Donor-Dependent Variations in Systemic Oxidative Stress and Their Association with One-Year Graft Outcomes in Kidney Transplantation.

INTRODUCTION: Oxidative stress has been implicated in complications after kidney transplantation (KT), including delayed graft function (DGF) and rejection. However, its role in long-term posttransplant outcomes remains unclear. METHODS: We investigated oxidative damage and antioxidant defense dynamics, and their impact on the graft outcomes, in 41 KT recipients categorized by type of donation over 12 months. Oxidative status was determined using OxyScore and AntioxyScore indexes, which comprise several circulating biomarkers of oxidative damage and antioxidant defense. Donor types included donation after brain death (DBD [61.0%]), donation after circulatory death (DCD [26.8%]), and living donation (LD [12.1%]). RESULTS: There was an overall increase in oxidative damage early after transplantation, which was significantly higher in DCD as compared to DBD and LD recipients. The multivariate adjustment confirmed the independent association of OxyScore and type of deceased donation with DGF, donor kidney function, and induction therapy with antithymocyte globulin. There were no differences in terms of antioxidant defense. Lower oxidative damage at day 7 predicted better graft function at 1-year posttransplant only in DBD recipients. CONCLUSION: DCD induced greater short-term oxidative damage after KT, whereas the early levels of oxidative damage were predictive of the graft function 1 year after KT among DBD recipients.

Serum ß2-Microglobulin Predicts Time to Recovery of Delayed Graft Function in Kidney Transplant Recipients.

BACKGROUND: Delayed graft function (DGF) after kidney transplantation is associated with adverse patients and allograft outcomes. A longer duration of DGF is predictive of worse graft outcomes compared to a shorter duration. Posttransplant serum ß2-microglobulin (B2M) is associated with long-term graft outcomes, but its relationship with DGF recovery is unknown. METHODS: We included all kidney-only transplant recipients with DGF enrolled in the E-DGF trial. Duration of DGF was defined as the interval between the transplant and the last dialysis session. We analyzed the association of standardized serum creatinine (Scr) and B2M on postoperative Days (POD) 1-7 during the subsequent days of DGF with the recovery of DGF. RESULTS: A total of 97 recipients with DGF were included. The mean duration of DGF was 11.0 ± 11.2 days. Higher Scr was not associated with the duration of DGF in unadjusted or adjusted models. Higher standardized B2M, in contrast, was associated with a prolonged duration of DGF. This association remained in models adjusting for baseline characteristics from POD 2 (3.19 days longer, 95% CI: 0.46-5.93; p = 0.02) through Day 6 of DGF (4.97 days longer, 95% CI: 0.75-9.20; p = 0.02). There was minimal change in mean Scr (0.01 ± 0. 10 mg/dL per day; p = 0.32), while B2M significantly decreased as the time to recovery approached (-0.14 ± 0.05 mg/L per day; p = 0.006), among recipients with DGF. CONCLUSION: B2M is more strongly associated with DGF recovery than Scr. Posttransplant B2M may be an important biomarker to monitor during DGF. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03864926.

Transforming growth factor beta 1 levels in the blood of pediatric liver recipients: Clinical and biochemical correlations.

TGF-ß1 is a cytokine with profibrogenic and immunosuppressive activities, which suggest the clinical significance of TGF-ß1 for the assessment of graft function after LT. We analyzed the dynamics of TGF-ß1 levels in the blood after LDLT in 135 pediatric liver recipients and examined the relationship between the cytokine levels and the laboratory and clinical variables. We found that TGF-ß1 levels in the blood of patients with ESLD were lower than that in healthy children of the same age, P = .001. Moreover, blood levels of TGF-ß1 were associated with liver disease etiology (r = .23) and hepatic fibrosis severity (r = .33). Before LDLT, TGF-ß1 levels were significantly higher in children with good outcomes than in recipients who developed graft dysfunction early in the post-transplant period, P = .047. One month after LDLT, TGF-ß1 levels in blood plasma increased in pediatric recipients, P = .002. Cytokine levels were significantly correlated with gender (r = .21) and HLA (r = -.24) mismatches, as well as with TAC dosage (r = -.32) later in the post-transplant period. One year after LDLT, TGF-ß1 plasma levels were higher (P = .01) than those before LDLT and did not correlate with most of the investigated biochemical and clinical variables. Conclusion: Blood levels of TGF-ß1 are associated with hepatic fibrosis severity, graft dysfunction development, and TAC dosage and can be regarded as a potential prognostic biomarker for the assessment of graft function and the optimization of immunosuppressant dosage in pediatric recipients after LDLT.

