Delayed Graft Function Patients Research Articles

Prediction of delayed graft function by early salivary microbiota following kidney transplantation

Delayed graft function (DGF) is a frequently observed complication following kidney transplantation (KT). Our prior research revealed dynamic shifts in salivary microbiota post-KT with immediate graft function (IGF), yet its behavior during DGF remains unexplored. Five recipients with DGF and 35 recipients with IGF were enrolled. Saliva samples were collected during the perioperative period, and 16S rRNA gene sequencing was performed. The salivary microbiota of IGFs changed significantly and gradually stabilized with the recovery of renal function. The salivary microbiota composition of DGFs was significantly different from that of IGFs, although the trend of variation appeared to be similar to that of IGFs. Salivary microbiota that differed significantly between patients with DGF and IGF at 1 day after transplantation were able to accurately distinguish the two groups in the randomForest algorithm (accuracy = 0.8333, sensitivity = 0.7778, specificity = 1, and area under curve = 0.85), with Selenomonas playing an important role. Bacteroidales (Spearman’s r = − 0.4872 and p = 0.0293) and Veillonella (Spearmen’s r = − 0.5474 and p = 0.0125) were significantly associated with the serum creatinine in DGF patients. Moreover, the significant differences in overall salivary microbiota structure between DGF and IGF patients disappeared upon long-term follow-up. This is the first study to investigate the dynamic changes in salivary microbiota in DGFs. Our findings suggested that salivary microbiota was able to predict DGF in the early stages after kidney transplantation, which might help the perioperative clinical management and early-stage intervention of kidney transplant recipients.Key points• Salivary microbiota on the first day after KT could predict DGF.• Alterations in salivary taxa after KT are related to recovery of renal function.

Association between peri-transplant acid-base parameters and graft dysfunction types in kidney transplantation.

Perioperative acid-base disturbance could be informative regarding the possible slow graft function (SGF) or delayed graft function (DGF) development. There is a lack of data regarding the relationship between perioperative acid-base parameters and graft dysfunction in kidney transplant (KT) recipients. We aim to determine the incidence of graft dysfunction types and the association between them and acid-base parameters. We performed a prospective, cohort study on 54 adults, KT recipients, between 1st of January 2019 and 31st of December 2019. Graft function was defined and classified in three categories: immediate graft function (IGF) (serum creatinine < 3 mg/dL at day 5 after KT), SGF (serum creatinine ≥ 3mg/dL at day 5 or ≥ 2.5mg dL at day 7 after KT) and DGF (the need for at least one dialysis treatment in the first week after kidney transplantation). Among the 54 KT recipients, the incidence of SGF and DGF was 13% and 11.1%, respectively. SGF was significantly associated with lower intraoperative pH (7.26± 0.05 vs 7.35± 0.06, p= 0.004), preoperative and intraoperative base excess (BE) [-7.0 (-10.0 ߝ -6.0) vs -3.4 (-7.8 ߝ - 2.1) mmol/L, p= 0.04 and -10.3 (-11.0 ߝ -9.1) vs -4.0 (-6.3 ߝ - 3.0) mmol/L, p= 0.002, respectively] and serum bicarbonate (HCO3-) (16.0± 2.7 vs 19.3± 3.4 mmol/L, p= 0.01 and 14.1± 1.9 vs 18.8± 3.2 mmol/L, p= 0.002 respectively), compared to IGF. DGF was significantly associated with lower intraoperative values of pH (7.27± 0.05 vs 7.35± 0.06, p= 0.003), BE [-7.1 (-10.9 ߝ -6.1) vs -4.0 (-6.3 ߝ - 3.0) mmol/L, p= 0.02] and HCO3- (15.9± 2.4 vs 18.8± 3.2 mmol/L, p=0.02) compared to IGF. No differences were observed between SGF and DGF patients in any of the perioperative acid-base parameters. In conclusion we found that kidney graft dysfunction types are associated with perioperative acid-base parameters and perioperative metabolic acidosis could provide important information to predict SGF or DGF occurrence.

Comprehensive analysis of necroptosis-related genes in renal ischemia-reperfusion injury.

