Remote ischemic conditioning may improve graft function following kidney transplantation: a systematic review and meta-analysis with trial sequential analysis.

BACKGROUND: Remote ischemic conditioning (RIC) has the potential to benefit graft function following kidney transplantation by reducing ischemia-reperfusion injury; however, the current clinical evidence is inconclusive. This meta-analysis with trial sequential analysis (TSA) aimed to determine whether RIC improves graft function after kidney transplantation. METHODS: A comprehensive search was conducted on PubMed, Cochrane Library, and EMBASE databases until June 20, 2023, to identify all randomized controlled trials that examined the impact of RIC on graft function after kidney transplantation. The primary outcome was the incidence of delayed graft function (DGF) post-kidney transplantation. The secondary outcomes included the incidence of acute rejection, graft loss, 3- and 12-month estimated glomerular filtration rates (eGFR), and the length of hospital stay. Subgroup analyses were conducted based on RIC procedures (preconditioning, perconditioning, or postconditioning), implementation sites (upper or lower extremity), and graft source (living or deceased donor). RESULTS: Our meta-analysis included eight trials involving 1038 patients. Compared with the control, RIC did not significantly reduce the incidence of DGF (8.8% vs. 15.3%; risk ratio = 0.76, 95% confidence interval [CI], 0.48-1.21, P = 0.25, I2 = 16%), and TSA results showed that the required information size was not reached. However, the RIC group had a significantly increased eGFR at 3 months after transplantation (mean difference = 2.74 ml/min/1.73 m2, 95% CI: 1.44-4.05 ml/min/1.73 m2, P < 0.0001, I2 = 0%), with a sufficient evidence suggested by TSA. The secondary outcomes were comparable between the other secondary outcomes. The treatment effect of RIC did not differ between the subgroup analyses. CONCLUSION: In this meta-analysis with trial sequential analysis, RIC did not lead to a significant reduction in the incidence of DGF after kidney transplantation. Nonetheless, RIC demonstrated a positive correlation with 3-month eGFR. Given the limited number of patients included in this study, well-designed clinical trials with large sample sizes are required to validate the renoprotective benefits of RIC. TRIAL REGISTRATION: This systematic review and meta-analysis was registered at the International Prospective Register of Systematic Reviews (Number CRD42023464447).

Prospective assessment of the impact of intraoperative diuretics in kidney transplant recipient surgery.

BACKGROUND: The use of intraoperative diuretics, such as furosemide or mannitol, during kidney transplantation has been suggested to reduce the rate of delayed graft function (DGF). The evidence base for this is sparse, however, and there is substantial variation in practice. We sought to evaluate whether the use of intraoperative diuretics during kidney transplantation translated into a reduction in DGF. METHODS: We conducted a cohort study evaluating the use of furosemide or mannitol given intraoperatively before kidney reperfusion compared with control (no diuretic). Adult patients receiving a kidney transplant for end-stage renal disease were allocated to receive furosemide, mannitol, or no diuretic. The primary outcome was DGF; secondary outcomes were graft function at 30 days and perioperative changes in potassium levels. Descriptive and comparative statistics were used where appropriate. RESULTS: A total of 162 patients who received a kidney transplant from a deceased donor (either donation after neurologic determination of death or donation after circulatory death) were included over a 2-year period, with no significant between-group differences. There was no significant difference in DGF rates between the furosemide, mannitol, and control groups. When the furosemide and mannitol groups were pooled (any diuretic use) and compared with the control group, however, there was a significant improvement in the odds that patients would be free of DGF (odds ratio 2.10, 95% confidence interval 1.06-4.16, 26% v. 44%, p = 0.03). There were no significant differences noted in any secondary outcomes. CONCLUSION: This study suggests the use of an intraoperative diuretic (furosemide or mannitol) may result in a reduction in DGF in patients undergoing kidney transplantation. Further study in the form of a randomized controlled trial is warranted.

Ex vivo kidney machine perfusion: meta-analysis of randomized clinical trials.

