Necroptosis-related genes allow novel insights into predicting graft loss and diagnosing delayed graft function in renal transplantation.

Ischemia-reperfusion injury (IRI) is an inevitable pathophysiological phenomenon in kidney transplantation. Necroptosis is an undoubtedly important contributing mechanism in renal IRI. We first screened differentially expressed necroptosis-related genes (DENRGs) from public databases. Eight DENRGs were validated by independent datasets and verified by qRT-PCR in a rat IRI model. We used univariate and multivariate Cox regression analyses to establish a prognostic signature, and graft survival analysis was performed. Immune infiltrating landscape analysis and gene set enrichment analysis (GSEA) were performed to understand the underlying mechanisms of graft loss, which suggested that necroptosis may aggravate the immune response, resulting in graft loss. Subsequently, a delayed graft function (DGF) diagnostic signature was constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) and exhibited robust efficacy in validation datasets. After comprehensively analyzing DENRGs during IRI, we successfully constructed a prognostic signature and DGF predictive signature, which may provide clinical insights for kidney transplant.

The hepatocyte growth factor mimetic, ANG-3777, in kidney transplant recipients with delayed graft function: Results from a randomized phase 3 trial.

In kidney transplant recipients, delayed graft function increases the risk of graft failure and mortality. In a phase 3, randomized, double-blind, placebo-controlled trial, we investigated the hepatocyte growth factor mimetic, ANG-3777 (once daily for 3 consecutive days, starting ≤30 hours posttransplant), in 248 patients receiving a first kidney transplant from a deceased donor. At day 360, estimated glomerular filtration rate (primary endpoint) was not significantly different between the ANG-3777 and placebo groups. There were no significant between-group differences in the duration of dialysis through day 30 or in the percentage of patients with an estimated glomerular filtration rate of >30 mL/min/1.73 m2 at day 360. The incidence of both delayed graft function and acute rejection was similar between ANG-3777 and placebo groups (68.5% vs 69.4% and 8.1% vs 6.5%, respectively). ANG-3777 was well tolerated, and there was a numerically lower incidence of graft failure versus placebo (3.2% vs 8.1%). Although there is insufficient evidence to support an indication of ANG-3777 for patients at risk of renal dysfunction after deceased-donor kidney transplantation, these findings indicate potential biological activity that may warrant further investigation.

Establishing targets for goal-directed anesthesia in renal transplantation: A cohort analysis of high-saliency surgical time courses.

Delayed graft function (DGF) increases morbidity and mortality in kidney transplant recipients. Operative parameters, including hemodynamic manipulation through vasopressors and fluids, can impact perfusion to the newly transplanted kidney and influence DGF incidence. We analyzed intraoperative time-series data in 5-minute intervals from kidney transplant recipient operations (N = 545) in conjunction with pretransplant characteristics and postsurgical outcomes, including DGF incidence, 60-day creatinine, and graft survival. Of the operations, 127 DGF events were captured in our cohort from a single academic transplant center (57/278 donations after brainstem death [DBDs], 65/150 donations after circulatory/cardiac death [DCDs], 5/117 live donations). In multiple regression, postanastomosis hypotension defined as mean arterial pressure (MAP) <75 mmHg was a risk factor for DGF independent of conventional predictors of DGF in DCD and DBD kidneys. DCD recipients with DGF had lower average postanastomosis MAP (DGF: 80.1 ± 8.1 mmHg vs no DGF: 76.4 ± 6.7 mmHg, P = .004). Interaction analysis demonstrated above-average doses of vasopressors and crystalloids were associated with improved outcomes when used at MAPs ≤75 mmHg, but they were associated with increased DGF at MAPs >75 mmHg, suggesting that the incidence of DGF can be highly influenced by intraoperative hemodynamic controls. This analysis of surgical time courses has identified potential new strategies for goal-directed anesthesia in renal transplantation.

The differential impact of early graft dysfunction in kidney donation after brain death and after circulatory death: Insights from the Dutch National Transplant Registry.