Oxidative stress is the primary cause of ischemia-reperfusion injury (IRI) in kidney transplantation, leading to delayed graft function (DGF) and implications on patient health. Necroptosis is believed to play a role in renal IRI. This research presents a comprehensive analysis of necroptosis-related genes and their functional implications in the context of IRI in renal transplantation. The necroptosis-related differentially expressed genes (NR-DEGs) were identified using gene expression data from pre- and post-reperfusion renal biopsies, and consensus clustering analysis was performed to distinguish necroptosis-related clusters. A predictive model for DGF was developed based on the NR-DEGs and patients were divided into high- and low-risk groups. We investigated the differences in functional enrichment and immune infiltration between different clusters and risk groups and further validated them in single-cell RNA-sequencing (scRNA-seq) data. Finally, we verified the expression changes of NR-DEGs in an IRI mouse model. Five NR-DEGs were identified and were involved in various biological processes. The renal samples were further stratified into two necroptosis-related clusters (C1 and C2) showing different occurrences of DGF. The predictive model had a reliable performance in identifying patients at higher risk of DGF with the area under the curve as 0.798. Additionally, immune infiltration analysis indicated more abundant proinflammatory cells in the high-risk group, which was also found in C2 cluster with more DGF patients. Validation of NR-DEG in scRNA-seq data further supported their involvement in immune cells. Lastly, the mouse model validated the up-regulation of NR-DEGs after IR and indicated the correlations with kidney function markers. Our research provides valuable insights into the identification and functional characterization of NR-DEGs in the context of renal transplantation and sheds light on their involvement in immune responses and the progression of IRI and DGF.

Early kinetics of donor-derived cell-free DNA after transplantation predicts renal graft recovery and long-term function.

Ischemia-reperfusion injury (IRI) upon transplantation is one of the most impactful events that the kidney graft suffers during its life. Its clinical manifestation in the recipient, delayed graft function (DGF), has serious prognostic consequences. However, the different definitions of DGF are subject to physicians' choices and centers' policies, and a more objective tool to quantify IRI is needed. Here, we propose the use of donor-derived cell-free DNA (ddcfDNA) for this scope. ddcfDNA was assessed in 61 kidney transplant recipients of either living or deceased donors at 24 h, and 7, 14 and 30 days after transplantation using the AlloSeq cfDNA Kit (CareDx, San Francisco, CA, USA). Patients were followed-up for 6 months and 7-year graft survival was estimated through the complete and functional iBox tool. Twenty-four-hour ddcfDNA was associated with functional DGF [7.20% (2.35%-15.50%) in patients with functional DGF versus 2.70% (1.55%-4.05%) in patients without it, P=.023] and 6-month estimated glomerular filtration rate (r=-0.311, P=.023). At Day 7 after transplantation, ddcfDNA was associated with dialysis duration in DGF patients (r=0.612, P=.005) and worse 7-year iBox-estimated graft survival probability (β -0.42, P=.001) at multivariable analysis. Patients with early normalization of ddcfDNA (<0.5% at 1 week) had improved functional iBox-estimated probability of graft survival (79.5±16.8%) in comparison with patients with 7-day ddcfDNA ≥0.5% (67.7±24.1%) (P=.047). ddcfDNA early kinetics after transplantation reflect recovery from IRI and are associated with short-, medium- and long-term graft outcome. This may provide a more objective estimate of IRI severity in comparison with the clinical-based definitions of DGF.

Current opinions on DGF management practices: A survey of the United States and Canada.

Significant center-to-center variation in attitudes and management of delayed graft function (DGF) remains common. A survey to describe current DGF practices was developed by workgroup members sponsored by the National Kidney Foundation (NKF) and was distributed to both the NKF DGF workgroup members, kidney transplant program directors and the transplant community within the United States and Canada. Seventy-one percent of NKF workgroup members completed the survey along with 70 unique the United States and three Canadian kidney transplant programs. All Organ Procurement and Transplantation Network (OPTN) regions were represented. DGF was reported to occur at rate of 20%-40% for most centers with 3.9% indicating their incidence to be>60%. Most centers reported longer hospital lengths of stay and more frequent outpatient visits. Despite the commonality of DGF, only half of centers reported having an established protocol to manage DGF. Kidney allograft biopsies were the only consistent DGF management strategy observed, although use of machine perfusion was also heavily favored. Other DGF management strategies voiced by a minority included having established outpatient practices to care for DGF patients and administering outpatient community-based hemodialysis. Although approximately a third of survey responders indicated that risk of DGF played a role in their willingness to accept organs, most did not feel that increased cost or clinical impact on outcomes was a deterrent. Future strategies, including broader sharing of best practices, redefining terminology specific to DGF, the establishment of DGF dialysis guidelines and improving access to machine perfusion across OPOs may help reduce discard and improve utilization of kidneys at risk for DGF.