Changes in double-strand DNA breaks predict delayed graft function (DGF) in Japanese renal allograft recipients.

BACKGROUND: Although delayed graft function (DGF) is a serious complication following kidney transplantation, a reliable and early diagnostic test is lacking to identify the grade of DGF. METHODS: We investigated changes in double-strand DNA breaks (DSBs), and factors related to DGF, such as ischemic times at transplantation and serum creatinine (sCr) levels. DSBs were detected by phospho-histone H2A.X (γ-H2AX) expression and cellular regeneration by Ki-67 before (0 h) and 1 h after allograft reperfusion (1 h) in each subject. RESULTS: The expression of γ-H2AX or Ki-67 at 0 h showed no difference between the living and deceased donors. γ-H2AX at 1 h decreased in the living donors, but increased in the deceased donors compared with that of 0 h(p = 0.017). Changes (Δ) in γ-H2AX between 0 and 1 h were different among subgroups, i.e., immediate function, slow graft function with dialysis < 7 days, DGF with dialysis < 4 weeks, severe DGF with dialysis > 4 weeks, or primary non-function (PNF) (p = 0.04). Severe DGF and PNF cases showed greater increase in Δγ-H2AX (p = 0.019), and were distinguished by > 12% of Δγ-H2AX at 100% sensitivity and 88.2% specificity (ROC analysis, AUC: 0.922, p = 0.023). In a multivariate regression analysis, donor sCr and Δγ-H2AX were two main predictors of the grade of DGF (p = 0.002). The expression of Ki-67 was very low at both 0 h and 1 h. CONCLUSION: The combination of donor sCr and Δγ-H2AX from 0 to 1 h after reperfusion may predict severe DGF and PNF in the early phase.

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.

Increased soluble fms-like tyrosine kinase 1 after ischemia reperfusion contributes to adverse clinical outcomes following kidney transplantation.

Renal ischemia reperfusion injury (IRI) adversely affects clinical outcomes following kidney transplantation. Understanding the cellular mechanisms and the changes in gene/protein expression following IRI may help to improve these outcomes. Serum soluble fms-like tyrosine kinase 1 (sFlt-1), a circulating antiangiogenic protein, is increased in the first week following kidney transplantation. We evaluated the casual relationship of elevated sFlt-1 levels with renal microvascular dysfunction following IRI in a longitudinal study of 93 kidney transplant recipients and in several animal models. Transplant recipients with higher sFlt-1 levels had higher odds of delayed graft function, graft rejection, impaired graft function, and death. In a subgroup of 25 participants who underwent kidney biopsy within 4 months of kidney transplantation, peritubular capillary area was lower in those with elevated serum sFtl-1 levels. The administration of recombinant sFlt-1 into rodents resulted in significant structural and functional changes of the renal microvasculature, including reduced peritubular capillary density and intracapillary blood volume, and lead to increased expression of inflammatory genes and increased fibrosis. In a murine model of IRI, the kidney was a site of sFlt-1 production, and systemic neutralization of sFlt-1 preserved peritubular capillary density and alleviated renal fibrosis. Our data indicate that high sFlt-1 levels after IRI play an important role in the pathogenesis of microvascular dysfunction, thereby contributing to adverse clinical outcomes following kidney transplantation.

Therapeutic concentration achievement and allograft survival comparing usage of conventional tacrolimus doses and CYP3A5 genotype-guided doses in renal transplantation patients.

