Normothermic machine perfusion of kidneys: current strategies and future perspectives.

PURPOSE OF REVIEW: This review aims to summarize the latest original preclinical and clinical articles in the setting of normothermic machine perfusion (NMP) of kidney grafts. RECENT FINDINGS: Kidney NMP can be safely translated into the clinical routine and there is increasing evidence that NMP may be beneficial in graft preservation especially in marginal kidney grafts. Due to the near-physiological state during NMP, this technology may be used as an ex-vivo organ assessment and treatment platform. There are reports on the application of mesenchymal stromal/stem cells, multipotent adult progenitor cells and microRNA during kidney NMP, with first data indicating that these therapies indeed lead to a decrease in inflammatory response and kidney injury. Together with the demonstrated possibility of prolonged ex-vivo perfusion without significant graft damage, NMP could not only be used as a tool to perform preimplant graft assessment. Some evidence exists that it truly has the potential to be a platform to treat and repair injured kidney grafts, thereby significantly reducing the number of declined organs. SUMMARY: Kidney NMP is feasible and can potentially increase the donor pool not only by preimplant graft assessment, but also by ex-vivo graft treatment.

Assessment of Mitochondrial Function and Oxygen Consumption Measured During Ex Vivo Normothermic Machine Perfusion of Injured Pig Kidneys Helps to Monitor Organ Viability.

Donor kidney assessment may improve organ utilisation. Normothermic Machine Perfusion (NMP) has the potential to facilitate this advance. The mechanism of action is not yet determined and we aimed to assess mitochondrial function during NMP. Anaesthetised pigs (n = 6) had one kidney clamped for 60 min. The healthy contralateral kidney was removed and underwent NMP for 8 h (healthy control (HC), n = 6). Following 60 min warm ischaemia the injured kidney underwent HMP for 24 h, followed by NMP for 8 h (n = 6). Mitochondria were extracted from fresh tissue for analysis. Injured kidneys were analysed as two separate groups (IMa, n = 3 and IMb, n = 3). Renal resistance was higher (0.39ï, ± 0.29 vs. 1.65ï, ± 0.85; p = 0.01) and flow was lower (55ï, ± 28 vs. 7ï, ± 4; p = 0.03) during HMP in IMb than IMa. NMP blood flow was higher in IMa versus IMb (2-way ANOVA; p < 0.001) After 60 min NMP, O2 consumption was significantly lower in IMb versus IMa (p ≤ 0.002). State-3 respiration was significantly different between the groups (37ï, ± 19 vs. 24ï, ± 14 vs. 10ï, ± 8; nmolO2/min/mg; p = 0.049). Lactate levels were significantly lower in IMa versus IMb (p = 0.028). Mitochondrial respiration levels during NMP may be suggestive of kidney viability. Oxygen consumption, renal blood flow and lactate can differentiate severity of kidney injury during NMP.

Ischemia-Reperfusion Injuries Assessment during Pancreas Preservation.

Maintaining organ viability between donation and transplantation is of critical importance for optimal graft function and survival. To date in pancreas transplantation, static cold storage (SCS) is the most widely practiced method of organ preservation. The first experiments in ex vivo perfusion of the pancreas were performed at the beginning of the 20th century. These perfusions led to organ oedema, hemorrhage, and venous congestion after revascularization. Despite these early hurdles, a number of factors now favor the use of perfusion during preservation: the encouraging results of HMP in kidney transplantation, the development of new perfusion solutions, and the development of organ perfusion machines for the lung, heart, kidneys and liver. This has led to a resurgence of research in machine perfusion for whole organ pancreas preservation. This review highlights the ischemia-reperfusion injuries assessment during ex vivo pancreas perfusion, both for assessment in pre-clinical experimental models as well for future use in the clinic. We evaluated perfusion dynamics, oedema assessment, especially by impedance analysis and MRI, whole organ oxygen consumption, tissue oxygen tension, metabolite concentrations in tissue and perfusate, mitochondrial respiration, cell death, especially by histology, total cell free DNA, caspase activation, and exocrine and endocrine assessment.

