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Introduction: Targeted temperature management (TTM) is considered to be a neuroprotective strategy during cardiopulmonary bypass (CPB) assisted procedures, possibly through the activation of cold shock proteins. We therefore investigated the effects of mild compared with deep hypothermia on the neuroinflammatory response and cold shock protein expression after CPB in rats., Methods: Wistar rats were subjected to 1 hr of mild (33 °C) or deep (18 °C) hypothermia during CPB or sham procedure. PET scan analyses using TSPO ligand [ 11 C]PBR28 were performed on day 1 (short-term) or day 3 and 7 post-procedure (long-term) to assess neuroinflammation. Hippocampal and cortical samples were obtained at day 1 in the short-term group and at day 7 in the long-term group. mRNA expression of M1 and M2 microglia associated cytokines was analysed with RT-PCR. Cold shock protein RNA-binding motive 3 (RBM3) and tyrosine receptor kinase B (TrkB) receptor protein expression were determined with Western Blot and quantified., Results: In both groups target temperature was reached within an hour. Standard uptake values (SUV) of [ 11 C]PBR28 in CPB rats at 1 day and 3 days were similar to that of sham animals. At 7 days after CPB the SUV was significantly higher in amygdala and hippocampal regions of the CPB 18 °C group as compared to the CPB 33 °C group. No differences were observed in the expression of M1 and M2 microglia-related cytokines between TTM 18 °C and 33 °C. RBM3 protein levels in cortex and hippocampus were significantly higher in CPB 33 °C compared to CPB 18 °C and sham 33 °C, at day 1 and day 7, respectively., Conclusions: TTM at 18 °C increased the neuroinflammatory response in amygdala and hippocampus compared to TTM at 33 °C in rats undergoing a CPB procedure. Additionally, TTM at 33 °C induced increased expression of TrkB and RBM3 in cortex and hippocampus of rats on CPB compared to TTM at 18 °C. Together, these data indicate that neuroinflammation is alleviated by TTM at 33 °C, possibly by recruiting protective mechanisms through cold shock protein induction., 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. Published by Elsevier Inc.)

Background: Postoperative cognitive dysfunction (POCD) is a common complication in older patients with cancer and is associated with decreased quality of life and increased disability and mortality rates. Systemic inflammation resulting in neuroinflammation is considered important in the pathogenesis of POCD. The aim of this study was to explore the association between the early surgery-induced inflammatory response and POCD within 3 months after surgery in older cancer patients., Methods: Patients ≥65 years in need of surgery for a solid tumor were included in a prospective cohort study. Plasma levels of C-reactive protein (CRP), interleukin-1 beta (IL-1β), IL-6, IL-10, and Neutrophil gelatinase-associated lipocalin (NGAL) were measured perioperatively. Cognitive performance was assessed preoperatively and 3 months after surgery. POCD was defined as a decline in cognitive test scores of ≥25% on ≥2 of five tests within the different cognitive domains of memory, executive functioning, and information processing speed. Logistic regression analysis was performed., Results: POCD was observed in 44 (17.7%) of 248 included patients. Age >75, preoperative Mini-Mental State Examination (MMSE) score ≤26 and major surgery were independent significant predictors for POCD. In multivariate logistic regression analysis, no significant associations were shown between the early surgery-induced inflammatory response and either POCD or decline within the different cognitive domains., Conclusions: This study shows that one out of six older patients with cancer developed POCD within 3 months after surgery. The early surgery-induced inflammatory response was neither associated with POCD, nor with decline in the separate cognitive domains. Further research is necessary for better understanding of the complex etiology of POCD., (© 2024 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Kidney transplantation is the best treatment for kidney failure in older patients. However, little is known regarding changes in health-related quality of life (HRQoL) from before to after transplantation and determinants of HRQoL in older kidney transplant recipients (KTR). We studied both, using data of older (≥65 years) patients waitlisted for kidney transplantation and older KTR 1 year after transplantation from the TransplantLines Biobank and Cohort Study. HRQoL was assessed using the SF-36 questionnaire. We included 145 older waitlisted patients (68% male, age 70 ± 4 years) and 115 older KTR at 1 year after transplantation (73% male, age 70 ± 4 years). Both mental (48.5 ± 8.4 versus 51.2 ± 7.7, p = 0.009) and physical (47.4 ± 8.5 versus 52.1 ± 7.2, p < 0.001) HRQoL were higher among included KTR, compared to the waitlisted patients. In paired analyses among 46 patients with HRQoL-data both before and after transplantation, there was a trend towards increased mental HRQoL (49.1 ± 8.4 to 51.6 ± 7.5, p = 0.054), and significantly increased physical HRQoL (48.1 ± 8.0 to 52.4 ± 6.7, p = 0.001) after transplantation. Among all assessed factors, the number of patient-reported immunosuppressive drug-related side effects was most strongly negatively associated with both mental and physical HRQoL. In conclusion, HRQoL is significantly higher among older KTR after kidney transplantation compared to older waitlisted patients., 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 © 2024 de Boer, Knobbe, Kremer, van Munster, Nieuwenhuijs-Moeke, Pol, Bakker, Berger and Sanders.)

