Delayed Graft Function in Pediatric Kidney Transplant: Risk Factors and Outcomes.

OBJECTIVES: We aimed to identify risk factors and outcomes of delayed graft function in pediatric kidney transplant. MATERIALS AND METHODS: This retrospective study included all kidney transplant recipients ≤19 years old followed up in our department for a period of 34 years, from January 1989 to December 2022. RESULTS: We included 113 kidney transplant recipients. Delayed graft function occurred in 17 cases (15%). Posttransplant red blood cell transfusion was strongly associated with delayed graft function (adjusted odds ratio = 23.91; 95% CI, 2.889-197.915). Use of allografts with multiple arteries and cold ischemia time >20 hours were risk factors for delayed graft function (adjusted odds ratio = 52.51 and 49.4; 95% CI, 2.576-1070.407 and 1.833-1334.204, respectively). Sex-matched transplants and living donors were protective factors for delayed graft function (adjusted odds ratio = 0.043 and 0.027; 95% CI, 0.005-0.344 and 0.003-0.247, respectively). Total HLA mismatches <3 played a protective role for delayed graft function (adjusted odds ratio = 0.114; 95% CI, 0.020-0.662), whereas transplant within compatible but different blood types increased the risk of delayed graft function (adjusted odds ratio = 20.54; 95% CI, 1.960- 215.263). No significant correlation was shown between delayed graft function and allograft survival (P = .190). Our study suggested delayed graft function as a key factor in allograft rejection-free survival (adjusted odds ratio = 3.832; 95% CI, 1.186-12.377). Delayed graft function was a negative factor for early graft function; patients with delayed graft function had a lower estimated glomerular filtration rate at discharge (P = .024) and at 3 (P = .034), 6 (P = .019), and 12 months (P = .011) posttransplant. CONCLUSIONS: Delayed graft function is a major determinant of early graft function and allograft rejection-free survival. Further research is required to establish proper preventive measures.

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.

An analysis of the relationship between donor and recipient biomarkers and kidney graft function, dysfunction, and rejection.

BACKGROUND: The study aimed to find predictive biomarkers to evaluate donor kidney function to predict graft dysfunction as well as to assess an early signs of acute graft rejection. METHOD: Twenty-seven deceased donors and 54 recipients who underwent a successful kidney transplantation were enrolled in the study. An assessment was made in serum and urine from donors and recipients to measure the following biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), tissue inhibitor of metalloproteinase 2 (TIMP-2) and urinary N-acetyl-b-D-glucosaminidase (uNAG). These biomarkers were used to establish a model for predicting a reduced graft function (RGF) classified as either a delayed or slow graft function. RESULT: Our analysis suggest that out of four tested biomarkers, the serum TIMP-2 and uNAG levels of the donors had a predictive value for RGF; the area under the receiver operating characteristic curves (AUROC) of serum TIMP-2 and uNAG were 0.714 and 0.779, respectively. The combined best fitting prediction model of serum TIMP-2, uNAG, and creatinine levels was better in predicting RGF than the serum creatinine level alone. In addition, the recipient serum TIMP-2 level on the third day post-transplantation (D3) was associated with the estimated glomerular filtration rate (eGFR) on the seventh day post-transplantation (D7; OR 1.119, 95% CI 1.016-1.233, p = 0.022). Furthermore, the ROC curve value revealed that the AUROC of TIMP-2 on D3 was 0.99 (95% CI 0.97-1, p < 0.001), and this was the best predictive value of the renal function on D7. CONCLUSIONS: Donor serum TIMP-2 and uNAG levels are useful predictive biomarkers because they can provide the donor-based prediction for RGF.

Total Cell-Free DNA as a Noninvasive Biomarker of a Delayed Graft Function After Kidney Transplantation From Donors After Cardiac Death.

