bilirubin on POD 7 > POD 14), and 43 patients (22.3%) in the ascites group (only satisfying ascites criteria)., Results: There was no significant difference in survival between patients with grade A SFSS and those without SFSS (P = 0.152). The up-trend group showed a higher 90-d mortality rate than the down-trend and ascites groups (P = 0.025). The 1-y survival rate differed significantly between the groups (87.6%, 91.9%, and 97.7%, respectively; P = 0.044). The independent risk factors for survival were up-trend of total bilirubin, recipient age (65 y and older), model for end-stage liver disease score (≥30), and ABO incompatibility. Patients with ≥2 risk factors had worse survival rates than those with none and only 1 risk factor (P < 0.001)., Conclusions: Although the survival rate was comparable between the grade A SFSS and non-SFSS cohorts, the up-trend group showed worse survival. Aggressive interventions should be considered for up-trend patients with risk factors., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: In the Netherlands, organ donation after euthanasia (donation after circulatory death type V [DCD-V]) has been increasingly performed since 2012. However, the outcomes of DCD-V kidney grafts have not been thoroughly investigated. It is critical to assess the outcomes of these kidney grafts to ascertain whether DCD-V is a safe and valuable way to increase the kidney donor pool., Objectives: To investigate the outcomes of DCD-V kidney transplantation and compare them with outcomes of kidney transplantation after circulatory death after withdrawal of life-sustaining therapies (DCD type III [DCD-III]) and donation after brain death (DBD)., Design, Setting, and Participants: A retrospective cohort study was conducted using the database from the Dutch Transplant Foundation. All kidney transplants in the Netherlands between January 2012 (start of the euthanasia program) and July 2023 were included. Follow-up was obtained through 5 years after transplantation. Data analysis was performed from November 2023 until February 2024., Exposures: Kidney transplantation with a DCD-V graft compared with DCD-III and DBD grafts., Main Outcomes and Measures: The primary outcome was death-censored graft survival until 5 years after transplantation. Secondary outcomes were the incidence of delayed graft function (DGF), permanent nonfunction (PNF), serum creatinine concentration, and patient survival until 5 years after kidney transplantation., Results: A total of 145 DCD-V kidney transplants were compared with 1936 DCD-III and 1255 DBD kidney transplants. Median (IQR) recipient age was 59 (46-66) years in the DCD-V cohort, compared with 61 (50-68) years in the DCD-III cohort and 61 (50-68) years in the DBD cohort. The incidence of DGF with DCD-V kidney transplants (26%) was significantly less than that with DCD-III kidney transplants (49%; P < .001) and similar to that with DBD kidney transplants (22%; P = .46). PNF occurrence with DCD-V kidneys (6%) was similar to that with DCD-III kidneys (6%; P = .79) and higher than in DBD kidneys (4%; P < .001). There was no difference in 5-year death-censored graft survival between DCD-V grafts (82%) and DCD-III (86%; P = .99) or DBD (84%; P = .99) grafts. There was no difference in 5-year patient survival between DCD-V kidney transplants (69%) and DCD-III (76%; P = .45) or DBD (73%; P = .74) kidney transplants. A propensity score analysis was performed to match the DCD-V and DCD-III cohort, showing results similar to those of the unmatched cohort., Conclusions and Relevance: This study found that DCD-V kidney transplantation yielded a lower incidence of DGF compared with DCD-III kidney transplantation and yielded long-term results similar to those of DCD-III and DBD kidney transplantation. The findings suggest that DCD-V is a safe and valuable way to increase the kidney donor pool.

Background: Despite early diagnosis and medical interventions, patients with methylmalonic acidemia (MMA) suffer from multi-organ damage and recurrent metabolic decompensations., Methods: We conducted the largest retrospective multi-center cohort study so far, involving five transplant centers (NCCHD, KUH, KUHP, ATAK, and EMC), and identified all MMA patients (n = 38) undergoing LDLT in the past two decades. Our primary outcome was patient survival, and secondary outcomes included death-censored graft survival and posttransplant complications., Results: The overall 10-year patient survival and death-censored graft survival rates were 92% and 97%, respectively. Patients who underwent LDLT within 2 years of MMA onset showed significantly higher 10-year patient survival compared to those with an interval more than 2 years (100% vs. 81%, p = 0.038), although the death-censored graft survival were not statistically different (100% vs. 93%, p = 0.22). Over the long-term follow-up, 14 patients (37%) experienced intellectual disability, while two patients developed neurological complications, three patients experienced renal dysfunction, and one patient had biliary anastomotic stricture. The MMA level significantly decreased from 2218.5 mmol/L preoperative to 307.5 mmol/L postoperative (p = 0.038)., Conclusions: LDLT achieves favorable long-term patient and graft survival outcomes for MMA patients. While not resulting in complete cure, our findings support the consideration of early LDLT within 2 years of disease onset. This approach holds the potential to mitigate recurrent metabolic decompensations, and preserve the long-term renal function., (© 2024 Wiley Periodicals LLC.)