Kidneys donated after circulatory death (DCD) perform similarly to kidneys donated after brain death (DBD). However, the respective incidences of delayed graft function (DGF) differ. This questions the donor type-specific impact of early graft function on long-term outcomes. Using competing risk and Cox-regression analysis, we compared death-censored graft loss between types of early graft function: DGF (temporary dialysis dependency started within 7 days after transplantation), slow graft function (3-day plasma creatinine decline less than 10% per day), and immediate graft function. In 1061 DBD and 1605 DCD graft recipients (January 2014 until January 2023), graft survival was similar. DGF was associated with death-censored graft loss in DBD and DCD (adjusted hazard ratios: DGF in DBD: 1.79 [1.04-2.91], P = .027, DGF in DCD: 1.84 [1.18-2.87], P = .008; Reference: no DGF). Slow graft function was associated with death-censored graft loss in DBD, but not significantly in DCD (adjusted hazard ratios DBD: 2.82 (1.34-5.93), P = .007, and DCD: 1.54 (0.72-3.35), P = .262; Reference: immediate graft function). Early graft dysfunction has a differential impact on graft outcome in DBD and DCD. The differences between DBD and DCD should be accounted for in research and the clinic.

Interaction between cold ischemia time and Kidney Donor Profile Index on postrenal transplant outcomes.

We analyzed whether there is an interaction between the Kidney Donor Profile Index (KDPI) and cold ischemia time (CIT) in recipients of deceased donor kidney transplant (KTs). Adults who underwent KTs in the United States between 2014 and 2020 were included and divided into 3 KDPI groups (≤20%, 21%-85%, >85%) and 4 CIT strata (<12, 12-17.9, 18-23.9, ≥24 hours). Multivariate analyses were used to test the interaction between KDPI and CIT for the following outcomes: primary graft nonfunction (PGNF), delayed graft function (DGF), estimated glomerular filtration rate (eGFR) at 6 and 12 months, patient survival, graft survival, and death-censored graft survival (DCGS). A total of 69,490 recipients were analyzed: 18,241 (26.3%) received a graft with KDPI ≤20%, 46,953 (67.6%) with KDPI 21%-85%, and 4,296 (6.2%) with KDPI >85%. Increasing KDPI and CIT were associated with worse post-KT outcomes. Contrary to our hypothesis, howerver, the interaction between KDPI and CIT was statistically significant only for PGNF and DGF and eGFR at 6 months. Paradoxically, the negative coefficient of the interaction suggested that increasing duration of CIT was more detrimental for low and intermediate-KDPI organs relative to high-KDPI grafts. Conversely, for mortality, graft survival, and DCGS, we found that the interaction between CIT and KDPI was not statistically significant. We conclude that, high KDPI and prolonged CIT are independent risk factors for inferior outcomes after KT. Their interaction, however, is statistically significant only for the short-term outcomes and more pronounced on low and intermediate-KDPI grafts than high-KDPI kidneys.

An integrated machine learning model enhances delayed graft function prediction in pediatric renal transplantation from deceased donors.

BACKGROUND: Kidney transplantation is the optimal renal replacement therapy for children with end-stage renal disease; however, delayed graft function (DGF), a common post-operative complication, may negatively impact the long-term outcomes of both the graft and the pediatric recipient. However, there is limited research on DGF in pediatric kidney transplant recipients. This study aims to develop a predictive model for the risk of DGF occurrence after pediatric kidney transplantation by integrating donor and recipient characteristics and utilizing machine learning algorithms, ultimately providing guidance for clinical decision-making. METHODS: This single-center retrospective cohort study includes all recipients under 18 years of age who underwent single-donor kidney transplantation at our hospital between 2016 and 2023, along with their corresponding donors. Demographic, clinical, and laboratory examination data were collected from both donors and recipients. Univariate logistic regression models and differential analysis were employed to identify features associated with DGF. Subsequently, a risk score for predicting DGF occurrence (DGF-RS) was constructed based on machine learning combinations. Model performance was evaluated using the receiver operating characteristic curves, decision curve analysis (DCA), and other methods. RESULTS: The study included a total of 140 pediatric kidney transplant recipients, among whom 37 (26.4%) developed DGF. Univariate analysis revealed that high-density lipoprotein cholesterol (HDLC), donor after circulatory death (DCD), warm ischemia time (WIT), cold ischemia time (CIT), gender match, and donor creatinine were significantly associated with DGF (P < 0.05). Based on these six features, the random forest model (mtry = 5, 75%p) exhibited the best predictive performance among 97 machine learning models, with the area under the curve values reaching 0.983, 1, and 0.905 for the entire cohort, training set, and validation set, respectively. This model significantly outperformed single indicators. The DCA curve confirmed the clinical utility of this model. CONCLUSIONS: In this study, we developed a machine learning-based predictive model for DGF following pediatric kidney transplantation, termed DGF-RS, which integrates both donor and recipient characteristics. The model demonstrated excellent predictive accuracy and provides essential guidance for clinical decision-making. These findings contribute to our understanding of the pathogenesis of DGF.

