Randox (United Kingdom)

IntroductionCurrently there are no biomarkers that are predictive of when patients with type-2 diabetes (T2D) will progress to more serious kidney disease i.e., diabetic nephropathy (DN). Biomarkers that could identify patients at risk of progression would allow earlier, more aggressive treatment intervention and management, reducing patient morbidity and mortality.Materials and MethodsStudy participants (N=88; control n=26; T2D n=32; DN n=30) were recruited from the renal unit at Antrim Area Hospital, Antrim, UK; Whiteabbey Hospital Diabetic Clinic, Newtownabbey, UK; Ulster University (UU), Belfast, UK; and the University of the Third Age (U3A), Belfast, UK; between 2019 and 2020. Venous blood and urine were collected with a detailed clinical history for each study participant.ResultsIn total, 13/25 (52.0%) biomarkers measured in urine and 25/34 (73.5%) biomarkers measured in serum were identified as significantly different between control, T2D and DN participants. DN patients, were older, smoked more, had higher systolic blood pressure and higher serum creatinine levels and lower eGFR function. Serum biomarkers significantly inversely correlated with eGFR.ConclusionThis pilot-study identified several serum biomarkers that could be used to predict progression of T2D to more serious kidney disease: namely, midkine, sTNFR1 and 2, H-FABP and Cystatin C. Our results warrant confirmation in a longitudinal study using a larger patient cohort.

BackgroundIncreased perioperative pro-inflammatory biomarkers, renal hypoperfusion and ischemia reperfusion injury (IRI) heighten cardiac surgery acute kidney injury (CS-AKI) risk. Increased urinary anti-inflammatory cytokines attenuate risk. We evaluated whether blood and urinary anti-inflammatory biomarkers, when expressed as ratios with biomarkers of inflammation, hypoperfusion and IRI are increased in CS-AKI patients.MethodsPreoperative and 24-h postoperative blood and urinary pro-inflammatory and anti-inflammatory cytokines, blood VEGF and H-FABP (hypoperfusion biomarkers), and MK, a biomarker for IRI, were measured in 401 cardiac surgery patients. Pre- and postoperative concentrations of biomarkers and selected ratios thereof, were compared between non-CS-AKI and CS-AKI patients.ResultsCompared with non-CS-AKI, blood pro-inflammatory (pre- and post-op TNFα, IP-10, IL-12p40, MIP-1α, NGAL; pre-op IL-6; post-op IL-8, MK) and anti-inflammatory (pre- and post-op sTNFsr1, sTNFsr2, IL-1RA) biomarkers together with urinary pro-inflammatory (pre- and post-op uIL-12p40; post-op uIP-10, uNGAL) and anti-inflammatory (pre- and post-op usTNFsr1, usTNFsr2, uIL-1RA) biomarkers, were significantly higher in CS-AKI patients. Urinary anti-inflammatory biomarkers, when expressed as ratios with biomarkers of inflammation (blood and urine), hypoperfusion (blood H-FABP and VEGF) and IRI (blood MK) were decreased in CS-AKI. In contrast, blood anti-inflammatory biomarkers expressed as similar ratios with blood biomarkers were increased in CS-AKI.ConclusionsThe urinary anti-inflammatory response may protect against the injurious effects of perioperative inflammation, hypoperfusion and IRI. These finding may have clinical utility in bioprediction and earlier diagnosis of CS-AKI and informing future therapeutic strategies for CS-AKI patients.

