Correction: P-NGAL Day 1 predicts early but not one year graft function following deceased donor kidney transplantation-The CONTEXT study.

[This corrects the article DOI: 10.1371/journal.pone.0212676.].

The Diagnostic Yield and Clinical Impact of Systematic Screening of Kidney Transplant Candidates by Cardiac Computed Tomography: A Cohort Study.

BACKGROUND: Although cardiovascular screening of kidney transplant candidates is recommended, the optimal approach is debated. Previous studies show that noninvasive imaging provides prognostic information, but systematic screening may have less recognized effects, such as additional investigations, incidental findings, procedural complications, and delay of transplantation. To address this, we characterized the diagnostic yield and clinical implications of systematic screening for cardiovascular disease using cardiac computed tomography (CT) in potential kidney transplant candidates. METHODS: This was a single-center, observational cohort study including all potential kidney transplant candidates >40 years of age or with diabetes or on dialysis treatment for >5 years, systematically referred to cardiac computed tomography (CT; non-contrast CT and coronary CT angiography) between 2014 and 2019 before evaluation for kidney transplantation at Aarhus University Hospital. Patient records were examined for data on baseline characteristics, additional investigations and complications, plasma creatinine, dialysis initiation, time until wait-listing, and incidental findings. RESULTS: Of 473 patients who underwent cardiac CT, additional cardiac investigations were performed in 156 (33%), and 32 (7%) were revascularized. Twenty-two patients had significant incidental nonvascular findings on cardiac CT. No patient was rejected for transplantation based on cardiac CT. In patients not yet on dialysis, the slope in the estimated glomerular filtration rate decline did not change significantly after coronary CT angiography. CONCLUSION: Screening by cardiac CT led to additional cardiac investigations in one-third of patients; only a few patients were revascularized, with unknown benefits in asymptomatic patients. Cardiac CT was safe in this population; however, the clinical consequences of the screening were limited.

Pretransplant endotrophin predicts delayed graft function after kidney transplantation.

Delayed graft function after kidney transplantation is common and increases morbidity and health care costs. There is evidence that endotrophin, a specific fragment of pro-collagen type VI, promotes the inflammatory response in kidney diseases. We tested the hypothesis that pretransplant endotrophin in kidney transplant recipients may be associated with the risk of delayed graft function. Pretransplant plasma endotrophin was assessed using an enzyme-linked immunosorbent assay in three independent cohorts with 806 kidney transplant recipients. The primary outcome was delayed graft function, i.e., the necessity of at least one dialysis session within one-week posttransplant. In the discovery cohort median pretransplant plasma endotrophin was higher in 32 recipients (12%) who showed delayed graft function when compared to 225 recipients without delayed graft function (58.4 ng/mL [IQR 33.4-69.0]; N = 32; vs. 39.5 ng/mL [IQR 30.6-54.5]; N = 225; P = 0.009). Multivariable logistic regression, fully adjusted for confounders showed, that pretransplant plasma endotrophin as a continuous variable was independently associated with delayed graft function in both validation cohorts, odds ratio 2.09 [95% CI 1.30-3.36] and 2.06 [95% CI 1.43-2.97]. Pretransplant plasma endotrophin, a potentially modifiable factor, was independently associated with increased risk of delayed graft function and may be a new avenue for therapeutic interventions.

Prognostic value of computed tomography derived fractional flow reserve for predicting cardiac events and mortality in kidney transplant candidates.

BACKGROUND: Cardiac screening using coronary computed tomography angiography (CCTA) in kidney transplant candidates before transplantation yields both diagnostic and prognostic information. Whether CT-derived fractional flow reserve (FFRCT) analysis provides prognostic information is unknown. This study aimed to assess the prognostic value of FFRCT for predicting major adverse cardiac events (MACE) and all-cause mortality in kidney transplant candidates. METHODS: Among 553 consecutive kidney transplant candidates, 340 CCTA scans (61%) were evaluated with FFRCT analysis. Patients were categorized into groups based on lowest distal FFRCT; normal >0.80, intermediate 0.80-0.76, and low ≤0.75. In patients with ≥50% stenosis, a lesion-specific FFRCT was defined as; normal >0.80 and abnormal ≤0.80. The primary endpoint was MACE (cardiac death, resuscitated cardiac arrest, myocardial infarction or revascularization). The secondary endpoint was all-cause mortality. RESULTS: Median follow-up was 3.3 years [2.0-5.1]. MACE occurred in 28 patients (8.2%), 29 patients (8.5%) died. When adjusting for risk factors and transplantation during follow-up, MACE occurred more frequently in patients with distal FFRCT ≤0.75 compared to patients with distal FFRCT >0.80: Hazard Ratio (HR): 3.8 (95%CI: 1.5-9.7), p â€‹< â€‹0.01. In the lesion-specific analysis with <50% stenosis as reference, patients with lesion-specific FFRCT >0.80 had a HR for MACE of 1.5 (95%CI: 0.4-4.8), p â€‹= â€‹0.55 while patients with lesion-specific FFRCT ≤0.80 had a HR of 6.0 (95%CI: 2.5-14.4), p â€‹< â€‹0.01. Abnormal FFRCT values were not associated with increased mortality. CONCLUSION: In kidney transplant candidates, abnormal FFRCT values were associated with increased MACE but not mortality. Use of FFRCT may improve cardiac evaluation prior to transplantation.