Improved Normothermic Machine Perfusion After Short Oxygenated Hypothermic Machine Perfusion of Ischemically Injured Porcine Kidneys.

BACKGROUND: In an era where global kidney shortage has pushed the field of transplantation towards using more marginal donors, modified kidney preservation techniques are currently being reviewed. Some techniques require further optimization before implementation in full scale transplantation studies. Using a porcine donation after circulatory death kidney model, we investigated whether initial kidney hemodynamics improved during normothermic machine perfusion if this was preceded by a short period of oxygenated hypothermic machine perfusion (oxHMP) rather than static cold storage (SCS). METHODS: Kidneys subjected to 75 minutes of warm ischemia were randomly assigned to either SCS (n = 4) or SCS + oxHMP (n = 4), with a total cold storage time of 240 minutes. Cold preservation was followed by 120 minutes of normothermic machine perfusion with continuous measurement of hemodynamic parameters and renal function. RESULTS: oxHMP preserved kidneys maintained significantly lower renal resistance throughout the normothermic machine perfusion period compared to SCS kidneys (P < 0.001), reaching lowest levels at 60 minutes with means of 0.71 ± 0.35 mm Hg/mL/min/100 g (SCS) and 0.45 ± 0.15 mm Hg/mL/min/100 g (oxHMP). Accordingly, the oxHMP group had a higher mean renal blood flow versus SCS kidneys (P < 0.001). oxHMP kidneys had higher oxygen consumption during normothermic machine perfusion compared to SCS preserved kidneys (P < 0.001). Creatinine clearance remained similar between groups (P = 0.665). CONCLUSIONS: Preceding oxHMP significantly improved initial normothermic machine perfusion hemodynamics and increased total oxygen consumption. With the long period of warm ischemia, immediate kidney function was not observed, reflected by the findings of low creatinine clearance in both groups.

Hemodynamics and Metabolic Parameters in Normothermic Kidney Preservation Are Linked With Donor Factors, Perfusate Cells, and Cytokines.

Kidney transplantation is the best renal-replacement option for most patients with end-stage renal disease. Normothermic machine preservation (NMP) of the kidney has been studied extensively during the last two decades and implemented in clinical trials. Biomarker research led to success in identifying molecules with diagnostic, predictive and therapeutic properties in chronic kidney disease. However, perfusate biomarkers and potential predictive mechanisms in NMP have not been identified yet. Twelve discarded human kidneys (n = 7 DBD, n = 5 DCD) underwent NMP for up to 24 h. Eight were perfused applying urine recirculation (URC), four with replacement of urine (UR) using Ringer's lactate. The aim of our study was to investigate biomarkers (NGAL, KIM-1, and L-FABP), cells and cytokines in the perfusate in context with donor characteristics, perfusate hemodynamics and metabolic parameters. Cold ischemia time did not correlate with any of the markers. Perfusates of DBD kidneys had a significantly lower number of leukocytes after 6 h of NMP compared to DCD. Arterial flow, pH, NGAL and L-FABP correlated with donor creatinine and eGFR. Arterial flow was higher in kidneys with lower perfusate lactate. Perfusate TNF-α was higher in kidneys with lower arterial flow. The cytokines IL-1ß and GM-CSF decreased during 6 h of NMP. Kidneys with more urine output had lower perfusate KIM-1 levels. Median and 6-h values of lactate, arterial flow, pH, NGAL, KIM-1, and L-FABP correlated with each other indicating a 6-h period being applicable for kidney viability assessment. The study results demonstrate a comparable cytokine and cell profile in perfusates with URC and UR. In conclusion, clinically available perfusate and hemodynamic parameters correlate well with donor characteristics and measured biomarkers in a discarded human NMP model.

Ex vivo delivery of Mirococept: A dose-finding study in pig kidney after showing a low dose is insufficient to reduce delayed graft function in human kidney.