MiR-20a-5p alleviates kidney ischemia/reperfusion injury by targeting ACSL4-dependent ferroptosis

Ischemia/reperfusion injury (IRI) is prone to occur after kidney transplantation, leading to delayed graft function (DGF). MicroRNAs play a crucial role in the pathogenesis of ischemia/reperfusion–induced acute kidney injury, and miR-20a-5p was found to be the most significantly upregulated gene in a DGF patient cohort. However, the roles of microRNAs in transplanted kidneys remain largely unknown. In this study, we found that miR-20a-5p was upregulated in the kidneys of acute kidney injury mice and in patients with DGF. We identified early growth response-1 as a critical upstream target and verified the binding of early growth response-1 to a predicted sequence in the promoter region of the miR-20a-5p gene. Functionally, the miR-20a-5p mimic attenuated IRI and postischemic renal fibrosis, whereas the miR-20a-5p inhibitor delivery aggravated IRI and fibrosis. Importantly, delivery of the miR-20a-5p mimic or inhibitor in the donor kidneys attenuated or aggravated renal loss and structural damage in cold storage transplantation injury. Furthermore, our study identified miR-20a-5p as a negative regulator of acyl-CoA synthetase long-chain family member 4 (ACSL4) by targeting the 3′ untranslated region of ACSL4 mRNA, thereby inhibiting ACSL4-dependent ferroptosis. Our results suggest a potential therapeutic application of miR-20a-5p in kidney transplantation through the inhibition of ACSL4-dependent ferroptosis.

Intravoxel Incoherent Motion-Diffusion-Weighted MRI for Investigation of Delayed Graft Function Immediately after Kidney Transplantation.

Purpose A non-invasive way of assessing post-transplant renal graft function has been needed. This study aimed to assess the micro-structural and micro-functional status of graft kidneys by using intravoxel incoherent motion- (IVIM-) diffusion-weighted imaging (DWI) to investigate delayed graft function (DGF) immediately after transplantation. Method A prospective study was conducted on 37 patients, 14 with early graft function (EGF) and 23 with DGF (9 with complication, 14 without) who underwent IVIM-DWI, most often within 1-7 days after kidney transplantation. A total of 37 cases were collected and all the participants have been well-informed and signed their consents. In addition, the study conducted in this paper was approved by the Ethics Committee of Clinical Research, Taichung Veterans General Hospital (IRB number: CE14065). Using biexponential analysis of slow diffusion coefficient (Dslow), fast diffusion coefficient (Dfast), and perfusion fraction was performed. The apparent diffusion coefficient (ADC) was calculated by use of a monoexponential model. All parameters were measured from three different regions-of-interest (ROI), covering the entire renal parenchyma, cortex, and medulla. Results D slow, perfusion fraction, and ADC were significantly higher in patients with EGF than DGF (all p values values <0.001). Especially, ADC measured from ROI covering the entire kidney parenchyma had the best cut-off value (1.93μm2/msec) with the highest area under the receiver operating characteristic curve (AUC 0.943) in differentiating EGF from DGF. For analysis of pair-wise differences, only the perfusion fraction values, measured from the ROI covering the renal cortex, were significantly higher in 14 DGF patients with no complications than in the 9 DGF patients with complications, with the best cut-off value of 12.3% and the AUC of 0.844. Conclusion Noninvasive IVIM-DWI reliably differentiates DGF from EGF after kidney transplantation, and it may aid in identifying posttransplant complications and indications for renal biopsy.

