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In this international randomized, controlled trial, one kidney from each pair from 336 consecutive deceased donors was randomly assigned to machine perfusion and the other to cold storage. All recipients were followed for 1 year. Hypothermic machine perfusion was associated with a reduced risk of the primary end point — delayed graft function — and improved graft survival in the first year after transplantation. In this trial, one kidney from each pair from deceased donors was randomly assigned to machine perfusion and the other to cold storage. Hypothermic machine perfusion was associated with a reduced risk of the primary end point — delayed graft function — and improved graft survival in the first year after transplantation. Two different forms of organ preservation — static cold storage and hypothermic machine perfusion — are used clinically for renal allografts obtained from deceased donors. In static cold storage, the kidney is flushed, cooled with one of several cold preservation solutions, and transported on ice. In hypothermic machine perfusion, after an initial washout of blood, the kidney is connected to a perfusion device, and a solution is pumped continuously through the renal vasculature at temperatures between 1 and 10°C. 1 The typical deceased kidney donor today is older and has been exposed to more concomitant disease than donors were several decades . . .

Background Extended criteria donor (ECD) and donation after circulatory death (DCD) kidneys are at increased risk of delayed graft function (DGF). Experimental evidence suggests that erythropoietin (EPO) attenuates renal damage in acute kidney injury. This study piloted the administration of high dose recombinant human EPO-beta at implantation of ECD and DCD kidneys, and evaluated biomarkers of kidney injury post-transplant. Methods Forty patients were randomly assigned to receive either rhEPO-b (100,000 iu) (n = 19 in the intervention group, as 1 patient was un-transplantable post randomisation), or placebo (n = 20) in this, double blind, placebo-controlled trial at Manchester Royal Infirmary from August 2007 to June 2009. Participants received either an ECD (n = 17) or DCD (n = 22) kidney. Adverse events, renal function, haematopoietic markers, and rejections were recorded out to 90 days post-transplant. Biomarkers of kidney injury (neutrophil gelatinase-associated lipocalin, Kidney Injury Molecule-1 and IL-18) were measured in blood and urine during the first post-operative week. Results The incidence of DGF (53% vs 55%) (RR = 1.0; CI = 0.5-1.6; p = 0.93) and slow graft function (SGF) (32% vs 25%) (RR = 1.1; CI = 0.5-1.9; p = 0.73) respectively, serum creatinine, eGFR, haemoglobin and haematocrit, blood pressure, and acute rejection were similar in the 2 study arms. High dose rhEPO-b had little effect on the temporal profiles of the biomarkers. Conclusions High dose rhEPO-b appears to be safe and well tolerated in the early post- transplant period in this study, but has little effect on delayed or slow graft function in recipients of kidneys from DCD and ECD donors. Comparing the profiles of biomarkers of kidney injury (NGAL, IL-18 and KIM-1) showed little difference between the rhEPO-b treated and placebo groups. A meta-analysis of five trials yielded an overall estimate of the RR for DGF of 0.89 (CI = 0.73; 1.07), a modest effect favouring EPO but not a significant difference. A definitive trial based on this estimate would require 1000-2500 patients per arm for populations with base DGF rates of 50-30% and 90% power. Such a trial is clearly unfeasible. Trial registration EudraCT Number 2006-005373-22 ISRCTN ISRCTN85447324 registered 19/08/09.