Background: Living donor liver transplantation (LDLT) is the best option for end-stage liver disease patients. Older potential donors are increasingly requesting donation. This study aims to systematically assess the differences in donor perioperative and postoperative complications, mortality, and quality of life (QoL) between younger and older living liver donors., Materials and Methods: Embase, Medline, and Cochrane were searched for studies published between 2002 and 2 June 2023. Donor complications, major complications, biliary complications, mortality, and QoL were systematically reviewed, including meta-analyses. Donors aged >50 years were considered older. The methodological quality of the studies was assessed using the Newcastle-Ottawa quality assessment Scale., Results: The search yielded 8320 studies, of which 17 were included. The risk ratio (RR) for complications in younger donors was 1.08 [0.90-1.31] ( P =0.41). RRs for major complications in younger donors were 0.98 [0.64, 1.48] and 0.89 [0.50, 1.57] using Clavien-Dindo ≥III and ≥IIIb as major complication. RR for biliary complications in younger donors was 1.59 [1.05-2.42] ( P =0.03). Mortality rate in younger donors was 47/13 238 (0.4%) and in older donors 13/989 (1.3%). Physical component summary (PCS) in younger donors was 51.87 and in older donors 51.29. Mental component summary (MCS) in younger donors was 52.93 and in older donors 55.40., Conclusion: Older donors do not have a higher complication or mortality rate than younger donors after LDLT. They may have a lower rate of biliary complications. Additionally, older donors have a similar QoL after LDLT. With careful selection, older donors can be included in screening programs for living liver donation to expand the donor pool., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Machine perfusion is the preferred preservation method for deceased donor kidneys. Perfusate fluid, which contains a complex mixture of components, offers potential insight into the organ's viability and function. This study explored immune cell release, particularly tissue-resident lymphocytes (TRLs), during donor kidney machine perfusion and its correlation with injury markers., Methods: Perfusate samples from hypothermic machine perfusion (HMP; n = 26) and normothermic machine perfusion (NMP; n = 16) of human donor kidneys were analyzed for TRLs using flow cytometry. Residency was defined by expressions of CD69, CD103, and CD49as. TRL release was quantified exclusively in NMP. Additionally, levels of cell-free DNA, neutrophil gelatinase-associated lipocalin, and soluble E-cadherin (sE-cadherin) were measured in NMP supernatants with quantitative polymerase chain reaction and enzyme-linked immunosorbent assay., Results: Both HMP and NMP samples contained a heterogeneous population of TRLs, including CD4 + tissue-resident memory T cells, CD8 + tissue-resident memory T cells, tissue-resident natural killer cells, tissue-resident natural killer T cells, and helper-like innate lymphoid cells. Median TRL proportions among total CD45 + lymphocytes were 0.89% (NMP) and 0.84% (HMP). TRL quantities in NMP did not correlate with donor characteristics, perfusion parameters, posttransplant outcomes, or cell-free DNA and neutrophil gelatinase-associated lipocalin concentrations. However, CD103 + TRL release positively correlated with the release of sE-cadherin, the ligand for the CD103 integrin., Conclusions: Human donor kidneys release TRLs during both HMP and NMP. The release of CD103 + TRLs was associated with the loss of their ligand sE-cadherin but not with general transplant injury biomarkers., Competing Interests: D.A.H. received lecture fees and consulting fees from Astellas Pharma, AstraZeneca, Chiesi Pharma, Medincell, Novartis Pharma, Sangamo Therapeutics, and Vifor Pharma. He received grant support from Astellas Pharma, Bristol-Myers Squibb, and Chiesi Pharma (paid to his institution). D.A.H. does not have employment or stock ownership at any of these companies, and neither does he have patents or patent applications. The other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Renal ex vivo normothermic machine perfusion (NMP) is under development as an assessment tool for high-risk kidney grafts and as a means of achieving more physiologically accurate organ preservation. On-going hemolysis has been reported during NMP, as this technique relies on red blood cells for oxygen delivery. In this study, we confirm the occurrence of progressive hemolysis during 6-hour kidney NMP. NMP-associated erythrostasis in the glomeruli and in peri-glomerular vascular networks points to an interaction between the red blood cells and the graft. Continuous hemolysis resulted in prooxidative changes in the perfusate, which could be quenched by addition of fresh frozen plasma. In a cell-based system, this hemolysis induced redox stress and exhibited toxic effects at high concentrations. These findings highlight the need for a more refined oxygen carrier in the context of renal NMP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Malnutrition is highly prevalent in patients with kidney failure. Since body weight does not reflect body composition, other methods are needed to determine muscle mass, often estimated by fat-free mass (FFM). Bioimpedance spectroscopy (BIS) is frequently used for monitoring body composition in patients with kidney failure. Unfortunately, BIS-derived lean tissue mass (LTM BIS ) is not suitable for comparison with FFM cutoff values for the diagnosis of malnutrition, or for calculating dietary protein requirements. Hypothetically, FFM could be derived from BIS (FFM BIS ). This study aims to compare FFM BIS and LTM BIS with computed tomography (CT) derived FFM (FFM CT ). Secondarily, we aimed to explore the impact of different methods on calculated protein requirements., Methods: CT scans of 60 patients with kidney failure stages 4-5 were analyzed at the L3 level for muscle cross-sectional area, which was converted to FFM CT . Spearman rank correlation coefficient and 95% limits of agreement were calculated to compare FFM BIS and LTM BIS with FFM CT . Protein requirements were determined based on FFM CT , FFM BIS , and adjusted body weight. Deviations over 10% were considered clinically relevant., Results: FFM CT correlated most strongly with FFM BIS (r = 0.78, P < .001), in males (r = 0.72, P < .001) and in females (r = 0.60, P < .001). A mean difference of -0.54 kg was found between FFM BIS and FFM CT (limits of agreement: -14.88 to 13.7 kg, P = .544). Between LTM BIS and FFM CT a mean difference of -12.2 kg was apparent (limits of agreement: -28.7 to 4.2 kg, P < .001). Using FFM CT as a reference, FFM BIS best predicted protein requirements. The mean difference between protein requirements according to FFM BIS and FFM CT was -0.7 ± 9.9 g in males and -0.9 ± 10.9 g in females., Conclusion: FFM BIS correlates well with FFM CT at a group level, but shows large variation within individuals. As expected, large clinically relevant differences were observed in calculated protein requirements., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Kidney transplant (KTx) biopsies showing transplant glomerulopathy (TG) (glomerular basement membrane double contours (cg) > 0) and microvascular inflammation (MVI) in the absence of C4d staining and donor-specific antibodies (DSAs) do not fulfill the criteria for chronic active antibody-mediated rejection (CA-AMR) diagnosis and do not fit into any other Banff category. To investigate this, we initiated a multicenter intercontinental study encompassing 36 cases, comparing the immunomic and transcriptomic profiles of 14 KTx biopsies classified as cg+MVI DSA - /C4d - with 22 classified as CA-AMR DSA + /C4d + through novel transcriptomic analysis using the NanoString Banff-Human Organ Transplant (B-HOT) panel and subsequent orthogonal subset analysis using two innovative 5-marker multiplex immunofluorescent panels. Nineteen genes were differentially expressed between the two study groups. Samples diagnosed with CA-AMR DSA + /C4d + showed a higher glomerular abundance of natural killer cells and higher transcriptomic cell type scores for macrophages in an environment characterized by increased expression of complement-related genes (i.e., C5AR1) and higher activity of angiogenesis, interstitial fibrosis tubular atrophy, CA-AMR, and DSA-related pathways when compared to samples diagnosed with cg+MVI DSA - /C4d - . Samples diagnosed with cg+MVI DSA - /C4d - displayed a higher glomerular abundance and activity of T cells (CD3 + , CD3 + CD8 + , and CD3 + CD8 - ). Thus, we show that using novel multiomic techniques, KTx biopsies with cg+MVI DSA - /C4d - have a prominent T-cell presence and activity, putting forward the possibility that these represent a more T-cell dominant phenotype., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Due to the shortage of kidneys donated for transplantation, surgeons are forced to use the organs with an elevated risk of poor function or even failure. Although the existing methods for pre-transplant quality evaluation have been validated over decades in population cohort studies across the world, new methods are needed as long as delayed graft function or failure in a kidney transplant occurs. In this study, we explored the potential of utilizing photoacoustic (PA) imaging during normothermic machine perfusion (NMP) as a means of evaluating kidney quality. We closely monitored twenty-two porcine kidneys using 3D PA imaging during a two-hour NMP session. Based on biochemical analyses of perfusate and produced urine, the kidneys were categorized into 'non-functional' and 'functional' groups. Our primary focus was to quantify oxygenation ( sO 2 ) within the kidney cortical layer of depths 2 mm, 4 mm, and 6 mm using two-wavelength PA imaging. Next, receiver operating characteristic (ROC) analysis was performed to determine an optimal cortical layer depth and time point for the quantification of sO 2 to discriminate between functional and non-functional organs. Finally, for each depth, we assessed the correlation between sO 2 and creatinine clearance ( CrCl ), oxygen consumption ( VO 2 ), and renal blood flow (RBF). We found that hypoxia of the renal cortex is associated with poor renal function. In addition, the determination of sO 2 within the 2 mm depth of the renal cortex after 30 min of NMP effectively distinguishes between functional and non-functional kidneys. The non-functional kidneys can be detected with the sensitivity and specificity of 80% and 85% respectively, using the cut-off point of sO 2 < 39%. Oxygenation significantly correlates with RBF and VO 2 in all kidneys. In functional kidneys, sO 2 correlated with CrCl, which is not the case for non-functional kidneys. We conclude that the presented technique has a high potential for supporting organ selection for kidney transplantation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: The impact of aortoiliac occlusive disease on kidney transplantation remains unclear. This study aims to investigate the clinical outcomes of kidney transplant patients with aortoiliac atherosclerotic stenosis., Methods: Retrospective data from our transplant center were used to identify patients undergoing kidney transplantation between January 2010 and December 2020. Aortoiliac atherosclerotic stenosis was screened and stratified by the Trans-Atlantic Inter-Society Consensus (TASC) II classification. The primary outcome was patient survival. Secondary outcomes were 90-day mortality, death-censored graft survival, graft function, and arterial complications. Propensity score matching was used to match all patients in the stenosis group with patients without stenosis sharing similar characteristics., Results: The analysis included 655 patients, 524 without stenosis and 131 with aortoiliac stenosis (95 with TASC A/B stenosis and 36 with TASC C/D stenosis). Recipient age [median (IQR), 66 (60-70) vs. 66 (59-71) years; P =0.47], sex [male: 87 (66%) vs. 355 (68%), P =0.85], and comorbidities were comparable between the stenosis and no-stenosis groups. Forty-six (35%) patients with stenosis were symptomatic. Patient survival was significantly lower in the stenosis group compared with the no-stenosis group (TASC A/B: 30.6% vs. no-stenosis: 44.1%, P =0.013; TASC C/D: 11.4% vs. no-stenosis: 44.1%, P <0.001). The incidence rates of artery dissection, lower extremity ischemia, and acute thrombosis were significantly higher in the stenosis group ( P <0.001). However, death-censored graft survival (TASC A/B: 73.6% vs. no-stenosis: 72.9%, P =0.62; TASC C/D: 58.1% vs. no-stenosis: 72.9%, P =0.16) and graft function were comparable between the groups., Conclusions: Aortoiliac atherosclerotic stenosis significantly impacts patient survival but not graft survival. Our analyses suggest that patients with TASC A/B stenosis have prolonged survival and enhanced quality of life through kidney transplantation. However, for patients with TASC C/D stenosis, kidney transplantation improves quality of life without bringing survival benefits., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Renal artery aneurysm (RAA) is a rare vascular disease with a mortality rate of up to 80% upon rupture. This study aimed to investigate the safety and efficacy of ex situ repair and autotransplantation for endovascularly untreatable RAA., Methods: A retrospective nationwide cohort study was conducted in RAA patients undergoing ex situ repair and autotransplantation in the Netherlands. Surgical techniques, postoperative complications, and graft outcomes were assessed., Results: Ex situ repair was performed in 9 patients with 11 RAAs. Eight RAAs were located at the first bifurcation, one on the main trunk, one on the first branch, and one on the second branch. Nephrectomy was performed via laparoscopy (n = 7), robotic-assisted laparoscopy (n = 1), and laparotomy (n = 1). Postoperative complications were recorded in 4 patients, including bowel obstruction, delirium, pneumonia, and hydronephrosis due to double-J dislocation. The median estimated glomerular filtration rate was 83 mL/min/1.73 m2 pretransplant and 88 mL/min/1.73 m2 posttransplant. By an average follow-up of 32 months, 2 patients had died due to lung adenocarcinoma and stroke, while all autotransplanted kidneys had good patency and remained functional., Conclusions: Ex situ repair and autotransplantation are safe and feasible for endovascularly untreatable RAA cases. Larger cohorts with longer follow-up periods are necessary to further evaluate the role of this surgical approach., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Surgical resection for perihilar cholangiocarcinoma (pCCA) is associated with high operative risks. Impaired liver regeneration in patients with pre-existing liver disease may contribute to posthepatectomy liver failure (PHLF) and postoperative mortality. This study aimed to determine the incidence of hepatic steatosis and fibrosis and their association with PHLF and 90-day postoperative mortality in pCCA patients., Methods: Patients who underwent a major liver resection for pCCA were included in the study between 2000 and 2021 from three tertiary referral hospitals. Histopathologic assessment of hepatic steatosis and fibrosis was performed. The primary outcomes were PHLF and 90-day mortality., Results: Of the 401 included patients, steatosis was absent in 334 patients (83.3%), mild in 58 patients (14.5%) and moderate to severe in 9 patients (2.2%). There was no fibrosis in 92 patients (23.1%), periportal fibrosis in 150 patients (37.6%), septal fibrosis in 123 patients (30.8%), and biliary cirrhosis in 34 patients (8.5%). Steatosis (≥ 5%) was not associated with PHLF (odds ratio [OR] 1.36; 95% confidence interval [CI] 0.69-2.68) or 90-day mortality (OR 1.22; 95% CI 0.62-2.39). Neither was fibrosis (i.e., periportal, septal, or biliary cirrhosis) associated with PHLF (OR 0.76; 95% CI 0.41-1.41) or 90-day mortality (OR 0.60; 95% CI 0.33-1.06). The independent risk factors for PHLF were preoperative cholangitis (OR 2.38; 95% CI 1. 36-4.17) and future liver remnant smaller than 40% (OR 2.40; 95% CI 1.31-4.38). The independent risk factors for 90-day mortality were age of 65 years or older (OR 2.40; 95% CI 1.36-4.23) and preoperative cholangitis (OR 2.25; 95% CI 1.30-3.87)., Conclusion: In this study, no association could be demonstrated between hepatic steatosis or fibrosis and postoperative outcomes after resection of pCCA., (© 2023. The Author(s).)