AIMS: Although cytochromeP450(CYP)3A5 gene polymorphism affects personalized tacrolimus doses, there is no consensus as to whether CYP3A5 genotypes should be determined to adjust the doses. The aims were to compare the therapeutic ranges and clinical outcomes between the conventional and genotype-guided tacrolimus doses. METHODS: This randomized controlled study compared 63 cases of the conventional tacrolimus dose group (0.1 mg/kg/day) with 62 cases of the genotype-guided doses group of 0.125, 0.1 and 0.08 mg/kg for CYP3A5*1/*1, *1/*3, and *3/*3 genotypes for the initial 3 days of kidney transplantation. After day 3, dose adjustment occurred in both groups to achieve therapeutic concentrations. RESULTS: The genotype-guided group had an increased proportion of patients with tacrolimus concentrations in the therapeutic range at the steady state on day 3 (40.3 vs 23.8%, P = .048). A lower proportion of over-therapeutic concentration patients was noted in the genotype-guided group in the CYP3A5*3/*3 genotype (9.7 vs 27%, P = .013). Unexpectedly, more delayed graft functions (DGFs) were in the genotype-guided group (41.9 vs 22.2%, P = .018) especially in the CYP3A5*1/*1 participants who might have had an aggravated DGF by a longer ischaemic time and higher serum donor creatinine levels than in the control group. There were no significant differences of glomerular filtration rates or graft or patient survivals over a median 37-month follow-up period. CONCLUSIONS: Determination of the CYP3A5 genotype improved therapeutic range achievement. CYP3A5*1/*1 patients who have high risks of DGF should be closely monitored because of an increased risk of DGF and reduced glomerular filtration rate with high tacrolimus doses.

Comparison of urine and blood NGAL for early prediction of delayed graft function in adult kidney transplant recipients: a meta-analysis of observational studies.

BACKGROUND: Neutrophil gelatinase-assoicated lipocalin (NGAL) appears to be a promising proximal tubular injury biomarker for early prediction of delayed graft function (DGF) in kidney transplant recipients. However, its predictive values in urine and blood were varied among different studies. Here, we performed the meta-analysis to compare the predictive values of urine NGAL (uNGAL) and blood NGAL (bNGAL) for DGF in adult kidney transplant recipients. METHODS: We systematically searched Medline, Cochrane library and Embase for relevant studies from inception to May 2018. The summary receiver operating characteristic (SROC) curves, the pooled sensitivity, specificity and diagnostic odds ratio (DOR) were used to evaluate the prognostic performance of uNGAL and bNGAL for the identification of DGF. RESULTS: A total of 1036 patients from 14 eligible studies were included in the analysis. 8 studies focused on NGAL in urine and 6 reported NGAL in serum or plasma. The composite area under the ROC (AUC) for 24 h uNGAL was 0.91 (95% CI, 0.89-0.94) and the overall DOR for 24 h uNGAL was 24.17(95% CI, 9.94-58.75) with a sensitivity of 0.88 (95% CI, 0.75-0.94) and a specificity of 0.81 (95% CI, 0.68-0.89). The composite AUC for 24 h bNGAL was 0.95 (95% CI, 0.93-0.97) and the overall DOR for 24 h bNGAL was 43.11 (95% CI, 16.43-113.12) with a sensitivity of 0.91 (95% CI, 0.81-0.96) and a specificity of 0.86 (95% CI, 0.78-0.92). CONCLUSIONS: Urine and serum/plasma NGAL were valuable biomarkers for early identification of DGF in kidney transplantation. In addition, the bNGAL was superior to uNGAL in early prediction of DGF.

Neutrophil Gelatinase-Associated Lipocalin as a Biomarker of Allograft Function After Renal Transplantation: Evaluation of the Current Status and Future Insights.

Neutrophil gelatinase-associated lipocalin (NGAL), a protein belonging to the lipocalin superfamily initially found in activated neutrophils, is expressed by several cell types, including kidney tubule. The increase in NGAL production and release from tubular cells in response to various insults has been proven to predict acute kidney injury (AKI). For this reason, it has emerged as a valuable noninvasive biomarker of AKI in clinical nephrology. Also in the renal transplant setting, different studies have indicated NGAL as a valuable tool, especially in the early postoperative period, since the currently available clinical and laboratory parameters remain poorly sensitive to monitor immediate posttransplant graft function. This is an analysis of the recent literature to assess the utility of plasma and urinary NGAL, exosomal mRNA for NGAL, and NGAL levels in the perfusate of machine-perfused kidneys for the prediction of graft function recovery in the early postsurgery phase after renal transplantation. We found that NGAL appears as a promising troponin-like biomarker to detect short-term impairment of graft function after renal transplant, but there are still some limitations in its clinical application, essentially related to its low specificity. Moreover, comparing NGAL assayed in serum, urine, machine-perfusate, or as exosomal mRNA, each one has shown limitations and benefits in terms of predictive performance for DGF, according to various existing studies, feasibly due to different cut-off levels, designs and patient sample sizes.

Protective Effects of L-Carnitine Against Delayed Graft Function in Kidney Transplant Recipients: A Pilot, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial.

