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Pathogenic role of inflammatory response during Shiga toxin-associated hemolytic uremic syndrome (HUS)

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Abstract

Hemolytic uremic syndrome (HUS) is defined as a triad of noninmune microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The most frequent presentation is secondary to Shiga toxin (Stx)-producing Escherichia coli (STEC) infections, which is termed postdiarrheal, epidemiologic or Stx-HUS, considering that Stx is the necessary etiological factor. After ingestion, STEC colonize the intestine and produce Stx, which translocates across the intestinal epithelium. Once Stx enters the bloodstream, it interacts with renal endothelial and epithelial cells, and leukocytes. This review summarizes the current evidence about the involvement of inflammatory components as central pathogenic factors that could determine outcome of STEC infections. Intestinal inflammation may favor epithelial leakage and subsequent passage of Stx to the systemic circulation. Vascular damage triggered by Stx promotes not only release of thrombin and increased fibrin concentration but also production of cytokines and chemokines by endothelial cells. Recent evidence from animal models and patients strongly indicate that several immune cells types may participate in HUS physiopathology: neutrophils, through release of proteases and reactive oxygen species (ROS); monocytes/macrophages through secretion of cytokines and chemokines. In addition, high levels of Bb factor and soluble C5b-9 (sC5b-9) in plasma as well as complement factors adhered to platelet-leukocyte complexes, microparticles and microvesicles, suggest activation of the alternative pathway of complement. Thus, acute immune response secondary to STEC infection, the Stx stimulatory effect on different immune cells, and inflammatory stimulus secondary to endothelial damage all together converge to define a strong inflammatory status that worsens Stx toxicity and disease.

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Acknowledgements

This work was supported by a grant from Agencia Nacional de Promoción Científica y Tecnológica, Argentina (PIDC 2014/0020).

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Authors and Affiliations

  1. Departamento de Nefrología, Hospital Municipal del Niño, San Justo, Provincia de Buenos Aires, Argentina

    Ramon Alfonso Exeni & Adriana Patricia Santiago

  2. Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental Medicine (IMEX-CONICET), Academia Nacional de Medicina, Buenos Aires, Argentina

    Romina Jimena Fernandez-Brando, Gabriela Alejandra Fiorentino, Maria Victoria Ramos & Marina Sandra Palermo

  3. Laboratorio, Hospital Municipal del Niño, San Justo, Provincia de Buenos Aires, Argentina

    Gabriela Alejandra Fiorentino

  4. Servicio de Nefrología, Hospital Austral, Pilar, Provincia de Buenos Aires, Argentina

    Andrea Mariana Exeni

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  1. Ramon Alfonso Exeni
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Correspondence to Marina Sandra Palermo.

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1. a; 2. c; 3. d; 4. a; 5. b

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Exeni, R.A., Fernandez-Brando, R.J., Santiago, A.P. et al. Pathogenic role of inflammatory response during Shiga toxin-associated hemolytic uremic syndrome (HUS). Pediatr Nephrol 33, 2057–2071 (2018). https://doi.org/10.1007/s00467-017-3876-0

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