BACKGROUND: Because of the organ shortage, donation after cardiac death (DCD) kidney transplantation (KTx) is an alternative way of achieving KTx using brain-dead donors (BDs). Although the prognosis of DCD-KTx is improving, the graft suffers from delayed graft function (DGF), the management of which is essential. With progress in understanding the characteristics of cell-free DNA (CF-DNA), we consider plasma total CF-DNA (tCF-DNA) to be a useful biomarker for predicting DGF in DCD-KTx. STUDY DESIGN AND METHOD: Consecutive patients from living donors (LDs; n = 9), BDs (n = 8), or DCD donors (n = 13) were enrolled. Plasma samples were collected after KTx and on postoperative days 3 and 5. CF-DNA was isolated, and tCF-DNA was quantified using the TapeStation 2200 software program. RESULTS: The tCF-DNA levels after BD-KTx and DCD-KTx were higher than those after LD-KTx (LD, 78 ± 27 (ng/mL); BD, 99 ± 20; DCD, 150 ± 23); the difference between DCD-KTx and LD-KTx was statistically significant (P < .05). The tCF-DNA levels declined at postoperative day 5 (LD, 45 ± 10; BD, 51 ± 11; DCD, 66 ± 13). tCF-DNA levels were significantly increased in patients with DGF after KTx (DGF, 139 ± 22; immediate function, 91 ± 18; P < .05). The tCF-DNA level was correlated with the duration of DGF (r = 0.5825, P < .05). CONCLUSION: Although the mechanism underlying DNA release from transplanted grafts into the recipient circulation remains unclear, cell death by apoptosis or necrosis and the active secretion of the immune system may play important roles in DGF. These data suggest that monitoring tCF-DNA may help predict graft recovery after DCD-KTx.

Deceased Donor Kidney Transplantation From Donors With Acute Kidney Injury: Realities and Costs.

OBJECTIVES: Transplant of kidneys from donors with acute kidney injury has shown favorable outcomes. We investigated the outcomes of kidney transplant recipients with deceased donors who developed acute kidney injury before organ procurement. MATERIALS AND METHODS: We retrospectively reviewed the medical records of recipients from January 2016 to December 2021 in a single center. Outcomes in recipients of kidney grafts from donors with and without acute kidney injury were compared. RESULTS: The mean follow-up time was 40 months. Our study included 129 (34%) kidneys transplanted from donors with acute kidney injury and 251 (66%) kidneys from donors without acute kidney injury. Delayed graft function rate in recipients was 33% in the acute kidney injury group and 25.5% in the group without acute kidney injury (P = .099). Readmission rate at 30 days was significantly higher among recipients of kidneys with acute kidney injury compared with recipients of kidneys without acute kidney injury (45% vs 33.5%; P = .02). The mean overall costs of transplant in the acute kidney injury group were comparable to the group without acute kidney injury ($253 865 vs $253 611; P = .97). The acute rejection rate was comparable between the 2 groups (4% in both groups; P = .96). Delayed graft function rate was increased with increased stage of acute kidney injury (18% stage 1, 45% stage 2, 36% stage 3; P = .03). However, the overall length of hospital stay and costs were comparable among recipients of different stages of acute kidney injury. CONCLUSIONS: Our study showed that kidney transplants from donors with acute kidney injury have early and late outcomes comparable to kidney transplants from donors without acute kidney injury. Allografts from donors with acute kidney injury can be used safely and can expand the donor pool in kidney transplant without increasing perioperative resource utilization.

Biopsy-proven fungal pyelonephritis complicating delayed graft function in a renal transplant patient.

Delayed graft function (DGF) is a common phenomenon following renal transplantation, which can be due to several factors. A rare cause includes invasive fungal infections, which can often be a challenge to diagnose. Nonetheless, prompt identification of such infections particularly within transplant patients is essential as they can lead to severe downstream sequelae, including graft loss and even death. We describe here a challenging case of fungal pyelonephritis complicating and potentially leading to DGF and further dialysis dependence within a renal transplant patient. Notably, we highlight the importance and clinical utility of biopsy to confirm the diagnosis, as investigations may be largely normal otherwise. Furthermore, we emphasise that with early identification of these infections, effective antifungal treatment can be commenced in a timely fashion leading to better patient outcomes and good graft function.

A Multiparametric Nomogram for Predicting Delayed Graft Function in Adult Recipients of Pediatric Donor Kidneys.