OBJECTIVE: Delayed graft function (DGF) is an early complication after deceased donor kidney transplantation with significant adverse effects on graft outcomes. Ischemia-reperfusion injury during transplantation is a major cause of DGF. Tissue concentrations of carnitine, an antioxidant and regulator of cellular energy supply, decrease in the kidney following ischemia-reperfusion insult. Based on promising animal data, this study evaluated the possible protective effect of L-carnitine against DGF. DESIGN: This study is a pilot, randomized, double-blind, placebo-controlled clinical trial that was conducted on kidney transplantation patients in kidney transplant ward of Imam Khomeini hospital complex affiliated to Tehran University of Medical Sciences, Tehran, Iran. SUBJECTS: Patients older than 14 years old undergoing their first kidney transplantation from a deceased donor were evaluated for eligibility to take part in this study. Fifty-six patients were randomly assigned to L-carnitine or placebo groups. INTERVENTION: During this trial, 3 g of oral L-carnitine or placebo was administered in 3 divided doses each day for 4 consecutive days starting the day before kidney transplantation (i.e., days -1, 0, 1, and 2). MAIN OUTCOME MEASURE: The need for dialysis within the first week after transplantation, serum creatinine and urine output were assessed daily. After hospital discharge, patients were followed for 3 months regarding organ function. RESULTS: DGF incidence did not differ between the L-carnitine and placebo groups (18.51% vs. 23.8%, respectively; P = .68). Total allograft failure within 3 months after kidney transplantation happened in 6 patients in the placebo and 1 patient in the L-carnitine group (P = .05). CONCLUSION: This study showed no protective effects of oral L-carnitine supplementation against DGF occurrence recipients; however, 3-month graft loss was lower in the L-carnitine supplemented group.

Anti-LG3 Antibodies Aggravate Renal Ischemia-Reperfusion Injury and Long-Term Renal Allograft Dysfunction.

Pretransplant autoantibodies to LG3 and angiotensin II type 1 receptors (AT1R) are associated with acute rejection in kidney transplant recipients, whereas antivimentin autoantibodies participate in heart transplant rejection. Ischemia-reperfusion injury (IRI) can modify self-antigenic targets. We hypothesized that ischemia-reperfusion creates permissive conditions for autoantibodies to interact with their antigenic targets and leads to enhanced renal damage and dysfunction. In 172 kidney transplant recipients, we found that pretransplant anti-LG3 antibodies were associated with an increased risk of delayed graft function (DGF). Pretransplant anti-LG3 antibodies are inversely associated with graft function at 1 year after transplantation in patients who experienced DGF, independent of rejection. Pretransplant anti-AT1R and antivimentin were not associated with DGF or its functional outcome. In a model of renal IRI in mice, passive transfer of anti-LG3 IgG led to enhanced dysfunction and microvascular injury compared with passive transfer with control IgG. Passive transfer of anti-LG3 antibodies also favored intrarenal microvascular complement activation, microvascular rarefaction and fibrosis after IRI. Our results suggest that anti-LG3 antibodies are novel aggravating factors for renal IRI. These results provide novel insights into the pathways that modulate the severity of renal injury at the time of transplantation and their impact on long-term outcomes.

Normal saline versus lower-chloride solutions for kidney transplantation.