Background: Because of perioperative splanchnic hypoperfusion, the gut wall becomes more permeable for intraluminal microbes to enter the splanchnic circulation, possibly contributing to development of complications. Hypoperfusion-related injured enterocytes release intestinal fatty acid binding protein (I-FABP) into plasma, which is used as proxy of intestinal integrity. This study investigates the occurrence of intestinal integrity loss during oncologic surgery, measured by I-FABP change. Secondary the relationship between compromised intestinal integrity, and related variables and complications were studied., Methods: Patients undergoing oncologic surgery from prospective cohort studies were included. Urine I-FABP samples were collected preoperatively (T0) and at wound closure (T1), and in a subgroup on Day 1 (D1) and Day 2 (D2) postoperatively. I-FABP dynamics were investigated and logistic regression analyses were performed to study the association between I-FABP levels and patient-related, surgical variables and complications., Results: A total of 297 patients were included with median age of 70 years. Median I-FABP value increased from 80.0 pg/mL at T0 (interquartile range [IQR] 38.0-142.0) to 115 pg/mL at T1 (IQR 48.0-198.0) (p < 0.05). Age (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.02-1.08) and anesthesia time (OR 1.13, 95% CI 1.02-1.25) were related to stronger I-FABP increase. When comparing I-FABP change in patients experiencing any complications versus no complications, relative I-FABP change at T1 was 145% of T0 (IQR 86-260) versus 113% (IQR 44-184) respectively (p < 0.05)., Conclusions: A significant change in I-FABP levels was seen perioperatively indicating compromised intestinal integrity. Age and anesthesia time were related to higher I-FABP increase. In patients experiencing postoperative complications, a higher I-FABP increase was found., (© 2024. The Author(s).)

Volatile anesthetics have been shown in different studies to reduce ischemia reperfusion injury (IRI). Ex vivo lung perfusion (EVLP) facilitates graft evaluation, extends preservation time and potentially enables injury repair and improvement of lung quality. We hypothesized that ventilating lungs with sevoflurane during EVLP would reduce lung injury and improve lung function. We performed a pilot study to test this hypothesis in a slaughterhouse sheep DCD model. Lungs were harvested, flushed and stored on ice for 3 h, after which EVLP was performed for 4 h. Lungs were ventilated with either an FiO 2 of 0.4 (EVLP, n = 5) or FiO 2 of 0.4 plus sevoflurane at a 2% end-tidal concentration (C et ) (S-EVLP, n = 5). Perfusate, tissue samples and functional measurements were collected and analyzed. A steady state of the target C et sevoflurane was reached with measurable concentrations in perfusate. Lungs in the S-EVLP group showed significantly better dynamic lung compliance than those in the EVLP group ( p = 0.003). Oxygenation capacity was not different in treated lungs for delta partial oxygen pressure (PO 2 ; +3.8 (-4.9/11.1) vs. -11.7 (-12.0/-3.2) kPa, p = 0.151), but there was a trend of a better PO 2 /FiO 2 ratio ( p = 0.054). Perfusate ASAT levels in S-EVLP were significantly reduced compared to the control group (198.1 ± 93.66 vs. 223.9 ± 105.7 IU/L, p = 0.02). We conclude that ventilating lungs with sevoflurane during EVLP is feasible and could be useful to improve graft function.

Background: Postoperative neurocognitive disorder (pNCD) is common after surgery. Exposure to anaesthetic drugs has been implicated as a potential cause of pNCD. Although several studies have investigated risk factors for the development of cognitive impairment in the early postoperative phase, risk factors for pNCD at 3 months have been less well studied. The aim of this study was to identify potential anaesthesia-related risk factors for pNCD at 3 months after surgery., Methods: We analysed data obtained for a prospective observational study in patients aged ≥ 65 years who underwent surgery for excision of a solid tumour. Cognitive function was assessed preoperatively and at 3 months postoperatively using 5 neuropsychological tests. Postoperative NCD was defined as a postoperative decline of ≥ 25% relative to baseline in ≥ 2 tests. The association between anaesthesia-related factors (type of anaesthesia, duration of anaesthesia, agents used for induction and maintenance of anaesthesia and analgesia, the use of additional vasoactive medication, depth of anaesthesia [bispectral index] and mean arterial pressure) and pNCD was analysed using logistic regression analyses. Furthermore, the relation between anaesthesia-related factors and change in cognitive test scores expressed as a continuous variable was analysed using a z-score., Results: Of the 196 included patients, 23 (12%) fulfilled the criteria for pNCD at 3 months postoperatively. A low preoperative score on Mini-Mental State Examination (OR, 8.9 [95% CI, (2.8-27.9)], p < 0.001) and a longer duration of anaesthesia (OR, 1.003 [95% CI, (1.001-1.005)], p = 0.013) were identified as risk factors for pNCD. On average, patients scored higher on postoperative tests (mean z-score 2.35[± 3.13])., Conclusion: In this cohort, duration of anaesthesia, which is probably an expression of the complexity of the surgery, was the only anaesthesia-related predictor of pNCD. On average, patients' scores on cognitive tests improved postoperatively., (© 2023. The Author(s).)