Delayed Graft Function Duration in Deceased Donor Kidney Transplants

Delayed graft function (DGF) is an important prognostic indicator after kidney transplantation. Depending on the severity of the ischemia-reperfusion injury, DGF can have several clinical presentations, with different renal function recovery times. Both the presence and duration of DGF can have an impact on kidney transplantation outcomes. However, the definition of the cutoff point, above which the outcomes are worse, varies widely in the literature. To investigate the impact of DGF and its duration on patient and graft survivals, a single-center retrospective study including all deceased donor kidney transplants was performed between November 2008 and December 2015 (n=188). Through the analysis on the receiver operating characteristic curve, the cutoff point that determined the worst outcome was reached. DGF patients were then divided according to the duration of DGF (<8 days or ≥8 days). The overall incidence of DGF was 62.2%. Higher HLA mismatches was an independent risk factor for prolonged DGF. DGF ≥8 days was associated with acute rejection and this one was associated with patient death in 3 years. DGF with a duration of more than 8 days associated with higher HLA mismatches increases the risk of acute rejection, but graft loss and patient survival are not affected by DGF, regardless of its duration.

Quantitative assessment of inflammatory infiltrates in kidney transplant biopsies using multiplex tyramide signal amplification and deep learning

Delayed graft function (DGF) is a strong risk factor for development of interstitial fibrosis and tubular atrophy (IFTA) in kidney transplants. Quantitative assessment of inflammatory infiltrates in kidney biopsies of DGF patients can reveal predictive markers for IFTA development. In this study, we combined multiplex tyramide signal amplification (mTSA) and convolutional neural networks (CNNs) to assess the inflammatory microenvironment in kidney biopsies of DGF patients (n = 22) taken at 6 weeks post-transplantation. Patients were stratified for IFTA development (<10% versus ≥10%) from 6 weeks to 6 months post-transplantation, based on histopathological assessment by three kidney pathologists. One mTSA panel was developed for visualization of capillaries, T- and B-lymphocytes and macrophages and a second mTSA panel for T-helper cell and macrophage subsets. The slides were multi spectrally imaged and custom-made python scripts enabled conversion to artificial brightfield whole-slide images (WSI). We used an existing CNN for the detection of lymphocytes with cytoplasmatic staining patterns in immunohistochemistry and developed two new CNNs for the detection of macrophages and nuclear-stained lymphocytes. F1-scores were 0.77 (nuclear-stained lymphocytes), 0.81 (cytoplasmatic-stained lymphocytes), and 0.82 (macrophages) on a test set of artificial brightfield WSI. The CNNs were used to detect inflammatory cells, after which we assessed the peritubular capillary extent, cell density, cell ratios, and cell distance in the two patient groups. In this cohort, distance of macrophages to other immune cells and peritubular capillary extent did not vary significantly at 6 weeks post-transplantation between patient groups. CD163+ cell density was higher in patients with ≥10% IFTA development 6 months post-transplantation (p < 0.05). CD3+CD8−/CD3+CD8+ ratios were higher in patients with <10% IFTA development (p < 0.05). We observed a high correlation between CD163+ and CD4+GATA3+ cell density (R = 0.74, p < 0.001). Our study demonstrates that CNNs can be used to leverage reliable, quantitative results from mTSA-stained, multi spectrally imaged slides of kidney transplant biopsies.This study describes a methodology to assess the microenvironment in sparse tissue samples. Deep learning, multiplex immunohistochemistry, and mathematical image processing techniques were incorporated to quantify lymphocytes, macrophages, and capillaries in kidney transplant biopsies of delayed graft function patients. The quantitative results were used to assess correlations with development of interstitial fibrosis and tubular atrophy.