BACKGROUND: Delayed graft function (DGF) is one of the most common postoperative complications after kidney transplantation. The ability to predict DGF after transplantation can greatly aid clinical decision-making. Several models have been proposed to predict DGF in adult recipients of adult donor kidneys, but there is currently no model to predict DGF in adult recipients of pediatric donor transplants. Therefore, based on our medical records, we retrospectively investigated the pretransplant risk factors of DGF in transplants from pediatric donors to adult recipients. METHODS: Our center is in compliance with national laws, the Declaration of Istanbul, and the Helsinki Congress. The donors used by us were organs donated after the death of citizens and the participants were neither paid nor coerced. A retrospective review of 84 adult patients who received pediatric donor kidneys at a single center from April 4, 2015 to November 17, 2021 was conducted to investigate the pretransplant risk factors for the development of DGF. RESULTS: DGF was observed in 45 of 68 patients (66.17%) in the training group and 9 of 16 patients (56.25%) in the validation group. Multivariate logistic analysis showed that kidney donor profile index, cold ischemia time, number of human leukocyte antigen mismatches, and pretransplant dialysis duration were significant independent risk factors for DGF. By integrating these 4 factors, we constructed a nomogram model to predict DGF. According to the prediction model, the area under the curve of DGF of the training group and validation group was 0.899 and 0.905, respectively. CONCLUSION: We have constructed a novel, reliable, and accurate visual nomogram that provides a practical tool for predicting DGF in adult recipients of pediatric donor kidneys.

Effect of creatinine metrics on outcome after transplantation of marginal donor kidneys.

INTRODUCTION: Predicting outcome after transplantation of marginal kidneys is a challenging task. Donor creatinine or estimated glomerular filtration rate (eGFR) are integral components of the respective risk scores. However, there is uncertainty on which of their values obtained successively during procurement is the most suitable. MATERIAL AND METHODS: This is a retrospective study of 221 adult brain death donors with marginal kidneys, transplanted in 223 recipients. We applied logistic regression analysis to investigate the association between initial (at hospital admission), nadir (lowest), zenith (highest) and terminal (at recovery) donor eGFR with primary non-function (PNF), delayed graft function (DGF), 3- and 12-month graft function and 1- and 3-year patient- and death-censored graft survival. RESULTS: In the multivariate analysis, admission, terminal, and the lowest donor eGFR could most accurately predict DGF. The respective ORs [95% CI] were: 0.875 [0.771-0.993], 0.818 [95% CI: 0.726-0.922] and 0.793 [0.689-0.900]. Although not being significant for DGF (OR 0.931 [95% CI: 0.817-1.106]), the highest eGFR was the best predictor of 3-month graft function (adjusted b coefficient 1.161 [95% CI: 0.355-1.968]). Analysis of primary nonfunction showed that determination of initial and the highest eGFR proved to be the best predictors. The respective ORs [95% CI] were: 0.804 [0.667-0.968] and 0.750 [0.611-0.919]. There were no differences in the risk associations of each of the four eGFR recordings with patient- and graft survival. CONCLUSION: The various eGFR recordings determined during the procurement process of marginal donors can predict PNF, DGF and 3- and 12-month graft function. Regarding short-term patient- and graft survival, there appears to be impacted by recipient factors rather than donor kidney function.

The Role of Platelet-Lymphocyte Ratio and Neutrophil-Lymphocyte Ratio in Predicting the Delayed Graft Function in Pediatric Renal Transplant Patients.

OBJECTIVES: Delayed graft function is a common adverse outcome after renal transplant. Attempts for early prediction and prevention of delayed graft function are often challenging and misleading. Herein, we investigated for the first time the correlation between delayed graft function and preoperative noninvasive hematologic parameters to predict the possible adverse outcomes for renal transplant in pediatric patients. MATERIALS AND METHODS: In this study, preoperative hematologic parameters of 51 pediatric renal transplant recipients followed between 2015 and 2021 were analyzed retrospectively. The selected 16 renal transplant patients with delayed graft function and 35 patients without delayed graft function had no concomitant comorbidities. The cutoff values for platelet-to-lymphocyte ratio of <5 and neutrophilto- lymphocyte ratio of <175 were considered low. RESULTS: We retrospectively evaluated a total of 51 (male/female, 33/18) pediatric kidney transplant recipients with a median age of 12 (interquartile range, 8-18) years. Median level of circulating lymphocytes was significantly higher in patients with delayed graft function compared with patients without delayed graft function (2 vs 1, P = .040). The preoperative low values for platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio were more prevalent in recipients who developed delayed graft function versus those who did not develop delayed graft function (68.8% vs 31.4% [P = .014] and 68.8% vs 34.3% [P = .023], respectively). CONCLUSIONS: Pretransplant low platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte were associated with increased number of delayed graft dysfunction. These novels and noninvasive inflammatory biomarkers may contribute to an early prediction of delayed graft function in pediatric kidney transplant recipients.