BACKGROUND: Machine perfusion is an organ preservation strategy used to improve function over simple storage in a cold environment. This article presents an updated systematic review and meta-analysis of machine perfusion in deceased donor kidneys. METHODS: RCTs from November 2018 to July 2023 comparing machine perfusion versus static cold storage in kidney transplantation were evaluated for systematic review. The primary outcome in meta-analysis was delayed graft function. RESULTS: A total 19 studies were included, and 16 comparing hypothermic machine perfusion with static cold storage were analysed. The risk of delayed graft function was lower with hypothermic machine perfusion (risk ratio (RR) 0.77, 95% c.i. 0.69 to 0.86), even in kidneys after circulatory death (RR 0.78, 0.68 to 0.90) or brain death (RR 0.73, 0.63 to 0.84). Full hypothermic machine perfusion decreased the risk of delayed graft function (RR 0.69, 0.60 to 0.79), whereas partial hypothermic machine perfusion did not (RR 0.92, 0.69 to 1.22). Normothermic machine perfusion or short-term oxygenated hypothermic machine perfusion preservation after static cold storage was equivalent to static cold storage in terms of delayed graft function and 1-year graft survival. CONCLUSION: Hypothermic machine perfusion reduces delayed graft function risks and normothermic approaches show promise.

The effect of goal-directed fluid therapy on delayed graft function in kidney transplant recipients: A systematic review and meta-analysis.

Delayed graft function (DGF) is a common post-operative complication with potential long-term sequelae for many kidney transplant recipients, and hemodynamic factors and fluid status play a role. Fixed perioperative fluid infusions are the standard of care, but more recent evidence in the non-transplant population has suggested benefit with goal-directed fluid strategies based on hemodynamic targets. We searched MEDLINE, EMBASE, Cochrane Controlled Trials Registry and Google Scholar through December 2022 for randomized controlled trials comparing risk of DGF between goal-directed and conventional fluid therapy in adults receiving a living or deceased donor kidney transplant. Effect estimates were reported with odds ratios (OR) and pooled using random effects meta-analysis. We identified 4 studies (205 participants) that met the inclusion criteria. The use of goal-directed fluid therapy had no significant effect on DGF (OR 1.37 95% CI, 0.34-5.6; p = 0.52; I2 = 0.11). Subgroup analysis examining effects among deceased and living kidney donation did not reveal significant differences in the effects of fluid strategy on DGF between subgroups. Overall, the strength of the evidence for goal-directed versus conventional fluid therapy to reduce DGF was of low certainty. Our findings highlight the need for larger trials to determine the effect of goal-directed fluid therapy on this patient-centered outcome.

[Delayed graft function : an ongoing clinical challenge]. / Reprise retardée de fonction du greffon après transplantation rénale : un challenge clinique toujours d'actualité.

Delayed Graft Function (DGF) is defined as the need for dialysis during the first week after transplantation. DGF is frequent and mostly derived from the ischemia/reperfusion cascade to which the graft is subjected throughout the transplantation process. A graft biopsy is recommended after 7 days of DGF to exclude an episode of acute rejection. Note that DGF per se is associated with an increased risk of acute graft rejection, as well as with a shorter long-term graft survival. Several strategies are being studied to mitigate the ischaemic damage, thereby improving graft quality. Among these, cellular therapy using mesenchymal stromal cells (MSC) is promising, in particular via the administration of MSC in the machine perfusion during the preservation of the graft. We will discuss here the different definitions of DGF and the main predictive factors of DGF, as well as the impact on the graft outcomes. The current strategies to prevent DGF will be briefly reviewed.

La reprise retardée de fonction du greffon rénal (DGF en anglais pour Delayed Graft Function), définie notamment par la nécessité de dialyse durant la 1ère semaine après transplantation, reste un événement fréquent. La DGF résulte principalement des phénomènes d'ischémie/reperfusion auxquels le greffon est soumis tout au long du processus de transplantation. Néanmoins, une biopsie du greffon est préconisée après 7 jours de DGF afin d'exclure une cause non ischémique telle qu'un rejet aigu. La DGF est per se associée à un risque accru de rejet du greffon, ainsi qu'à une moins bonne survie du greffon rénal au long cours. Plusieurs stratégies sont étudiées afin d'atténuer les dommages ischémiques et améliorer la qualité du greffon. Parmi celles-ci, la thérapie cellulaire par cellules stromales mésenchymateuses est prometteuse, notamment via l'administration de celles-ci dans la machine de perfusion lors de la préservation du greffon. Nous aborderons les différentes définitions de la DGF ainsi que ses principaux facteurs prédictifs, l'impact sur le devenir du greffon et, brièvement, les stratégies actuelles dans le cadre de la prévention de la DGF.