Activation of final complement components after kidney transplantation as a marker of delayed graft function severity

BackgroundIschaemia–reperfusion (I/R) damage is a relevant cause of delayed graft function (DGF). Complement activation is involved in experimental I/R injury, but few data are available from kidney transplant (KT) patients. We studied the dynamics of membrane attack complex (C5b-9) as a soluble fraction (SC5b-9) and the histological deposit pattern of C3b, complement Factor H (FH) and C5b-9 in DGF patients.MethodsWe evaluated SC5b-9 levels in 59 recipients: 38 with immediate graft function and 21 with DGF. The SC5b-9 was measured at admission for KT and 7 days after KT. DGF-kidney biopsies (n = 12) and a control group of 1-year protocol biopsies without tissue damage (n = 4) were stained for C5b-9, C3b and FH.ResultsSC5b-9 increased significantly in DGF patients (Day 0: 6621 ± 2202 mAU/L versus Day 7: 9626 ± 4142 mAU/L; P = 0.006), while it remained stable in non-DGF patients. Days 0–7 increase >5% was the better cut-off associated with DGF versus non-DGF patient discrimination (sensitivity = 81%). In addition, SC5b-9 increase was related to DGF duration and worse graft function, and independently associated with DGF occurrence. SC5b-9, C3b and FH stains were observed in tubular epithelial cells basal membrane. DGF-kidney biopsies showed a more frequently high-intensity stain, a higher number of tubules with positive stain and larger perimeter of tubules with positive stains for SC5b-9, C3b and FH than control patients.ConclusionsBoth SC5b-9 levels and SC5b-9, C3b and FH deposits in tubular epithelial cells basal membrane are highly expressed in patients experiencing DGF. SC5b-9 levels increase could be useful as a marker of DGF severity.

Analysis of risk factors for early urinary tract infection after kidney transplantation.

BackgroundUrinary tract infection (UTI) is the most common kind of infection in the early stage after kidney transplantation. Although many studies have investigated the risk factors for UTI following kidney transplantation, few studies have focused on the risk factors for UTI in the early stage after transplantation.MethodsThe early-stage data of patients who underwent kidney transplantation between January 2018 and December 2019 in a first-class tertiary hospital in Suzhou, China, were retrospectively analyzed. The general and UTI information of the recipients was subjected to univariate analysis. Variables with statistical significance in the univariate analysis were included in a multivariate logistic regression model.ResultsA total of 129 recipients were recruited, among whom 62 patients had a UTI in the early stage after kidney transplantation (48.1%), and the median (interquartile range) of onset time was 5 (4, 10) days after the surgery. A total of 324 strains of UTI pathogens were detected in the 62 recipients after kidney transplantation, 279 of which were gram-negative bacilli (86.1%). Multivariate logistic regression analysis showed that female sex and delayed graft function (DGF) were independent risk factors for early-stage UTI, with odds ratios of 0.095 and 3.753, respectively.ConclusionsThe incidence of early UTI after kidney transplantation is high. Females and DGF patients are more prone to UTIs. Comprehensive prevention and treatment measures should be taken as early as possible against the risk factors to reduce the incidence of UTI.

Delayed Graft Function and Acute Rejection in Kidney Transplant Patients with Positive Panel-Reactive Antibody and Negative Donor-Specific Antibodies

Background: Delayed graft function (DGF) and acute rejection (AR) are common complications in kidney transplant patients. Objectives: The study evaluated DGF and AR in highly sensitized patients and their effects on kidney function for six months post-transplantation. Methods: We enrolled 95 patients with kidney transplants from living donors who were divided into two groups. Group 1 included 47 highly sensitized patients with panel reactive antibody (PRA) &lt; 20.0% and negative donor-specific antigen, and group 2 included 48 patients with negative PRA. All patients were followed for the state of DGF, AR, and kidney function for six months. Results: Group 1 showed a significantly higher proportion of DGF and AR than group 2 (27.7% versus 2.1%, P &lt; 0.001 and 14.9% versus 2.1%, P = 0.031, respectively). The rates of positive PRA in DGF and AR patients were significantly higher than those in non-DGF and non-AR patients (92.9% versus 42.0%, P &lt; 0.001 and 87.5% versus 46.0%, P = 0.031, respectively). Transplanted kidney function was significantly worse in patients with PRA and DGF and/or AR than in patients with negative PRA and non-DGF and non-AR only in the seventh-day post-transplantation. Conclusions: Kidney transplant in highly sensitized patients with positive PRA was related to the increased ratio of DGF and AR.

