Am J Transplant. 2021 Sep;21(9):3055-3065 doi: 10.1111/ajt.16528.
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Lancet. 2020 Nov 21;396(10263):1653-1662 doi: 10.1016/S0140-6736(20)32411-9.
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Am J Transplant. 2019 Mar;19(3):811-822 doi: 10.1111/ajt.15081.
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Ann Surg. 2023 Nov 1;278(5):676-682 doi: 10.1097/SLA.0000000000006046.
CET Conclusion
OBJECTIVE:
To provide mechanistic insight into key biological alterations in donation after circulatory death kidneys during continuous pefusion we performed mass spectrometry profiling of perfusate samples collected during a phase 3 randomized double-blind paired clinical trial of hypothermic machine perfusion with and without oxygen (COMPARE). BACKGROUND:Despite the clinical benefits of novel perfusion technologies aiming to better preserve donor organs, biological processes that may be altered during perfusion have remained largely unexplored. The collection of serial perfusate samples during the COMPARE clinical trial provided a unique resource to study perfusate proteomic profiles, with the hypothesis that in-depth profiling may reveal biologically meaningful information on how donor kidneys benefit from this intervention. METHODS:Multiplexed liquid chromatography-tandem mass spectrometry was used to obtain a proteome profile of 210 perfusate samples. Partial least squares discriminant analysis and multivariate analysis involving clinical and perfusion parameters were used to identify associations between profiles and clinical outcomes. RESULTS:Identification and quantitation of 1716 proteins indicated that proteins released during perfusion originate from the kidney tissue and blood, with blood-based proteins being the majority. Data show that the overall hypothermic machine perfusion duration is associated with increasing levels of a subgroup of proteins. Notably, high-density lipoprotein and complement cascade proteins are associated with 12-month outcomes, and blood-derived proteins are enriched in the perfusate of kidneys that developed acute rejection. CONCLUSIONS:Perfusate profiling by mass spectrometry was informative and revealed proteomic changes that are biologically meaningful and, in part, explain the clinical observations of the COMPARE trial. |
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J Endourol. 2023 Oct;37(10):1129-1138 doi: 10.1089/end.2023.0224.
Background: Patients who have undergone renal transplant may have a concomitant benign prostatic hyperplasia (BPH), a condition that can potentially hinder the recovery of the renal graft and necessitate surgical intervention. However, endoscopic treatment of BPH should be performed carefully because of the associated perioperative risks. We aimed to systematically assess the factors affecting surgical indications and perioperative outcomes of BPH surgical treatment in renal transplantation (RT) recipients. Methods: A systematic literature search was performed on January 28, 2023, using Scopus, PubMed, and EMBASE with no date limit. Preclinical and animal studies, reviews, letters to the editor, case reports, and meeting abstracts were excluded. Results: Eighteen articles were accepted and included. Clinical BPH has a high incidence rate after RT, particularly in elderly men. Secondary events associated with BPH, such as acute urinary retention and urinary tract infections, can lead to a gradual decline of renal graft function and patient survival. BPH procedure can prevent these events and guarantee improvements in serum creatinine levels, voiding parameters, and lower urinary tract symptoms. When the urine culture is negative, the endoscopic procedure of the prostate may be performed within 1 month of the initial procedure, particularly in older patients, more prone to develop voiding dysfunction. Alternatively, a transurethral incision of the prostate may be recommended for patients with smaller prostates who wish to preserve ejaculatory function. Data on comparative BPH surgical procedures are lacking. Conclusions: BPH procedure should be offered in RT recipients who develop bladder outlet obstruction owing to BPH. Endoscopic treatment should be performed after a few weeks from RT to avoid further graft deterioration. |
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PLoS One. 2023 Jun 23;18(6):e0287713 doi: 10.1371/journal.pone.0287713.
CET Conclusion
Hypothermic machine perfusion (HMP) provides preservation superior to cold storage and may allow for organ assessment prior to transplantation. Since flavin mononucleotide (FMN) in perfusate has been proposed as a biomarker of organ quality during HMP of donor livers, the aim of this study was to validate FMN as a biomarker for organ quality in the context of HMP preserved kidneys. Perfusate samples (n = 422) from the paired randomised controlled COPE-COMPARE-trial, comparing HMP with oxygenation (HMPO2) versus standard HMP in kidneys, were used. Fluorescence intensity (FI) was assessed using fluorescence spectroscopy (excitation 450nm; emission 500-600nm) and validated by fluorospectrophotometer and targeted liquid chromatography mass spectrometry (LC-MS/MS). Fluorescence intensity (FI)(ex450;em500-600) increased over time during machine perfusion in both groups (p<0.0001). This increase was similar for both groups (p = 0.83). No correlation, however, was found between FI(ex450;em500-600) and post-transplant outcomes, including day 5 or 7 serum creatinine (p = 0.11; p = 0.16), immediate graft function (p = 0.91), creatinine clearance and biopsy-proven rejection at one year (p = 0.14; p = 0.59). LC-MS/MS validation experiments of samples detected FMN in only one perfusate sample, whilst the majority of samples with the highest fluorescence (n = 37/38, 97.4%) remained negative. In the context of clinical kidney HMP, fluorescence spectroscopy unfortunately appears to be not specific and probably unsuitable for FMN. This study shows that FMN does not classify as a clinically relevant predictive biomarker of kidney graft function after transplantation. |
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J Clin Med. 2023 Jun 6;12(12) doi: 10.3390/jcm12123871.