BACKGROUND: The ideal intravenous fluid for kidney transplantation has not been defined, despite the common use of normal saline during the peri-operative period. The high chloride content of normal saline is associated with an increased risk of hyperchloraemic metabolic acidosis, which may in turn increase the risk of hyperkalaemia and delayed graft function. Balanced electrolyte solutions have a lower chloride content which may decrease this risk and avoid the need for dialysis due to hyperkalaemia in the immediate post-transplant period. Randomised controlled trials (RCTs) addressing this issue have used biochemical outcomes to compare fluids and have been underpowered to address patient-centred outcomes such as delayed graft function. OBJECTIVES: To examine the effect of lower-chloride solutions versus normal saline on delayed graft function, hyperkalaemia and acid-base status in kidney transplant recipients. SEARCH METHODS: We searched the Cochrane Kidney and Transplant's Specialised Register to 26 November 2015 through contact with the Information Specialist using search terms relevant to this review. SELECTION CRITERIA: RCTs of kidney transplant recipients that compared peri-operative intravenous lower-chloride solutions to normal saline were included. DATA COLLECTION AND ANALYSIS: Two independent investigators assessed studies for eligibility and risk of bias. Data from individual studies were extracted using standardised forms and pooled according to a published protocol. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. MAIN RESULTS: Six studies (477 participants) were included in the review. All participants were adult kidney transplant recipients and 70% of participants underwent live-donor kidney transplantation. The overall risk of bias was low for selection bias and unclear for remaining domains. There was no difference in the risk of delayed graft function (3 studies, 298 participants: RR 1.03, 95% CI 0.62 to 1.70) or hyperkalaemia (2 studies, 199 participants: RR 0.48, 95% CI 0.04 to 6.10) for participants who received balanced electrolyte solutions compared to normal saline. Intraoperative balanced electrolyte solutions compared to normal saline were associated with higher blood pH (3 studies, 193 participants: MD 0.07, 95% CI 0.05 to 0.09), higher serum bicarbonate (3 studies, 215 participants: MD 3.02 mEq/L, 95% CI 2.00 to 4.05) and lower serum chloride (3 studies, 215 participants: MD -9.93 mmol/L, 95% CI -19.96 to 0.11). There were four cases of graft loss in the normal saline group and one in the balanced electrolyte solution group, and four cases of acute rejection in the normal saline group compared to two cases in the balanced electrolyte solution group. AUTHORS' CONCLUSIONS: Balanced electrolyte solutions are associated with less hyperchloraemic metabolic acidosis compared to normal saline, however it remains uncertain whether lower-chloride solutions lead to improved graft outcomes compared to normal saline.

Delayed Graft Function in Kidney Transplantation: Risk Factors and Impact on Early Graft Function.

CONTEXT: Although kidney transplantations are routinely performed at many centers in Turkey, the incidence and risk factors associated with delayed graft function (DGF) here have not yet been well defined. OBJECTIVE: The aim of this study is to evaluate the incidence and risk factors of DGF and its impact on early graft function. DESIGN: The medical charts of 154 adult patients who underwent deceased donor kidney transplantation between 2000 and 2014 in a single center were reviewed retrospectively. SETTING: Delayed graft function-related risk factors for donors, recipients, and the transplant surgery itself were analyzed, and their relation with graft function was evaluated. MAIN OUTCOMES MEASURES: The median recipient age was 39 years. The median cold ischemia time (CIT) was 840 minutes (14 hours). The incidence of DGF and acute rejection were 57.8% and 8.4%, respectively. Higher serum creatinine levels at 3, 6, and 12 months were observed in patients with DGF compared to other patients without DGF (P < .05). Patients with DGF had poor graft function (glomerular filtration rate ≤ 50) at 3 and 6 months (P < .05), but these correlations were not seen at 12 months (P = not significant). RESULTS: This study showed that DGF was a common and serious problem associated with poor graft functions at 3, 6, and 12 months after transplantation. Extra effort to shorten CIT as an independent risk factor for DGF could have protective effect on graft functions.

[Correlation between susceptibility weighted imaging manifestation and serum cystatin C for delayed graft function].

OBJECTIVE: To explore the correlation between susceptibility weighted imaging (SWI) manifestation and serum cystatin C level for delayed graft function (DGF). METHODS: The conventional MRI, SWI and serum cystatin C of 27 cases with DGF in nephrotransplantation center in Third Affiliated Hospital of Suzhou University from September 2014 and August 2015 were retrospectively analyzed.By contrasting conventional MRI images of transplanted kidney in DGF, the imaging manifestations of benign tumors such as cysts and angiomyolipomas were excluded on SWI images, and then making the renal cortex as the reference, if the abnormal signal lesions were found in the transplanted kidney, the location and signal intensity would be analyzed. The differences in serum cystatin C level between DGF groups without and with abnormal signal lesions were compared by using independent-sample t-test.The correlation between SWI manifestation and serum cystatin C level for DGF was assessed with Spearman rank correlation analysis. RESULTS: A total of 15 cases were found without abnormal signal lesions and the average value of their serum cystatin C level was (2.92±0.44) mg/L.A total of 12 cases were found with abnormal low signal lesions located at junctional zone between cortex and medulla, and the average value of their serum cystatin C level was (6.91±0.96) mg/L. The differences in serum cystatin C level between the two DGF groups were statistically significant (t=-4.040, P=0.000). There was a positive correlation between the abnormal low signal lesions on SWI and serum cystatin C level (r=0.660, P=0.000). CONCLUSION: The status of renal function impairment could be reflected by being with or without abnormal signal lesions on SWI. A relatively big renal function impairment may be predicted by the appearance of abnormal low signal lesions at junctional zone between cortex and medulla on SWI.