PRE-TRANSPLANT HLA ANTIBODIES AND DELAYED GRAFT FUNCTION IN THE CURRENT ERA OF KIDNEY TRANSPLANTATION

Collaborative Transplant Study. Introduction: We reported previously that early adverse events in deceased donor kidney transplantation, such as delayed graft function (DGF) and rejection episodes, are associated with pre-transplant presence of HLA antibodies and that patients with adverse events show significantly impaired graft survival rates. In the meantime, the introduction of sensitive antibody detection techniques is expected to have diminished the involvement of overlooked HLA antibodies in DGF. On the other hand, DGF risk might have increased due to growing use of kidneys from elderly donors. 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 HLA antibodies in the new era of transplantation. Methods: 1,724 patients who received a deceased donor kidney transplant during 2008–2017 and on whom a pre-transplant serum sample and the information on immediate function within the first 24 hours after transplantation, dialysis during the first week, and biopsy-proven rejection during the first 3 months were available. Graft survival after day 7 during the first 3 years post-transplant was analyzed by multivariable Cox regression. Predictors of DGF and influence of DGF and pre-transplant HLA antibodies on biopsy-proven rejections during days 8–90 were determined by multivariable logistic regression. DGF was defined as either no graft function during the first 24 hours and/or dialysis during the first week. In 44% of cases, we were informed by the centers on the presence or absence of pre-transplant donor-specific antibodies (DSA) as determined by single antigen technique. Results and Discussion: Donor age ≥50 years, simultaneous presence of HLA class I and II antibodies pre-transplant, diabetes mellitus as original disease, cold ischemia time ≥18 hours, and time on dialysis >5 years were associated with an increased risk of DGF. DGF alone doubled the risk for all cause 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 (HR=4.75, P<0.001) or donor-specific HLA antibodies (DSA, HR=7.39, P<0.001) were present prior to transplantation. In the presence of HLA antibodies or DSA, the incidence of biopsy-proven 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 post-transplant, whereas patients with both DGF and rejection showed the lowest rate of good kidney function. Our data indicate that, in the current era of transplantation, besides non-immunological factors, also the pre-transplant presence of HLA class I and II antibodies increase the risk of DGF. Conclusion: Patients with DGF require special attention, especially in the presence of HLA antibodies.

Pre-transplant HLA Antibodies and Delayed Graft Function in the Current Era of 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, P < 0.001) or donor-specific HLA antibodies (DSA, HR=7.39, P < 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.

Relevance of KDPI value and acute rejection on kidney transplant outcomes in recipients with delayed graft function - a retrospective study.

Delayed graft function (DGF) is associated with poorer graft survival and higher rate of acute rejection (AR). It is unknown whether this negative influence relies on the increased risk of AR or the DGF itself. The different Kidney Donor Profile Index (KDPI) values may also play a role in this interaction. Retrospective study aimed to evaluate the impact of DGF on graft function and graft survival in a subset of KT recipients (2004-2017). We also analyzed the relationship between KDPI and DGF. The study includes 601 KT, 226 of them (37%) developed DGF. Graft survival was lower in patients with DGF compared with non-DGF patients. Multivariable analysis revealed DGF as risk factor for graft loss, independently of the presence or not of acute rejection. Between DGF patients, we observed poorer graft survival in patients with higher KDPI value (>85%). We observed a trend of a greater impact of KDPI in patients with DGF, although this interaction was not statistically significant. Additionally, we observed poorer 12-month graft function in DGF patients. DGF is related to poorer graft survival independently of the developed acute rejection. This negative impact might be influenced by high KDPI values.

P1601COMPLEMENT MEMBRANE ATTACK COMPLEX DURING THE FIRST WEEK AFTER KIDNEY TRANSPLANTATION AS SEVERITY BIOMARKER TO DELAYED GRAFT FUNCTION