During ischemia and reperfusion injury (IRI), mitochondria may release mitochondrial DNA (mtDNA). mtDNA can serve as a propagator of further injury but in specific settings has anti-inflammatory capacities as well. Therefore, the aim of this study was to study the perioperative dynamics of plasma mtDNA during living donor kidney transplantation (LDKT) and its potential as a marker of graft outcome. Fifty-six donor-recipient couples from the Volatile Anesthetic Protection of Renal Transplants-1 (VAPOR-1) trial were included. Systemic venous, systemic arterial, and renal venous samples were taken at multiple timepoints during and after LDKT. Levels of mtDNA genes changed over time and between vascular compartments. Several donor, recipient, and transplantation-related variables significantly explained the course of mtDNA genes over time. mtDNA genes predicted 1-month and 24-month estimated glomerular filtration rate (eGFR) and acute rejection episodes in the two-year follow-up period. To conclude, mtDNA is released in plasma during the process of LDKT, either from the kidney or from the whole body in response to transplantation. While circulating mtDNA levels positively and negatively predict post-transplantation outcomes, the exact mechanisms and difference between mtDNA genes are not yet understood and need further exploration.

In this Pro-Con commentary article, we discuss whether all general anesthesia should be done using target-controlled propofol anesthesia guided by monitoring of depth of anesthesia. This is an ongoing debate since more than 25 years, representing a scientific, cultural as well as geographical divide in the anesthesia community. The Pro side argues that total intravenous anesthesia causes less postoperative nausea and higher patient satisfaction than anesthesia using volatile anesthetics. Target-controlled infusion (TCI) of anesthetic agents allows for better titration of intravenous anesthesia using pharmacokinetic models. Processed EEG monitors, such as bispectral index monitoring, allows for better assessing the effect of TCI anesthesia than solely assessment of clinical parameters, such as ECG or blood pressure. The combination of TCI propofol and objective depth of anesthesia monitoring allows creating a pharmacokinetic-pharmacodynamic profile for each patient. Finally, anesthesia using volatile anesthetics poses health risks for healthcare professionals and contributes to greenhouse effect. The Con side argues that for procedures accompanied with ischemia and reperfusion injury of an organ or tissue and for patients suffering from a severe inflammation' the use of volatile anesthetics might well have its advantages above propofol. In times of sudden shortage of drugs, volatile anesthetics can overcome the restriction in the operating theater or even on the intensive care unit, which is another advantage. Volatile anesthetics can be used for induction of anesthesia when IV access is impossible, end-tidal measurements of volatile anesthetic concentration allows confirmation that patients receive anesthetics. Taking environmental considerations into account, both propofol and volatile anesthetics bear certain harm to the environment, be it as waste product or as greenhouse gases. The authors therefore suggest to carefully considering advantages and disadvantages for each patient in its according environment. A well-balanced choice based on the available literature is recommended. The authors recommend careful consideration of advantages and disadvantages of each technique when tailoring an anesthetic to meet patient needs. Where appropriate, anesthesia providers are encouraged to account for unique features of anesthetic drug behavior, patient-reported and observed postoperative outcomes, and economic and environmental considerations when choosing any of the 2 described techniques., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2022 International Anesthesia Research Society.)

Nowadays, the main cause for early graft loss is renal graft thrombosis because kidney transplant outcomes have improved drastically owing to advances in immunological techniques and immunosuppression. However, data regarding the efficacy of antithrombotic therapy in the prevention of renal graft thrombosis are scarce. Adequate antithrombotic management requires a good understanding of the pathophysiological changes in the hemostatic system in patients with end-stage kidney disease (ESKD). Specifically, ESKD and dialysis disrupt the fine balance between pro- and anticoagulation in the body, and further changes in the hemostatic system occur during kidney transplantation. Consequently, kidney transplant recipients paradoxically are at risk for both thrombosis and bleeding. This overview focuses on the pathophysiological changes in hemostasis in ESKD and kidney transplantation and provides a comprehensive summary of the current evidence for antithrombotic management in (adult) kidney transplant recipients., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Early non-invasive detection and prediction of graft function after kidney transplantation is essential since interventions might prevent further deterioration. The aim of this study was to analyze the dynamics and predictive value of four urinary biomarkers: kidney injury molecule-1 (KIM-1), heart-type fatty acid binding protein (H-FABP), N-acetyl-β-D-glucosaminidase (NAG), and neutrophil gelatinase-associated lipocalin (NGAL) in a living donor kidney transplantation (LDKT) cohort. Biomarkers were measured up to 9 days after the transplantation of 57 recipients participating in the VAPOR-1 trial. Dynamics of KIM-1, NAG, NGAL, and H-FABP significantly changed over the course of 9 days after transplantation. KIM-1 at day 1 and NAG at day 2 after transplantation were significant predictors for the estimated glomerular filtration rate (eGFR) at various timepoints after transplantation with a positive estimate ( p < 0.05), whereas NGAL and NAG at day 1 after transplantation were negative significant predictors ( p < 0.05). Multivariable analysis models for eGFR outcome improved after the addition of these biomarker levels. Several donor, recipient and transplantation factors significantly affected the baseline of urinary biomarkers. In conclusion, urinary biomarkers are of added value for the prediction of graft outcome, but influencing factors such as the timing of measurement and transplantation factors need to be considered.