Hypothermia or Machine Perfusion in Kidney Donors.

BACKGROUND: Therapeutic hypothermia in brain-dead organ donors has been shown to reduce delayed graft function in kidney recipients after transplantation. Data are needed on the effect of hypothermia as compared with machine perfusion on outcomes after kidney transplantation. METHODS: At six organ-procurement facilities in the United States, we randomly assigned brain-dead kidney donors to undergo therapeutic hypothermia (hypothermia group), ex situ kidney hypothermic machine perfusion (machine-perfusion group), or both (combination-therapy group). The primary outcome was delayed graft function in the kidney transplant recipients (defined as the initiation of dialysis during the first 7 days after transplantation). We also evaluated whether hypothermia alone was noninferior to machine perfusion alone and whether the combination of both methods was superior to each of the individual therapies. Secondary outcomes included graft survival at 1 year after transplantation. RESULTS: From 725 enrolled donors, 1349 kidneys were transplanted: 359 kidneys in the hypothermia group, 511 in the machine-perfusion group, and 479 in the combined-therapy group. Delayed graft function occurred in 109 patients (30%) in the hypothermia group, in 99 patients (19%) in the machine-perfusion group, and in 103 patients (22%) in the combination-therapy group. Adjusted risk ratios for delayed graft function were 1.72 (95% confidence interval [CI], 1.35 to 2.17) for hypothermia as compared with machine perfusion, 1.57 (95% CI, 1.26 to 1.96) for hypothermia as compared with combination therapy, and 1.09 (95% CI, 0.85 to 1.40) for combination therapy as compared with machine perfusion. At 1 year, the frequency of graft survival was similar in the three groups. A total of 10 adverse events were reported, including cardiovascular instability in 9 donors and organ loss in 1 donor owing to perfusion malfunction. CONCLUSIONS: Among brain-dead organ donors, therapeutic hypothermia was inferior to machine perfusion of the kidney in reducing delayed graft function after transplantation. The combination of hypothermia and machine perfusion did not provide additional protection. (Funded by Arnold Ventures; ClinicalTrials.gov number, NCT02525510.).

Delayed graft function: current status and future directions.

PURPOSE OF REVIEW: Delayed graft function is a common early posttransplant event predictive of adverse outcomes including hospital readmission, impaired long-term graft function, and decreased graft and patient survival. The purpose of this review is to summarize recent literature describing delayed graft function in hopes of better understanding and managing this condition. RECENT FINDINGS: Recent research efforts have been garnered towards risk factor modification, prevention, and earlier detection of delayed graft function. In this review, we aim to summarize current innovative approaches and future directions. SUMMARY: Delayed graft function portends worse graft and patient outcomes. Continued research to prevent, and detect early perturbations in allograft function, and more optimally manage this disease will hopefully improve graft function, along with graft/patient survival.

Effects of Plasma-Lyte® and 0. 9% saline in renal function after deceased-donor kidney transplant: a randomized controlled trial

Abstract Background The influence of different crystalloid solutions infused during deceased-donor kidney transplant on the incidence of delayed graft function remains unclear. We investigated the influence of Plasma-Lyte® vs. 0.9% saline on the incidence of delayed graft function in deceased-donor kidney transplant recipients. Methods We conducted a single-blind randomized controlled trial of 104 patients aged 18 to 65 years who underwent deceased-donor kidney transplant under general anesthesia. Patients were randomly assigned to receive either Plasma-Lyte® (n = 52) or 0.9% saline (n = 52), at the same infusion volume, for intraoperative fluid replacement. The primary outcome was the occurrence of delayed graft function. Secondary outcomes included metabolic and electrolytic changes at the end of surgery. Results Two patients in the Plasma-Lyte® group and one in the 0.9% saline group died postoperatively and were not included for analysis. The incidence of delayed graft function in Plasma-Lyte® and 0.9% saline groups were 60.0% (95% Confidence Interval [95% CI 46.2-72.4]) and 74.5% (95% CI 61.1-84.4), respectively (p= 0.140). Mean (standard deviation) values of immediate postoperative pH and serum chloride levels in Plasma-Lyte® and 0.9% saline groups were 7.306 (0.071) and 7.273 (0.061) (p= 0.013), and 99.6 (4.2) mEq.L-1 and 103.3 (5.6) mEq.L-1, respectively (p< 0.001). All other postoperative metabolic and electrolyte variables were not statistically different at the immediate postoperative period (p> 0.05). Conclusion In deceased-donor kidney transplant recipients, the incidence of delayed graft function is not influenced by Plasma-Lyte® or 0.9% saline used for intraoperative fluid replacement.