The value of cystatin C in predicting perioperative and long-term prognosis of renal transplantation.

This study aimed to evaluate the value of cystatin C (Cys C) in predicting the perioperative and long-term prognosis of renal transplantation (RT). The clinical data of 198 RT recipients were collected. Blood samples were obtained daily until 7 d after transplantation and then discharge day to determine the serum levels of Cys C. The receiver-operating characteristic (ROC) analysis and the area under the curve (AUC) were used to determine the diagnostic accuracy of Cys C for delayed graft function (DGF). The presence of shrunken pore syndrome (SPS) with a cystatin C-based estimate of glomerular filtration rate less than 70% of a creatinine-based estimate, was also evaluated as a prognostic factor for the development of DGF. The serum Cys C levels of patients with DGF were higher than those of the non-DGF group. Cys C showed a higher AUC (0.928) in the ROC analysis than did sCr (0.862). Compared to the non-SPS group, there were more patients diagnosed with SPS in the DGF group (p < .05). The follow-up data showed that patients diagnosed with SPS had higher levels of sCr and Cys C compared to other patients, suggesting a poor long-term prognosis. Our findings suggest that Cys C is a sensitive indicator of renal function during the perioperative period. Cys C at a concentration of 4.9 mg/L had the highest sum of sensitivity and specificity for prediction of DGF, with a sensitivity of 0.889 and a specificity of 0.8. SPS is associated with the development of DGF and the poor long-term prognosis of RT.

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

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

Biomarkers as diagnostic tests for delayed graft function in kidney transplantation.

Delayed graft function (DGF) after kidney transplantation is associated with inferior outcomes and higher healthcare costs. DGF is currently defined as the requirement for dialysis within seven days post-transplant; however, this definition is subjective and nonspecific. Novel biomarkers have potential to improve objectivity and enable earlier diagnosis of DGF. We reviewed the literature to describe the range of novel biomarkers previously studied to predict DGF. We identified marked heterogeneity and low reporting quality of published studies. Among the novel biomarkers, serum NGAL had the greatest potential as a biomarker to predict DGF, but requires further assessment and validation through larger scale studies of diagnostic test performance. Given inadequacies in the dialysis-based definition, coupled with the high incidence and impact of DGF, such studies should be pursued.

Perioperative Normal Saline Administration and Delayed Graft Function in Patients Undergoing Kidney Transplantation: A Retrospective Cohort Study.

BACKGROUND: Perioperative normal saline administration remains common practice during kidney transplantation. The authors hypothesized that the proportion of balanced crystalloids versus normal saline administered during the perioperative period would be associated with the likelihood of delayed graft function. METHODS: The authors linked outcome data from a national transplant registry with institutional anesthesia records from 2005 to 2015. The cohort included adult living and deceased donor transplants, and recipients with or without need for dialysis before transplant. The primary exposure was the percent normal saline of the total amount of crystalloids administered perioperatively, categorized into a low (less than or equal to 30%), intermediate (greater than 30% but less than 80%), and high normal saline group (greater than or equal to 80%). The primary outcome was the incidence of delayed graft function, defined as the need for dialysis within 1 week of transplant. The authors adjusted for the following potential confounders and covariates: transplant year, total crystalloid volume, surgical duration, vasopressor infusions, and erythrocyte transfusions; recipient sex, age, body mass index, race, number of human leukocyte antigen mismatches, and dialysis vintage; and donor type, age, and sex. RESULTS: The authors analyzed 2,515 records. The incidence of delayed graft function in the low, intermediate, and high normal saline group was 15.8% (61/385), 17.5% (113/646), and 21% (311/1,484), respectively. The adjusted odds ratio (95% CI) for delayed graft function was 1.24 (0.85 to 1.81) for the intermediate and 1.55 (1.09 to 2.19) for the high normal saline group compared with the low normal saline group. For deceased donor transplants, delayed graft function in the low, intermediate, and high normal saline group was 24% (54/225 [reference]), 28.6% (99/346; adjusted odds ratio, 1.28 [0.85 to 1.93]), and 30.8% (277/901; adjusted odds ratio, 1.52 [1.05 to 2.21]); and for living donor transplants, 4.4% (7/160 [reference]), 4.7% (14/300; adjusted odds ratio, 1.15 [0.42 to 3.10]), and 5.8% (34/583; adjusted odds ratio, 1.66 [0.65 to 4.25]), respectively. CONCLUSIONS: High percent normal saline administration is associated with delayed graft function in kidney transplant recipients.