During ischemia−reperfusion injury (IRI), reactive oxygen species are produced that can be scavenged by free sulfhydryl groups (R-SH, free thiols). In this study, we hypothesized that R-SH levels decrease as a consequence of renal IRI and that R-SH levels reflect post-transplant graft function. Systemic venous, arterial, renal venous, and urinary samples were collected in donors and recipients before, during, and after transplantation. R-SH was measured colorimetrically. Systemic arterial R-SH levels in recipients increased significantly up to 30 sec after reperfusion (p < 0.001). In contrast, renal venous R-SH levels significantly decreased at 5 and 10 min compared to 30 sec after reperfusion (both p < 0.001). This resulted in a significant decrease in delta R-SH (defined as the difference between renal venous and systemic arterial R-SH levels) till 30 sec after reperfusion (p < 0.001), indicating a net decrease in R-SH levels across the transplanted kidney. Overall, these results suggest trans-renal oxidative stress as a consequence of IRI during kidney transplantation, reflected by systemic and renal changes in R-SH levels in transplant recipients.

Nonsteroidal anti-inflammatory drugs are among the most commonly administered drugs in the perioperative period due to their prominent role in pain management. However, they potentially have perioperative consequences due to immune-modulating effects through the inhibition of prostanoid synthesis, thereby affecting the levels of various cytokines. These effects may have a direct impact on the postoperative outcome of patients since the immune system aims to restore homeostasis and plays an indispensable role in regeneration and repair. By affecting the immune response, consequences can be expected on various organ systems. This narrative review aims to highlight these potential immune system-related consequences, which include systemic inflammatory response syndrome, acute respiratory distress syndrome, immediate and persistent postoperative pain, effects on oncological and neurologic outcome, and wound, anastomotic, and bone healing., (Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved.)

In kidney transplantation, microthrombi and fibrin deposition may lead to local perfusion disorders and subsequently poor initial graft function. Microthrombi are often regarded as donor-derived. However, the incidence, time of development, and potential difference between living donor kidneys (LDK) and deceased donor kidneys(DDK), remains unclear. Two open-needle biopsies, taken at preimplantation and after reperfusion, were obtained from 17 LDK and 28 DDK transplanted between 2005 and 2008. Paraffin-embedded sections were immunohistochemically stained with anti-fibrinogen antibody. Fibrin deposition intensity in peritubular capillaries(PTC) and glomeruli was categorized as negative, weak, moderate or strong and the number of microthrombi/mm 2 was quantified. Reperfusion biopsies showed more fibrin deposition (20% to 100% moderate/strong, p < 0.001) and more microthrombi/mm 2 (0.97 ± 1.12 vs. 0.28 ± 0.53, p < 0.01) than preimplantation biopsies. In addition, more microthrombi/mm 2 (0.38 ± 0.61 vs. 0.09 ± 0.22, p = 0.02) and stronger fibrin intensity in glomeruli (28% vs. 0%, p < 0.01) and PTC (14% vs. 0%, p = 0.02) were observed in preimplantation DDK than LDK biopsies. After reperfusion, microthrombi/mm 2 were comparable (p = 0.23) for LDK (0.09 ± 0.22 to 0.76 ± 0.49, p = 0.03) and DDK (0.38 ± 0.61 to 0.90 ± 1.11, p = 0.07). Upon reperfusion, there is an aggravation of microthrombus formation and fibrin deposition within the graft. The prominent increase of microthrombi in LDK indicates that they are not merely donor-derived., (© 2021. The Author(s).)

Frailty is a multidimensional condition and is the result of the body's age-associated decline in physical, cognitive, physiological, and immune reserves. The aim of this systematic review is to assess the quality of evidence of the included studies, determine the prevalence of frailty among kidney transplant candidates, and evaluate the relationship between frailty and associated patient characteristics and outcomes after kidney transplantation., Methods: A systematic search was performed for relevant literature on frailty and kidney transplantation. This was followed by a meta-analysis for patient characteristics and outcomes reported by a minimum of 2 studies including mean age, gender, mean body mass index, type of kidney transplantation, dialysis, previous kidney transplantation, comorbidities, hypertension, race, preemptive kidney transplantation, delayed graft function, and length of stay., Results: A total of 18 studies were included in the systematic review and 14 of those studies were suitable for meta-analysis. The overall pooled prevalence of frailty before transplantation was estimated at 17.1% (95% confidence interval [CI], 15.4-18.7). Frailty was significantly associated with higher age (mean difference, 3.6; 95% CI, 1.4-5.9), lower rate of preemptive transplantation (relative risk, 0.60; 95% CI, 0.4-0.9), longer duration of delayed graft function (relative risk, 1.80; 95% CI, 1.1-3.0), and length of stay longer than 2 wk (odds ratio, 1.64; 95% CI, 1.2-2.3)., Conclusions: One in 6 kidney transplant recipients is frail before transplantation. The presence of frailty is associated with lower rates of preemptive transplantation, older recipient age, higher rates of delayed graft function, and longer length of stay. Future research is required to explore the association of frailty with other adverse outcomes after kidney transplantation and the effects of intervention programs to improve the different frailty domains., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Ischemia reperfusion injury (IRI) is inevitable in kidney transplantation and negatively impacts graft and patient outcome. Reperfusion takes place in the recipient and most of the injury following ischemia and reperfusion occurs during this reperfusion phase; therefore, the intra-operative period seems an attractive window of opportunity to modulate IRI and improve short- and potentially long-term graft outcome. Commonly used volatile anesthetics such as sevoflurane and isoflurane have been shown to interfere with many of the pathophysiological processes involved in the injurious cascade of IRI. Therefore, volatile anesthetic (VA) agents might be the preferred anesthetics used during the transplantation procedure. This review highlights the molecular and cellular protective points of engagement of VA shown in in vitro studies and in vivo animal experiments, and the potential translation of these results to the clinical setting of kidney transplantation.