The complement system plays a pivotal role in the pathogenesis of ischemia-reperfusion injury in solid organ transplantation. Mirococept is a potent membrane-localizing complement inhibitor that can be administered ex vivo to the donor kidney prior to transplantation. To evaluate the efficacy of Mirococept in reducing delayed graft function (DGF) in deceased donor renal transplantation, we undertook the efficacy of mirococept (APT070) for preventing ischaemia-reperfusion injury in the kidney allograft (EMPIRIKAL) trial (ISRCTN49958194). A dose range of 5-25 mg would be tested, starting with 10 mg in cohort 1. No significant difference between Mirococept at 10 mg and control was detected; hence the study was stopped to enable a further dose saturation study in a porcine kidney model. The optimal dose of Mirococept in pig kidney was 80 mg. This dose did not induce any additional histological damage compared to controls or after a subsequent 3 hours of normothermic machine perfusion. The amount of unbound Mirococept postperfusion was found to be within the systemic dose range considered safe in the Phase I trial. The ex vivo administration of Mirococept is a safe and feasible approach to treat DGF in deceased donor kidney transplantation. The porcine kidney study identified an optimal dose of 80 mg (equivalent to 120 mg in human kidney) that provides a basis for further clinical development.

Urinary Biomarkers for Diagnosis and Prediction of Acute Kidney Allograft Rejection: A Systematic Review.

Noninvasive tools for diagnosis or prediction of acute kidney allograft rejection have been extensively investigated in recent years. Biochemical and molecular analyses of blood and urine provide a liquid biopsy that could offer new possibilities for rejection prevention, monitoring, and therefore, treatment. Nevertheless, these tools are not yet available for routine use in clinical practice. In this systematic review, MEDLINE was searched for articles assessing urinary biomarkers for diagnosis or prediction of kidney allograft acute rejection published in the last five years (from January 1, 2015 to May 31, 2020). This review follows the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Articles providing targeted or unbiased urine sample analysis for the diagnosis or prediction of both acute cellular and antibody-mediated kidney allograft rejection were included, analyzed, and graded for methodological quality with a particular focus on study design and diagnostic test accuracy measures. Urinary C-X-C motif chemokine ligands were the most promising and frequently studied biomarkers. The combination of precise diagnostic reference in training sets with accurate validation in real-life cohorts provided the most relevant results and exciting groundwork for future studies.

Urine Recirculation Improves Hemodynamics and Enhances Function in Normothermic Kidney Perfusion.

The study compares urine recirculation (URC) to urine replacement (UR) with Ringer's lactate in a porcine normothermic kidney machine perfusion (NMP) model using a preclinical prototype device. METHODS: Kidney pairs were recovered uninjured (as live-donor nephrectomy) and perfused consecutively. Pig kidneys (n = 10) were allocated to either NMP with URC (n = 5) or NMP with volume replacement (n = 5). Cold ischemia time was either 2 or 27 hours for the first or second perfusion (URC or UR) of a kidney pair. An autologous blood-based perfusate, leukocyte-filtered, was used and NMP performed up to 24 hours. Perfusion parameters, biochemistry/metabolic parameters were monitored and samples collected. RESULTS: Physiological mean arterial pressures and flows were achieved in both groups but were sustainable only with URC. Significantly higher arterial flow was observed with URC (326.7 ± 1.8 versus 242.5 ± 14.3 mL/min, P = 0.001). Perfusate sodium levels were lower with URC, 129.6 ± 0.7 versus 170.3±2.7 mmol/L, P < 0.001). Stable physiological pH levels were only observed with URC. Perfusate lactate levels were lower with URC (2.2 ± 0.1 versus 7.2 ± 0.5 mmol/L, P < 0.001). Furthermore, the hourly rate of urine output was lower with URC and closer to physiological levels (150 versus 548 mL/h, P = 0.008). Normothermic kidney perfusion with URC was associated with longer achievable durations of perfusion: the objective in all experiments was a 24-hour perfusion, but this was not achieved in every case. The mean perfusions were 17.3 ± 9.2 hours with URC versus 5.3 ± 1.3 hours NMP with UR; P = 0.02. There appeared to be no differences in baseline tubular condition with and without URC. CONCLUSIONS: URC facilitates long-term kidney NMP in a porcine model. Perfusate homeostasis and stability of renal arterial flow throughout the perfusion period was only achievable with URC, independent of cold ischemia time duration.