Allogeneic transplant organs are potentially highly immunogenic. The endothelial cells (ECs) located within the vascular system serve as the primary interface between the recipient's immune system and the donor organ, playing a key role in the alloimmune response. In this study, we investigated the potential use of recipient-derived ECs in a vein recellularization model. In this study, human iliac veins underwent complete decellularization using a Triton X-100 protocol. We demonstrated the feasibility of re-endothelializing acellular blood vessels using either human umbilical cord vein endothelial cell or human venous-derived ECs, with this re- endothelialization being sustainable for up to 28 days in vitro. The re-endothelialized veins exhibited the restoration of vascular barrier function, along with the restoration of innate immunoregulatory capabilities, evident through the facilitation of monocytic cell transmigration and their polarization toward a macrophage phenotype following transendothelial extravasation. Finally, we explored whether recellularization with EC of a different donor could prevent antibody-mediated rejection. We demonstrated that in chimeric vessels, allogeneic EC became a target of the humoral anti-donor response after activation of the classical immune complement pathway whereas autologous EC were spared, emphasizing their potential utility before transplantation. In conclusion, our study demonstrates that replacement of EC in transplants could reduce the immunological challenges associated with allogeneic grafts.

Competing Interests: Competing interests: We have read and understood the BMJ policy on declaration of interests and have no relevant interests to declare.

Introduction: Food can build social bonds and enhance interpersonal relationships. An area of research perhaps at odds with food abundance, is caloric restriction (CR), intermittent fasting (IF) or short-term fasting (STF). We aimed to study the impact of offering treats on the audience during presentations on IF and STF and whether this impacted the audience's reception of the subject. The contradiction of the tempting nature of sharing brownies juxtaposed with the potential health benefits presented is a light-hearted subject in a world where nutritional intake and health outcomes are the object of intense academic discussion., Objective: Investigate how treats influence hospital personnel interpretation of information presented on the potential benefits of CR, IF and STF., Methods: This trial consists of a cross-sectional study (CSS) and a randomised controlled trial (RCT) conducted at three study centres. The CSS involved a survey administered to healthcare professionals to assess their knowledge, experience and willingness regarding IF and/or STF. In the RCT, brownies were randomly provided to healthcare staff attending a scientific meeting on restricting calories., Results: 135 participants were included in the CSS and 64 participants joined the randomised experiment. We found that the randomisation had no statistically significant effect. Only 2 out of 64 were aware of the irony of the provided treatment. In the CSS, participants most often cited the expected beneficial effects on their short-term and long-term health as important reasons for adhering to IF and/or STF. Perceiving fasting as beneficial was mostly influenced by knowledge on the topic and previously adhering to a fasting diet., Discussion: In this light-hearted, holiday-inspired exploratory study, we found that providing your audience with treats does not influence participants' opinion of you or your research, even when it focuses on the benefits of reducing calorie intake. The recipients of the treat will remain critical of presented findings, and due to prior experiences will be receptive to the counterintuitive topic of fasting., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Tissue-resident lymphocytes (TRLs) are critical for local protection against viral pathogens in peripheral tissue. However, it is unclear if TRLs perform a similar role in transplanted organs under chronic immunosuppressed conditions. In this study, we aimed to characterize the TRL compartment in human kidney transplant nephrectomies and examine its potential role in antiviral immunity. The TRL compartment of kidney transplants contained diverse innate, innate-like, and adaptive TRL populations expressing the canonical residency markers CD69, CD103, and CD49a. Chimerism of donor and recipient cells was present in 43% of kidney transplants and occurred in all TRL subpopulations. Paired single-cell transcriptome and T cell receptor (TCR) sequencing showed that donor and recipient tissue-resident memory T (TRM) cells exhibit striking similarities in their transcriptomic profiles and share numerous TCR clonotypes predicted to target viral pathogens. Virus dextramer staining further confirmed that CD8 TRM cells of both donor and recipient origin express TCRs with specificities against common viruses, including CMV, EBV, BK polyomavirus, and influenza A. Overall, the study results demonstrate that a diverse population of TRLs resides in kidney transplants and offer compelling evidence that TRM cells of both donor and recipient origin reside within this TRL population and may contribute to local protection against viral pathogens.