Purpose: Frailty is the body's failure to return to homeostasis after every day or acute stressful events, causing adverse outcomes. To study its dynamics in kidney transplant recipients (KTR), we determined whether the degree of frailty and its domains are affected by kidney transplantation (KT)., Methods: Between 2015 and 2017, 176 KTR were included. Frailty scores were measured using the Groningen Frailty Indicator (GFI), assessed preoperatively and during follow-up. Transitions in frailty state and changes in the individual domains were determined., Results: Mean age (±SD) was 51.8 (± 14.1) years, and 63.1% of KTR were male. Thirty patients were considered frail (GFI ≥ 4) at baseline. After a mean follow-up of 22.8 ± 8.3 months, 34 non-frail patients (19.3%) became frail, 125 patients (71.0%) remained the same, and 17 frail patients (9.7%) became non-frail (GFI < 4). In the domain psychosocial functioning, 28.4% of the patients had an increase in GFI score after follow-up. Patients who scored a point in the domain cognition at baseline had a greater chance of becoming frail (OR 4.38, 95% CI 0.59-32.24)., Conclusion: In conclusion, almost one-fifth of non-frail KTR transitioned to a frail state after their transplantation. These results could be used to predict the impact of KT on frailty course and help with implementing prehabilitation for patients at risk.

Ischemia and reperfusion injury (IRI) is a complex pathophysiological phenomenon, inevitable in kidney transplantation and one of the most important mechanisms for non- or delayed function immediately after transplantation. Long term, it is associated with acute rejection and chronic graft dysfunction due to interstitial fibrosis and tubular atrophy. Recently, more insight has been gained in the underlying molecular pathways and signalling cascades involved, which opens the door to new therapeutic opportunities aiming to reduce IRI and improve graft survival. This review systemically discusses the specific molecular pathways involved in the pathophysiology of IRI and highlights new therapeutic strategies targeting these pathways.

Background: Ischaemia-reperfusion injury in kidney transplantation leads to delayed graft function (DGF), which is associated with reduced long term graft function. Remote ischaemic conditioning (RIC) improved early kidney graft function in a porcine model of donation after brain death and was associated with improved long-term cardiac outcome after myocardial ischaemia. This randomised, double-blinded trial evaluated the effect of RIC on kidney graft outcome in the first year, and examined the predictive value of a new measure of initial kidney graft function, i.e. the estimated time to a 50% reduction in plasma creatinine post-transplantation (tCr50)., Methods: A total of 225 patients undergoing deceased donor kidney transplantation were randomised to RIC or a sham procedure performed prior to kidney reperfusion. Up to four repetitive cycles of five minutes of leg ischaemia and five minutes of reperfusion were given. GFR, plasma creatinine, cystatin C and neutrophil gelatinase associated lipocalin (NGAL) were measured at three and twelve months and estimated GFR was calculated using four different equations. Other secondary outcomes were identified from patient files., Results: RIC did not affect GFR or other outcomes when compared to the sham procedure at three or twelve months. tCr50 correlated with one year graft function (p<0.0001 for both mGFR and eGFR estimates). In contrast, DGF i.e. "need of dialysis the first week" did not correlate significantly with one year GFR., Conclusion: RIC during deceased donor kidney transplantation did not improve one year outcome. However, tCr50 may be a relevant marker for studies aiming to improve graft onset., Trial Registration: www.ClinicalTrials.gov Identifier: NCT01395719., Competing Interests: The authors declare no conflict of interests.

Background: In 2016 we observed a marked increase in functional delayed graft function (fDGF) in our living donor kidney transplantation (LDKT) recipients from 8.5% in 2014 and 8.8% in 2015 to 23.0% in 2016. This increase coincided with the introduction of a goal-directed fluid therapy (GDFT) protocol in our kidney transplant recipients. Hereupon, we changed our intraoperative fluid regimen to a fixed amount of 50 mL/kg body weight (BW) and questioned whether the intraoperative fluid regimen was related to this increase in fDGF., Methods: a retrospective cohort analysis of all donors and recipients in our LDKT program between January 2014-February 2017 ( n = 275 pairs)., Results: Univariate analysis detected various risk factors for fDGF. Dialysis dependent recipients were more likely to develop fDGF compared to pre-emptively transplanted patients ( p < 0.001). Recipients developing fDGF received less intraoperative fluid (36 (25.9-50.0) mL/kg BW vs. 47 (37.3-55.6) mL/kg BW ( p = 0.007)). The GDFT protocol resulted in a reduction of intraoperative fluid administration on average by 850 mL in total volume and 21% in mL/kg BW compared to our old protocol ( p < 0.001). In the unadjusted analysis, a higher intraoperative fluid volume in mL/kg BW was associated with a lower risk for the developing fDGF (OR 0.967, CI (0.941-0.993)). After adjustment for the confounders, prior dialysis and the use of intraoperative noradrenaline, the relationship of fDGF with fluid volume was still apparent (OR 0.970, CI (0.943-0.998))., Conclusion: Implementation of a GDFT protocol led to reduced intraoperative fluid administration in the LDKT recipients. This intraoperative fluid restriction was associated with the development of fDGF.

