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IntroductionSubclinical inflammation is an important predictor of death-censored graft loss, and its treatment has been shown to improve graft outcomes. Urine CXCL10 outperforms standard post-transplant surveillance in observational studies, by detecting subclinical rejection and early clinical rejection before graft functional decline in kidney transplant recipients.Methods and analysisThis is a phase ii/iii multicentre, international randomised controlled parallel group trial to determine if the early treatment of rejection, as detected by urine CXCL10, will improve kidney allograft outcomes. Incident adult kidney transplant patients (n~420) will be enrolled to undergo routine urine CXCL10 monitoring postkidney transplant. Patients at high risk of rejection, defined as confirmed elevated urine CXCL10 level, will be randomised 1:1 stratified by centre (n=250). The intervention arm (n=125) will undergo a study biopsy to check for subclinical rejection and biopsy-proven rejection will be treated per protocol. The control arm (n=125) will undergo routine post-transplant monitoring. The primary outcome at 12 months is a composite of death-censored graft loss, clinical biopsy-proven acute rejection, de novo donor-specific antibody, inflammation in areas of interstitial fibrosis and tubular atrophy (Banff i-IFTA, chronic active T-cell mediated rejection) and subclinical tubulitis on 12-month surveillance biopsy. The secondary outcomes include decline of graft function, microvascular inflammation at 12 months, development of IFTA at 12 months, days from transplantation to clinical biopsy-proven rejection, albuminuria, EuroQol five-dimension five-level instrument, cost-effectiveness analysis of the urine CXCL10 monitoring strategy and the urine CXCL10 kinetics in response to rejection therapy.Ethics and disseminationThe study has been approved by the University of Manitoba Health Research Ethics Board (HS20861, B2017:076) and the local research ethics boards of participating centres. Recruitment commenced in March 2018 and results are expected to be published in 2023. De-identified data may be shared with other researchers according to international guidelines (International Committee of Medical Journal Editors [ICJME]).Trial registration number NCT03206801; Pre-results.

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

Delayed graft function (DGF) is a consequence of ischemia-reperfusion injuries in kidney allografts, for which no definite treatment is available. The neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL-18) are introduced as the most promising urine biomarkers to detect DGF. N-acetylcysteine (NAC) and vitamin C, well-known potent antioxidants that scavenge free radicals, may alleviate kidney injury. This study investigated the protective effects of NAC alone and in combination with vitamin C on DGF, by measuring IL-18 and NGAL in living donor kidney transplantations.INTRODUCTIONDelayed graft function (DGF) is a consequence of ischemia-reperfusion injuries in kidney allografts, for which no definite treatment is available. The neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL-18) are introduced as the most promising urine biomarkers to detect DGF. N-acetylcysteine (NAC) and vitamin C, well-known potent antioxidants that scavenge free radicals, may alleviate kidney injury. This study investigated the protective effects of NAC alone and in combination with vitamin C on DGF, by measuring IL-18 and NGAL in living donor kidney transplantations.Patients transplanted between January 2011 and February 2013 were randomly divided into 3 groups to receive routine anti-rejection medication only (n = 32), NAC plus routine immunosuppressive regimen (NAC group; n = 33), and NAC and vitamin C plus routine regimen (NAC and vitamin C group; n = 19). Urine samples were taken 4 hours and 24 hours after transplantation. Enzyme-linked immunosorbent assay kits were utilized for measuring urine NGAL and IL-18.MATERIALS AND METHODSPatients transplanted between January 2011 and February 2013 were randomly divided into 3 groups to receive routine anti-rejection medication only (n = 32), NAC plus routine immunosuppressive regimen (NAC group; n = 33), and NAC and vitamin C plus routine regimen (NAC and vitamin C group; n = 19). Urine samples were taken 4 hours and 24 hours after transplantation. Enzyme-linked immunosorbent assay kits were utilized for measuring urine NGAL and IL-18.There were no significant differences in the DGF prevalence and its duration between the study arms. Although the levels of NGAL and IL-18 decreased in the NAC and NAC and vitamin C groups, these reductions were not significant. Glomerular filtration rate at 30 and 60 days after transplantation were not significantly different between study groups, either.RESULTSThere were no significant differences in the DGF prevalence and its duration between the study arms. Although the levels of NGAL and IL-18 decreased in the NAC and NAC and vitamin C groups, these reductions were not significant. Glomerular filtration rate at 30 and 60 days after transplantation were not significantly different between study groups, either.Our results showed that NAC is a safe drug without significant adverse effects in kidney transplant recipients; however, its potential useful effects on urinary biomarkers of DGF were not illustrated in the present study.CONCLUSIONSOur results showed that NAC is a safe drug without significant adverse effects in kidney transplant recipients; however, its potential useful effects on urinary biomarkers of DGF were not illustrated in the present study.