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

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

Circulating CXCL10 and IL-6 in solid organ donors after brain death predict graft outcomes.

We tested the hypothesis that circulating CXCL10 and IL-6 in donor after brain death provide independent additional predictors of graft outcome. From January 1, 2010 to June 30, 2012 all donors after brain death managed by the NITp (n = 1100) were prospectively included in this study. CXCL10 and IL-6 were measured on serum collected for the crossmatch at the beginning of the observation period. Graft outcome in recipients who received kidney (n = 1325, follow-up 4.9 years), liver (n = 815, follow-up 4.3 years) and heart (n = 272, follow-up 5 years) was evaluated. Both CXCL-10 and IL-6 showed increased concentration in donors after brain death. The intensive care unit stay, the hemodynamic instability, the cause of death, the presence of risk factors for cardiovascular disease and the presence of ongoing infection resulted as significant determinants of IL-6 and CXCL10 donor concentrations. Both cytokines resulted as independent predictors of Immediate Graft Function. Donor IL-6 or CXCL10 were associated with graft failure after liver transplant, and acted as predictors of recipient survival after kidney, liver and heart transplantation. Serum donor IL-6 and CXCL10 concentration can provide independent incremental prediction of graft outcome among recipients followed according to standard clinical practice.

Value of Plasmatic Villin-1 in the Prediction of Early Graft Dysfunction in Kidney Transplant Recipients: Diagnostic Accuracy Test.

OBJECTIVES: One of the complications of kidney transplant is delayed graft function. Villin-1 has been detected in urine of patients with acute kidney injury. In addition, it is redistributed during acute kidney injury from the brush borders of the proximal tubular cells toward the basolateral membrane, which positions villin-1 closer to the renal vasculature, suggesting that it could be also released in the blood and thus can be a novel biomarker for delayed graft function. MATERIALS AND METHODS: In this diagnostic accuracy test multicenter study, 41 patients undergoing kidney transplant and attending renal transplant clinics were assigned into 2 groups according to serum creatinine levels during the first 2 days posttransplant: delayed graft function group and normal graft function group. We measured plasmatic villin-1 in comparison to serum creatinine levels at the time of declamping (time 0) and at 1, 3, 5, 7, 12, 24, 48, 72, 96, and 120 hours after declamping. RESULTS: Statistically significant differences were noted in comparisons between groups at same time points with regard to plasmatic villin-1 levels; also, plasmatic villin-1 started to increase above reference range in patients with end-stage renal disease at 5 hours after declamping; a peak was shown at hour 7 in the delayed graft function group, which decreased but did not reach the reference range until 120 hours after declamping. CONCLUSIONS: Plasmatic villin-1 is a promising novel biomarker for detection of early graft dysfunction in kidney transplant recipients.

Automated En Masse Machine Learning Model Generation Shows Comparable Performance as Classic Regression Models for Predicting Delayed Graft Function in Renal Allografts.

BACKGROUND: Several groups have previously developed logistic regression models for predicting delayed graft function (DGF). In this study, we used an automated machine learning (ML) modeling pipeline to generate and optimize DGF prediction models en masse. METHODS: Deceased donor renal transplants at our institution from 2010 to 2018 were included. Input data consisted of 21 donor features from United Network for Organ Sharing. A training set composed of ~50%/50% split in DGF-positive and DGF-negative cases was used to generate 400 869 models. Each model was based on 1 of 7 ML algorithms (gradient boosting machine, k-nearest neighbor, logistic regression, neural network, naive Bayes, random forest, support vector machine) with various combinations of feature sets and hyperparameter values. Performance of each model was based on a separate secondary test dataset and assessed by common statistical metrics. RESULTS: The best performing models were based on neural network algorithms, with the highest area under the receiver operating characteristic curve of 0.7595. This model used 10 out of the original 21 donor features, including age, height, weight, ethnicity, serum creatinine, blood urea nitrogen, hypertension history, donation after cardiac death status, cause of death, and cold ischemia time. With the same donor data, the highest area under the receiver operating characteristic curve for logistic regression models was 0.7484, using all donor features. CONCLUSIONS: Our automated en masse ML modeling approach was able to rapidly generate ML models for DGF prediction. The performance of the ML models was comparable with classic logistic regression models.

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.

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction.

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.