Background: Data on chronic pain after kidney donation are sparse. The aim of this study was to assess the incidence of chronic pain after hand-assisted laparoscopic nephrectomy., Methods: Living kidney donors who donated between 2011 and 2017 at the University Medical Centre Groningen were included. All patients underwent hand-assisted laparoscopic donor nephrectomy. Postdonation pain and movement disabilities were assessed using the Carolinas Comfort Scale (CCS) and a visual analogue scale (VAS). The prevalence, severity of pain and the need for analgesics were reported., Results: Some 333 living kidney donors with a mean age of 56 years were included. At a median of 19 (i.q.r. 10-33) months after donation, 82 donors (24·6 per cent) had a CCS score above 0, of which 58 (71 per cent) had a CCS score of at least 2 and 57 (70 per cent) reported movement limitations. Some 110 donors (33·0 per cent) had a VAS score of more than 0. Complaints mainly occurred during bending over (12·3 per cent) and exercising (12·4 per cent). Thirty-two donors (9·7 per cent) required analgesics during follow-up between donation and the time of measurement, and six of 82 (7 per cent) reported chronic inguinal pain. In multivariable analysis, donor age (odds ratio (OR) 0·97, 95 per cent c.i. 0·95 to 0·99; P = 0·020) and length of hospital stay (OR 1·21, 1·01 to 1·51; P = 0·041) were independently associated with chronic pain., Conclusion: One-quarter of donors experienced chronic postdonation pain or discomfort, most of which was bothersome. Younger donors and those with a longer postoperative hospital stay had more symptoms., (© 2019 The Authors. BJS published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Perioperative antithrombotic therapy could play a role in preventing thromboembolic complications (TEC) after kidney transplantation (KTx), but little is known on postoperative bleeding risks. This retrospective analysis comprises 2000 single-organ KTx recipients transplanted between 2011 and 2016 in the two largest transplant centers of the Netherlands. TEC and bleeding events were scored ≤7 days post-KTx. Primary analyses were for associations of antithrombotic therapy with incidence of TEC and bleeding. Secondary analyses were for associations of other potential risk factors. Mean age was 55 ± 14 years, 59% was male and 60% received a living donor kidney. Twenty-one patients (1.1%) had a TEC. Multiple donor arteries [OR 2.79 (1.15-6.79)] and obesity [OR 2.85 (1.19-6.82)] were identified as potential risk factors for TEC. Bleeding occurred in 88 patients (4.4%) and incidence varied significantly between different antithrombotic therapies (P = 0.006). Cardiovascular disease [OR 2.01 (1.18-3.42)], pre-emptive KTx [OR 2.23 (1.28-3.89)], postoperative heparin infusion [OR 1.69 (1.00-2.85)], and vitamin K antagonists [OR 6.60 (2.95-14.77)] were associated with an increased bleeding risk. Intraoperative heparin and antiplatelet therapy were not associated with increased bleeding risk. These regimens appear to be safe for the possible prevention of TEC without increasing the risk for bleeding after KTx., (© 2018 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

Background: Early markers to predict delayed kidney graft function (DGF) may support clinical management. We studied the ability of four biomarkers (neutrophil gelatinase associated lipocalin (NGAL), liver-type fatty acid-binding protein (L-FABP), cystatin C, and YKL-40) to predict DGF after deceased donor transplantation, and their association with early graft function and GFR at three and twelve months., Methods: 225 deceased donor kidney transplant recipients were included. Biomarkers were measured using automated assays or ELISA. We calculated their ability to predict the need for dialysis post-transplant and correlated with the estimated time to a 50% reduction in plasma creatinine (tCr50), measured glomerular filtration rate (mGFR) and estimated GFR (eGFR)., Results: All biomarkers measured at Day 1, except urinary L-FABP, significantly correlated with tCr50 and mGFR at Day 5. Plasma NGAL at Day 1 and a timed urine output predicted DGF (AUC = 0.91 and AUC 0.98). Nil or only weak correlations were identified between early biomarker levels and mGFR or eGFR at three or twelve months., Conclusion: High plasma NGAL at Day 1 predicts DGF and is associated with initial graft function, but may not prove better than P-creatinine or a timed urine output. Early biomarker levels do not correlate with one-year graft function., Trial Registration: ClinicalTrials.gov NCT01395719., Competing Interests: The authors have declared that no competing interests exist.