The high demand for organs in kidney transplantation and the expansion of the donor pool have led to the widespread implementation of machine perfusion technologies. In this study, we aim to provide an up-to-date systematic review of the developments in this expanding field over the past 10 years, with the aim of answering the question: "which perfusion technique is the most promising technique in kidney transplantation?" A systematic review of the literature related to machine perfusion in kidney transplantation was performed. The primary outcome measure was delayed graft function (DGF), and secondary outcomes included rates of rejection, graft survival, and patient survival rates after 1 year. Based on the available data, a meta-analysis was performed. The results were compared with data from static cold storage, which is still the standard of care in many centers worldwide. A total of 56 studies conducted in humans were included, and 43 studies reported outcomes of hypothermic machine perfusion (HMP), with a DGF rate of 26.4%. A meta-analysis of 16 studies showed significantly lower DGF rates in the HMP group compared to those of static cold storage (SCS). Five studies reported outcomes of hypothermic machine perfusion + O2, with an overall DGF rate of 29.7%. Two studies explored normothermic machine perfusion (NMP). These were pilot studies, designed to assess the feasibility of this perfusion approach in the clinical setting. Six studies reported outcomes of normothermic regional perfusion (NRP). The overall incidence of DGF was 71.5%, as it was primarily used in uncontrolled DCD (Maastricht category I-II). Three studies comparing NRP to in situ cold perfusion showed a significantly lower rate of DGF with NRP. The systematic review and meta-analysis provide evidence that dynamic preservation strategies can improve outcomes following kidney transplantation. More recent approaches such as normothermic machine perfusion and hypothermic machine perfusion + O2 do show promising results but need further results from the clinical setting. This study shows that the implementation of perfusion strategies could play an important role in safely expanding the donor pool. |
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Nat Med. 2023 Jun;29(6):1511-1519 doi: 10.1038/s41591-023-02376-7.
CET Conclusion
Kidney transplantation is the optimal treatment for end-stage renal disease, but it is still severely limited by a lack of suitable organ donors. Kidneys from donation after circulatory death (DCD) donors have been used to increase transplant rates, but these organs are susceptible to cold ischemic injury in the storage period before transplantation, the clinical consequence of which is high rates of delayed graft function (DGF). Normothermic machine perfusion (NMP) is an emerging technique that circulates a warmed, oxygenated red-cell-based perfusate through the kidney to maintain near-physiological conditions. We conducted a randomized controlled trial to compare the outcome of DCD kidney transplants after conventional static cold storage (SCS) alone or SCS plus 1-h NMP. A total of 338 kidneys were randomly allocated to SCS (n = 168) or NMP (n = 170), and 277 kidneys were included in the final intention-to-treat analysis. The primary endpoint was DGF, defined as the requirement for dialysis in the first 7 d after transplant. The rate of DGF was 82 of 135 (60.7%) in NMP kidneys versus 83 of 142 (58.5%) in SCS kidneys (adjusted odds ratio (95% confidence interval) 1.13 (0.69-1.84); P = 0.624). NMP was not associated with any increase in transplant thrombosis, infectious complications or any other adverse events. A 1-h period of NMP at the end of SCS did not reduce the rate of DGF in DCD kidneys. NMP was demonstrated to be feasible, safe and suitable for clinical application. Trial registration number: ISRCTN15821205 . |
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Trials. 2023 May 1;24(1):302 doi: 10.1186/s13063-023-07302-3.