Expanded criteria donors (ECD) have the potential to greatly increase the donor organ pool but pose a higher risk of delayed graft function (DGF) post-transplantation. Uridine diphosphate-glucose (UDP-Glc) plays a significant role in extracellular signaling related to tissue damage and retains stability for detection. Donor urinary UDP-Glc level may be an appropriate and effective biomarker for predicting DGF. Recipients who underwent successful kidney transplantation, with corresponding collection of donor urine samples, between June 2023 and August 2024 were included. We measured preoperative donor urinary UDP-Glc levels and analyzed their correlation with graft recovery. The study was registered in the Clinical Trial Registry (no. NCT06707272). Preoperative donor urinary UDP-Glc levels were different between immediated, slowed, and delayed graft function subgroups (7.23 vs. 9.04 vs. 10.13 ug/mL, 0.001). Donor urinary UDP-Glc level was an independent risk factor for DGF (odds ratio [OR] = 1.741, 95% confidence interval [CI]: 1.311-2.312, 0.001). Furthermore, donor urinary UDP-Glc showed a better predictive value for DGF (AUROC = 0.791, 95% CI: 0.707-0.875, 0.001), and combining donor urinary UDP-Glc and donor terminal serum creatinine improved the model predictive value for DGF (AUROC = 0.832, 95% CI: 0.756-0.908, Youden index = 0.56, sensitivity = 0.81, specificity = 0.75, PPV = 0.72, NPV = 0.83, 0.001). Additionally, the donor urinary UDP-Glc level was related to the recipient serum creatinine level at 1 month post-transplantation (r = 0.475, 0.001). Donor urinary UDP-Glc level is an independent risk factor for DGF and can provide surgeons with a novel strategy to predict DGF earlier and more accurately without invasive procedures. https://clinicaltrials.gov, NCT06707272 identifier.

TIMP-2 and IGFBP7 have been identified and validated for the early detection of renal injury in critically ill patients, but data on recovery of allograft function after kidney transplantation (KTx) are scarce. In a prospective observational multicenter cohort study of renal transplant recipients, urinary [TIMP-2] × [IGFBP7] was evaluated daily from day 1 to 7 after KTx. Different stages of early graft function were defined: immediate graft function (IGF) (decrease ≥ 10% in serum creatinine (s-crea) within 24 h post KTx); slow graft function (SGF) (decrease in s-crea < 10% within 24 h post KTx); and delayed graft function (DGF) (any dialysis needed within the first week after KTx). A total of 186 patients were analyzed. [TIMP-2] × [IGFBP7] was significantly elevated as early as day 1 in patients with DGF compared to SGF and IGF. ROC analysis of [TIMP-2] × [IGFBP7] at day 1 post-transplant for event “Non-DGF” revealed a cut-off value of 0.9 (ng/mL)2/1000 with a sensitivity of 87% and a specificity of 71%. The positive predictive value for non-DGF was 93%. [TIMP-2] × [IGFBP7] measured at day 1 after KTx can predict early recovery of transplant function and is therefore a valuable biomarker for clinical decision making.

Predicting immediate and subsequent graft function is important in clinical decision-making around kidney transplantation, but is difficult using available approaches. Here we have evaluated urinary microRNAs as biomarkers in this context. Profiling of 377 microRNAs in the first urine passed post-transplantation identified 6 microRNAs, confirmed to be upregulated by RT-qPCR in an expanded cohort (miR-9, -10a, -21, -29a, -221, and -429, n = 33, P < 0.05 for each). Receiver operating characteristic analysis showed Area Under the Curve 0.94 for this panel. To establish whether this early signal was sustained, miR-21 was measured daily for 5 days post-transplant, and was consistently elevated in those developing Delayed Graft Function (n = 165 samples from 33 patients, p < 0.05). The biomarker panel was then evaluated in an independent cohort, sampled at varying times in the first week post-transplantation in a separate transplant center. When considered individually, all miRs in the panel showed a trend to increase or a significant increase in those developing delayed Graft Function (miR-9: P = 0.068, mIR-10a: P = 0.397, miR-21: P = 0.003, miR-29a: P = 0.019, miR-221: P = 0.1, and miR-429: P = 0.013, n = 47) with Area Under the Curve 0.75 for the panel. In conclusion, combined measurement of six microRNAs had predictive value for delayed graft function following kidney transplantation.

Delayed graft function (DGF), especially long-lasting DGF, complicates kidney transplant outcome. Neutrophil gelatinase-associated lipocalin (NGAL) is an acute kidney injury marker; therefore, we tested whether urine NGAL could predict DGF, prolonged DGF (lasting over 14 days), or the quality of kidney function in transplant recipients without DGF (non-DGF). We collected urine samples from 176 recipients transplanted with deceased donor kidneys before and various days after transplantation. A total of 70 transplantations had DGF, of which 26 were prolonged. Patients who developed DGF had a significantly slower decrease in urinary NGAL compared with those without DGF, such that day 1 NGAL predicted DGF (area under the curve (AUC) 0.75) and predicted DGF in 15 of 112 cases with day 1 urine output over 1l (AUC 0.70) and in 19 of 86 cases with a day 1 decrease in creatinine over 50μmol/l (AUC 0.74). The urinary NGAL level on day 1 predicted prolonged DGF (AUC 0.75), which had significantly worse 1-year graft survival (73%), compared with shorter DGF (100%). In non-DGF, high day 3 NGAL (greater than the mean) was associated with significantly worse kidney function at 3 weeks compared with low NGAL, but not at 3 months and 1 year. NGAL did not correlate with long-term function in DGF. Hence, day 1 urinary NGAL predicted DGF even when it was not clinically expected early on, and importantly, it predicted prolonged DGF that led to worse graft survival.