Assessment of neutrophil gelatinase-associated lipocalin in the brain-dead organ donor to predict immediate graft function in kidney recipients: a prospective, multicenter study.

BACKGROUND: Delayed graft function is a major determinant of long-term renal allograft survival. Despite considerable efforts to improve donor selection and matching, incidence of delayed graft function remains close to 25%. As neutrophil gelatinase-associated lipocalin (NGAL) has been shown to predict acute renal failure, the authors tested the hypothesis that NGAL measurement in brain-dead donors predicts delayed graft function in kidney recipients. METHODS: In a prospective, multicenter, observational study, serum NGAL was measured in donors at the time of transfer to operating room. The primary endpoint was the delayed graft function, defined as the need for renal replacement therapy during the first week posttransplantation. RESULTS: Among 159 included brain-dead donors, 146 were analyzable leading to 243 renal transplantations. Of these, 56 (23%) needed renal replacement therapy. Donors' NGAL values were similar in case of both delayed and normal graft function in recipients. The area under the receiver-operating curve for NGAL to predict the need for renal replacement therapy before day 8 was 0.50 (95% CI, 0.42 to 0.59). The area under curve for NGAL to predict failure to return to a normal graft function at day 8 was 0.51 (95% CI, 0.44 to 0.59). Using multivariate analysis, NGAL was not associated to the need for renal replacement therapy (odds ratio, 0.99; 95% CI, 0.98 to1.00) or failure to return to a normal graft function at day 8 (odds ratio, 1.00; 95% CI, 0.99 to 1.00). CONCLUSION: NGAL measurement in brain-dead donors at the time of recovery failed to predict delayed or normal graft function in kidney recipients.

Serum liver-type fatty acid-binding protein predicts recovery of graft function after kidney transplantation from donors after cardiac death.

Kidneys procured by donation after cardiac death (DCD) may increase the donor pool but are associated with high incidence of delayed graft function (DGF). Urinary liver-type fatty acid-binding protein (L-FABP) level is an early biomarker of renal injury after kidney transplantation (KTx); however, its utility is limited in DGF cases owing to urine sample unavailability. We examined whether serum L-FABP level predicts functional recovery of transplanted DCD kidneys. Consecutive patients undergoing KTx from living related donors (LD), brain-dead donors (BD), or DCD were retrospectively enrolled. Serum L-FABP levels were measured from samples collected before and after KTx. Serum L-FABP decreased rapidly in patients with immediate function, slowly in DGF patients, and somewhat increased in DGF patients requiring hemodialysis (HD) for >1 wk. Receiver-operating characteristic curve analysis demonstrated that DGF was predicted with 84% sensitivity (SE) and 86% specificity (SP) at cutoff of 9.0 ng/mL on post-operative day (POD) 1 and 68% SE and 90% SP at 6.0 on POD 2. DGF >7 d was predicted with 83% SE and 78% SP at 11.0 on POD 1 and 67% SE and 78% SP at 6.5 on POD 2. Serum L-FABP levels may predict graft recovery and need for HD after DCD KTx.

Serum neutrophil gelatinase-associated lipocalin and recovery of kidney graft function after transplantation.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is a marker for acute kidney injury. We studied whether serum NGAL predicts delayed graft function (DGF) and recovery of kidney function after transplantation. METHODS: Serum NGAL was analyzed using commercial ELISA and point-of-care (POC) (Triage®, Biosite) methods. Serum samples were collected from 176 consecutive, deceased-donor kidney recipients just before transplant surgery and on day 1 and 14 after transplantation. The first 132 samples were analyzed with both methods and the remaining samples with the POC method. RESULTS: The correlation between the ELISA and POC methods was 0.89, p < 0.0001 and hence the POC method was used for the remaining analyses. DGF was seen in 66/176 patients. Day 1 sNGAL was significantly higher in DGF (588 ng/ml, SD 189.6) compared to early graft function (355 ng/ml, SD 166.2, p < 0.0001) and this difference persisted on day 14. Day 1 sNGAL predicted DGF with an area under the curve (AUC) of 0.853 (CI 0.792-0.914, p < 0.0001). At the optimal cutoff level of 423 ng/ml the sensitivity was 87% and the specificity 77%. In a multivariate analysis, day 1 sNGAL emerged as an independent predictor of DGF. The sNGAL also predicted DGF lasting longer than 14 days with an AUC of 0.825 (CI 0.751-0.899, p < 0.0001). At the optimal cutoff level of 486 ng/ml, the sensitivity was 80% and specificity 75%. CONCLUSION: Serum NGAL predicts clinically significant DGF and is useful in the care of kidney transplant recipients.