BACKGROUND:
Preventing ischemia‒reperfusion injury (IRI) is a major issue in kidney transplantation, particularly for transplant recipients receiving a kidney from extended criteria donors (ECD). The main consequence of IRI is delayed graft function (DGF). Hypoxia is one of the key factors in IRI, suggesting that the use of an oxygen carrier as an additive to preservation solution may be useful. In the OxyOp trial, we showed that the organs preserved using the oxygen carrier HEMO2life® displayed significantly less DGF. In the OxyOp2 trial, we aim to definitively test and quantify the efficacy of HEMO2life® for organ preservation in a large population of kidney grafts. METHODS:OxyOp2 is a prospective, multicenter, randomized, comparative, single-blinded, parallel-group study versus standard of care in renal transplantation. After the selection of a suitable donor according to the inclusion/exclusion criteria, both kidneys will be used in the study. Depending on the characteristics of the donor, both kidneys will be preserved either in static cold storage (standard donors) or on machine perfusion (for ECD and deceased-after-cardiac-death donors (DCD)). The kidneys resulting from one donor will be randomized: one to the standard-of-care arm (organ preserved in preservation solution routinely used according to the local practice) and the other to the active treatment arm (HEMO2life® on top of routinely used preservation solution). HEMO2life® will be used for ex vivo graft preservation at a dose of 1 g/l preservation solution. The primary outcome is the occurrence of DGF, defined as the need for renal replacement therapy during the first week after transplantation. DISCUSSION:The use of HEMO2life® in preservation solutions is a novel approach allowing, for the first time, the delivery of oxygen to organs. Improving graft survival by limiting ischemic lesions is a major public-health goal in the field of organ transplantation. TRIAL REGISTRATION:ClinicalTrials.gov, ID: NCT04181710 . registered on November 29, 2019. |
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Lancet. 2023 Feb 18;401(10376):557-567 doi: 10.1016/S0140-6736(22)02606-X.
CET Conclusion
BACKGROUND:
Metabolic acidosis is common in kidney transplant recipients and is associated with declining graft function. Sodium bicarbonate treatment effectively corrects metabolic acidosis, but no prospective studies have examined its effect on graft function. Therefore, we aimed to test whether sodium bicarbonate treatment would preserve graft function and slow the progression of estimated glomerular filtration rate (GFR) decline in kidney transplant recipients. METHODS:The Preserve-Transplant Study was a multicentre, randomised, single-blind, placebo-controlled, phase 3 trial at three University Hospitals in Switzerland (Zurich, Bern, and Geneva), which recruited adult (aged ≥18 years) male and female long-term kidney transplant recipients if they had undergone transplantation more than 1 year ago. Key inclusion criteria were an estimated GFR between 15 mL/min per 1·73 m2 and 89 mL/min per 1·73 m2, stable allograft function in the last 6 months before study inclusion (<15% change in serum creatinine), and a serum bicarbonate of 22 mmol/L or less. We randomly assigned patients (1:1) to either oral sodium bicarbonate 1·5-4·5 g per day or matching placebo using web-based data management software. Randomisation was stratified by study centre and gender using a permuted block design to guarantee balanced allocation. We did multi-block randomisation with variable block sizes of two and four. Treatment duration was 2 years. Acid-resistant soft gelatine capsules of 500 mg sodium bicarbonate or matching 500 mg placebo capsules were given at an initial dose of 500 mg (if bodyweight was <70 kg) or 1000 mg (if bodyweight was ≥70 kg) three times daily. The primary endpoint was the estimated GFR slope over the 24-month treatment phase. The primary efficacy analyses were applied to a modified intention-to-treat population that comprised all randomly assigned participants who had a baseline visit. The safety population comprised all participants who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT03102996. FINDINGS:Between June 12, 2017, and July 10, 2019, 1114 kidney transplant recipients with metabolic acidosis were assessed for trial eligibility. 872 patients were excluded and 242 were randomly assigned to the study groups (122 [50%] to the placebo group and 120 [50%] to the sodium bicarbonate group). After secondary exclusion of two patients, 240 patients were included in the intention-to-treat analysis. The calculated yearly estimated GFR slopes over the 2-year treatment period were a median -0·722 mL/min per 1·73 m2 (IQR -4·081 to 1·440) and mean -1·862 mL/min per 1·73 m2 (SD 6·344) per year in the placebo group versus median -1·413 mL/min per 1·73 m2 (IQR -4·503 to 1·139) and mean -1·830 mL/min per 1·73 m2 (SD 6·233) per year in the sodium bicarbonate group (Wilcoxon rank sum test p=0·51; Welch t-test p=0·97). The mean difference was 0·032 mL/min per 1·73 m2 per year (95% CI -1·644 to 1·707). There were no significant differences in estimated GFR slopes in a subgroup analysis and a sensitivity analysis confirmed the primary analysis. Although the estimated GFR slope did not show a significant difference between the treatment groups, treatment with sodium bicarbonate effectively corrected metabolic acidosis by increasing serum bicarbonate from 21·3 mmol/L (SD 2·6) to 23·0 mmol/L (2·7) and blood pH from 7·37 (SD 0·06) to 7·39 (0·04) over the 2-year treatment period. Adverse events and serious adverse events were similar in both groups. Three study participants died. In the placebo group, one (1%) patient died from acute respiratory distress syndrome due to SARS-CoV-2 and one (1%) from cardiac arrest after severe dehydration following diarrhoea with hypotension, acute kidney injury, and metabolic acidosis. In the sodium bicarbonate group, one (1%) patient had sudden cardiac death. INTERPRETATION:In adult kidney transplant recipients, correction of metabolic acidosis by treatment with sodium bicarbonate over 2 years did not affect the decline in estimated GFR. Thus, treatment with sodium bicarbonate should not be generally recommended to preserve estimated GFR (a surrogate marker for graft function) in kidney transplant recipients with chronic kidney disease who have metabolic acidosis. FUNDING:Swiss National Science Foundation. |
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N Engl J Med. 2023 Feb 2;388(5):418-426 doi: 10.1056/NEJMoa2118265.