Recipients of donation after circulatory death (DCD) kidneys are at high risk for delayed graft function (DGF) due to severe ischemia-reperfusion injury. We compared urinary biomarkers in predicting the duration of DGF with the tubular function slope (TFS) as the gold standard. In 89 DCD kidney transplant recipients, urinary TIMP-2, IGFBP7, B2M, NGAL, KIM1, CXCL9, and UMOD were quantified by LC-MS/MS analysis on postoperative days (PODs) 1, 4 and 10. Interstitial fibrosis and tubular atrophy (IF/TA) were assessed with protocol biopsies at POD 10. TFS was calculated with Tc-MAG3 renography. Predictive performance was compared with AUCs from ROC analyses. Of all 89 recipients, 22% experienced no (<7), 22% mild (≥7-14), 29% moderate (≥14-<21) and 26% severe (≥21 days) fDGF. The OR for the presence of IF/TA was 1.9 (95% CI:0.4; 10.0) for mild to moderate and 15.0 (95% CI:2.7; 84.8) for severe compared to no fDGF. At POD 4, urinary NGAL and fractional NGAL excretion (FE-NGAL) outperformed TFS and other biomarkers in predicting fDGF with AUCs of 0.97, 0.98 and 0.92, respectively. At POD10, FE-NGAL and PCR best predicted severe vs mild to moderate fDGF, with AUCs of 0.74 and 0.76 versus 0.65 for TFS. Therefore, urinary NGAL and FE-NGAL may provide a viable alternative to TcMAG3 renography for monitoring fDGF clearance or guiding kidney transplant biopsy to exclude additional acute rejection.

Background Proteinuria is a common manifestation of chronic kidney disease (CKD), and there is a high incidence of CDK and its complications following renal transplantation. However, little data are available on the association between proteinuria and graft/patient survival in the paediatric transplant population. The primary aim of this study was to investigate the associations between posttransplant proteinuria and graft/patient survival in children after renal transplantation. Methods In this retrospective study, we screened all 91 children receiving renal allografts at a single institution between 1997 and 2007. The inclusion criteria were a functioning graft at 1 year posttransplant, data availability and no recurrence of focal-segmental glomerulosclerosis. The final cohort included 75 patients. Proteinuria was considered to be pathologic if the urinary protein/creatinine ratio was >30 mg/mmol. Donor and recipient characteristics, data on proteinuria, estimated glomerular filtration rate (eGFR) and rejection episodes were analysed. The most recent of the biopsies performed during the follow-up after 1 year posttransplant were analysed separately in the proteinuric group and the non-proteinuric group. Results Proteinuria at 1-year posttransplant was pathologic in 35 % of patients. The 5-year graft survival rate was significantly lower in the proteinuric group than in the non-proteinuric group (77 vs. 100 %; p  < 0.001). Proteinuria at 1 year posttransplant was associated with reduced long-term graft survival independent of other risk factors, including decreased eGFR or episodes of acute corticosensitive and corticoresistant rejection. The most frequent histologic finding in the proteinuric group was chronic rejection. There was no significant difference in the 5-year patient survival rate between the proteinuric group and the non-proteinuric group. Conclusion This study emphasizes the importance of proteinuria as a prognostic factor of renal allograft survival in children.

In this study, we examined whether the IL-8 content of urine sampled on day 1 and day 14 after renal transplantation is a marker of early and long-term renal function. Moreover, we assessed whether its concentration is positively correlated with the matrix metalloproteinase-9 (MMP-9) content of urine sampled on day 1 and day 30 and 12 months after renal transplantation. Our analysis covered 87 patients who underwent a kidney transplant. The patients were observed for an average of 30 months (12–60 months). The IL-8 concentration determined on day 1 was significantly negatively correlated with creatinine clearance early after renal transplantation (on days 1, 7, 14 and 30), as well as during long-term observations. IL-8 concentration in urine sampled on day 1 and day 14 was higher in patients demonstrating DGF than in those without DGF. No relationship was found between IL-8 content and cold ischaemia time. MMP-9 activity determined on day 1 and month 3 after renal transplantation was positively correlated with the IL-8 content determined in urine sampled on day 1, Rs = +0.32, p < .05 and Rs = +0.31, p < .05, respectively. The results of this study suggest that a high IL-8 content in urine sampled on day 1 after renal transplantation is an unfavourable marker of early and long-term (years-long) graft function. A high IL-8 content in urine sampled on day 1 after renal transplantation was positively correlated with the activity of metalloproteinase-9 in urine. This proves that both of these chemokines cooperate in ischaemia–reperfusion injuries in transplanted kidneys.