Proteinuria is accompanied by intratubular complement activation and apical membrane deposition of C3dg and C5b-9 in kidney transplant recipients.

Proteinuria predicts accelerated decline in kidney function in kidney transplant recipients (KTRs). We hypothesized that aberrant filtration of complement factors causes intraluminal activation, apical membrane attack on tubular cells, and progressive injury. Biobanked samples from two previous studies in albuminuric KTRs were used. The complement-activation split products C3c, C3dg, and soluble C5b-9-associated C9 neoantigen were analyzed by ELISA in urine and plasma using neoepitope-specific antibodies. Urinary extracellular vesicles (uEVs) were enriched by lectin and immunoaffinity isolation and analyzed by immunoblot analysis. Urine complement excretion increased significantly in KTRs with an albumin-to-creatinine ratio of ≥300 mg/g compared with <30 mg/g. Urine C3dg and C9 neoantigen excretion correlated significantly to changes in albumin excretion from 3 to 12 mo after transplantation. Fractional excretion of C9 neoantigen was significantly higher than for albumin, indicating postfiltration generation. C9 neoantigen was detected in uEVs in six of the nine albuminuric KTRs but was absent in non-albuminuric controls (n = 8). In C9 neoantigen-positive KTRs, lectin affinity enrichment of uEVs from the proximal tubules yielded signal for iC3b, C3dg, C9 neoantigen, and Na+-glucose transporter 2 but only weakly for aquaporin 2. Coisolation of podocyte markers and Tamm-Horsfall protein was minimal. Our findings show that albuminuria is associated with aberrant filtration and intratubular activation of complement with deposition of C3 activation split products and C5b-9-associated C9 neoantigen on uEVs from the proximal tubular apical membrane. Intratubular complement activation may contribute to progressive kidney injury in proteinuric kidney grafts.NEW & NOTEWORTHY The present study proposes a mechanistic coupling between proteinuria and aberrant filtration of complement precursors, intratubular complement activation, and apical membrane attack in kidney transplant recipients. C3dg and C5b-9-associated C9 neoantigen associate with proximal tubular apical membranes as demonstrated in urine extracellular vesicles. The discovery suggests intratubular complement as a mediator between proteinuria and progressive kidney damage. Inhibitors of soluble and/or luminal complement activation with access to the tubular lumen may be beneficial.

Dynamics of circulating dendritic cells and cytokines after kidney transplantation-No effect of remote ischaemic conditioning.

Inflammation resulting from ischaemia/reperfusion injury can cause kidney graft dysfunction, increase the risk of delayed graft function and possibly reduce long-term graft survival. Remote ischaemic conditioning may protect against ischaemia/reperfusion injury and mitigate the immunological response to the graft. We investigated the immunological effects of remote ischaemic conditioning on kidney transplantation from deceased donors in the randomized CONTEXT study. Three circulating dendritic cell (DC) subtypes identified in peripheral blood from kidney transplant recipients [myeloid DCs, plasmacytoid DCs and immunoglobulin-like transcript (ILT)3+ DCs] were measured at baseline, days 1, 3 and 5 and 1 and 3 months after transplantation. We also quantified 21 cytokines at baseline, days 1 and 5 and 3 months after transplantation. Neither DC counts nor cytokine levels differed between patients receiving remote ischaemic conditioning and controls; however, several parameters exhibited dynamic and parallel alterations in the two groups over time, reflecting the immunological response to the kidney transplantation and immunosuppression.

Elevated plasma free thiols are associated with early and one-year graft function in renal transplant recipients.

BACKGROUND: Reduced free thiols in plasma are indicative of oxidative stress, which is an important contributor to ischaemia-reperfusion injury (IRI) in kidney transplantation leading to kidney damage and possibly delayed graft function (DGF). In a post-hoc, exploratory analysis of the randomised controlled CONTEXT trial, we investigated whether higher (i.e. less oxidised) plasma levels of free thiols as a biomarker of reduced oxidative stress are associated with a better initial graft function or a higher GFR. METHODS: Free thiol levels were measured in plasma at baseline, 30 and 90 minutes after reperfusion of the kidney as well as at Day 1, Day 5 and twelve months after kidney transplantation in 217 patients from the CONTEXT study. Free thiol levels were compared to the kidney graft function measured as the estimated time to a 50% reduction in plasma creatinine (tCr50), the risk of DGF and measured GFR (mGFR) at Day 5 and twelve months after transplantation. RESULTS: Higher levels of free thiols at Day 1 and Day 5 are associated with higher mGFR at Day 5 (p<0.001, r2adj. = 0.16; p<0.001, r2adj. = 0.25), as well as with mGFR at twelve months (p<0.001, r2adj. = 0.20; p<0.001, r2adj. = 0.16). However, plasma levels of free thiols at 30 minutes and 90 minutes, but not Day 1, were significantly higher among patients experiencing DGF. CONCLUSION: Higher levels of plasma free thiols at Day 1 and Day 5, which are reflective of lower levels of oxidative stress, are associated with better early and late graft function in recipients of a kidney graft from deceased donors. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01395719.