New biomarkers of early and late graft dysfunction are needed in renal transplant to improve management of complications and prolong graft survival. A wide range of potential diagnostic and prognostic biomarkers, measured in different biological fluids (serum, plasma, urine) and in renal tissues, have been proposed for post-transplant delayed graft function (DGF), acute rejection (AR), and chronic allograft dysfunction (CAD). This review investigates old and new potential biomarkers for each of these clinical domains, seeking to underline their limits and strengths. OMICs technology has allowed identifying many candidate biomarkers, providing diagnostic and prognostic information at very early stages of pathological processes, such as AR. Donor-derived cell-free DNA (ddcfDNA) and extracellular vesicles (EVs) are further promising tools. Although most of these biomarkers still need to be validated in multiple independent cohorts and standardized, they are paving the way for substantial advances, such as the possibility of accurately predicting risk of DGF before graft is implanted, of making a “molecular” diagnosis of subclinical rejection even before histological lesions develop, or of dissecting etiology of CAD. Identification of “immunoquiescent” or even tolerant patients to guide minimization of immunosuppressive therapy is another area of active research. The parallel progress in imaging techniques, bioinformatics, and artificial intelligence (AI) is helping to fully exploit the wealth of information provided by biomarkers, leading to improved disease nosology of old entities such as transplant glomerulopathy. Prospective studies are needed to assess whether introduction of these new sets of biomarkers into clinical practice could actually reduce the need for renal biopsy, integrate traditional tools, and ultimately improve graft survival compared to current management.

Increasing evidence suggests a detrimental effect of donor-specific antibodies directed against the human leukocyte antigen (HLA)-A, -B, and -DR loci on renal allograft outcomes. Limited data exist on the impact of de novo HLA-DQ antibodies. Over a 3-year period, we prospectively monitored 347 renal transplant recipients without pre-transplant donor-specific antibodies for their development de novo. After 26 months of follow-up, 62 patients developed donor-specific antibodies, of which 48 had a HLA-DQ antibody either alone (33 patients) or in combination with an HLA-A, -B, or -DR antibody (15 patients). Only 14 patients developed a donor-specific HLA-A, -B, or -DR antibody without a HLA-DQ antibody present. Acute rejection occurred in 21% of the HLA-DQ–only patients, insignificant when compared with 11% of patients without donor-specific antibodies. At the last follow-up, the mean serum creatinine and the fraction of patients with proteinuria were significantly higher in those that developed only HLA-DQ than those without antibodies. The 3-year graft survival was significantly worse when HLA-DQ antibodies were combined with non-DQ antibodies (52%) compared with HLA-DQ alone, non-DQ antibodies alone, or no antibodies (92–94%). Thus, our prospective monitoring study found that donor-specific HLA-DQ antibodies were the most common type detected and these antibodies may contribute to inferior graft outcomes. Ongoing surveillance is necessary to determine the long-term outcome of patients developing HLA-DQ donor-specific antibodies.

Accurate assessment of graft function trajectories after kidney transplantation is essential for optimizing patient management. Slow graft function (SGF) and delayed graft function (DGF) are associated with impaired recovery, yet current diagnostic tools lack granularity for timely risk stratification. Proenkephalin A 119-159 (penKid) may improve graft function assessment, enhancing risk stratification for SGF, DGF, and associated outcomes. This prospective study evaluated 159 kidney transplant recipients at Heidelberg University Hospital to compare plasma penKid levels with current risk-indicators for poor (functional) graft trajectories. Validation was conducted using an independent transplant cohort from Sydney. Clinical relevance of biomarker-indicated changes in graft function was assessed using multivariable regression models and AUROC analyses. From day one post-transplant, penKid outperformed serum creatinine (SCr) in identifying functional trajectories associated with DGF (AUROC penKid: 0.87 vs. SCr: 0.56) and differentiated SGF from DGF (AUROC penKid: 0.79 vs. SCr: 0.33) up to eight days earlier. PenKid further demonstrated superior granularity in assessing DGF severity and 30-day outcomes. After adjustment for common risk factors, penKid remained the strongest risk stratifier for all tested outcomes. PenKid is a superior biomarker for earlier assessment of graft function trajectories, offering potential to enhance personalized care and clinical trial designs in kidney transplantation.