Background: In The Netherlands, 60% of deceased-donor kidney offers are after donation after circulatory death. Cold and warm ischemia times are known risk factors for delayed graft function (DGF) and inferior allograft survival. Extraction time is a relatively new ischemia time. During procurement, cooling of the kidneys is suboptimal with ongoing ischemia. However, evidence is lacking on whether extraction time has an impact on DGF if all ischemic periods are included., Methods: Between 2012 and 2018, 1524 donation after circulatory death kidneys were procured and transplanted in The Netherlands. Donation and transplantation-related data were obtained from the database of the Dutch Transplant Foundation. The primary outcome parameter was the incidence of DGF., Results: In our cohort, extraction time ranged from 14 to 237 min, with a mean of 62 min (SD 32). In multivariate logistic regression analysis, extraction time was an independent risk factor for incidence of DGF (odds ratio per minute increase 1.008; 95% confidence interval, 1.003-1.013; P  = 0.001). The agonal phase, hypoperfusion time, and anastomosis time were not independent risk factors for incidence of DGF., Conclusions: Considering all known ischemic periods during the donation after the circulatory death process, prolonged kidney extraction time increased the risk of DGF after kidney transplantation., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Objectives: Normothermic machine perfusion (NMP) provides a platform for pre-transplant kidney quality assessment that is essential for the use of marginal donor kidneys. Laser speckle contrast imaging (LSCI) presents distinct advantages as a real-time and noncontact imaging technique for measuring microcirculation. In this study, we aimed to assess the value of LSCI in visualizing renal cortical perfusion and investigate the additional value of dual-side LSCI measurements compared to single aspect measurement during NMP., Methods: Porcine kidneys were obtained from a slaughterhouse and then underwent NMP. LSCI was used to measure one-sided cortical perfusion in the first 100 min of NMP. Thereafter, the inferior renal artery branch was occluded to induce partial ischemia and LSCI measurements on both ventral and dorsal sides were performed., Results: LSCI fluxes correlated linearly with the renal blood flow (R 2  = 0.90, p < 0.001). After renal artery branch occlusion, absence of renal cortical perfusion could be visualized and semiquantified by LSCI. The overall ischemic area percentage of the ventral and dorsal sides was comparable (median interquartile range [IQR], 38 [24-43]% vs. 29 [17-46]%, p = 0.43), but heterogenous patterns between the two aspects were observed. There was a significant difference in oxygen consumption (mean ± standard deviation [SD], 2.57 ± 0.63 vs. 1.83 ± 0.49 mLO 2 /min/100 g, p < 0.001), urine output (median [IQR], 1.3 [1.1-1.7] vs. 0.8 [0.6-1.3] mL/min, p < 0.05), lactate dehydrogenase (mean ± SD, 768 ± 370 vs. 905 ± 401 U/L, p < 0.05) and AST (mean ± SD, 352 ± 285 vs. 462 ± 383 U/L, p < 0.01) before and after renal artery occlusion, while no significant difference was found in creatinine clearance, fractional excretion of sodium, total sodium reabsorption and histological damage., Conclusions: LSCI fluxes correlated linearly with renal blood flow during NMP. Renal cortical microcirculation and absent perfusion can be visualized and semiquantified by LSCI. It provides a relative understanding of perfusion levels, allowing for a qualitative comparison between regions in the kidney. Dual-side LSCI measurements are of added value compared to single aspect measurement and renal function markers., (© 2023 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals LLC.)

Introduction: To this day, a discrepancy exists between donor liver demand and supply. Domino liver transplantation (DLT) can contribute to increasing the number of donor livers available for transplantation., Methods: The design of this systematic review was based on the Preferred Reporting Items for Systematic Reviews (PRISMA). A qualitative analysis of included studies was performed. Primary outcomes were mortality and peri- and postoperative complications related to DLT., Results: Twelve studies met the inclusion criteria. All included studies showed that DLT outcomes were comparable to outcomes of deceased donor liver transplantation (DDLT) in terms of mortality and complications. One-year patient survival rate ranged from 66.7% to 100%. Re-transplantation rate varied from 0 to 12.5%. Most frequent complications were related to biliary (3.7%-37.5%), hepatic artery (1.6%-9.1%), portal vein (12.5-33.3%) and hepatic vein events (1.6%), recurrence of domino donor disease (3.3%-17.4%) and graft rejection (16.7%-37.7%). The quality of the evidence was rated as moderate according to the Newcastle-Ottawa scale (NOS)., Conclusion: DLT outcomes were similar to DDLT in terms of mortality and complications. Even though DLT will not solve the entire problem of organ shortage, transplant programs should always consider using this tool to maximize the availability of liver grafts., Competing Interests: Conflict of interest None to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Normothermic machine perfusion (NMP) is an alternative to hypothermic machine perfusion (HMP) for donor kidney preservation before transplantation. Contrary to HMP, NMP allows for functional assessment of donor kidneys because normothermic conditions allow for metabolic activity. The kidneys are key producers of hormones. Yet, it remains unknown whether donor kidneys during NMP display endocrine functions., Methods: Fifteen donor kidneys were subjected to HMP followed by 2 h of NMP before transplantation. NMP perfusate was collected at 3 time points (0, 1, 2 h) for the measurements of prorenin/renin, erythropoietin (EPO), and vitamin D, and urine samples were collected at 1 h and 2 h for urodilatin measurement. Fifteen HMP perfusate samples were collected for the same measurements., Results: Kidneys on NMP secreted significantly more prorenin, renin, EPO, and active vitamin D than during HMP. EPO and vitamin D secretion remained stable during 2 h of NMP, whereas the prorenin release rate increased and renin release rate decreased after 1 h. Donation after brain death kidneys secreted more vitamin D and less EPO during NMP than donation after circulatory death kidneys. Twelve donor kidneys produced urine during NMP and released detectable levels of urodilatin. Kidneys exhibited a large variation in hormone release rates. No significant differences were found in hormone release capacity between delayed graft function (DGF) and non-DGF kidneys, and no significant correlations were found between hormone release rates and the duration of DGF or 1-mo posttransplant serum creatinine levels., Conclusions: Human transplant kidneys display endocrine activity during NMP. To explore whether correlations exist between hormone release rates and posttransplant kidney function, large numbers of kidneys are required., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: Obesity is becoming more prevalent in the end-stage renal disease population. Bariatric surgery (BS) is increasingly considered as an approach to become eligible for kidney transplant (KT) or reduce obesity-related morbidities., Objectives: To assess the short- and long-term outcomes of patients who underwent both BS and KT and to determine the optimal timing of BS., Methods: Patients who underwent both KT and BS between January 2000 and December 2020 were included and stratified according to the sequence of the 2 operations. The primary outcomes were patient and graft survival. The secondary outcomes were postoperative complications and efficacy of weight loss., Results: Twenty-two patients were included in the KT first group and 34 in the BS first group. Death-uncensored graft survival in the KT first group was significantly higher than in the BS first group (90.9% versus 71.4%, P = .009), without significant difference in patient survival and death-censored graft survival (100% versus 90.5%, P = .082; 90.9% versus 81.0%, P = .058). There was no significant difference in 1-year total weight loss (1-yr TWL: median [interquartile range {IQR}], 36.0 [28.0-42.0] kg versus 29.6 [21.5-40.6] kg, P = .424), 1-year percentage of excess weight loss (1-yr %EWL: median [IQR], 74.9 [54.1-99.0] versus 57.9 [47.5-79.4], P = .155), and the incidence of postoperative complications (36.4% versus 50.0%, P = .316) between the KT first and BS first groups., Conclusion: Both pre- and posttransplant BS are effective and safe. Different conditions of each transplant candidate should be considered in detail to determine the optimal timing of BS., (Copyright © 2023 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Little is known about the influence of the duration of the kidney back-table preparation period and kidney temperature on graft outcomes after transplantation. The aim of this study is to investigate the back-table duration and its relation to graft outcome and the relation between kidney temperature and graft outcome., Methods: In this prospective cohort study, deceased donor kidney temperature is measured at fixed time points using an infrared thermometer during back-table preparation and transplantation. Additionally, the back-table duration is measured using a timer., Results: Between September 2020 and July 2021, 49 kidneys were prospectively included in this study. Median back-table duration was 33.7 (standard deviation ± 14.1) min and donor kidney temperature increased up to 14.9 °C (±2.8) after 60 min of back-table preparation. Mean implantation time was 24.9 (±7.6) min and kidney temperature increased up to 25.9 °C (±2.4) after 30 min of implantation time. Longer back-table duration was significantly associated with higher rates of delayed graft function ( p = 0.037). However, this observation did not sustain at 3 and 6-months post-transplantation. No association was found between kidney temperature and graft outcomes., Conclusion: Longer back-table duration is significantly associated with DGF after deceased donor kidney transplantation. No association was observed between kidney temperature and graft outcomes of deceased donor kidneys.