Optimal Timing of Serum Creatinine Measurement for KDPI Scoring to Predict Postoperative Renal Function in Deceased Donor Kidney Transplantation.

INTRODUCTION: The widely employed Kidney Donor Profile Index (KDPI) scoring system, designed for assessing deceased donors (DD), plays a pivotal role in predicting graft function post kidney transplantation (KT). Given the dynamic nature of renal function, including serum creatinine (sCr), in managing DDs, it remains uncertain optimal timing to use KDPI for assessing postoperative graft function. METHODS: In this retrospective review, we assessed 246 DDs who were managed within a donor management program from January 2010 to December 2021. We collected sCr values for KDPI scoring at admission, peak, and last measurements before KT. Recipient data included occurrence of slow graft function (SGF), delayed graft function (DGF), and glomerular filtration rate (GFR) at one-year post-transplantation (1 Y). Using Receiver Operating Characteristic (ROC) and Pearson correlation analyses, we explored correlations of KDPI score (admission, peak, last) with graft function (SGF, DGF, GFR 1 Y). RESULTS: The average age of DDs and recipients was 49.78 ± 13.37 and 52.54 ± 10.49 years, respectively, with mean KDPI values at admission, peak, and last measurements of 62.36 ± 25.44, 66.94 ± 24.73, and 63.75 ± 25.80. After transplantation, SGF was observed in 81 recipients (32.9%) and DGF in 32 (13.0%). For SGF, the Area Under the Curve (AUC) from ROC analysis were 0.684 (95% CI, 0.615-0.753; P < .001) at admission, 0.691 (0.623-0.759; P < .001) at peak, and 0.697 (0.630-0.765; P < .001) at the last measurement. In predicting DGF, the corresponding AUC values were 0.746 (0.661-0.831; P < .001) at admission, 0.724 (0.637-0.810; P < .001) at peak, and 0.721 (0.643-0.809; P < .001) at the last. Moreover, KDPI scores at all time points-admission, peak, and last-moderately correlated with GFR 1 Y (R = -0.426, -0.423, -0.417). CONCLUSION: KDPI measurements at all time points, particularly admission, would be more effective in predicting DGF in DDKT.

Serum aminoacylase-1 is a novel biomarker with potential prognostic utility for long-term outcome in patients with delayed graft function following renal transplantation.

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

Increased resistin in brain dead organ donors is associated with delayed graft function after kidney transplantation.

INTRODUCTION: Resistin increases during several inflammatory diseases and after intracerebral bleeding or head trauma. Resistin activates the endothelium and may initiate an inflammatory response. No data are available on resistin in brain dead donors (DBD) that regularly manifest a pronounced inflammatory state. METHODS: We analyzed plasma resistin in 63 DBDs and correlated results with donor variables and the postoperative course following kidney transplantation using organs from these donors. Endocan and monocyte chemotactic protein (MCP)-1 were also studied. Twenty-six live kidney donors (LD) and the corresponding kidney transplantations were used as controls. RESULTS: DBDs had higher resistin (median/range 30.75 ng/ml, 5.41-173.6) than LD (7.71 ng/ml, 2.41-15.74, p < 0.0001). Resistin in DBD correlated with delayed graft function (DGF) in the kidney recipients (r = 0.321, p < 0.01); receiver operating characteristic curve revealed an area under the curve of 0.765 (95% confidence interval [CI] 0.648-0.881, p < 0.01) and a cut-off value for resistin of 25 ng/ml; MCP-1 and endocan were higher in DBDs (p < 0.0001) but did not correlate with DGF or acute rejection. No relationship was found between the studied molecules and the postoperative course of LD kidney transplants. CONCLUSIONS: High resistin levels in the DBD before organ retrieval are associated with DGF after kidney transplantation. The resistin increase seems related to the inflammatory state after brain death but not to the cause of death.