Remote ischaemic conditioning and early changes in plasma creatinine as markers of one year kidney graft function-A follow-up of the CONTEXT study.

BACKGROUND: Ischaemia-reperfusion injury in kidney transplantation leads to delayed graft function (DGF), which is associated with reduced long term graft function. Remote ischaemic conditioning (RIC) improved early kidney graft function in a porcine model of donation after brain death and was associated with improved long-term cardiac outcome after myocardial ischaemia. This randomised, double-blinded trial evaluated the effect of RIC on kidney graft outcome in the first year, and examined the predictive value of a new measure of initial kidney graft function, i.e. the estimated time to a 50% reduction in plasma creatinine post-transplantation (tCr50). METHODS: A total of 225 patients undergoing deceased donor kidney transplantation were randomised to RIC or a sham procedure performed prior to kidney reperfusion. Up to four repetitive cycles of five minutes of leg ischaemia and five minutes of reperfusion were given. GFR, plasma creatinine, cystatin C and neutrophil gelatinase associated lipocalin (NGAL) were measured at three and twelve months and estimated GFR was calculated using four different equations. Other secondary outcomes were identified from patient files. RESULTS: RIC did not affect GFR or other outcomes when compared to the sham procedure at three or twelve months. tCr50 correlated with one year graft function (p<0.0001 for both mGFR and eGFR estimates). In contrast, DGF i.e. "need of dialysis the first week" did not correlate significantly with one year GFR. CONCLUSION: RIC during deceased donor kidney transplantation did not improve one year outcome. However, tCr50 may be a relevant marker for studies aiming to improve graft onset. TRIAL REGISTRATION: www.ClinicalTrials.gov Identifier: NCT01395719.

Whole Genome Sequencing of Aggregatibacter actinomycetemcomitans Cultured from Blood Stream Infections Reveals Three Major Phylogenetic Groups Including a Novel Lineage Expressing Serotype a Membrane O Polysaccharide.

Twenty-nine strains of Aggregatibacter actinomycetemcomitans cultured from blood stream infections in Denmark were characterised. Serotyping was unremarkable, with almost equal proportions of the three major types plus a single serotype e strain. Whole genome sequencing positioned the serotype e strain outside the species boundary; moreover, one of the serotype a strains was unrelated to other strains of the major serotypes and to deposited sequences in the public databases. We identified five additional strains of this type in our collections. The particularity of the group was corroborated by phylogenetic analysis of concatenated core genes present in all strains of the species, and by uneven distribution of accessory genes only present in a subset of strains. Currently, the most accurate depiction of A. actinomycetemcomitans is a division into three lineages that differ in genomic content and competence for transformation. The clinical relevance of the different lineages is not known, and even strains excluded from the species sensu stricto can cause serious human infections. Serotyping is insufficient for characterisation, and serotypes a and e are not confined to specific lineages.

P-NGAL Day 1 predicts early but not one year graft function following deceased donor kidney transplantation - The CONTEXT study.

BACKGROUND: Early markers to predict delayed kidney graft function (DGF) may support clinical management. We studied the ability of four biomarkers (neutrophil gelatinase associated lipocalin (NGAL), liver-type fatty acid-binding protein (L-FABP), cystatin C, and YKL-40) to predict DGF after deceased donor transplantation, and their association with early graft function and GFR at three and twelve months. METHODS: 225 deceased donor kidney transplant recipients were included. Biomarkers were measured using automated assays or ELISA. We calculated their ability to predict the need for dialysis post-transplant and correlated with the estimated time to a 50% reduction in plasma creatinine (tCr50), measured glomerular filtration rate (mGFR) and estimated GFR (eGFR). RESULTS: All biomarkers measured at Day 1, except urinary L-FABP, significantly correlated with tCr50 and mGFR at Day 5. Plasma NGAL at Day 1 and a timed urine output predicted DGF (AUC = 0.91 and AUC 0.98). Nil or only weak correlations were identified between early biomarker levels and mGFR or eGFR at three or twelve months. CONCLUSION: High plasma NGAL at Day 1 predicts DGF and is associated with initial graft function, but may not prove better than P-creatinine or a timed urine output. Early biomarker levels do not correlate with one-year graft function. TRIAL REGISTRATION: ClinicalTrials.gov NCT01395719.