Understanding Delayed Graft Function to Improve Organ Utilization and Patient Outcomes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.

Delayed graft function (DGF) is a common complication after kidney transplant. Despite extensive literature on the topic, the extant definition of DGF has not been conducive to advancing the scientific understanding of the influences and mechanisms contributing to its onset, duration, resolution, or long-term prognostic implications. In 2022, the National Kidney Foundation sponsored a multidisciplinary scientific workshop to comprehensively review the current state of knowledge about the diagnosis, therapy, and management of DGF and conducted a survey of relevant stakeholders on topics of clinical and regulatory interest. In this Special Report, we propose and defend a novel taxonomy for the clinical and research definitions of DGF, address key regulatory and clinical practice issues surrounding DGF, review the current state of therapies to reduce and/or attenuate DGF, offer considerations for clinical practice related to the outpatient management of DGF, and outline a prospective research and policy agenda.

Untargeted NMR-based metabolomics analysis of kidney allograft perfusates identifies a signature of delayed graft function.

INTRODUCTION: Kidney transplantation (KTx) necessarily conveys an ischemia/reperfusion (I/R) process, which impacts on allograft outcomes. Delayed graft function (DGF) is defined as a non-decrease of serum creatinine by at least 10% daily on 3 consecutive days during the first 7 days post-KTx. DGF significantly conditions both short- and long-term graft outcomes. Still there is a lack of DGF predictive biomarkers. OBJECTIVES: This study aimed to explore the potential of kidney graft perfusate metabolomics to predict DGF occurrence. METHODS: 49 human perfusates from grafts categorized upon donor type [donation after brain death (DBD)/donation after circulatory death (DCD)] and DGF occurrence and 19 perfusates from a murine model classified upon death type (DBD/DCD) were collected and analyzed by NMR-based metabolomics. RESULTS: The multivariate analysis of the murine data highlighted significant differences between perfusate metabolomes of DBD versus DCD. These differences were similarly observed in the human perfusates. After correcting for the type of donor, multivariate analysis of human data demonstrated a metabolomics signature that could be correlated with DGF occurrence. CONCLUSIONS: The metabolome of kidney grafts is influenced by the donor's type in both human and pre-clinical studies and could be correlated with DGF in the human DBD cohort. Thus, metabolomic analysis of perfusate applied prior to KTx may represent a new predictive tool for clinicians in a more personalized management of DGF. Moreover, our data paves the way to better understand the impact of donor's types on the biochemical events occurring between death and the hypothermic storage.

Diagnostic and Prognostic Potential of Multiparametric Renal MRI in Kidney Transplant Patients.