Effect of Perioperative Dexmedetomidine on Delayed Graft Function Following a Donation-After-Cardiac-Death Kidney Transplant: A Randomized Clinical Trial.

Importance: Delayed graft function (DGF) is a risk factor for acute rejection and graft failure after kidney transplant. Previous studies have suggested that dexmedetomidine may be renoprotective, but whether the use of dexmedetomidine would improve kidney allograft function is unknown. Objective: To investigate the effects of perioperative dexmedetomidine on DGF following a donation-after-cardiac-death (DCD) kidney transplant. Design, Setting, and Participants: This single-center, double-blind, placebo-controlled randomized clinical trial was conducted at The First Affiliated Hospital of Soochow University in Suzhou, China. Adults (18 years or older) who were scheduled for DCD kidney transplant were enrolled between September 1, 2019, and January 28, 2021, and then randomized to receive either dexmedetomidine or normal saline (placebo). One-year postoperative outcomes were recorded. All analyses were based on the modified intention-to-treat population. Interventions: Patients who were randomized to the dexmedetomidine group received a 24-hour perioperative dexmedetomidine intravenous infusion (0.4 µg/kg/h intraoperatively and 0.1 µg/kg/h postoperatively). Patients who were randomized to the normal saline group received an intravenous infusion of the placebo with the same dose regimen as the dexmedetomidine. Main Outcomes and Measures: The primary outcome was the incidence of DGF, defined as the need for dialysis in the first posttransplant week. The prespecified secondary outcomes were in-hospital repeated dialysis in the first posttransplant week, in-hospital acute rejection, and serum creatinine, serum cystatin C, estimated glomerular filtration rate, need for dialysis, and patient survival on posttransplant day 30. Results: Of the 114 patients enrolled, 111 completed the study (mean [SD] age, 43.4 [10.8] years; 64 male patients [57.7%]), of whom 56 were randomized to the dexmedetomidine group and 55 to the normal saline group. Dexmedetomidine infusion compared with normal saline reduced the incidence of DGF (17.9% vs 34.5%; odds ratio [OR], 0.41; 95% CI, 0.17-0.98; P = .04) and repeated dialysis (12.5% vs 30.9%; OR, 0.32; 95% CI, 0.13-0.88; P = .02, which was not statistically significant after multiple testing corrections), without significant effect on other secondary outcomes. Dexmedetomidine vs normal saline infusion led to a higher median (IQR) creatinine clearance rate on postoperative days 1 (9.9 [4.9-21.2] mL/min vs 7.9 [2.0-10.4] mL/min) and 2 (29.6 [9.7-67.4] mL/min vs 14.6 [3.8-45.1] mL/min) as well as increased median (IQR) urine output on postoperative days 2 (106.5 [66.3-175.6] mL/h vs 82.9 [27.1-141.9] mL/h) and 7 (126.1 [98.0-151.3] mL/h vs 107.0 [82.5-137.5] mL/h) and at hospital discharge discharge (110.4 [92.8-121.9] mL/h vs 97.1 [77.5-113.8] mL/h). Three patients (5.5%) from the normal saline group developed allograft failure by the post hoc 1-year follow-up visit. Conclusions and Relevance: This randomized clinical trial found that 24-hour perioperative dexmedetomidine decreased the incidence of DGF after DCD kidney transplant. The findings support the use of dexmedetomidine in kidney transplants. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR1900025493.

Statistical analysis plan for Better Evidence for Selecting Transplant Fluids (BEST-Fluids): a randomised controlled trial of the effect of intravenous fluid therapy with balanced crystalloid versus saline on the incidence of delayed graft function in deceased donor kidney transplantation.