Background: Transcriptome analysis could be an additional diagnostic parameter in diagnosing kidney transplant (KTx) rejection. Here, we assessed feasibility and potential of NanoString nCounter analysis of KTx biopsies to aid the classification of rejection in clinical practice using both the Banff-Human Organ Transplant (B-HOT) panel and a customized antibody-mediated rejection (AMR)-specific NanoString nCounter Elements (Elements) panel. Additionally, we explored the potential for the classification of KTx rejection building and testing a classifier within our dataset., Methods: Ninety-six formalin-fixed paraffin-embedded KTx biopsies were retrieved from the archives of the ErasmusMC Rotterdam and the University Hospital Cologne. Biopsies with AMR, borderline or T cell-mediated rejections (BLorTCMR), and no rejection were compared using the B-HOT and Elements panels., Results: High correlation between gene expression levels was found when comparing the 2 chemistries pairwise (r = 0.76-0.88). Differential gene expression (false discovery rate; P  < 0.05) was identified in biopsies diagnosed with AMR (B-HOT: 294; Elements: 76) and BLorTCMR (B-HOT: 353; Elements: 57) compared with no rejection. Using the most predictive genes from the B-HOT analysis and the Element analysis, 2 least absolute shrinkage and selection operators-based regression models to classify biopsies as AMR versus no AMR (BLorTCMR or no rejection) were developed achieving an receiver-operating-characteristic curve of 0.994 and 0.894, sensitivity of 0.821 and 0.480, and specificity of 1.00 and 0.979, respectively, during cross-validation., Conclusions: Transcriptomic analysis is feasible on KTx biopsies previously used for diagnostic purposes. The B-HOT panel has the potential to differentiate AMR from BLorTCMR or no rejection and could prove valuable in aiding kidney transplant rejection classification., Competing Interests: M.C.C.v.G. has Astellas project funding paid to the Erasmus MC. J.U.B. is advisor for Sanofi. The other authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Aorto-iliac calcification (AIC) is a well-studied risk factor for post-transplant cardiovascular events and mortality. Its effect on graft function remains unknown. The primary aim of this prospective cohort study was to assess the association between AIC and estimated glomerular filtration rate (eGFR) in the first year post-transplant. Eligibility criteria were: ≥50 years of age or ≥30 years with at least one risk factor for vascular disease. A non-contrast-enhanced CT-scan was performed with quantification of AIC using the modified Agatston score. The association between AIC and eGFR was investigated with a linear mixed model adjusted for predefined variables. One-hundred-and-forty patients were included with a median of 31 (interquartile range 26-39) eGFR measurements per patient. No direct association between AIC and eGFR was found. We observed a significant interaction between follow-up time and ipsilateral AIC, indicating that patients with higher AIC scores had lower eGFR trajectory over time starting 100 days after transplant ( p = 0.014). To conclude, severe AIC is not directly associated with lower post-transplant eGFR. The significant interaction indicates that patients with more severe AIC have a lower eGFR trajectory after 100 days in the first year post-transplant., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rijkse, Roodnat, Baart, Bijdevaate, Dijkshoorn, Kimenai, van de Wetering, IJzermans and Minnee.)

Atherosclerosis of the aortoiliac vessels can adversely affect kidney perfusion after kidney transplantation. Atherosclerosis severity can be determined using the calcium score (CaScore). Potential problems with posttransplantation kidney perfusion can be determined using the intrarenal resistance index (RI). This study investigated the association between aortoiliac CaScore and RI in kidney transplant recipients., Methods: Kidney transplant recipients (2004-2019), for whom the CaScore and RI were determined, were included in this dual-center cohort study. CaScore was measured in 3 aortoiliac segments using noncontrast CT imaging. RI was determined using Doppler ultrasound. Multivariable linear regression analyses were performed between the CaScore and RI, adjusted for confounding variables., Results: The mean age of the 389 included patients was 59 (±13) y. The mean RI (unitless) was 0.71 (±0.09)' and the median CaScore (unitless) was 3340 (399-7833). In univariable linear regression analyses with RI as the dependent variable, CaScore ( β = 0.011; P < 0.001) was positively associated with RI. Moreover, recipient age ( β = 0.014; P < 0.001), history of diabetes ( β = 0.029; P = 0.003), recipient history of vascular interventions ( β = 0.032; P = 0.002), prior dialysis ( β = 0.029; P = 0.003), deceased donor transplantation ( β = 0.042; P < 0.001), donation after cardiac death ( β = 0.036; P = 0.001), an increase in cold ischemia time ( β = 0.011; P < 0.001), and the Comprehensive Complication Index ( β = 0.006; P = 0.002) were also positively associated with RI, whereas preoperative recipient diastolic blood pressure ( β = -0.007; P = 0.030) was inversely associated. In multivariable analyses, CaScore and RI remained significantly ( P = 0.010) associated, independent of adjustment for potential confounders. Furthermore, in univariable linear regression analyses, multiple graft function characteristics were associated with RI., Conclusions: A significant association was found between CaScore and RI, independent of adjustment for multiple potential confounding factors, leading to a better insight into the development and interpretation of RI. Aortoiliac atherosclerosis should be considered when interpreting the RI and determining the possible cause of malperfusion and graft failure after kidney transplantation., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

In kidney transplantation (KTx), renal graft thrombosis (RGT) is one of the main reasons for early graft loss. Although evidence-based guidance on prevention of RGT is lacking, thromboprophylaxis is widely used. The aim of this survey was to obtain a European view of the different thromboprophylactic strategies applied in KTx. An online 22-question survey, addressed to KTx professionals, was distributed by email and via platforms of the European Society for Organ Transplantation. Seventy-five responses (21 countries, 51 centers) were received: 75% had over 10 years' clinical experience, 64% were surgeons, 29% nephrologists, and 4% urologists. A written antithrombotic management protocol was available in 75% of centers. In 8 (16%) centers, respondents contradicted each other regarding the availability of a written protocol. Thromboprophylaxis is preferred by 78% of respondents, independent of existing antithrombotic management protocols. Ninety-two percent of respondents indicated that an anticipated bleeding risk is the main reason to discontinue chronic antithrombotic therapy preoperatively. Intraoperatively, 32% of respondents administer unfractionated heparin (400-10,000 international units with a median of 5,000) in selected cases. Despite an overall preference for perioperative thromboprophylaxis in KTx, there is a high variation within Europe regarding type, timing, and dosage, most likely due to the paucity of high-quality studies. Further research is warranted in order to develop better guidelines., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Background: Kidney transplantation is the optimal treatment of end-stage renal disease. Extracellular vesicles (EVs) have tremendous therapeutic potential, but their role in modulating immune responses in kidney transplantation remains unclear., Methods: We performed a systematic review and meta-analysis to investigate the therapeutic efficacy of EVs in preclinical kidney transplant models. Outcomes for meta-analysis were graft survival and renal function. Subgroup analysis was conducted between immune cell derived EVs (immune cell-EVs) and mesenchymal stromal cell derived EVs (MSC-EVs)., Results: Seven studies published from 2013 to 2021 were included. The overall effects showed that EVs had a positive role in prolonging allograft survival (standardized mean difference (SMD) = 2.00; 95% confidence interval (CI), 0.79 to 3.21; P < 0.01; I 2  = 94%), reducing serum creatinine (SCr) (SMD = -2.19; 95%CI, -3.35 to -1.04; P < 0.01; I 2  = 93%) and blood urea nitrogen (BUN) concentrations (SMD = -1.69; 95%CI, -2.98 to -0.40; P = 0.01; I 2  = 94%). Subgroup analyses indicated that only immune cell-EVs significantly prolonged graft survival and improve renal function but not MSC-EVs., Conclusions: EVs are promising candidates to suppress allograft rejection and improve kidney transplant outcome. Immune cell-EVs showed their superiority over MSC-EVs in prolonging graft survival and improving renal function. For interpretation of the outcomes, additional studies are needed to validate these findings., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Extracellular vesicles (EVs) are tissue-specific particles released by cells containing valuable diagnostic information in the form of various biomolecules. The characterization of EVs released by kidney grafts during normothermic machine perfusion (NMP) may present a promising avenue to assess graft status before transplantation., Methods: We phenotyped and determined the concentrations of EVs in the perfusate of 8 discarded expanded-criteria donor human kidneys during 6 h of NMP. Perfusate samples were taken at 0/60/180/360 min and examined with nanoparticle tracking analysis and imaging flow cytometry (IFCM). Using IFCM, EVs were identified by their expression of common EV markers CD9, CD63, and CD81 (tetraspanins) in combination with either platelet endothelial cell adhesion molecule (CD31), pan-leukocyte protein (CD45), or carboxyfluorescein succiminidyl ester (CFSE) fluorescence., Results: Nanoparticle tracking analysis measurements revealed the release of nanoparticles <400 nm into the perfusate during NMP. With IFCM, tetraspanin protein signatures of the released nanoparticles were characterized, and the majority (~75%) of CFSE+ EVs were found to be CD81+, whereas ~16% were CD9+ and ~8% CD63+. Correlation analysis of concentrations of identified EV subsets with crude donor characteristics and NMP viability characteristics revealed significant correlations with cold ischemia time, donor age, and renal flow., Conclusions: Our findings demonstrate that discarded expanded-criteria donor kidney grafts release distinct EV subsets during NMP. Because these subsets correlate with well-established indicators of transplant outcome, EVs might represent new potential candidates for assessment of kidney graft quality., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