Abstract Background and Aims Ischemia-reperfusion (I/R) damage is a relevant cause of delayed graft function (DGF). Complement activation is involved in experimental I/R injury, but few data are available about the expression of the complement cascade final component -membrane attack complex (MAC)- and I/R injury in KT patients. We studied the dynamics of membrane attack complex (MAC) as plasma fraction (pMAC) and the histological deposit pattern of C3b, complement factor H (FH) and MAC in DGF patients. Method We evaluated pMAC levels in 59 recipients, 38 with immediate graft function and 21 without serum creatinine decreased at day 7 (DGF). pMAC was measured at admission for KT (day 0) and 7 days after KT (day 7). Sandwich ELISAs were used to measure MAC. Additionally, we performed imunohistoquimical stained for MAC, C3b and kidney biopsies (KB) with DGF (n=12) and a control group of one-year protocol biopsies without damage (n=4) Results Patients in the DGF group were older, more frequently diabetics and received kidneys from older donors and more frequently controlled cardio-circulatory death type. Day0 and day7 post-KT pMAC levels were similar in non-DGF patients 5902±3049 mAu/L vs 6178±2882 mAu/L; p=0.686). However, patients with DGF showed a significant increase of pMAC levels between day0 and day7 (6621±2202 mAu/L vs 9625±4142 mAu/L; p=0.006. Figure 1 Percentage pMAC levels increase (Δ0-7 pMAC%) discriminative assessment analyzed by ROC curve showed a good discriminative value for DGF with an AUC of 0.78; p&amp;lt;0.001 (sensitivity 81%, specificity 66% by cut-off point of 5%). In patients with DGF longer than ten days, we found more frequently patients with a Δ0-7 pMAC &amp;gt;5% (83% vs 17% Δ0-7 pMAC &amp;lt;5% ; p=0.003).Patients with DGF showed renal function at 3 and 6 months, but worse renal function 1 year after KT (serum creatinine 1.78±0.61 vs 1.35±0.30 mg/dl in non-DGF patients). DGF patients with Δ0-7 pMAC &amp;gt;5% displayed worse renal function 1 and 2 year after KT compared to DGF patients with Δ0-7 pMAC &amp;lt;5%. MAC, C3b and FH stains were observed in tubular epithelial cells basal membrane. DGF-kidney biopsies showed more frequently high-intensity stain for MAC and FH than controls, without differences to C3b stain. DGF-kidney biopsies also showed a higher number of tubules with positive stain and larger perimeter of tubules with positive stains for MAC, C3b and FH than the controls. Figure 2. Among the 12 patients with DGF-biopsies, three (25%) never recovered renal function, all of them presented Δ0-7 pMAC &amp;gt;5% and intense, diffuse and positive staining in more than 50% of tubular perimeter for MAC, FH and C3b Conclusion Complement activation during peritrasplant period could be related with the severity of graft injury and the presence of DGF. Therefore, the determination of MAC levels could be useful to identify patients with possible complement dependent graft injury that might benefit from complement inhibitor therapies

Comparison of low-dose and standard-dose mycophenolate mofetil in kidney transplant patients with delayed graft function

Objective To investigate the effects of different doses of mycophenolate mofetil (MMF) in delayed graft function (DGF) patients in the early stage after kidney transplantation. Methods This one-year, single-center retrospective study was designed to compare complications such as infection and rejection of different doses of MMF in DGF patients in the early stage after kidney transplantation. The DGF patients were divided into two groups according to their oral MMF dose: a standard-dose group (SMDGF, n=17) and a low-dose group (LMDGF, n=16). Thirty non-DGF recipients (NDGF) were selected as a control group during this period. Results The results showed that the glomerulosclerosis rate was an independent risk factor for infection in DGF patients [odds ratio (OR): 0.37; 95% confidence interval (CI): 0.19-0.73; P<0.01]. The infection rate was significantly higher in the SMDGF group than in the NDGF group (58.8% vs. 26.7%, χ2=4.748, P<0.05) and in the LMDGF group (18.8% vs. 58.8%, χ2=5.544, P<0.05). The mycophenolic acid area under curve of the low-dose MMF regimen was within the therapeutic window. The low-dose MMF regimen did not increase the risk of acute rejection in DGF patients. Conclusion For patients with DGF, low-dose MMF reduces the infection rate, while the risk of acute rejection does not increase. Key words: Delayed graft function; Mycophenolate mofetil; Renal biopsy; Kidney transplantation

The Lifetime Health Burden of Delayed Graft Function in Kidney Transplant Recipients in the United States.