Abstract BackgroundThe role of plasma soluble tumor necrosis factor receptor (sTNFR)1 and sTNFR2 in the prognosis of clinical events after hospitalization with or without acute kidney injury (AKI) is unknown.MethodsWe measured sTNFR1 and sTNFR2 obtained 3 months post-discharge using samples from Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) and AKI Risk in Derby (ARID) that enrolled patients with and without AKI. The associations between biomarkers with longitudinal kidney disease incidence and progression, heart failure and death were evaluated. Analyses were adjusted for demographics and key covariates at the 3-month visit.ResultsAmong 1474 participants with plasma biomarker measurements, 19% developed kidney disease progression, 14% had later heart failure, and 21% died over a median follow-up of 4.4 years. For the kidney outcome, the adjusted HRs per doubling in concentration were 2.9 (2.2-3.9) for sTNFR1 and 1.9 (1.5-2.5) for sTNFR2. AKI during the index hospitalization did not modify the association between biomarkers and kidney events. For heart failure, the adjusted HRs per doubling in concentration were 1.9 (1.4-2.5) for sTNFR1 and 1.5 (1.2-2.0) for sTNFR2. For mortality, the adjusted HRs were 3.3 (2.5-4.3) for sTNFR1 and 2.5 (2.0-3.1) for sTNFR2. The findings in ARID were qualitatively similar for the magnitude of association between biomarkers and outcomes.ConclusionPlasma sTNFR1 and sTNFR2 measured 3 months after discharge were independently associated with clinical events, regardless of AKI status during the index admission. sTNFR1 and sTNFR2 may assist with the risk stratification of patients during follow-up.Significance StatementSoluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 associate with kidney outcomes in patients with chronic kidney disease with and without diabetes mellitus. However, their role in the post-hospitalization stage is unknown. High sTNFR1 and sTNFR2 obtained 3 months after discharge associate with kidney events, heart failure hospitalizations, and death among patients who did and did not have acute kidney injury (AKI). Furthermore, sTNFRs provide discriminative value at the time of predicting kidney events. These findings were demonstrated in two large independent prospective cohorts. sTNFR1 and sTNFR2 may detect patients at risk of future adverse events even when patients do not meet the clinical criteria for AKI or exhibit biochemical abnormalities.

BackgroundDecreased expression of thrombomodulin (TM) in bladder cancer tissue has been shown to be associated with cell proliferation, increased malignancy and a poor prognosis. The aim of this study was to investigate the immunoexpression of TM in bladder tissue cores by immunohistochemistry (IHC) and the relationship between TM score and patient survival for the following pathologies: transitional cell papillary carcinoma (TCPC), transitional cell carcinoma (non-papillary) (TCC), squamous cell carcinoma (SCC), adenocarcinoma, and sarcoma. TM immunoexpression was also evaluated in normal adjacent bladder tissue cores.MethodsTM immunoexpression was assessed in n=185 formalin-fixed paraffin-embedded (FFPE) bladder tissue cores from n=98 patients by IHC. Tissue cores included TCPC (n=29), TCC (n=85), SCC (n=21), adenocarcinoma (n=12), sarcoma (n=4), and normal tissue cores (n=34).ResultsTM immunoexpression scores are stronger in TCPC, TCC and SCC bladder cancer tissue cores with respect to adenocarcinoma and sarcoma (mean TM immunoexpression scores: 3.04, 2.57, 2.55, 1.55 and 1.19, respectively) (Kruskal–Wallis p<0.001). TM immunoexpression scores significantly decreased in bladder cancer tissue cores across both stage (p<0.001) and grade (p<0.001) (Kruskal–Wallis). Survival data were available for n=45 bladder cancer patients (mean follow-up of 34 months). Applying a TM immunoexpression cut-off score of 3.0 demonstrated that patients with bladder cancer who had a TM immunoexpression score <3.0 had lower survival rates (median survival 23.5 months). In contrast, patients with TM immunoexpression scores ≥3.0 had longer survival rates (median survival 40 months) (log-rank; p=0.045).ConclusionTM immunoexpression in bladder cancer tissue may be a clinically relevant predictor of tumor progression and survival. Low expression of TM in bladder cancer biopsies or in recurrent bladder cancer may be indicative of a poor prognosis. TM immunoexpression could be used to guide clinical decision making.

BackgroundIRE1α-mediated unconventional splicing of XBP1 is emerging as a biomarker in several disease states and is indicative of activation of the unfolded protein response sensor IRE1. Splicing of XBP1 mRNA results in the translation of two distinct XBP1 protein isoforms (XBP1s and XBP1u) which, due to post-translational regulation, do not correlate with mRNA levels. As both XBP1 isoforms are implicated in pathogenic or disease progression mechanisms there is a need for a reliable, clinically applicable method to detect them.MethodsA multiplexed isoform-specific XBP1 array utilising Biochip array technology (BAT™) was assessed for specificity and suitability when using cell protein lysates. The array was applied to RIPA protein lysates from several relevant pre-clinical models with an aim to quantify XBP1 isoforms in comparison with RT-PCR or immunoblot reference methods.ResultsA novel reliable, specific and sensitive XBP1 biochip was successfully utilised in pre-clinical research. Application of this biochip to detect XBP1 splicing at the protein level in relevant breast cancer models, under basal conditions as well as pharmacological inhibition and paclitaxel induction, confirmed the findings of previous studies. The biochip was also applied to non-adherent cells and used to quantify changes in the XBP1 isoforms upon activation of the NLRP3 inflammasome.ConclusionsThe XBP1 biochip enables isoform specific quantification of protein level changes upon activation and inhibition of IRE1α RNase activity, using a routine clinical methodology. As such it provides a research tool and potential clinical tool with a quantified, simultaneous, rapid output that is not available from any other published method.