BACKGROUND: Multiparametric MRI provides assessment of functional and structural parameters in kidney allografts. It offers a non-invasive alternative to the current reference standard of kidney biopsy. PURPOSE: To evaluate the diagnostic and prognostic utility of MRI parameters in the assessment of allograft function in the first 3-months post-transplantation. STUDY TYPE: Prospective. SUBJECTS: 32 transplant recipients (54 ± 17 years, 20 females), divided into two groups according to estimated glomerular filtration rate (eGFR) at 3-months post-transplantation: inferior graft function (IGF; eGFR<45 mL/min/1.73 m2 , n = 10) and superior graft function (SGF; eGFR ≥ 45 mL/min/1.73 m2 , n = 22). Further categorization was based on the need for hemodialysis (C1) and decrease in s-creatinine (C2) at 1-week post-transplantation: delayed-graft-function (DGF: n = 4 C1, n = 10 C2) and early graft-function (EGF: n = 28 C1, n = 22 C2). FIELD STRENGTH/SEQUENCE: 3-T, pseudo-continuous arterial spin labeling, T1-mapping, and diffusion-weighted imaging. ASSESSMENT: Multiparametric MRI was evaluated at 1-week in all patients and 3-months after transplantation in 28 patients. Renal blood flow (RBF), diffusion coefficients (ADC, ΔADC, D, ∆ $$ \Delta $$ D, D*, flowing fraction f), T1 and ∆ $$ \Delta $$ T1 were calculated in cortex and medulla. The diagnostic and prognostic value of these parameters, obtained at 3-months and 1-week post-transplantation, respectively, was evaluated in the cortex to discriminate between DGF and EGF, and between SGF and IGF. STATISTICAL TESTS: Logistic regression, receiver-operating-characteristics, area-under-the-curve (AUC), confidence intervals (CIs), analysis-of-variance, t-test, Wilcoxon-Mann-Whitney test, Fisher's exact test, Pearson's correlation. P-value<0.05 was considered significant. RESULTS: DGF patients exhibited significantly lower cortical RBF and f and higher D*. The diagnostic value of MRI for detecting DGF was excellent (AUC = 100%). Significant differences between patients with IGF and SGF were found in RBF, ∆T1 , and ∆D. Multiparametric MRI showed higher diagnostic (AUC = 95.32%; CI: 88%-100%) and prognostic (AUC = 97.47%, CI: 92%-100%) values for detecting IGF than eGFR (AUC = 89.50%, CI: 79%-100%). DATA CONCLUSION: Multiparametric MRI may show high diagnostic and prognostic value in transplanted patients, yielding better results compared to eGFR measurements. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

2-Step-Scores with optional nephropathology for the prediction of adverse outcomes for brain-dead donor kidneys in Eurotransplant.

BACKGROUND AND HYPOTHESIS: The decision for acceptance or discard of the increasingly rare and marginal brain-dead donor kidneys in Eurotransplant (ET) countries has to be made without solid evidence. Thus, we developed and validated flexible clinicopathological scores called 2-Step Scores for the prognosis of delayed graft function (DGF) and one-year death-censored transplant loss (1y-tl) reflecting the current practice of six ET countries including Croatia and Belgium. METHODS: The training set was n=620 for DGF and n=711 for 1y-tl, with validation sets n=158 and n=162. In step 1, stepwise logistic regression models including only clinical predictors were used to estimate the risks. In step 2, risk estimates were updated for statistically relevant intermediate risk percentiles with nephropathology. RESULTS: Step 1 revealed an increased risk of DGF with increased cold ischaemia time, donor and recipient BMI, dialysis vintage, number of HLA-DR mismatches or recipient CMV IgG positivity. On the training and validation set, c-statistics were 0.672 and 0.704, respectively. At a range between 18% and 36%, accuracy of DGF-prognostication improved with nephropathology including number of glomeruli and Banff cv (updated overall c statistics of 0.696 and 0.701, respectively).Risk of 1y-tl increased in recipients with cold ischaemia time, sum of HLA-A. -B, -DR mismatches and donor age. On training and validation sets, c-statistics were 0.700 and 0.769, respectively. Accuracy of 1y-tl prediction improved (c-statistics = 0.706 and 0.765) with Banff ct. Overall, calibration was good on the training, but moderate on the validation set; discrimination was at least as good as established scores when applied to the validation set. CONCLUSION: Our flexible 2-Step Scores with optional inclusion of time-consuming and often unavailable nephropathology should yield good results for clinical practice in ET, and may be superior to established scores. Our scores are adaptable to donation after cardiac death and perfusion pump use.

Association of Pre-Existing Type 2 Diabetes on Kidney Transplant Outcomes and Factors Correlating With Survival: A Single-Center Analysis.