The use of extended criteria donor grafts is a promising strategy to increase the number of organ transplantations and reduce waitlist mortality. However, these organs are often compromised and/or damaged, are more susceptible to preservation injury, and are at risk for developing post-transplant complications. Ex vivo organ perfusion is a novel technology to preserve donor organs while providing oxygen and nutrients at distinct perfusion temperatures. This preservation method allows to resuscitate grafts and optimize function with therapeutic interventions prior to solid organ transplantation. Stem cell-based therapies are increasingly explored for their ability to promote regeneration and reduce the inflammatory response associated with in vivo reperfusion. The aim of this review is to describe the current state of stem cell-based therapies during ex vivo organ perfusion for the kidney, liver, lung, and heart. We discuss different strategies, including type of cells, route of administration, mechanisms of action, efficacy, and safety. The progress made within lung transplantation justifies the initiation of clinical trials, whereas more research is likely required for the kidney, liver, and heart to progress into clinical application. We emphasize the need for standardization of methodology to increase comparability between future (clinical) studies., (© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Introduction: A decentralized and multi-platform-compatible molecular diagnostic tool for kidney transplant biopsies could improve the dissemination and exploitation of this technology, increasing its clinical impact. As a first step towards this molecular diagnostic tool, we developed and validated a classifier using the genes of the Banff-Human Organ Transplant (B-HOT) panel extracted from a historical Molecular Microscope ® Diagnostic system microarray dataset. Furthermore, we evaluated the discriminative power of the B-HOT panel in a clinical scenario., Materials and Methods: Gene expression data from 1,181 kidney transplant biopsies were used as training data for three random forest models to predict kidney transplant biopsy Banff categories, including non-rejection (NR), antibody-mediated rejection (ABMR), and T-cell-mediated rejection (TCMR). Performance was evaluated using nested cross-validation. The three models used different sets of input features: the first model (B-HOT Model) was trained on only the genes included in the B-HOT panel, the second model (Feature Selection Model) was based on sequential forward feature selection from all available genes, and the third model (B-HOT+ Model) was based on the combination of the two models, i.e. B-HOT panel genes plus highly predictive genes from the sequential forward feature selection. After performance assessment on cross-validation, the best-performing model was validated on an external independent dataset based on a different microarray version., Results: The best performances were achieved by the B-HOT+ Model, a multilabel random forest model trained on B-HOT panel genes with the addition of the 6 most predictive genes of the Feature Selection Model ( ST7 , KLRC4-KLRK1 , TRBC1 , TRBV6-5 , TRBV19 , and ZFX ), with a mean accuracy of 92.1% during cross-validation. On the validation set, the same model achieved Area Under the ROC Curve (AUC) of 0.965 and 0.982 for NR and ABMR respectively., Discussion: This kidney transplant biopsy classifier is one step closer to the development of a decentralized kidney transplant biopsy classifier that is effective on data derived from different gene expression platforms. The B-HOT panel proved to be a reliable highly-predictive panel for kidney transplant rejection classification. Furthermore, we propose to include the aforementioned 6 genes in the B-HOT panel for further optimization of this commercially available panel., Competing Interests: Author MB was employed by company Omnigen BV. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 van Baardwijk, Cristoferi, Ju, Varol, Minnee, Reinders, Li, Stubbs and Clahsen-van Groningen.)

Studies have been carried out to investigate the effect of a prolonged cold ischaemia time (CIT) on the outcomes of living donor kidney transplantation (LDKT). There is no clear consensus in the literature about the effects of CIT on LDKT outcomes, and therefore, we performed a systematic review and meta-analysis to provide evidence on this subject. Searches were performed in five databases up to 12 July 2021. Articles comparing different CIT in LDKT describing delayed graft function (DGF), graft and patient survival, and acute rejection were considered for inclusion. This study is registered with PROSPERO, CRD42019131438. In total, 1452 articles were found, of which eight were finally eligible, including a total of 164,179 patients. Meta-analyses showed significantly lower incidence of DGF (odds ratio (OR) = 0.61, p < 0.01), and significantly higher 1-year graft survival (OR = 0.72, p < 0.001) and 5-year graft survival (OR = 0.88, p = 0.04), for CIT of less than 4 h. Our results underline the need to keep CIT as short as possible in LDKT (ideally < 4 h), as a shorter CIT in LDKT is associated with a statistically significant lower incidence of DGF and higher graft survival compared to a prolonged CIT. However, clinical impact seems limited, and therefore, in LDKT programmes in which the CIT might be prolonged, such as kidney exchange programmes, the benefits outweigh the risks. To minimize these risks, it is worth considering including CIT in kidney allocation algorithms and in general take precautions to protect high risk donor/recipient combinations.

Background: Robot-assisted kidney transplantation (RAKT) has emerged as an alternative for kidney transplant recipients with the potential benefits of minimally invasive surgery. The aim of this systematic review and meta-analysis is to compare the clinical outcomes of RAKT with open kidney transplantation (OKT)., Methods: MEDLINE, Embase, Web of Science and Cochrane databases were systematically searched. Baseline characteristics, intraoperative and postoperative outcomes were collected, as well as long-term renal function and data on graft and patient survival., Results: Eleven studies were included, which compared 482 RAKT procedures with 1316 OKT procedures. RAKT was associated with lower a risk of surgical site infection (Risk ratio (RR) = 0.15, p < 0.001), symptomatic lymphocele (RR = 0.20, p = 0.03), less postoperative pain (Mean difference (MD) = -1.38 points, p < 0.001), smaller incision length (MD = -8.51 cm, p < 0.001), and shorter length of hospital stay (MD = -1.69 days, p = 0.03) compared with OKT. No difference was found in renal function, graft, and patient survival., Conclusions: RAKT is a safe and feasible alternative to OKT with less surgical complications without compromising renal function, graft and patient survival., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Although kidney transplantation improves patient survival and quality of life, long-term results are hampered by both immune- and non-immune-mediated complications. Current biomarkers of post-transplant complications, such as allograft rejection, chronic renal allograft dysfunction, and cutaneous squamous cell carcinoma, have a suboptimal predictive value. DNA methylation is an epigenetic modification that directly affects gene expression and plays an important role in processes such as ischemia/reperfusion injury, fibrosis, and alloreactive immune response. Novel techniques can quickly assess the DNA methylation status of multiple loci in different cell types, allowing a deep and interesting study of cells' activity and function. Therefore, DNA methylation has the potential to become an important biomarker for prediction and monitoring in kidney transplantation., Purpose of the Study: The aim of this study was to evaluate the role of DNA methylation as a potential biomarker of graft survival and complications development in kidney transplantation. MATERIAL AND METHODS: A systematic review of several databases has been conducted. The Newcastle-Ottawa scale and the Jadad scale have been used to assess the risk of bias for observational and randomized studies, respectively., Results: Twenty articles reporting on DNA methylation as a biomarker for kidney transplantation were included, all using DNA methylation for prediction and monitoring. DNA methylation pattern alterations in cells isolated from different tissues, such as kidney biopsies, urine, and blood, have been associated with ischemia-reperfusion injury and chronic renal allograft dysfunction. These alterations occurred in different and specific loci. DNA methylation status has also proved to be important for immune response modulation, having a crucial role in regulatory T cell definition and activity. Research also focused on a better understanding of the role of this epigenetic modification assessment for regulatory T cells isolation and expansion for future tolerance induction-oriented therapies., Conclusions: Studies included in this review are heterogeneous in study design, biological samples, and outcome. More coordinated investigations are needed to affirm DNA methylation as a clinically relevant biomarker important for prevention, monitoring, and intervention., (© 2022. The Author(s).)