Currently, there are no tools to predict postsurgery outcome after kidney transplantation. This study assesses whether frailty influence 30-day postoperative complications after kidney transplantation. One-hundred and fifty kidney transplantations were prospectively included. Frailty was assessed using a frailty indicator, consisting of 15 questions, covering most domains of functioning. Postoperative complications were measured by the Comprehensive Complication Index (CCI). Using a linear regression model, 30-day postoperative complications and frailty correlation were adjusted for confounders, including sex, age, ASA Score, Charlson Comorbidity Index, hypertension, BMI, smoking, dialysis, duration of dialysis, type of transplantation, and retransplantation. The mean frailty score was 2.07(±1.6) and 23 patients were classified as frail (GFI ≥4). The mean CCI-score was 18(±15.6), the mean CCI-score for "frail" patients 30.1(±17.2) compared to 15.5 (±14.2) for "non-frail" patients (N = 116). In a regression analysis, a significant relationship between CCI-score and frailty (β = 13.3; 95% CI 5.7-20.9; P = 0.0007) and transplantation type (β = 4.9; 95% CI: 0.72-9.16; P = 0.02) was found, independent of confounders. In conclusion, frailty and type of transplantation are independent factors associated with an increased risk of postoperative complications., (© 2018 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

To prevent renal graft thrombosis in kidney transplantation, centres use different perioperative anticoagulant strategies, based on various risk factors. In our centre, patients transplanted preemptively are considered at increased risk of renal graft thrombosis compared to patients who are dialysis-dependent at time of transplantation. Therefore these patients are given a single dose of 5000 IU unfractionated heparin intraoperatively before clamping of the vessels. We questioned whether there is a difference in haemostatic state between preemptively and non-preemptively transplanted patients and whether the distinction in intraoperative heparin administration used in our center is justified. For this analysis, citrate samples of patients participating in the VAPOR-1 trial were used and several haemostatic and fibrinolytic parameters were measured in 29 preemptively and 28 non-preemptively transplanted patients and compared to 37 living kidney donors. Sample points were: induction anaesthesia (T1), 5 minutes after reperfusion (T2) and 2 hours postoperative (T3). At T1, recipient groups showed comparable elevated levels of platelet factor 4 (PF4, indicating platelet activation), prothrombin fragment F1+2 and D-dimer (indicating coagulation activation) and Von Willebrand Factor (indicating endothelial activation) compared to the donors. The Clot Lysis Time (CLT, a measure of fibrinolytic potential) was prolonged in both recipient groups compared to the donors. At T3, F1+2, PF4 and CLT were higher in non-preemptively transplanted recipients compared to preemptively transplanted recipients. Compared to donors, non-preemptive recipients showed a prolonged CLT, but comparable levels of PF4 and D-dimer. In conclusion pre-transplantation, preemptively and non-preemptively transplanted patients show a comparable enhanced haemostatic state. A distinction in intraoperative heparin administration between preemptive and non-preemptive transplantation does not seem justified., Competing Interests: The authors have declared that no competing interests exist.

Background: Kidney transplantation is associated with harmful processes affecting the viability of the graft. One of these processes is associated with the phenomenon of ischaemia-reperfusion injury. Anaesthetic conditioning is a widely described strategy to attenuate ischaemia-reperfusion injury. We therefore conducted the Volatile Anaesthetic Protection of Renal Transplants-1 trial, a pilot project evaluating the influence of two anaesthetic regimens, propofol- vs sevoflurane-based anaesthesia, on biochemical and clinical outcomes in living donor kidney transplantation., Methods: Sixty couples were randomly assigned to the following three groups: PROP (donor and recipient propofol), SEVO (donor and recipient sevoflurane), and PROSE (donor propofol and recipient sevoflurane). The primary outcome was renal injury reflected by urinary biomarkers. The follow-up period was 2 yr., Results: Three couples were excluded, leaving 57 couples for analysis. Concentrations of kidney injury molecule-1 (KIM-1), N -acetyl-β- d -glucosaminidase (NAG), and heart-type fatty acid binding protein (H-FABP) in the first urine upon reperfusion showed no differences. On day 2, KIM-1 concentrations were higher in SEVO [952.8 (interquartile range 311.8-1893.0) pg mmol -1 ] compared with PROP [301.2 (202.0-504.7) pg mmol -1 ]. This was the same for NAG: SEVO, 1.835 (1.162-2.457) IU mmol -1 vs PROP, 1.078 (0.819-1.713) IU mmol -1 . Concentrations of H-FABP showed no differences. Measured glomerular filtration rate at 3, 6, and 12 months showed no difference. After 2 yr, there was a difference in the acute rejection rate ( P =0.039). Post hoc testing revealed a difference between PROP (35%) and PROSE (5%; P =0.020). The difference between PROP and SEVO (11%) was not significant ( P =0.110)., Conclusions: The SEVO group showed higher urinary KIM-1 and NAG concentrations in living donor kidney transplantation on the second day after transplantation. This was not reflected in inferior graft outcome., Clinical Trial Registration: NCT01248871., (© The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Delayed graft function is a frequent complication following deceased donor renal transplantation, and is closely related to ischemia-reperfusion injury. Experimental and clinical studies have shown protection by remote ischemic conditioning (RIC). We hypothesized that recipient RIC before kidney graft reperfusion reduces the time to graft recovery. This multicenter, blinded, randomized, controlled clinical trial included 225 adult recipients of renal transplants from deceased donors at four transplantation centers in Denmark, Sweden, and the Netherlands. Participants were randomized 1:1 to RIC or sham-RIC. RIC consisted of 4 × 5-min thigh occlusion by an inflatable tourniquet each followed by 5-min deflation, performed during surgery prior to graft reperfusion. The tourniquet remained deflated for sham-RIC. The primary endpoint was the estimated time to a 50% decrease in baseline plasma creatinine (tCr50) calculated from plasma creatinine measurements 30 days posttransplant or 30 days after the last, posttransplant dialysis. No significant differences were observed between RIC and sham-RIC-treated patients in the primary outcome median tCr50 (122 h [95% confidence interval [CI] 98-151] vs. 112 h [95% CI 91-139], p = 0.58), or the number of patients receiving dialysis in the first posttransplant week (33% vs. 35%, p = 0.71). Recipient RIC does not reduce the time to graft recovery in kidney transplantation from deceased donors. ClinicalTrials.gov: NCT01395719., (© 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Introduction: Delayed graft function due to ischaemia-reperfusion injury is a frequent complication in deceased donor renal transplantation. Experimental evidence indicates that remote ischaemic conditioning (RIC) provides systemic protection against ischaemia-reperfusion injury in various tissues., Methods and Analysis: 'Remote ischaemic conditioning in renal transplantation--effect on immediate and extended kidney graft function' (the CONTEXT study) is an investigator initiated, multicentre, randomised controlled trial investigating whether RIC of the leg of the recipient improves short and long-term graft function following deceased donor kidney transplantation. The study will include 200 kidney transplant recipients of organ donation after brain death and 20 kidney transplant recipients of organ donation after circulatory death. Participants are randomised in a 1:1 design to RIC or sham-RIC (control). RIC consists of four cycles of 5 min occlusion of the thigh by a tourniquet inflated to 250 mm Hg, separated by 5 min of deflation. Primary end point is the time to a 50% reduction from the baseline plasma creatinine, estimated from the changes of plasma creatinine values 30 days post-transplant or 30 days after the last performed dialysis post-transplant. Secondary end points are: need of dialysis post-transplant, measured and estimated-glomerular filtration rate (GFR) at 3 and 12 months after transplantation, patient and renal graft survival, number of rejection episodes in the first year, and changes in biomarkers of acute kidney injury and inflammation in plasma, urine and graft tissue., Ethics and Dissemination: The study is approved by the local ethical committees and national data security agencies. Results are expected to be published in 2016., Trial Registration Number: NCT01395719., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Ischemia-reperfusion injury is the leading cause of acute kidney injury in a variety of clinical settings such as renal transplantation and hypovolemic and/or septic shock. Strategies to reduce ischemia-reperfusion injury are obviously clinically relevant. Ischemic conditioning is an inherent part of the renal defense mechanism against ischemia and can be triggered by short periods of intermittent ischemia and reperfusion. Understanding the signaling transduction pathways of renal ischemic conditioning can promote further clinical translation and pharmacological advancements in this era. This review summarizes research on the molecular mechanisms underlying both local and remote ischemic pre-, per- and postconditioning of the kidney. The different types of conditioning strategies in the kidney recruit similar powerful pro-survival mechanisms. Likewise, renal ischemic conditioning mobilizes many of the same protective signaling pathways as in other organs, but differences are recognized., (© 2015 S. Karger AG, Basel.)