A systematic review to identify whether perfusate biomarkers produced during hypothermic machine perfusion can predict graft outcomes in kidney transplantation.

There is good evidence to support the use of hypothermic machine perfusion (HMP) over static cold storage as the favoured preservation method for deceased donor kidneys. However, the utility of HMP as a tool to assess the viability of kidneys for transplant is unclear. There is a need to determine whether perfusate biomarkers produced during HMP can predict post-transplant outcomes and assess the suitability of organs for transplantation. Three different databases (MEDLINE, Embase, Transplant Library) were screened to 31 May 2019. Articles were included if a relationship was reported between one or more perfusate biomarkers and post-transplant outcomes. Studies were assessed and graded for methodological quality and strength of evidence. Glutathione S-transferase was the most promising biomarker for predicting delayed graft function, but its predictive ability was at best moderate. Analysis of primary nonfunction rates was challenging due to low occurrence rates and small sample sizes. Existing studies are limited in quality and have not yielded biomarkers for kidneys undergoing HMP that are able to predict post-transplant outcomes with sufficient accuracy to support routine clinical use. Further studies with larger samples and more robust methodology are needed. (PROSPERO registration: CRD42019121161).

The United Kingdom and Ireland experience of the Haemodialysis Reliable Outflow graft for vascular access.

OBJECTIVES:: To describe the UK and Ireland experience of the Haemodialysis Reliable Outflow graft in complex vascular access. DESIGN:: Observational, multi-centre case series. METHODS:: Data from any patient undergoing Haemodialysis Reliable Outflow graft were collected from eight UK and one Irish centre. Any Haemodialysis Reliable Outflow procedure between July 2013 and May 2016 was included. Demographics, primary and secondary patency rates, and complications were analysed. RESULTS:: A total of 52 patients underwent Haemodialysis Reliable Outflow graft insertion. Median age was 55 (20-86) years, 24 (46%) were male and 66% were Caucasian. Median follow-up was 290 (10-966) days and patient survival was 41/52 (79%). In total, 48 procedures were in the upper limb with 39 using the brachial artery as inflow (75%). The internal jugular vein and subclavian vein were most frequently used as access for outflow insertion. Primary patency rates at 6, 12, and 24 months were 51.2% (95% confidence interval, 38.8%-67.4%), 40.9% (95% confidence interval, 28.7%-58.2%), and 33.4% (95% confidence interval, 21.3%-52.5%), respectively. Secondary patency rates at 6, 12, and 24 months were 84.8% (95% confidence interval, 75%-95.9%), 76.5% (95% confidence interval, 64.5%-90.6%), and 70.6% (95% confidence interval, 56%-88.9%), respectively. There were 65 surgical and 49 radiological interventions resulting in 2.30 interventions per year to retain patency. Complications included four infections and two episodes of steal syndrome. CONCLUSION:: The Haemodialysis Reliable Outflow graft provides acceptable 12-month secondary patency rates and acceptable complication rates in a UK and Ireland multi-centre series of complex access patients. Haemodialysis Reliable Outflow should be considered in patients with central pathology as a potential alternative to lower limb grafts and long-term central venous catheters.

Twenty-four-hour normothermic perfusion of discarded human kidneys with urine recirculation.

