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Direct acute tubular damage contributes to Shigatoxin-mediated kidney failure.

ABSTRACT: The pathogenesis and therapy of Shigatoxin 2 (Stx2)-mediated kidney failure remain controversial. Our aim was to test whether, during an infection with Stx2-producing E. coli (STEC), Stx2 exerts direct effects on renal tubular epithelium and thereby possibly contributes to acute renal failure. Mice represent a suitable model because they, like humans, express the Stx2-receptor Gb3 in the tubular epithelium but, in contrast to humans, not in glomerular endothelia, and are thus free of glomerular thrombotic microangiopathy (TMA). In wild-type mice, Stx2 caused acute tubular dysfunction with consequent electrolyte disturbance, which was most likely the cause of death. Tubule-specific depletion of Gb3 protected the mice from acute renal failure. In vitro, Stx2 induced secretion of proinflammatory cytokines and apoptosis in human tubular epithelial cells, thus implicating a direct effect of Stx2 on the tubular epithelium. To correlate these results to human disease, kidney biopsies and outcome were analysed in patients with Stx2-associated kidney failure (n = 11, aged 22-44 years). The majority of kidney biopsies showed different stages of an ongoing TMA; however, no glomerular complement activation could be demonstrated. All biopsies, including those without TMA, showed severe acute tubular damage. Due to these findings, patients were treated with supportive therapy without complement-inhibiting antibodies (eculizumab) or immunoadsorption. Despite the severity of the initial disease [creatinine 6.34 (1.31-17.60) mg/dl, lactate dehydrogenase 1944 (753-2792) U/l, platelets 33 (19-124)/nl and haemoglobin 6.2 (5.2-7.8) g/dl; median (range)], all patients were discharged after 33 (range 19-43) days with no neurological symptoms and no dialysis requirement [creatinine 1.39 (range 0.84-2.86) mg/dl]. The creatinine decreased further to 0.90 (range 0.66-1.27) mg/dl after 24 months. Based on these data, one may surmise that acute tubular damage represents a separate pathophysiological mechanism, importantly contributing to Stx2-mediated acute kidney failure. Specifically in young adults, an excellent outcome can be achieved by supportive therapy only.

SUBMITTER: Porubsky S

PROVIDER: S-EPMC4282478 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Direct acute tubular damage contributes to Shigatoxin-mediated kidney failure.

Porubsky Stefan S Federico Giuseppina G Müthing Johannes J Jennemann Richard R Gretz Norbert N Büttner Stefan S Obermüller Nicholas N Jung Oliver O Hauser Ingeborg A IA Gröne Elisabeth E Geiger Helmut H Gröne Hermann-Josef HJ Betz Christoph C

The Journal of pathology 20140725 1

The pathogenesis and therapy of Shigatoxin 2 (Stx2)-mediated kidney failure remain controversial. Our aim was to test whether, during an infection with Stx2-producing E. coli (STEC), Stx2 exerts direct effects on renal tubular epithelium and thereby possibly contributes to acute renal failure. Mice represent a suitable model because they, like humans, express the Stx2-receptor Gb3 in the tubular epithelium but, in contrast to humans, not in glomerular endothelia, and are thus free of glomerular ...[more]

PMID: 24909663

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Project description:Background:Cardiac surgery-associated acute kidney injury (AKI) is associated with increased morbidity and mortality. We examined the utility of combining biomarkers of kidney function loss (serum cystatin C) and kidney tubular damage (urine neutrophil gelatinase-associated lipocalin [NGAL] and Kidney Injury Molecule-1 [KIM-1]) for the prediction of post-cardiac surgery AKI. Methods:Single-center prospective cohort study of 106 adults undergoing coronary artery bypass grafting and/or valve surgery with cardiopulmonary bypass (CPB). Primary outcome was postoperative in-hospital AKI defined by serum creatinine (SCr)-Kidney Disease: Improving Global Outcomes criteria. Biomarkers were measured preoperatively, 6 hours after CPB and on postoperative days (PODs) 1 to 4. Results:A total of 23 subjects (21.7%) developed AKI. After adjusting for preoperative left ventricular ejection fraction, body mass index >30 kg/m2, and estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2, the combination of peak serum cystatin C and peak urine KIM-1/creatinine (Cr) (6 hours post-CPB to POD 1) above optimal cutoff significantly associated with postoperative AKI (odds ratio [OR]: 5.32; 95% confidence interval [CI]: 1.31-21.67; P = 0.020). This biomarker combination significantly improved the performance of the clinical model for the prediction of postoperative AKI (area under the curve [AUC]: 0.77, 95% CI: 0.65-0.90 for the clinical model alone versus 0.83, 95% CI: 0.73-0.93 for the clinical model with the addition of biomarker data, P = 0.049). Conclusions:Combining biomarkers of postoperative kidney function loss and postoperative kidney tubular damage significantly improved prediction of in-hospital AKI following cardiac surgery. Future large, multicenter studies are warranted to assess whether panels of biomarkers reflecting distinct pathobiology can be used to guide interventions and improve short- and long-term outcomes in patients undergoing cardiac surgery.

Project description:BackgroundCombining tubular damage and functional biomarkers may improve prediction precision of acute kidney injury (AKI). Serum cystatin C (sCysC) represents functional damage of kidney, while urinary N-acetyl-β-D-glucosaminidase (uNAG) is considered as a tubular damage biomarker. So far, there is no nomogram containing this combination to predict AKI in septic cohort. We aimed to compare the performance of AKI prediction models with or without incorporating these two biomarkers and develop an effective nomogram for septic patients in intensive care unit (ICU).MethodsThis was a prospective study conducted in the mixed medical-surgical ICU of a tertiary care hospital. Adults with sepsis were enrolled. The patients were divided into development and validation cohorts in chronological order of ICU admission. A logistic regression model for AKI prediction was first constructed in the development cohort. The contribution of the biomarkers (sCysC, uNAG) to this model for AKI prediction was assessed with the area under the receiver operator characteristic curve (AUC), continuous net reclassification index (cNRI), and incremental discrimination improvement (IDI). Then nomogram was established based on the model with the best performance. This nomogram was validated in the validation cohort in terms of discrimination and calibration. The decision curve analysis (DCA) was performed to evaluate the nomogram's clinical utility.ResultsOf 358 enrolled patients, 232 were in the development cohort (69 AKI), while 126 in the validation cohort (52 AKI). The first clinical model included the APACHE II score, serum creatinine, and vasopressor used at ICU admission. Adding sCysC and uNAG to this model improved the AUC to 0.831. Furthermore, incorporating them significantly improved risk reclassification over the predictive model alone, with cNRI (0.575) and IDI (0.085). A nomogram was then established based on the new model including sCysC and uNAG. Application of this nomogram in the validation cohort yielded fair discrimination with an AUC of 0.784 and good calibration. The DCA revealed good clinical utility of this nomogram.ConclusionsA nomogram that incorporates functional marker (sCysC) and tubular damage marker (uNAG), together with routine clinical factors may be a useful prognostic tool for individualized prediction of AKI in septic patients.

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Direct acute tubular damage contributes to Shigatoxin-mediated kidney failure.

Publications

Direct acute tubular damage contributes to Shigatoxin-mediated kidney failure.

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