BACKGROUND: Delayed graft function, or the requirement for dialysis due to poor kidney function, is a frequent complication of deceased donor kidney transplantation that is associated with inferior outcomes. Intravenous fluids with a high chloride content, such as isotonic sodium chloride (0.9% saline), are widely used in transplantation but may increase the risk of poor kidney function. The primary objective of the BEST-Fluids trial is to compare the effect of a balanced low-chloride crystalloid, Plasma-Lyte 148 (Plasmalyte), versus 0.9% saline on the incidence of DGF in deceased donor kidney transplant recipients. This article describes the statistical analysis plan for the trial. METHODS AND DESIGN: BEST-Fluids is an investigator-initiated, pragmatic, registry-based, multi-centre, double-blind, randomised controlled trial. Eight hundred patients (adults and children) in Australia and New Zealand with end-stage kidney disease admitted for a deceased donor kidney transplant were randomised to intravenous fluid therapy with Plasmalyte or 0.9% saline in a 1:1 ratio using minimization. The primary outcome is delayed graft function (dialysis within seven days post-transplant), which will be modelled using a log-binomial generalised linear mixed model with fixed effects for treatment group, minimization variables, and ischaemic time and a random intercept for study centre. Secondary outcomes including early kidney transplant function (a ranked composite of dialysis duration and the rate of graft function recovery), treatment for hyperkalaemia, and graft survival and will be analysed using a similar modelling approach appropriate for the type of outcome. DISCUSSION: BEST-Fluids will determine whether Plasmalyte reduces the incidence of DGF and has a beneficial effect on early kidney transplant outcomes relative to 0.9% saline and will inform clinical guidelines on intravenous fluids for deceased donor kidney transplantation. The statistical analysis plan describes the analyses to be undertaken and specified before completion of follow-up and locking the trial databases. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12617000358347 . Prospectively registered on 8 March 2017 ClinicalTrials.gov identifier NCT03829488 . Registered on 4 February 2019.

Hypothermic Machine Perfusion as a National Standard Preservation Method for Deceased Donor Kidneys.

BACKGROUND: Recently, continuous nonoxygenated hypothermic machine perfusion (HMP) has been implemented as standard preservation method for deceased donor kidneys in the Netherlands. This study was designed to assess the effect of the implementation of HMP on early outcomes after transplantation. METHODS: Kidneys donated in the Netherlands in 2016 and 2017 were intended to be preserved by HMP. A historical cohort (2010-2014) preserved by static cold storage was chosen as the control group. Primary outcome was delayed graft function (DGF). Additional analyses were performed on safety, graft function, and survival up until 2 y after transplantation. RESULTS: Data were collected on 2493 kidneys. Analyses showed significantly more donation after circulatory death, preemptive transplantation, and retransplants in the project cohort. Of the 681 kidneys that were transplanted during the project, 81% were preserved by HMP. No kidneys were discarded due to HMP-related complications. DGF occurred in 38.2% of the project cohort versus 43.7% of the historical cohort (P < 0.001), with a significantly shorter duration within the project cohort (7 versus 9 d, P = 0.003). Multivariate regression analysis showed an odds ratio of 0.69 (95% confidence interval, 0.553-0.855) for the risk of DGF when using HMP compared with cold storage (P = 0.001). There was no significant difference in kidney function, graft survival, and recipient survival up until 2 y posttransplantation. CONCLUSIONS: This study showed that HMP as a standard preservation method for deceased donor kidneys is safe and feasible. HMP was associated with a significant reduction of DGF.

Effects of Plasma-Lyte.½ and 0.9% saline in renal function after deceased-donor kidney transplant: a randomized controlled trial.

BACKGROUND: The influence of different crystalloid solutions infused during deceased-donor kidney transplant on the incidence of delayed graft function remains unclear. We investigated the influence of Plasma-Lyte.½ vs. 0.9% saline on the incidence of delayed graft function in deceased-donor kidney transplant recipients. METHODS: We conducted a single-blind randomized controlled trial of 104 patients aged 18 to 65 years who underwent deceased-donor kidney transplant under general anesthesia. Patients were randomly assigned to receive either Plasma-Lyte.½ (n.ß=.ß52) or 0.9% saline (n.ß=.ß52), at the same infusion volume, for intraoperative fluid replacement. The primary outcome was the occurrence of delayed graft function. Secondary outcomes included metabolic and electrolytic changes at the end of surgery. RESULTS: Two patients in the Plasma-Lyte.½ group and one in the 0.9% saline group died postoperatively and were not included for analysis. The incidence of delayed graft function in Plasma-Lyte.½ and 0.9% saline groups were 60.0% (95% Confidence Interval [95% CI 46.2...72.4]) and 74.5% (95% CI 61.1...84.4), respectively (p.ß=.ß0.140). Mean (standard deviation) values of immediate postoperative pH and serum chloride levels in Plasma-Lyte.½ and 0.9% saline groups were 7.306 (0.071) and 7.273 (0.061) (p.ß=.ß0.013), and 99.6 (4.2) mEq.L-1 and 103.3 (5.6) mEq.L-1, respectively (p.ß<.ß0.001). All other postoperative metabolic and electrolyte variables were not statistically different at the immediate postoperative period (p.ß>.ß0.05). CONCLUSION: In deceased-donor kidney transplant recipients, the incidence of delayed graft function is not influenced by Plasma-Lyte.½ or 0.9% saline used for intraoperative fluid replacement.