Background: One of the main effectors on the quality of life of living-kidney donors is postoperative fatigue. Caloric restriction (CR) and short-term fasting (STF) are associated with improved fitness and increased resistance to acute stress. CR/STF increases the expression of cytoprotective genes, increases immunomodulation via increased anti-inflammatory cytokine production, and decreases the expression of pro-inflammatory markers. As such, nutritional preconditioning by CR or STF represents a non-invasive and cost-effective method that could mitigate the effects of acute surgery-induced stress and postoperative fatigue. To investigate whether preoperative STF contributes to a reduction in fatigue after living-kidney donation, a randomized clinical trial is indicated., Methods: We aim to determine whether 2.5 days of fasting reduces postoperative fatigue score in subjects undergoing living-kidney donation. In this randomized study, the intervention group will follow a preoperative fasting regime for 2.5 days with a low-dose laxative, while the control group will receive standard care. The main study endpoint is postoperative fatigue, 4 weeks after living-kidney donation. Secondary endpoints include the effect of preoperative fasting on postoperative hospital admission time, the feasibility of STF, and the postoperative recovery of donor and recipient kidney function. This study will provide us with knowledge of the feasibility of STF and confirm its effect on postoperative recovery., Discussion: Our study will provide clinically relevant information on the merits of caloric restriction for living-kidney donors and recipients. We expect to reduce the postoperative fatigue in living-kidney donors and improve the postoperative recovery of living-kidney recipients. It will provide evidence on the clinical merits and potential caveats of preoperative dietary interventions., Trial Registration: Netherlands Trial Register NL9262 . EudraCT 2020-005445-16 . MEC Erasmus MC MEC-2020-0778. CCMO NL74623.078.21., (© 2022. The Author(s).)

Prediction of the risk of cardiovascular events (CVE's) is important to optimize outcomes after kidney transplantation. Aortoiliac stenosis is frequently observed during pre-transplant screening. We hypothesized that these patients are at higher risk of post-transplant CVE's due to the joint underlying atherosclerotic disease. Therefore, we aimed to assess whether aortoiliac stenosis was associated with post-transplant CVE's. This retrospective, single-center cohort study included adult kidney transplant recipients, transplanted between 2000 and 2016, with contrast-enhanced imaging available. Aortoiliac stenosis was classified according to the Trans-Atlantic Inter-Society Consensus (TASC) II classification and was defined as significant in case of ≥50% lumen narrowing. The primary outcome was CVE-free survival. Eighty-nine of 367 patients had significant aortoiliac stenosis and were found to have worse CVE-free survival (median CVE-free survival: stenosis 4.5 years (95% confidence interval (CI) 2.8-6.2), controls 8.9 years (95% CI 6.8-11.0); log-rank test P < .001). TASC II C and D lesions were independent risk factors for a post-transplant CVE with a hazard ratio of 2.15 (95% CI 1.05-4.38) and 6.56 (95% CI 2.74-15.70), respectively. Thus, kidney transplant recipients with TASC II C and D aortoiliac stenosis require extensive cardiovascular risk management pre-, peri,- and post-transplantation., (© 2021 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

Introduction: Aorto-iliac vascular disease (AVD) is frequently found during the workup for kidney transplantation. However, recommendations on screening and management are lacking. We aimed to assess differences in screening, management, and acceptance of these patients for transplantation by performing a survey among transplant surgeons. Second, we aimed to identify center- and surgeon-related factors associated with decline or acceptance of kidney transplant candidates with AVD., Methods: A survey was sent to transplant surgeons and urologists. The survey contained general questions (part I) and 2 patient-based cases (part II) with Trans-Atlantic Inter-Society Consensus (TASC) D and B AVD supported with videos of their CT scans., Results: One hundred ninety-one (20.3%) participants responded; 171 were currently involved in kidney transplantation: 161 (94.2%) completed part I and 145 (84.8%) part II. Screening for AVD was often (38.5%) restricted to high-risk patients. The majority of respondents (67.7%) rated "technical problems" as the most important concern in case of AVD, followed by "increased mortality risk because of cardiovascular comorbidity" (29.8%). Pretransplant vascular interventions to facilitate transplantation were infrequently performed (71.4% mentioned <10 per year). Ninety (64.3%) respondents answered that an open vascular procedure should preferably be performed prior to kidney transplantation while 42 (30.0%) respondents preferred a simultaneous open vascular procedure. The decline rate was higher in the TASC D case compared to the TASC B case (26.9% and 9.7%, respectively). Respondents from centers with expertise in pretransplant vascular interventions were more likely to accept both patients with TASC D and B for transplantation., Conclusion: There is no uniformity in the screening, management, and acceptance of patients with AVD for transplantation. If a center declines a patient with AVD because of technical concerns, the patient should be referred for a second opinion to a tertiary center with expertise in pretransplant vascular interventions. Multidisciplinary meetings including a vascular surgeon and a cardiologist could help optimize these patients for transplantation., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Study Objective: To assess whether different intensities of intra-abdominal pressure and deep neuromuscular blockade influence the risk of intra-operative surgical complications during laparoscopic donor nephrectomy., Design: A pooled analysis of ten previously performed prospective randomized controlled trials., Setting: Laparoscopic donor nephrectomy performed in four academic hospitals in the Netherlands: Radboudumc, Leiden UMC, Erasmus MC Rotterdam, and Amsterdam UMC., Patients: Five hundred fifty-six patients undergoing a transperitoneal, fully laparoscopic donor nephrectomy enrolled in ten prospective, randomized controlled trials conducted in the Netherlands from 2001 to 2017., Interventions: Moderate (tetanic count of four > 1) versus deep (post-tetanic count 1-5) neuromuscular blockade and standard (≥10 mmHg) versus low (<10 mmHg) intra-abdominal pressure., Measurements: The primary endpoint is the number of intra-operative surgical complications defined as any deviation from the ideal intra-operative course occurring between skin incision and closure with five severity grades, according to ClassIntra. Multiple logistic regression analyses were used to identify predictors of intra- and postoperative complications., Main Results: In 53/556 (9.5%) patients, an intra-operative complication with ClassIntra grade ≥ 2 occurred. Multiple logistic regression analyses showed standard intra-abdominal pressure (OR 0.318, 95% CI 0.118-0.862; p = 0.024) as a predictor of less intra-operative complications and moderate neuromuscular blockade (OR 3.518, 95% CI 1.244-9.948; p = 0.018) as a predictor of more intra-operative complications. Postoperative complications occurred in 31/556 (6.8%), without significant predictors in multiple logistic regression analyses., Conclusions: Our data indicate that the use of deep neuromuscular blockade could increase safety during laparoscopic donor nephrectomy. Future randomized clinical trials should be performed to confirm this and to pursue whether it also applies to other types of laparoscopic surgery., Trial Registration: Clinicaltrials.gov LEOPARD-2 (NCT02146417), LEOPARD-3 trial (NCT02602964), and RELAX-1 study (NCT02838134), Klop et al. ( NTR 3096 ), Dols et al. 2014 ( NTR1433 )., (© 2021. The Author(s).)

Background: Since the introduction of the Model for End-stage Liver disease criteria in 2002, more combined liver kidney transplants are performed. Until 2017, no standard allocation policy for combined liver kidney transplant (CLKT) was available and each transplant center decided eligibility for CLKT or liver transplant alone (LTA) on a case-by-case basis. The aim of this systematic review was to compare the clinical outcomes of CLKT compared to LTA in patients with renal dysfunction., Methods: Databases were systematically searched for studies published between January 2010 and March 2021. Outcomes were expressed as risk ratios and pooled with a random-effects model. The primary outcome was patient survival., Results: Four studies were included. No differences were observed for mortality risk at 1 year (risk ratio (RR) 1.03 [confidence interval (CI) 0.97-1.09], 3 years (RR 1.06 [CI 0.99-1.13]) and 5 years (RR 1.08 [CI 0.98-1.19]). The risk of graft loss was similar in the first year (RR 1.10 [CI 0.93-1.30], while 3-year risk of graft loss was significantly lower in CLKT patients (RR 1.15 [CI 1.08-1.24])., Conclusions: CLKT has similar short-term graft and patient survival as LTA in patients with renal dysfunction. More data is needed to decide from which KDIGO stage patients benefit the most from CLKT., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