INTRODUCTION: Kidney transplantation (KT) is the treatment of choice for end-stage renal disease. Diabetes mellitus is the most common indication for KT, with most recipients having type 2 diabetes mellitus (T2DM). Previous studies have shown inferior patient survival in T2DM KT recipients. This single-center study aimed to understand the individual factors associated with negative long-term outcomes. METHODS: This is a single-center retrospective analysis of adult KT recipients, with and without T2DM from 2012 to 2017 with a follow-up through December 2022. Primary Outcomes were graft loss and patient survival. Univariate, Multivariate Cox regression, and Kaplan-Meier analyses were used to assess KT outcomes. RESULTS: We analyzed 1185 patients, 288 (24.3%) with T2DM. T2DM patients tended to be older, 56.6 ± 9.8 versus 47.1 ± 13.7 y. (P < 0.01), male (66.3% versus 58.2% P < 0.001) had a higher body mass index, 31.3 ± 5.4 versus 27.4 ± 5.7 P < 0.01) and less likely to get a living donor transplant (46.5% versus 58.4%, P < 0.01). T2DM patients after KT had a 50% higher risk for graft loss (hazard ratio 1.509, 95% CI 1.15-1.95, P < 0.001) and a 106% higher risk of death (hazard ratio 2.06 (95% CI 1.48-2.87, P < 0.0001). Among the T2DM patients, the most common cause of death was infection (39.9%). The average HbA1c at 1 y after transplant was 7.8%. CONCLUSIONS: The present study shows that T2DM is strongly associated with an increased risk of graft loss and death after KT, particularly in older recipients of deceased donor transplants with longer cold ischemia time that experience delayed graft function. This underscores the importance of avoiding delayed graft function in older, type 2 diabetic kidney transplant recipients and prioritizing living donors.

Intraoperative Mean Arterial Pressure and Postoperative Delayed Graft Function in Kidney Transplantation: Evaluating Three Commonly Used Thresholds.

BACKGROUND: Delayed graft function (DGF) is a common early complication after kidney transplantation (KT) and is associated with various long-term adverse outcomes. Despite numerous studies on hemodynamic management, the optimal hemodynamic goals during KT remain unclear. In this retrospective study, we aimed to investigate if three mean artery pressure (MAP) thresholds (≤75, 80, and 85 mmHg) that were commonly used in clinical practice were associated with DGF in adult patients undergoing KT. METHODS: We extracted de-identified data on adult patients who underwent deceased donor KT from our Discovery Data Repository. DGF was defined as the requirement for dialysis within the first 7 days after transplantation. Three MAP thresholds (≤75, 80, and 85 mmHg) and the duration of pressure below the three thresholds were recorded. Multivariable logistic analysis was used to identify risk factors for DGF. RESULTS: We included 2301 adult KT patients. The mean age was 52.5±12.9 years and 59% were male. DGF occurred in 1066 patients (46.3%). Patients frequently experienced MAP ≤75, 80, and 85 mmHg (approximately 70%, 80%, and 90% of patients experienced 10 min of MAP ≤75, 80, and 85 mmHg, respectively). Patients with DGF spent significantly longer durations below the three MAP thresholds during surgery compared with those without DGF. Further analysis revealed that the minimal time spent on MAP ≤75, 80, and 85 mmHg that were significantly associated with DGF were 6, 23, and 37 min, respectively. After adjusting for non-hemodynamic risk factors (age, basiliximab administration, and urine output), prolonged exposure to the three MAP thresholds remained significant predictors for DGF (for MAP ≤75 mmHg, OR 1.257, 95% CI 1.017-1.554, p = 0.034; MAP ≤80 mmHg, OR 1.220, 95% CI 1.018-1.463, p = 0.031; MAP ≤85 mmHg, OR 1.253, 95% CI 1.048-1.498, p = 0.013). CONCLUSION: Prolonged exposure to the three common MAP thresholds (≤75, 80, and 85 mmHg) occurred frequently during adult deceased donor KT and was associated with DGF.

Association of Intraoperative Hypotension With Delayed Graft Function Following Kidney Transplant: A Single Centre Retrospective Cohort Study.