CET Conclusion
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.). |
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Minerva Urol Nephrol. 2023 Feb;75(1):1-16 doi: 10.23736/S2724-6051.22.04881-9.
INTRODUCTION:
After transplantation, approximately 10% of renal cell carcinomas are detected in graft kidneys. These tumors (gRCC) present surgeons with the difficulty of finding a treatment that guarantees both oncological clearance and maintenance of function. We conducted a systematic review and an individual patient data meta-analysis on the oncology, safety and functional outcomes of the available treatments for gRCC. EVIDENCE ACQUISITION:A systematic search was performed across MEDLINE, EMBASE, and Web of Science including any study reporting perioperative, functional and survival outcomes for patients undergoing graft nephrectomy (GN), partial nephrectomy (PN) or thermal ablation (TA) for gRCC. Quade's ANCOVA, Spearman Rho and Pearson χ2, Kaplan-Meier, Log-rank and Standard Cox regression and other tests were used to compare treatments. Studies' quality was evaluated using a modified version of Newcastle Ottawa Scale. EVIDENCE SYNTHESIS:A number of 29 studies (357 patients) were included. No differences between TA and PN were found in terms of safety, functional and oncological outcomes for T1a gRCCs. When applied to pT1b gRCC, PN showed no difference in complications, progression or cancer-specific deaths compared to smaller lesions; PN validity for pT2 gRCCs should be considered unverified due to lack of sufficient evidence. The efficacy and safety of PN or TA for multiple gRCC remain controversial. In case of non-functioning, large (T≥2), complicated or metastatic gRCCs, GN appears to be the most reasonable choice. Quality of evidence ranged from very low to moderate. Studies with large cohorts and longer follow-up are still needed to clarify oncological and functional differences. CONCLUSIONS:PN and TA might be offered as a nephron-sparing treatment in patients with T1a gRCC. There is no significant difference between these options and GN in terms of oncological outcomes and complications. PN and TA offer similar functional outcomes and graft preservation. PN for T1b gRCC seems feasible and safe, but its validity should be considered unverified. |
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Transpl Infect Dis. 2022 Dec;24(6):e13979 doi: 10.1111/tid.13979.
CET Conclusion
BACKGROUND:
The role of culturing the graft preservation fluid (PF) is controversial and its impact on graft arteritis development remains unclear. METHODS:Systematic literature search retrieving observational studies comparing solid organ transplant (SOT) recipients with culture-positive PF versus culture-negative PF. The quality of included studies was independently assessed according to the ROBINS-I tool for observational studies. Meta-analysis was performed using Mantel-Haenszel random-effect models. Graft site arteritis within 180 days from transplant was selected as the primary outcome. RESULTS:Twenty-one observational studies (N = 2208 positive PF vs. 4458 negative) were included. Among positive PF, 857 (38.8%) were classified as high-risk group pathogens and 1351 (61.2%) as low-risk pathogens. Low-risk and negative PF showed similar odds ratios. A significant higher risk of graft arteritis was found in SOT recipients with a PF yielding a high-risk pathogen (odds ratio [OR] 18.43, 95% confidence interval [CI] 7.83-43.40) compared to low-risk and negative PF, with low heterogeneity (I2 = 2.24%). Similar results were found considering separately high-risk bacteria (OR 12.02, 95%CI 4.88-29.60) and fungi (OR 71.00, 95%CI 28.07-179.56), with no heterogeneity (I2 = 0%), and in the subgroup analyses of the liver (OR 16.78, 95%CI 2.95-95.47) and kidney (OR 19.90, 95%CI 4.78-82.79) recipients. However, data about diagnostic features of graft arteritis were very limited, indeed for only 11 of the 93 events histological or microbiological results were reported. CONCLUSIONS:Our results may support the performance of PF culturing and a preemptive diagnostic or therapeutic management upon isolation of high-risk pathogens. Further studies based on a reliable diagnosis of graft arteritis are needed. |