Complement Blockade in Recipients Prevents Delayed Graft Function and Delays Antibody-mediated Rejection in a Nonhuman Primate Model of Kidney Transplantation.

BACKGROUND: Complement activation in kidney transplantation is implicated in the pathogenesis of delayed graft function (DGF). This study evaluated the therapeutic efficacy of high-dose recombinant human C1 esterase inhibitor (rhC1INH) to prevent DGF in a nonhuman primate model of kidney transplantation after brain death and prolonged cold ischemia. METHODS: Brain death donors underwent 20 h of conventional management. Procured kidneys were stored on ice for 44-48 h, then transplanted into ABO-compatible major histocompatibility complex-mismatched recipients. Recipients were treated with vehicle (n = 5) or rhC1INH 500 U/kg plus heparin 40 U/kg (n = 8) before reperfusion, 12 h, and 24 h posttransplant. Recipients were followed up for 120 d. RESULTS: Of vehicle-treated recipients, 80% (4 of 5) developed DGF versus 12.5% (1 of 8) rhC1INH-treated recipients (P = 0.015). rhC1INH-treated recipients had faster creatinine recovery, superior urinary output, and reduced urinary neutrophil gelatinase-associated lipocalin and tissue inhibitor of metalloproteinases 2-insulin-like growth factor-binding protein 7 throughout the first week, indicating reduced allograft injury. Treated recipients presented lower postreperfusion plasma interleukin (IL)-6, IL-8, tumor necrosis factor-alpha, and IL-18, lower day 4 monocyte chemoattractant protein 1, and trended toward lower C5. Treated recipients exhibited less C3b/C5b-9 deposition on day 7 biopsies. rhC1INH-treated animals also trended toward prolonged mediated rejection-free survival. CONCLUSIONS: Our results recommend high-dose C1INH complement blockade in transplant recipients as an effective strategy to reduce kidney injury and inflammation, prevent DGF, delay antibody-mediated rejection development, and improve transplant outcomes.

The Impact of Cold Ischaemia Time on Outcomes of Living Donor Kidney Transplantation in the UK Living Kidney Sharing Scheme.

OBJECTIVE: To assess the impact of CIT on living donor kidney transplantation (LDKT) outcomes in the UKLKSS versus outside the scheme. BACKGROUND: LDKT provides the best treatment option for end-stage kidney disease patients. end-stage kidney disease patients with an incompatible living donor still have an opportunity to be transplanted through Kidney Exchange Programmes (KEP). In KEPs where kidneys travel rather than donors, cold ischaemia time (CIT) can be prolonged. METHODS: Data from all UK adult LDKT between 2007 and 2018 were analysed. RESULTS: 9969 LDKT were performed during this period, of which 1396 (14%) were transplanted through the UKLKSS, which we refer to as KEP. Median CIT was significantly different for KEP versus non-KEP (339 versus 182 minutes, P < 0.001). KEP LDKT had a higher incidence of delayed graft function (DGF) (2.91% versus 5.73%, P < 0.0001), lower 1-year (estimated Glomerular Filtration Rate (eGFR) 57.90 versus 55.25 ml/min, P = 0.04) and 5-year graft function (eGFR 55.62 versus 53.09 ml/min, P = 0.01) compared to the non-KEP group, but 1- and 5-year graft survival were similar. Within KEP, a prolonged CIT was associated with more DGF (3.47% versus 1.95%, P = 0.03), and lower graft function at 1 and 5-years (eGFR = 55 vs 50 ml/min, P = 0.02), but had no impact on graft survival. CONCLUSION: Whilst CIT was longer in KEP, associated with more DGF and lower graft function, excellent 5-year graft survival similar to non-KEP was found.

Clinical Features and Outcomes of Combined Pulmonary Fibrosis and Emphysema After Lung Transplantation.