Transportable normothermic kidney perfusion for 24 hours or longer could enable viability assessment of marginal grafts, increased organ use, and improved transplant logistics. Eleven clinically declined kidneys were perfused normothermically, with 6 being from donors after brain death (median cold ischemia time 33 ± 36.9 hours) and 5 being from donors after circulatory death (36.2 ± 38.3 hours). Three kidneys were perfused using Ringer's lactate to replace excreted urine volume, and 8 kidneys were perfused using urine recirculation to maintain perfusate volume without fluid replenishment. In all cases, normothermic perfusion either maintained or slightly improved the histopathologically assessed tubular condition, and there was effective urine production in kidneys from both donors after brain death and donors after circulatory death (2367 ± 1798 mL vs 744.4 ± 198.4 mL, respectively; P = .44). Biomarkers, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 were successfully detected and quantified in the perfusate. All kidneys with urine recirculation were readily perfused for 24 hours (n = 8) and exhibited physiological perfusate sodium levels (140.7 ± 1.2 mmol/L), while kidneys without urine recirculation (n = 3) achieved a reduced normothermic perfusion time of 7.7 ± 1.5 hours and significantly higher perfusate sodium levels (159.6 ± 4.63 mmol/:, P < .01). Normothermic machine perfusion of human kidneys for 24 hours appears to be feasible, and urine recirculation was found to facilitate the maintenance of perfusate volume and homeostasis.

Development of a Clinical Decision Support System for Living Kidney Donor Assessment Based on National Guidelines.

BACKGROUND: Live donor nephrectomy is an operation that places the donor at risk of complications without the possibility of medical benefit. Rigorous donor selection and assessment is therefore essential to ensure minimization of risk and for this reason robust national guidelines exist. Previous studies have demonstrated poor adherence to donor guidelines. METHODS: We developed a clinical decision support system (CDSS), based on national living donor guidelines, to facilitate the identification of contraindications, additional investigations, special considerations, and the decision as to nephrectomy side in potential living donors. The CDSS was then tested with patient data from 45 potential kidney donors. RESULTS: The CDSS comprises 17 core tasks completed by either patient or nurse, and 17 optional tasks that are triggered by certain patient demographics or conditions. Decision rules were able to identify contraindications, additional investigations, special considerations, and predicted operation side in our patient cohort. Seventeen of 45 patients went on to donate a kidney, of whom 7 had major contraindications defined in the national guidelines, many of which were not identified by the clinical team. Only 43% of additional investigations recommended by national guidelines were completed, with the most frequently missed investigations being oral glucose tolerance testing and routine cancer screening. CONCLUSIONS: We have demonstrated the feasibility of turning a complex set of national guidelines into an easy-to-use machine-readable CDSS. Comparison with real-world decisions suggests that use of this CDSS may improve compliance with guidelines and informed consent tailored to individual patient risks.

A Double Blind Randomized Clinical Trial of Remote Ischemic Conditioning in Live Donor Renal Transplantation.

Ischemic conditioning involves the delivery of short cycles of reversible ischemic injury in order to induce protection against subsequent more prolonged ischemia. This randomized controlled trial was designed to determine the safety and efficacy of remote ischemic conditioning (RC) in live donor kidney transplantation.This prospective randomized clinical trial, 80 patients undergoing live donor kidney transplantation were randomly assigned in a 1:1 ratio to either RC or to a control group. RC consisted of cycles of lower limb ischemia induced by an arterial tourniquet cuff placed around the patient's thigh. In the RC treatment group, the cuff was inflated to 200 mm Hg or systolic pressure +25 mm Hg for 4 cycles of 5 min ischemia followed by 5 min reperfusion. In the control group, the blood pressure cuff was inflated to 25 mm Hg. Patients and medical staff were blinded to treatment allocation. The primary end-point was renal function measured by estimated glomerular filtration rate (eGFR) at 1 and 3 months posttransplant.Donor and recipient demographics were similar in both groups (P < 0.05). There were no significant differences in eGFR at 1 month (control 52 ±â€Š14 vs RC 54 ±â€Š17 mL/min; P = 0.686) or 3 months (control 50 ±â€Š14 vs RC 49 ±â€Š18 mL/min; P = 0.678) between the control and RC treatment groups. The RC technique did not cause any serious adverse effects.RC, using the protocol described here, did not improve renal function after live donor kidney transplantation.

Hydrogen sulfide reduces inflammation following abdominal aortic occlusion in rats.