Background: ARA290 is a non-erythropoietic EPO derivative which only binds to the cytoprotective receptor complex (EPOR2-βcR2) consisting of two EPO-receptors (EPOR) and two β common receptors (βcR). ARA290 is renoprotective in renal ischemia/reperfusion (I/R). In a renal I/R model we focussed on timing of post-reperfusional administration of ARA290. Furthermore, we investigated the anti-inflammatory properties of ARA290., Methods: Twenty-six male Lewis/HanHsd rats were exposed to unilateral ischemia for 30 minutes, with subsequent removal of the contralateral kidney. Post-reperfusion, ARA290 was administered early (one hour), late (four hours) or repetitive (one and four hours). Saline was used as vehicle treatment. Rats were sacrificed after three days., Results: Early ARA290 treatment improved renal function. Late- or repetitive treatment tended to improve clinical markers. Furthermore, early ARA290 treatment reduced renal inflammation and acute kidney injury at three days post-reperfusion. Late- or repetitive treatment did not affect inflammation or acute kidney injury., Conclusions: ARA290 attenuated renal ischemia/reperfusion injury. This study showed the anti-inflammatory effect of ARA290 and suggests early administration in the post-reperfusional phase is most effective. ARA290 is a candidate drug for protection against ischemic injury following renal transplantation.

Background: In contrast with various pre-clinical studies, recent clinical trials suggest that high dose erythropoietin (EPO) treatment following kidney transplantation does not improve short-term outcome and that it even increases the risk of thrombotic events. ARA290 is a non-erythropoietic EPO derivative and does not increase the risk of cardiovascular events, but potentially has cytoprotective capacities in prevention of renal ischemia/reperfusion injury., Methods: Eight female Dutch Landrace pigs were exposed to unilateral renal ischemia for 45 minutes with simultaneous cannulation of the ureter of the ischemic kidney. ARA290 or saline was administered by an intravenous injection at 0, 2, 4 and 6 hours post-reperfusion. The animals were sacrificed seven days post-reperfusion., Results: ARA290 increased glomerular filtration rate during the observation period of seven days. Furthermore, ARA290 tended to reduce MCP-1 and IL-6 expression 15 minutes post-reperfusion. Seven days post-reperfusion ARA290 reduced interstitial fibrosis., Conclusions: The improvement in renal function following renal ischemia/reperfusion and reduced structural damage observed in this study by ARA290 warrants further investigation towards clinical application.