BACKGROUND: Combined pulmonary fibrosis and emphysema (CPFE) is recognized as a characteristic syndrome of smoking-related interstitial lung disease that has a worse prognosis than idiopathic pulmonary fibrosis (IPF). However, outcomes after lung transplantation for CPFE have not been reported. The aim of this study is to describe the clinical features and outcomes of CPFE after lung transplantation. RESEARCH QUESTION: What are the clinical features and outcomes of CPFE after lung transplantation? STUDY DESIGN AND METHODS: This is a single-center retrospective cohort study of patients with CPFE and IPF who underwent lung transplantation at our center between January 2011 and December 2016. We defined CPFE as ≥10% emphysema in the upper lung fields combined with fibrosis on high-resolution CT scan. We characterized the clinical features of patients with CPFE and compared their outcomes after lung transplantation with those with IPF. RESULTS: Twenty-seven of 172 (16%) patients with IPF met criteria for CPFE. Severe pulmonary hypertension was present in 16 of 27 (59%) patients with CPFE. On logistic regression analysis, CPFE was significantly associated with primary graft dysfunction (PGD) grade 3 (OR, 3.14; 95% CI, 1.18-8.37; P = .02). On competing risk regression analysis, CPFE was associated with acute cellular rejection (ACR) grade ≥ A2, and chronic lung allograft dysfunction (CLAD) (hazard ratio [HR], 1.89; 95% CI, 1.10-3.25; P = .02; HR, 1.96; 95% CI, 1.02-3.77; P = .04, respectively). Five-year survival was 79.0% for the CPFE group and 75.4% for the IPF group (log-rank P = .684). INTERPRETATION: After transplantation, patients with CPFE were more likely to develop PGD, ACR, and CLAD compared with those with IPF. However, survival was not significantly different between the two groups.

Recombinant apoptosis inhibitor of macrophage protein reduces delayed graft function in a murine model of kidney transplantation.

Reperfusion injury following cold and warm ischemia (IRI) is unavoidable during kidney transplantation and contributes to delayed graft function (DGF) and premature graft loss. Death of tubular epithelial cells (TECs) by necrosis during IRI releases pro-inflammatory mediators (e.g. HMGB1), propagating further inflammation (necroinflammation) and tissue damage. Kidney Injury Molecule-1 (KIM-1) is a phagocytic receptor upregulated on proximal TECs during acute kidney injury. We have previously shown that renal KIM-1 protects the graft against transplant associated IRI by enabling TECs to clear apoptotic and necrotic cells, and that recognition of necrotic cells by KIM-1 is augmented in the presence of the opsonin, apoptosis inhibitor of macrophages (AIM). Here, we tested whether recombinant AIM (rAIM) could be used to mitigate transplant associated IRI. We administered rAIM or vehicle control to nephrectomised B6 mice transplanted with a single B6 donor kidney. Compared to grafts in vehicle-treated recipients, grafts from rAIM-treated mice exhibited significantly less renal dysfunction, tubular cell death, tissue damage, tubular obstruction, as well as local and systemic inflammation. Both mouse and human rAIM enhanced the clearance of necrotic cells by murine and human TECs, respectively in vitro. These data support testing of rAIM as a potential therapeutic agent to reduce DGF following kidney transplantation.

Mitochondrial Consequences of Organ Preservation Techniques during Liver Transplantation.