BACKGROUND: Remote renal ischemia-reperfusion injury (IRI) following infra-renal aortic occlusion leads to acute kidney injury and systemic inflammation. Hydrogen sulfide is a mediator of IRI and can ameliorate tissue injury in many organ systems. Its role in vascular surgery has yet to be established. We assessed the role of hydrogen sulfide in a rodent model of aortic occlusion. METHODS: Wistar rats were divided into sham, control, and treatment groups (n = 6). Inflammation was assessed using a nonrecovery protocol. The infra-renal aorta was cross-clamped for 60 min and animals were reperfused for 120 min. Ten minutes before clamp release, treatment animals received hydrogen sulfide (10, 30, or 50 µg/kg) and control animals received 0.9% saline injected into the retroperitoneum. Renal injury and histology were assessed by a recovery protocol. The procedure was identical to the nonrecovery arm but with a single dose of hydrogen sulfide (30 µg/kg) and animals were recovered for 7 days. RESULTS: There was no difference in animal weight between the groups (P = 0.337). In the nonrecovery arm, there was a reduction in serum levels of tumor necrosis factor alpha in sulfide-treated animals compared with controls (909 ± 98 vs. 607 ± 159 pg/mL; P = 0.0038). There was also a reduction in myeloperoxidase-positive cells in renal tissue in the sulfide-treated animals compared with controls (8 ± 4 vs. 17 ± 9; P = 0.03). There was no difference in histological injury score or endothelin-1 levels. In the recovery arm, there was no difference in renal function, Kidney Injury Molecule-1 levels, or histological injury scores. CONCLUSION: Hydrogen sulfide has systemic and renal anti-inflammatory effects in remote IRI following aortic occlusion in rats.

In meta-analyses of proportion studies, funnel plots were found to be an inaccurate method of assessing publication bias.

OBJECTIVE: To assess the utility of funnel plots in assessing publication bias (PB) in meta-analyses of proportion studies. STUDY DESIGN AND SETTING: Meta-analysis simulation study and meta-analysis of published literature reporting peri-operative mortality after abdominal aortic aneurysm (AAA) repair. Data for the simulation study were stochastically generated. A literature search of Medline and Embase was performed to identify studies for inclusion in the published literature meta-analyses. RESULTS: The simulation study demonstrated that conventionally constructed funnel plots (log odds vs. 1/standard error [1/SE]) for extreme proportional outcomes were asymmetric despite no PB. Alternative funnel plots constructed using study size rather than 1/SE showed no asymmetry for extreme proportional outcomes. When used in meta-analyses of the mortality of AAA repair, these alternative funnel plots highlighted the possibility for conventional funnel plots to demonstrate asymmetry when there was no evidence of PB. CONCLUSION: Conventional funnel plots used to assess for potential PB in meta-analyses are inaccurate for meta-analyses of proportion studies with low proportion outcomes. Funnel plots of study size against log odds may be a more accurate way of assessing for PB in these studies.

Suprarenal graft fixation in endovascular abdominal aortic aneurysm repair is associated with a decrease in renal function.