Delayed graft function (DGF) occurs in a significant proportion of deceased donor kidney transplant recipients and was associated with graft injury and inferior clinical outcome. The aim of the present multi-center study was to identify the immunological and non-immunological predictors of DGF and to determine its influence on outcome in the presence and absence of human leukocyte antigen (HLA) antibodies. 1,724 patients who received a deceased donor kidney transplant during 2008-2017 and on whom a pre-transplant serum sample was available were studied. Graft survival during the first 3 post-transplant years was analyzed by multivariable Cox regression. Pre-transplant predictors of DGF and influence of DGF and pre-transplant HLA antibodies on biopsy-proven rejections in the first 3 post-transplant months were determined by multivariable logistic regression. Donor age ≥50 years, simultaneous pre-transplant presence of HLA class I and II antibodies, diabetes mellitus as cause of end-stage renal disease, cold ischemia time ≥18 h, and time on dialysis >5 years were associated with increased risk of DGF, while the risk was reduced if gender of donor or recipient was female or the reason for death of donor was trauma. DGF alone doubled the risk for graft loss, more due to impaired death-censored graft than patient survival. In DGF patients, the risk of death-censored graft loss increased further if HLA antibodies (hazard ratio HR=4.75, < 0.001) or donor-specific HLA antibodies (DSA, HR=7.39, < 0.001) were present pre-transplant. In the presence of HLA antibodies or DSA, the incidence of biopsy-proven rejections, including antibody-mediated rejections, increased significantly in patients with as well as without DGF. Recipients without DGF and without biopsy-proven rejections during the first 3 months had the highest fraction of patients with good kidney function at year 1, whereas patients with both DGF and rejection showed the lowest rate of good kidney function, especially when organs from ≥65-year-old donors were used. In this new era of transplantation, besides non-immunological factors, also the pre-transplant presence of HLA class I and II antibodies increase the risk of DGF. Measures to prevent the strong negative impact of DGF on outcome are necessary, especially during organ allocation for presensitized patients.

Incidence of delayed graft function (DGF) increases due to the decline in donor kidney quality and the increased use of marginal allografts, while the promising biomarkers for early DGF prediction are lacking. Previous analyses showed that Tenascin-C (TNC) was associated with acute kidney injury; however, its correlation with DGF is unclear. This study aimed to evaluate the ability of TNC to predict DGF. This prospective study included 36 perioperative kidney transplant recipients. Serum and urine samples were collected at regular intervals before and during the 10 days after transplantation to measure TNC and other conventional biomarkers. Pre-implantation graft renal biopsies were analyzed using Remuzzi and TNC staining scores. These data were then combined with clinical risk factors to construct a DGF prediction model. In recipients with DGF, sTNC levels peaked on postoperative day 4, and were associated with increased risk of composite events (DGF and rehospitalization). uTNC levels were significantly higher in recipients without DGF, peaking at 8 hours postoperatively. sTNC levels at postoperative day 4 and TNC immunohistochemical scores were identified as independent risk factors for DGF. Incorporating the above two factors into a model comprising recipient age, cholesterol levels, donor cold ischemia time, and surgery duration significantly improved its ability to predict DGF, with the area under the curve increasing from 0.6790 to 0.9321. This study highlights the TNC levels in perioperative kidney transplant recipients and their correlation with DGF. sTNC levels and TNC immunohistochemical staining scores may serve as potential biomarker predicting DGF.

Delayed graft function (DGF) shortens the survival time of transplanted kidneys and increases the risk of rejection. Current methods are inadequate in predicting DGF. More precise tools are required to assess kidney suitability for transplantation. Cold-inducible RNA-binding protein (CIRBP) expression has been linked to acute kidney injury, suggesting its potential as a new biomarker for transplanted kidney function. We included deceased donors and recipients who had undergone successful kidney transplantation between 2016 and 2019. Recipients and their paired donors are assigned to either the DGF or immediate graft function (IGF) group, based on the recipient's recovery of graft renal function. Donor plasma CIRBP levels were measured using an enzyme-linked immunosorbent assay kit to assess their relationships with DGF. Donor plasma CIRBP concentrations in the DGF group were approximately twice as high as those in the IGF group (6.82 vs. 3.44; P<0.001). DGF occurred in all cases where CIRBP concentrations exceeded 7.92 ng/mL. Furthermore, univariate and multivariate analyses (odds ratio [OR]=1.660; P<0.001) confirmed that donor plasma CIRBP level was an independent risk factor for DGF. Additionally, higher CIRBP levels were associated with increased plasma creatinine at 6 months (R²=0.08; P<0.001), and survival analysis showed shorter kidney survival in recipients with DGF (P=0.002). This study demonstrated that donor plasma CIRBP levels can effectively predict the occurrence of DGF. CIRBP is a potential novel biomarker for evaluating transplanted kidney function. https://clinicaltrials.gov, identifier NCT06641622.