We present an updated overview of the literature comparing normothermic with hypothermic machine perfusion in porcine kidneys. We conducted a systematic literature review in Embase, Medline Epub (Ovid), Cochrane Central, Web of Science, and Google Scholar on studies comparing normothermic (NMP) to hypothermic machine perfusion (HMP) in porcine kidneys. A meta-analysis was judged inappropriate because of heterogeneity in study design and perfusion methods. The quality of evidence of each included study was assessed. We included 8 studies. One out of 5 studies reported a significant difference in peak renal blood flow in favor of NMP. Oxygen consumption was significantly higher in NMP kidneys in 2 out of 5 studies. Peak creatinine clearance in NMP was significantly higher than that in HMP in 1 out of 6 studies. Two out of 4 studies reported a higher degree of epithelial vacuolation in kidneys receiving NMP over HMP. None of the studies found a significant difference between NMP and HMP in peak serum creatinine or graft survival after autotransplantation. The results need to be interpreted with caution in view of the diversity in perfusion protocols, the low quality of evidence, and the limited sample sizes., (© 2021 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Screening for aorto-iliac stenosis is important in kidney transplant candidates as its presence affects pre-transplantation decisions regarding side of implantation and the need for an additional vascular procedure. Reliable imaging techniques to identify this condition require contrast fluid, which can be harmful in these patients. To guide patient selection for these imaging techniques, we aimed to develop a prediction model for the presence of aorto-iliac stenosis. Patients with contrast-enhanced imaging available in the pre-transplant screening between January 1st, 2000 and December 31st, 2018 were included. A prediction model was developed using multivariable logistic regression analysis and internally validated using bootstrap resampling. Model performance was assessed with the concordance index and calibration slope. Three hundred and seventy-three patients were included, 90 patients (24.1%) had imaging-proven aorto-iliac stenosis. Our final model included age, smoking, peripheral arterial disease, coronary artery disease, a previous transplant, intermittent claudication and the presence of a femoral artery murmur. The model yielded excellent discrimination (optimism-corrected concordance index: 0.83) and calibration (optimism-corrected calibration slope: 0.91). In conclusion, this prediction model can guide the development of standardized protocols to decide which patients should receive vascular screening to identify aorto-iliac stenosis. External validation is needed before this model can be implemented in patient care., (© 2021 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

Objectives: Renal artery aneurysm (RAA) is a rare vascular disease. Kidney autotransplantation (KAT) is the treatment option when endovascular approach is not available. However, the evidence on KAT for RAA is mostly limited to small case series or reports. Here, we describe our 2 center experience of KAT for RAA, and provide the results of our systematic literature review to evaluate the outcomes., Methods: A retrospective 2 center study was conducted in patients undergoing KAT for RAA between 2010 and 2018. Moreover, a systematic review was performed on medical databases to evaluate the outcomes of KAT for RAA., Results: Nine patients were surgically treated at our institutions: eight with laparoscopic nephrectomy (LN), and 1 with open followed heterotopic KAT. All RAAs were ex-vivo reconstructed, and in 3 cases a vein graft was used for reconstruction. There were 2 postoperative major complications including 1 graft loss. In the systematic review, 102 studies with 355 patients were included. In 35 patients (9.9%) a minimal invasive approach was performed. The incidence of postoperative major complications and graft loss was 9.4% and 4.1%., Conclusions: Our experiences showed that laparoscopic approach for nephrectomy followed heterotopic KAT was feasible with good postoperative outcomes. KAT is an effective treatment for RAA when endovascular approach is not feasible for interpretation of the outcomes, the quality and sample size of the evidence should be taken into consideration., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Ageing of the general population has led to an increase in the use of suboptimal kidneys from expanded criteria donation after brain death (ECD-DBD) and donation after circulatory death (DCD) donors. However, these kidneys have inferior graft outcomes and lower rates of immediate function. Normothermic machine perfusion (NMP) may improve outcomes of these suboptimal donor kidneys. Previous non-randomized studies have shown the safety of this technique and suggested its efficacy in improving the proportion of immediate functioning kidneys compared to static cold storage (SCS). However, its additional value to hypothermic machine perfusion (HMP), which has already been proved superior to SCS, has not yet been established., Methods and Analysis: This single-center, open-label, randomized controlled trial aims to assess immediate kidney function after 120 minutes additional, end-ischemic NMP compared to HMP alone. Immediate kidney function is defined as no dialysis treatment in the first week after transplant. Eighty recipients on dialysis at the time of transplant who receive an ECD-DBD or DCD kidney graft are eligible for inclusion. In the NMP group, the donor kidney is taken of HMP upon arrival in the recipient hospital and thereafter put on NMP for 120 minutes at 37 degrees Celsius followed by transplantation. In the control group, donor kidneys stay on HMP until transplantation. The primary outcome is immediate kidney function., Ethics and Dissemination: The protocol has been approved by the Medical Ethical Committee of Erasmus Medical Center (2020-0366). Results of this study will be submitted to peer-reviewed journals., Registration: registered in clinicaltrials.gov (NCT04882254)., Highlights: This is the first RCT to compare additional NMP to HMP alone.Extensive sampling will offer in-depth analysis of kidney physiology during NMP.This RCT may help identify biomarkers to predict clinical outcomes during NMP.Biomarkers can help develop NMP as assessment tool for declined kidneys., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2021 The Author(s).)

Background: The effect of mannitol usage during kidney donation and kidney transplantation is still unclear. Therefore, we performed a systematic review and meta-analysis to research the difference in graft function between kidney grafts treated with and without mannitol., Methods: A literature search was performed in 5 databases and included 8 eligible studies out of 3570 references, which were included up to July 12, 2021. Relevant outcomes for analysis were graft survival, rejection, acute renal failure, delayed graft function, renal failure, creatinine clearance, diuresis, and serum creatinine., Results: Eight studies were identified, 1 study examining the effect of mannitol during kidney donation and 7 studies during kidney transplantation, of which 6 eligible for meta-analysis. A total of 1143 patients were included in these studies. The following outcome measures demonstrated significant differences in favor of mannitol usage compared with a control group: acute renal failure (risk ratio [RR], 0.45; 95% confidence interval [CI], 0.26-0.79; P < .01]) and delayed graft function (RR, 0.25; 95% CI, 0.08-0.77; P = 0.02 and RR, 0.69; 95% CI, 0.51-0.94; P = 0.94). Differences in other outcome parameters were not significant., Conclusions: This systematic review and meta-analysis suggested that the use of mannitol during kidney transplantation leads to lower incidence of acute renal failure and delayed graft function. For all other outcomes, no significant difference was found. Further research should be conducted on the use of mannitol during donor nephrectomy because of the limited availability of studies. Finally, for interpretation of the outcomes, the quality of the evidence should be taken into consideration and we emphasize the need for more up-to-date research., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Donation after circulatory death (DCD) kidney transplantation has been introduced to address organ shortage. However, DCD kidneys are not accepted worldwide due to concerns about inferior quality. To investigate whether these concerns are justified, we performed a systematic review and meta-analysis to investigate DCD graft outcomes compared to donation after brain death (DBD)., Materials and Methods: EMBASE, Medline, Cochrane, Web of Science and Google Scholar were searched from database inception until September 2020. Exclusion criteria were studies reporting on pediatric/dual kidney transplants, multi-organ transplants or studies including normothermic perfusion techniques. The primary outcome was graft survival. Secondary outcomes were primary non-function (PNF), delayed graft function (DGF), 3-months biopsy-proven acute rejection (BPAR), 1-year estimated Glomerular Filtration Rate (eGFR), patient survival, and urologic complications. A random-effects model was used for meta-analysis. Meta-regression analysis was performed in case of high between-study heterogeneity., Results: Fifty-one studies were included, comprising 73,454 DCD and 518,229 DBD recipients. One-year graft loss was increased in DCD recipients (death-censored: risk ratio (RR) 1.10 (95%-confidence interval (CI) 1.04-1.16), all-cause: RR 1.13 (95%-CI 1.08-1.19)). Ten-year graft loss was similar to DBD (death-censored: RR 1.02 (95%-CI 0.92-1.13), all-cause: RR 1.03 (95%-CI 0.94-1.13)). DCD recipients had an increased risk of PNF (RR 1.43 (95%-CI 1.26-1.62)), DGF (RR 2.02 (95%-CI 1.88-2.16)), and 1-year mortality (RR 1.10 (95%-CI 1.01-1.21)). No differences were observed for 3-months BPAR, ureter stenosis/leakage, 1-year eGFR and 10-year mortality., Conclusion: Long-term DCD kidney transplant outcomes are similar to DBD despite a higher risk of PNF, DGF, and a 13% increased risk of graft loss in the first year after transplantation. These results should encourage implementation of DCD programs., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)