INTRODUCTION: Suprarenal endograft fixation is routinely used in the endovascular repair of abdominal aortic aneurysms (EVAR) to enhance proximal endograft attachment but can be associated with an adverse outcome in renal function. This prospective study assessed the effect of suprarenal fixation on serum creatinine concentration and estimated glomerular filtration rate (eGFR), calculated by the Modified Diet in Renal Disease equation, 12 months after elective EVAR. METHODS: Patients undergoing elective EVAR were divided into suprarenal vs infrarenal fixation groups matched for age, sex, smoking, and aneurysm diameter. Serum creatinine and eGFR were measured at baseline, 6, and 12 months. RESULTS: Included were 92 patients (two women) with a mean age of 71 ± 7 years, with 46 in each group. No device-related complications were noted. Serum creatinine did not differ significantly between groups at 6 (P = .24) or 12 (P = .08) months but significantly increased in the suprarenal group at 12 months (1.08 ± 0.36 to 1.16 ± 0.36 mg/dL; P < .001) vs baseline. The eGFR (mL/min/1.73 m(2)) did not differ significantly at baseline between the suprarenal (85 ± 27) and infrarenal (80 ± 28; P = .33) groups or at 6 months (88 ± 29 vs 77 ± 24, respectively; P = .07). At 12 months, the suprarenal group had a lower eGFR (73 ± 23) than the infrarenal group (84 ± 26; P = .027). The eGFR at 12 months showed a significant decrease in the suprarenal (80 ± 28 to 73 ± 23; P < .001) but not in the infrarenal group (85 ± 27 to 84 ± 26; P = .48). The drop in eGFR differed significantly at 12 months in the infrarenal vs the suprarenal (0.82 vs -6.94; P < .001) group. No patient progressed to end-stage renal disease or disclosed a drop in eGFR > 30%. CONCLUSIONS: In contrast to previous studies, this study suggests that suprarenal endograft fixation in elective EVAR is associated with a drop in eGFR at 12 months.

Anemia is associated with mortality following endovascular repair of abdominal aortic aneurysm.

AIM: The aim of this study was to compare midterm mortality between anemic and nonanemic patients undergoing endovascular repair of abdominal aortic aneurysm and to assess a correlation with markers of inflammation. METHODS: Anemia was defined as hemoglobin <13 (men) and <12 g/dL (women). The impact of anemia and inflammatory markers on mortality was assessed using Kaplan-Meier curves and Cox regression. RESULTS: A total of 224 patients (12 females [5.36%]; age: 69.73 ± 8.72 years) were included; 102 (45.53%) were anemic. Median follow-up was 17 months (interquartile range: 7-25 months). Nine patients died (1.79%; 8 anemic vs 1 nonanemic). Survival was lower for patients with anemia (log-rank, P = .01). White blood cell count and C-reactive protein (CRP) differed significantly (P < .001 and P = .01). Anemia and CRP were associated with decreased survival (Cox regression, P = .01, hazard ratio [HR]: 0.35, 95% confidence interval: 0.14-0.84 and P = .002, HR: 1.18, 95% CI: 1.06-1.31). CONCLUSION: Patients with anemia had decreased survival over the midterm; inflammatory markers were higher among this group.

Early urinary biomarkers of warm and cold ischemic injury in an experimental kidney model.

BACKGROUND: Early urinary biomarkers may be useful in determining the severity of ischemic injury in donation after circulatory death (DCD) kidneys. The aim of this study was to evaluate the efficacy of a collective series of urinary biomarkers in relation to the warm and cold ischemic intervals. METHODS: Porcine kidneys were retrieved after 0, 10, and 25 min of warm ischemia (WI), then preserved by static cold storage (CS) for period of 2 and 18 h. After preservation, kidneys were reperfused on an isolated organ perfusion system to assess renal function and injury. Levels of IL-6, TNFα, endothelin-1 (ET-1), and neutrophil gelatinase-associated lipocalin (NGAL) were measured in urine samples after 3 h of reperfusion. RESULTS: There was no significant difference in renal functional parameters or urinary biomarkers between the WI times when kidneys were stored for 2 h (P > 0.05). After 18 h CS, kidneys with 10 and 25 min of WI demonstrated a significant decline in renal function compared with kidneys without WI (P < 0.05). Levels of ET-1 and NGAL were significantly higher in kidneys with 25 min WI (25 m ET-1, 30.1 ± 21.2, versus 0 m 2.25 ± 1.5 pg/mL; P = 0.002: NGAL, 25 m 77 ± 51 versus 0 m 10 ± 0.1 pg/mL; P = 0.005). Levels of IL-6 and TNFα were significantly higher in kidneys with 10 and 25 min of WI (P = 0.001, 0.001). CONCLUSION: Early urinary biomarkers are a useful means to determine graft injury. ET-1 and NGAL are more accurate in predicting the severity of ischemic injury compared with inflammatory markers.