[This corrects the article DOI: 10.1371/journal.pone.0220902.].

IntroductionContrast induced acute kidney injury (CI-AKI), defined as a delta rise in creatinine of >26.5 umol/L or a 50% relative rise within 48 hours following iodinated contrast, is associated with considerable mortality risk. Our previous study of 301 patients undergoing contrast coronary angiography/percutaneous coronary intervention (PCI) highlighted a CI-AKI rate of 9.3% at index procedure. Few studies have looked at long term prognosis, adverse events and mortality following CI-AKI. Our objective is to assess the 5 year mortality rate following contrast coronary angiography and to evaluate independent risk factors and presence of index CI-AKI on 5 year mortality.MethodsA prospective cohort study in a single cardiology centre in the UK was carried out from 2011–2013, the results of which have been previously published.1 In total 2,519 patients were screened, 321 (12.7%) of which had CKD, in total 301 (93.7%) patients were recruited. Written consent was obtained from all patients. Patient demographics, CI-AKI risk factors, CKD stage and contrast dose at initial contrast angiography were recorded. A Mehran risk score was calculated for each patient. Samples for plasma NGAL, serum L-FABP, serum KIM-1, serum IL-18 and serum creatinine were previously collected pre and post contrast angiography and statistically analysed to assess prediction of CI-AKI as previously described.1 At 5 years following index contrast procedure we analysed for MACE and mortality by accessing up to date electronic medical records. Patient consent was granted to access medical notes. Statistical analysis was performed to assess the predicative ability of CI-AKI risk factors and Mehran risk score on 5 year mortality risk.ResultsAt 5 years follow up data was available for 292 (97%) of the original 301 patients. Type 2 diabetes, contrast volume, Mehran risk score, lower glomerular filtration rate (GFR) and use of intravenous fluids at index procedure were independently associated with five year mortality, p <0.05, table 1. A Mehran score ≥10 had an AUC of 0.67, p <0.001, sensitivity 65%, specificity 67%, PPV 41%, NPV 85%, RR 2.7 and OR 3.9 for five year mortality. 62 Table 1Baseline characteristics of patients with 5 year mortality DemographicAt 5 year follow up 76 (26.0%) of the total cohort of patient had died. Out of the 28 patients who developed CI-AKI at index contrast procedure 17 (60.7%) of the 28 patients had died at 5 years versus 58 (22.0%) of the 264 non CI-AKI patients (p<0.001), table 2, figure 1. At 5 year follow up MACE occurred in 20 (71.4%) of the 28 CI-AKI patients versus 78 (29.5%) of the 264 non CI-AKI patients. 62 Figure 1Percentage of 5 year mortality and MACE in CI-AKI vs non CI-AKI patients 62 Table 2Comparison of 5 year mortality and MACE in baseline CI-AKI vs non CI-AKIBold - statistically significant (p<0.05)ConclusionThis study highlights that index CI-AKI is an independent risk factor for 5 year mortality and MACE. Several risk factors act independently as surrogate markers of CI-AKI prior to administration of iodinated contrast, many of which are incorporated in the Mehran CI-AKI risk score. Furthermore, these are associated with adverse incidents and mortality at five years following index contrast procedure. A combination approach of these findings, including novel biomarkers as previously demonstrated, will help to reduce risk and early identify CI-AKI to facilitate timely therapeutic intervention.ReferenceConnolly M, Kinnin M, McEneaney D, Menown I, Kurth M, Lamont J, et al. Prediction of contrast induced acute kidney injury using novel biomarkers following contrast coronary angiography. Quarterly Journal of Medicine - An International Journal of Medicine 2018:103–110.Conflict of Interestn/a