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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.

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.

This study aimed to review the effects of performance enhancing drugs (PEDs), such as anabolic steroids, on clinical outcomes in critically ill patients. A systematic review and meta-analysis of randomized controlled trials comparing any of the known PEDs with placebo during intensive-care unit (ICU) admission was performed, excluding erythropoietin stimulating agents. Data were pooled using a random-effects model, while outcomes from non-eligible studies for meta-analysis were reported separately. Risk of bias was assessed through the cochrane risk of bias (ROB) 2 tool. Twenty-three studies were included. Only studies using growth hormone, nandrolone, and oxandrolone were found. Growth hormone improved nitrogen balance (standardized mean difference = 1.4 g, 95% confidence interval 0.47–2.32). While mortality was unaffected, it caused increased ICU and hospital stay. A substantial heterogeneity and a concerning risk of bias were present among the studies. PEDs showed no survival benefit but may improve nitrogen balance. A possible subgroup that could benefit from growth hormone or anabolic steroids are critically ill patients who have surpassed the acute inflammatory phase of critical illness. Further research into various aspects of PEDs is needed within the context of current clinical practices.

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). 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. 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. 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. www.ClinicalTrials.gov Identifier: NCT01395719.

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.

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. 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). 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. 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. ClinicalTrials.gov NCT01395719.

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.

[This corrects the article DOI: 10.1371/journal.pone.0212676.].

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.