Allograft ischemia during liver transplantation (LT) adversely affects the function of mitochondria, resulting in impairment of oxidative phosphorylation and compromised post-transplant recovery of the affected organ. Several preservation methods have been developed to improve donor organ quality; however, their effects on mitochondrial functions have not yet been compared. This study aimed to summarize the available data on mitochondrial effects of graft preservation methods in preclinical models of LT. Furthermore, a network meta-analysis was conducted to determine if any of these treatments provide a superior benefit, suggesting that they might be used on humans. A systematic search was conducted using electronic databases (EMBASE, MEDLINE (via PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science) for controlled animal studies using preservation methods for LT. The ATP content of the graft was the primary outcome, as this is an indicator overall mitochondrial function. Secondary outcomes were the respiratory activity of mitochondrial complexes, cytochrome c and aspartate aminotransferase (ALT) release. Both a random-effects model and the SYRCLE risk of bias analysis for animal studies were used. After a comprehensive search of the databases, 25 studies were enrolled in the analysis. Treatments that had the most significant protective effect on ATP content included hypothermic and subnormothermic machine perfusion (HMP and SNMP) (MD = -1.0, 95% CI: (-2.3, 0.3) and MD = -1.1, 95% CI: (-3.2, 1.02)), while the effects of warm ischemia (WI) without cold storage (WI) and normothermic machine perfusion (NMP) were less pronounced (MD = -1.8, 95% CI: (-2.9, -0.7) and MD = -2.1 MD; CI: (-4.6; 0.4)). The subgroup of static cold storage (SCS) with shorter preservation time (< 12 h) yielded better results than SCS ≥ 12 h, NMP and WI, in terms of ATP preservation and the respiratory capacity of complexes. HMP and SNMP stand out in terms of mitochondrial protection when compared to other treatments for LT in animals. The shorter storage time at lower temperatures, together with the dynamic preservation, provided superior protection for the grafts in terms of mitochondrial function. Additional clinical studies on human patients including marginal donors and longer ischemia times are needed to confirm any superiority of preservation methods with respect to mitochondrial function.

Parathyroidectomy or cinacalcet: Do we still not know the best option for graft function in kidney-transplanted patients? A meta-analysis.

BACKGROUND: Tertiary hyperparathyroidism occurs in 25% to 50% of kidney-transplanted patients. Indication of parathyroidectomy is now discussed, since the calcimimetic agent, cinacalcet, is an alternate option. The effects of either of these treatments on graft function remain controversial, studied only in small cohorts showing either decrease or absence of modification. We performed a meta-analysis to evaluate the evolution of graft function after surgical or medical treatment. METHODS: Studies assessing graft function in tertiary hyperparathyroidism after parathyroidectomy or cinacalcet introduction were enrolled into quantitative analysis using Pubmed, Embase, and Cochrane databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis reporting guidelines. Among 68 screened studies, 18 had no missing data and were included for statistical analyses. We performed random effect meta-analysis to determine changes in serum creatinine and estimated glomerular filtration rate. RESULTS: Seven studies assessing the evolution of graft function 6 and/or 12 months after parathyroidectomy and 13 after administration of cinacalcet were included. Meta-analysis found no significant variations after parathyroidectomy in serum creatinine (6 studies, 314 patients) and estimated glomerular filtration rate (2 studies, 105 patients). No significant variation was found after administration of cinacalcet in serum creatinine (10 studies, 404 patients) and estimated glomerular filtration rate (6 studies, 149 patients). A significant heterogeneity between the studies (P < .01, Cochran's Q) was found. CONCLUSION: Meta-analysis shows that parathyroidectomy and cinacalcet do not significantly impair graft function in patients with tertiary hyperparathyroidism. However, the significant heterogeneity between selected studies, partially explained by the lack of consensual definition of tertiary hyperparathyroidism, limits the conclusions of all previously published series.

Machine Perfusion Decreases Delayed Graft Function in Donor Grafts With High Kidney Donor Profile Index.

OBJECTIVES: Kidney transplant is the optimal treatment for patients with end-stage renal disease. The effects of using machine perfusion for donor kidneys with varying Kidney Donor Profile Index scores are unknown. We sought to assess the impact of machine perfusion on the incidence of delayed graft function in different score groups of kidney grafts classified with the Kidney Donor Profile Index. MATERIALS AND METHODS: We conducted a retrospective analysis from January 2008 through September 2017 of adult recipients (≥ 18 years old) undergoing kidney-only transplant from deceased donors. All transplant recipients were followed until December 2017. Recipients who received multiorgan transplants or kidneys from living donors were excluded from our analyses. Recipients were divided according to 5 donor categories of Kidney Donor Profile Index scores (0-20, 21-40, 41-60, 61-80, and 81-100). Logistic regression analysis was performed for each score group to determine the effects of machine perfusion on development of delayed graft function within each score group. RESULTS: Our study included 101222 recipients who met the inclusion criteria. Multivariate analysis revealed that machine perfusion was associated with significantly decreased development of delayed graft function only in donors with high-risk profiles: the 61 to 80 score group (odds ratio = 0.83; confidence interval, 0.78-0.89) and the 81 to 100 score group (odds ratio = 0.72; confidence interval, 0.67-0.78). CONCLUSIONS: Machine perfusion is beneficial in reducing delayed graft function only in donor kidneys with a higher risk profile.