BACKGROUND: Intraoperative hypotension is associated with acute kidney injury after surgery. However, the definition (duration and magnitude) of hypotension during kidney transplantation (KT) surgery on early graft function remains unclear. METHODS: We conducted a retrospective cohort study of KT recipients from December 1, 2009, to December 31, 2019. Exposure to intraoperative hypotension was characterized as the duration (minutes) of mean arterial pressure (MAP) <55, <65, <75, and <85 mmHg. Our co-primary outcomes were DGF-creatinine reduction ratio (DGF-CRR, <30% creatinine reduction, postoperative days 1 and 2), and DGF-dialysis (DGF-D, required dialysis within the week of KT for deceased donor recipients). Logistic regression models were fitted to assess this relationship between MAP and DGF. RESULTS: We included 1602 KT (939 deceased donors, 663 living donors) and 23 were excluded. DGF-CRR occurred in 33% of patients. DGF-CRR was associated with MAP < 65 (>5 min: OR 1.77, 95% confidence interval [CI]: 1.39-2.30; 6-10 min: OR 1.67, 95% CI: 0.97-2.86; 11-20 min: OR 2.18, 95% CI: 1.31-3.63) in unadjusted and <55 mmHg (5 min: OR 1.85, 95% CI: 1.47-2.32; 5-10 min: OR 2.41, 95% CI: 1.65-3.53; 11-20 min: OR 2.36, 95% CI: 1.60, 3.48) in adjusted models. There was also a signal for increased risk of DGF-CRR at MAP < 75 (>5 min: OR 1.69, 95% CI: 1.02-2.80). DGF-D (incidence 35%) in deceased donor KT was not associated with hypotension. CONCLUSIONS: We found an association between intraoperative hypotension and DGF-CRR at a threshold MAP of 55 mmHg, with a consistent signal toward increased risk at both 65 and 75 mmHg, as indicated by unadjusted models.

Oxalate Nephropathy After Kidney Transplantation: Risk Factors and Outcomes of Two Phenotypes.

Describing risk factors and outcomes in kidney transplant recipients with oxalate nephropathy (ON) may help elucidate the pathogenesis and guide treatment strategies. We used a large single-center database to identify patients with ON and categorized them into delayed graft function with ON (DGF-ON) and late ON. Incidence density sampling was used to select controls. A total of 37 ON cases were diagnosed between 1/2011 and 1/2021. DGF-ON (n = 13) was diagnosed in 1.05% of the DGF population. Pancreatic atrophy on imaging (36.4% vs. 2.9%, p = 0.002) and gastric bypass history (7.7% vs. 0%; p = 0.06) were more common in DGF-ON than with controls with DGF requiring biopsy but without evidence of ON. DGF-ON was not associated with worse graft survival (p = 0.98) or death-censored graft survival (p = 0.48). Late ON (n = 24) was diagnosed after a mean of 78.2 months. Late ON patients were older (mean age 55.1 vs. 48.4 years; p = 0.02), more likely to be women (61.7% vs. 37.5%; p = 0.03), have gastric bypass history (8.3% vs. 0.8%; p = 0.02) and pancreatic atrophy on imaging (38.9% vs. 13.3%; p = 0.02). Late ON was associated with an increased risk of graft failure (HR 2.0; p = 0.07) and death-censored graft loss (HR 2.5; p = 0.10). We describe two phenotypes of ON after kidney transplantation: DGF-ON and late ON. Our study is the first to our knowledge to evaluate DGF-ON with DGF controls without ON. Although limited by small sample size, DGF-ON was not associated with adverse outcomes when compared with controls. Late ON predicted worse allograft outcomes.

Early post-operative lactate increase following kidney transplant is associated with delayed graft function: A retrospective cohort study.

