Molecular Aspects of Volatile Anesthetic-Induced Organ Protection and Its Potential in Kidney Transplantation

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

Ischemia and reperfusion injury in kidney transplantation : relevant mechanisms in injury and repair

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

Pathophysiological Changes in the Hemostatic System and Antithrombotic Management in Kidney Transplant Recipients

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.</p

Renoprotective capacities of non-erythropoietic EPO derivative, ARA290, following renal ischemia/reperfusion injury

BACKGROUND: ARA290 is a non-erythropoietic EPO derivative which only binds to the cytoprotective receptor complex (EPOR(2)-βcR(2)) 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

Remote ischaemic conditioning and early changes in plasma creatinine as markers of one year kidney graft function-A follow-up of the CONTEXT study

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 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

Association between anaesthesia-related factors and postoperative neurocognitive disorder:a post-hoc analysis

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 &lt; 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.</p

Transitions in frailty state after 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

ARA290, a non-erythropoietic EPO derivative, attenuates renal ischemia/reperfusion injury

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

Intraoperative Fluid Restriction is Associated with Functional Delayed Graft Function in Living Donor Kidney Transplantation:A Retrospective Cohort Analysis

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