Background. Although delayed graft function (DGF) is associated with an increased risk of acute rejection and decreased graft survival, there are no estimates of the long-term or lifetime health burden of DGF. Objectives. To estimate the long-term and lifetime health burden of DGF, defined as the need for at least one dialysis session within the first week after transplantation, for a cohort representative of patients who had their first kidney transplant in 2014. Methods. Data from the United States Renal Data System (USRDS; 2001–2014) were used to estimate a semi-Markov parametric multi-state model with three disease states. Maximum length of follow-up was 13.7 years, and a microsimulation model was used to extrapolate results over a lifetime. The impact of DGF was assessed by simulating the model for each patient in the cohort with and without DGF. Results. At the end of 13.7 years of follow-up, DGF reduces the probability of having a functioning graft from 52% to 32%, increases the probability of being on dialysis from 10% to 19%, and increases the probability of death from 38% to 50% relative to transplant recipients who do not experience DGF. A typical transplant recipient with DGF (median age = 53) is observed to lose 0.87 quality-adjusted life-years (QALYs). Extrapolated over a lifetime, the same 53-year-old DGF patient is projected to lose 3.01 (95% confidence interval: 2.33, 3.70) QALYs relative to a transplant recipient with the same characteristics who does not experience DGF. Conclusions. The lifetime health burden of DGF is substantial. Understanding these consequences will help health care providers weigh kidney transplant decisions and inform policies for patients in the context of varying risks of DGF.

The recovery status from delayed graft function can predict long-term outcome after deceased donor kidney transplantation

The effect of delayed graft function (DGF) recovery on long-term graft outcome is unclear. The aim of this study was to examine the association of DGF recovery status with long-term outcome. We analyzed 385 recipients who underwent single kidney transplantation from brain-dead donors between 2004 and 2015. Patients were grouped according to renal function at 1 month post-transplantation: control (without DGF); recovered DGF (glomerular filtration rate [GFR] ≥ 30 mL/min/1.73 m2); and incompletely recovered DGF group (GFR < 30 mL/min/1.73 m2). DGF occurred in 104 of 385 (27%) recipients. Of the DGF patients, 70 recovered from DGF and 34 incompletely recovered from DGF. Death-censored graft survival rates for control, recovered DGF, and incompletely recovered DGF groups were 95.3%, 94.7%, and 80.7%, respectively, at 5 years post-transplantation (P = 0.003). Incompletely recovered DGF was an independent risk factor for death-censored graft loss (HR = 3.410, 95%CI, 1.114-10.437). DGF was associated with increased risk for patient death regardless of DGF recovery status. Mean GFRs at 5 years were 65.5 ± 20.8, 62.2 ± 27.0, and 45.8 ± 15.4 mL/min/1.73 m2 for control, recovered, and incompletely recovered DGF groups, respectively (P < 0.001). Control group and recovered DGF patients had similar renal outcomes. However, DGF was associated with increased risk for patient death regardless of DGF recovery status.

Intraoperative Pleth Variability Index Is Linked to Delayed Graft Function After Kidney Transplantation.

Delayed graft function (DGF) is an early postoperative complication of kidney transplantation (KT) predisposing to acute rejection and lower graft survival. Intraoperative arterial hypotension and hypovolemia are associated with DGF. Central venous pressure (CVP) is used to estimate volemia but its reliability has been criticized. Pleth variability index (PVI) is a hemodynamic parameter predicting fluid responsiveness. The aim of this study was to examine the relationship between intraoperative PVI and CVP values and the occurrence of DGF. This was a prospective, noninterventional, observational, single-center study. All consecutive patients with KT from deceased donors were included. Recipients received standard, CVP, and PVI monitoring. Intraoperative hemodynamic parameters were recorded from recipients at 5 time points during KT. Forty patients were enrolled. There was a poor correlation between PVI and CVP values (r2= 0.003; P= .44). Immediate graft function and DGF patients had similar hemodynamic values during KT, with the exception of PVI values, which were significantly higher in the DGF group. In particular, a PVI >9% before unclamping of the renal artery was the only predictive parameter of DGF in our multivariate analysis (P= .02). This study suggests that PVI values >9% during KT are associated with the occurrence of DGF.