INTRODUCTION: Delayed graft function (DGF) is a frequent complication following kidney transplant. This study aimed to assess the association between early post-operative lactate variation and DGF. METHODS: This was a single center, retrospective cohort study between February 2021 and December 2022 in Saint-Louis Hospital (APHP, France). Venous lactate levels were measured immediately (H0) and 4 h (H4) after kidney transplant. The primary outcome was the occurrence of DGF (need for renal replacement therapy between transplantation and day 7). Secondary outcome was the occurrence of complications (i.e., death, vascular thrombosis, hemorrhagic shock, urological complications (hematoma, urinoma), local or systemic infection) between transplant and day 7. RESULTS: Two hundred 12 patients were included, and 38 (17.9%) developed DGF. Venous lactate variation between H0 and H4 was higher in patients who developed DGF (-30 (IQR -83, -6)% vs. -15 (IQR -62, -11)%, p = .037), but the variation of level was more often positive (corresponding to an increased lactate production over time between H0 and H4) in patients who developed DGF ((28(85%) vs. 94(62%), p = .011). In multivariate logistic regression, positive venous lactate level variation between H0 and H4 was strongly associated with a reduced risk of developing DGF (OR .30 [.09-.79], p = .024). We did not find any association between post-operative hyperlactatemia and occurrence of complications between transplant and day 7. DISCUSSION: DGF is a frequent complication following kidney transplantation. Its early prediction could help physicians optimize treatment and protect the kidney. Early venous lactate variation after kidney transplant could help to predict the occurrence of DGF.

Does Severity of Donor Acute Kidney Injury Influence Outcomes Following Kidney Transplantation?

INTRODUCTION: The study purpose was to review retrospectively our single-center experience transplanting kidneys from deceased donors (DD) with acute kidney injury (AKI) according to terminal serum creatinine (tSCr) level. METHODS: AKI kidneys were defined by a doubling of the DD's admission SCr and a tSCr ≥ 2.0 mg/dL. RESULTS: From 1/07 to 11/21, we transplanted 236 AKI DD kidneys, including 100 with a tSCr ≥ 3.0 mg/dL (high SCr AKI group, mean tSCr 4.2 mg/dL), and the remaining 136 from DDs with a tSCr of 2.0-2.99 mg/dL (lower SCr AKI group, mean tSCr 2.4 mg/dL). These two AKI groups were compared to 996 concurrent control patients receiving DD kidneys with a tSCr < 1.0 mg/dL. Mean follow-up was 69 months. Delayed graft function (DGF) rates were 51% versus 46% versus 29% (p < 0.0001), and 5-year patient and death-censored kidney graft survival rates were 96.8% versus 83.5% versus 82.2% (p = 0.002) and 86.7% versus 77.8% versus 78.8% (p = 0.18) in the high tSCr AKI versus lower tSCr AKI versus control groups, respectively. CONCLUSIONS: Despite a higher incidence of DGF, patients receiving kidneys from DDs with tSCr levels ≥3.0 mg/dL have acceptable medium-term outcomes compared to either AKI DDs with a lower tSCr or DDs with a tSCr < 1.0 mg/dL.

Impaired immunoproteasomal function exacerbates renal ischemia-reperfusion injury.

Oxidative stress caused by reactive oxygen species (ROS) is involved in the pathogenesis of renal ischemia-reperfusion injury (I/R injury), a major cause of acute kidney injury and delayed graft function (DGF). DGF is an early transplant complication that worsens graft prognosis and patient survival, but the underlying molecular changes are unclear. The proteasome is a multicatalytic enzyme complex that degrades both normal and damaged proteins, and recent studies have revealed that the immunoproteasome, a specific proteasome isoform whose proteolytic activity enhances the generation of antigenic peptides, plays critical roles in the cellular response against oxidative stress. In this study, we demonstrate the impact of the immunoproteasome in human DGF and in a mouse model of I/R injury. In patients with DGF, the expression of ß5i, a specific immunoproteasome subunit, was decreased in vascular endothelial cells. In a mouse model, ß5i knockout (KO) exacerbated renal I/R injury. KO mice showed greater inflammation, oxidative stress, and endothelial damage compared with wild-type mice. Impaired immunoproteasomal activity also caused increased cell death, ROS production, and expression of inflammatory factors in mouse renal vascular endothelial cells under conditions of hypoxia and reoxygenation. In conclusion, reduced expression of the immunoproteasomal catalytic subunit ß5i exacerbates renal I/R injury in vivo, potentially increasing the risk of DGF. Further research targeting ß5i expression in DGF could lead to the development of novel therapeutic strategies and biomarkers.

Pre-Transplant Hyperparathyroidism and Graft or Patient Outcomes After Kidney Transplantation.