Early identification and prognostic stratification of delayed graft function following renal transplantation has significant potential to improve outcome. Mass spectrometry analysis of serum samples, before and on day 2 post transplant from five patients with delayed graft function and five with an uncomplicated transplant, identified aminoacylase-1 (ACY-1) as a potential outcome biomarker. Following assay development, analysis of longitudinal samples from an initial validation cohort of 55 patients confirmed that the ACY-1 level on day 1 or 2 was a moderate predictor of delayed graft function, similar to serum creatinine, complementing the strongest predictor cystatin C. A further validation cohort of 194 patients confirmed this association with area under ROC curves (95% CI) for day 1 serum (138 patients) of 0.74 (0.67–0.85) for ACY-1, 0.9 (0.84–0.95) for cystatin C, and 0.93 (0.88–0.97) for both combined. Significant differences in serum ACY-1 levels were apparent between delayed, slow, and immediate graft function. Analysis of long-term follow-up for 54 patients with delayed graft function showed a highly significant association between day 1 or 3 serum ACY-1 and dialysis-free survival, mainly associated with the donor–brain–dead transplant type. Thus, proteomic analysis provides novel insights into the potential clinical utility of serum ACY-1 levels immediately post transplantation, enabling subdivision of patients with delayed graft function in terms of long-term outcome. Our study requires independent confirmation.

Purpose To determine the predictive value of the atherogenic index of plasma before transplant for delayed graft function. Patients and Methods A cross‐sectional, longitudinal, non‐interventional, non‐controlled study of 167 patients undergoing kidney transplantation from living donors, with a mean age of 39.34 ± 11.86 years old, 53.3% male, and a pre‐transplant hemodialysis time of 14 (7–36) months. Delayed graft function was defined as decreased blood creatinine < 25% within the first 24 h compared to pre‐transplantation, and the patients needed hemodialysis in the first 7 days. The atherogenic index of plasma was calculated based on pre‐transplant plasma triglycerides and high‐density lipoprotein cholesterol concentrations. Results The ratio of delayed graft function in renal transplant recipients from living donors was 13.8% (23/167 patients). Hemodialysis time, the ratio of hepatitis infection, overweight and obese, atherosclerosis, positive PRA, and acute rejection in the DGF (+) group were higher than those of the DGF (−) group, p < 0.05 and < 0.001. In particular, plasma CRP‐hs level and AIP also were higher in DGF (+) patients compared to those of DGF (−) ones, p < 0.001. Long hemodialysis time, obesity, high plasma CRP‐hs, and high AIP in pre‐transplant patients were independent factors related to DGF and had predictive value for DGF after kidney transplantation, in which AIP had good predictive value: AUC = 0.859, p < 0.001. Conclusion Delayed graft function was relatively common in renal transplant recipients from living donors. AIP before kidney transplant was a good predictor for delayed graft function. The incidence of delayed graft function (DGF) in renal transplant recipients from living donors was 13.8% (23/167 patients). Factors such as longer hemodialysis duration, higher rates of hepatitis infection, overweight/obesity, atherosclerosis, positive PRA, and acute rejection were significantly more common in the DGF (+) group compared to the DGF (−) group. Notably, plasma CRP‐hs levels and AIP were also higher in the DGF (+) group. Long hemodialysis duration, obesity, elevated plasma CRP‐hs, and high AIP in pre‐transplant patients were independent factors associated with DGF, with AIP showing strong predictive value.