The impact of pre-transplant parathyroid hormone (PTH) levels on early or long-term kidney function after kidney transplantation is subject of debate. We assessed whether severe hyperparathyroidism is associated with delayed graft function (DGF), death-censored graft failure (DCGF), or all-cause mortality. In this single-center cohort study, we studied the relationship between PTH and other parameters related to bone and mineral metabolism, including serum alkaline phosphatase (ALP) at time of transplantation with the subsequent risk of DGF, DCGF and all-cause mortality using multivariable logistic and Cox regression analyses. In 1,576 kidney transplant recipients (51.6 ± 14.0 years, 57.3% male), severe hyperparathyroidism characterized by pre-transplant PTH ≥771 pg/mL (>9 times the upper limit) was present in 121 patients. During 5.2 [0.2-30.0] years follow-up, 278 (15.7%) patients developed DGF, 150 (9.9%) DCGF and 432 (28.6%) died. A higher pre-transplant PTH was not associated with DGF (HR 1.06 [0.90-1.25]), DCGF (HR 0.98 [0.87-1.13]), or all-cause mortality (HR 1.02 [0.93-1.11]). Results were consistent in sensitivity analyses. The same applied to other parameters related to bone and mineral metabolism, including ALP. Severe pre-transplant hyperparathyroidism was not associated with an increased risk of DGF, DCGF or all-cause mortality, not supporting the need of correction before kidney transplantation to improve graft or patient survival.

Delayed Graft Function After Kidney Transplantation: The Role of Residual Diuresis and Waste Products, as Oxalic Acid and Its Precursors.

Delayed graft function (DGF) after kidney transplantation heralds a worse prognosis. In patients with hyperoxaluria, the incidence of DGF is high. Oxalic acid is a waste product that accumulates when kidney function decreases. We hypothesize that residual diuresis and accumulated waste products influence the DGF incidence. Patients transplanted between 2018-2022 participated in the prospective cohort study. Pre-transplant concentrations of oxalic acid and its precursors were determined. Data on residual diuresis and other recipient, donor or transplant related variables were collected. 496 patients were included, 154 were not on dialysis. Oxalic acid, and glyoxylic acid, were above upper normal concentrations in 98.8%, and 100% of patients. Residual diuresis was ≤150 mL/min in 24% of patients. DGF occurred in 157 patients. Multivariable binary logistic regression analysis demonstrated a significant influence of dialysis type, recipient BMI, donor type, age, and serum creatinine on the DGF risk. Residual diuresis and glycolic acid concentration were inversely proportionally related to this risk, glyoxylic acid directly proportionally. Results in the dialysis population showed the same results, but glyoxylic acid lacked significance. In conclusion, low residual diuresis is associated with increased DGF incidence. Possibly accumulated waste products also play a role. Pre-emptive transplantation may decrease the incidence of DGF.

Characteristics of Delayed Graft Function and Long-Term Outcomes After Kidney Transplantation From Brain-Dead Donors: A Single-Center and Multicenter Registry-Based Retrospective Study.

Delayed graft function (DGF) after kidney transplantation is common and associated with worse graft outcomes. However, little is known about factors affecting graft survival post-DGF. We studied the association of cold ischemia time (CIT) and Kidney Donor Profile Index (KDPI) with the long-term outcomes of deceased brain-dead donor kidneys with and without DGF. Data from Finland (n = 2,637) and from the US Scientific Registry of Transplant Recipients (SRTR) registry (n = 61,405) was used. The association of KDPI and CIT with the graft survival of kidneys with or without DGF was studied using multivariable models. 849 (32%) kidneys had DGF in the Finnish cohort. DGF and KDPI were independent risk factors for graft loss, [HR 1.32 (95% CI 1.14-1.53), p < 0.001, and HR 1.01 per one point (95% CI 1.01-1.01), p < 0.001, respectively], but CIT was not, [HR 1.00 per CIT hour (95% CI 0.99-1.02), p = 0.84]. The association of DGF remained similar regardless of CIT and KDPI. The US cohort had similar results, but the association of DGF was stronger with higher KDPI. In conclusion, DGF and KDPI, but not CIT, are independently associated with graft survival. The association of DGF with worse graft survival is consistent across different CITs but stronger among marginal donors.