CONICET | Buscador de Institutos y Recursos Humanos

Severe Multisystemic Postdiarrheal Hemolytic Uremic Syndrome Patricia G Vallés. Pathophysiology Department. School of Medicine. University of Cuyo. Mendoza Argentina Nonimmune hemolytic anemia, thrombocytopenia, and acute renal failure are cardinal features of HUS after a prodromal period of bloody diarrhea caused by Shiga toxin from Escherichia coli (STEC) Multiorgan failure involving the central nervous system, heart or other systems or organs may accompany this disease. Although the clinical features of this D+ HUS are widely known, a clear understanding of its patho-physiology and treatment remain unclear. The inflammatory response of host endothelial cells is included in the development of vascular damage observed in STEC infection, resulting in HUS (1-2). A breakthrough in HUS pathophysiology was the discovery that endothelial cells treatment with sublethal doses of Stx2, leads to the upregulation of genes encoding chemokines and cytokines involved in the chemoattraction and activation of neutrophils and adhesion molecules mediating binding of inflammatory cells to the endothelium (3-4) These findings indicate the important role of Stxs in inducing a multifaceted host inflammatory response. Results from clinical trials have found that circulating inflammatory mediators, including ILs, chemokines, soluble adhesion molecules, cytokine receptors, and acute phase response proteins, are abnormally increased in children with D+ HUS (5,6,7,8). High circulating neutrophil (PMN) count has been correlated with a poor prognosis in D+HUS (9) Hypo-responsive PMN with features of previous degranulation indicating a preceding activation process, have been demonstrated in D+ HUS children(10). Although these studies do not prove that the elevated inflammatory mediators have a role in the pathogenesis of this disease, they indicate a marked host inflammatory response. The present prospective study was performed so as to report a group of patients HUS D+ with serological evidence of Shiga toxin, produced by Ecoli infection, in the presence of clinical septic shock parameters and multiple organ system failure. From a total of three hundred seventeen D+ HUS children, we prospectively studied twenty five D+HUS children (median age 2.5 ± 1.7 years range 1 to 8 years) with clinical hemodynamics parameters of septic shock and multiple organ system failure. Signs of severe neurological dysfunction at the time of admission were demonstrated.High leukocyte count was demonstrated. The twenty five patients with increased Prism score: 20 ± 2 after admission on Intensive Care Unit, required mechanical ventilator assistance for 9.7 ± 1.2 days, early inotropic drugs support for 10.2 ±1.7 days and dialysis for 16.3± 4 days, Neurological dysfunction included generalized tonic-clonic seizures lasted for 4.2 ±1.3 days, n:16. Focal seizures were present in the remaining patients. Dilated cardiomyopathy was present in 9 children. Nine children suffered haemorrhagic colitis. Twenty patients survived. Within one year of the injury, neurological sequelaes, GOS 3 and 4, were present in four patients, chronic renal failure in three patients. The adverse clinical outcome at short-term follow up, similar to septic shock, allows us to suggest an intense inflammatory amplified response after STx exposure in these patients. Future studies will be required to elucidate the mechanisms involved in this early severe clinical presentation in D+ HUS patients. References 1-Proulx F, Seidman EG, Karpman D. Pathogenesis of Shiga toxin-associated hemolytic uremic syndrome. Pediatr Res. 2001; 50: 163-171. 2- Westerholt S, Pieper AK, Griebel M, Volk HD, Hartung T, Oberhoffer R. Characterization of the cytokine immune response in children who have experienced an episode of typical hemolytic-uremic syndrome. Clin Diagn Lab Immunol. 2003; 10 (6):1090-5. 3-Brigotti M, Carnicelli D, Ravanelli E, Vara AG, Martinelli C, Alfieri RR, Petronini PG, Sestili P. Molecular damage and induction of proinflammatory cytokines in human endothelial cells exposed to Shiga toxin 1, Shiga toxin 2, and alpha-sarcin. Infect Immun. 2007; 75(5):2201-7 4- Zoja C, Angioletti S, Donadelli R, Zanchi C, Tomasoni S, Binda E, Imberti B, te Loo M, Monnens L, Remuzzi G, Morigi M. Shiga toxin-2 triggers endothelial leukocytes adhesion and transmigration via NF-B-dependent up-regulation of IL-8 and MCP-1. Kidney Int.2002; 62:846-856 5- Litalien C, Proulx F, Mariscalco MM, Robitaille P, Turgeon JP, Orrbine E, Rowe PC, McLaine PN, Seidman E Circulating inflammatory cytokine levels in hemolytic uremic syndrome. Pediatr Nephrol. 1999;13 (9): 840-5. 6- Murata A, Shimazu T, Yamamoto T, Taenaka N, Nagayama K, Honda T, Sugimoto H, Monden M, Matsuura N, Okada S.Profiles of circulating inflammatory- and antiinflammatory cytokines in patients with hemolytic uremic syndrome due to E. coli O157infection. Cytokine 1998; 10 : 544-548. 7-Westerholt S, Hartung T, Tollens M, Güstrau A, Oberhoffer M, Karch H, Klare B, Pfeffer K, Emmrich P, Oberhoffer R. Inflammatory and immunological parameters in children with haemolytic uremic syndrome (HUS) and gastroenteritis-pathophysiological and diagnostic clues. Cytokine 2000; 12:822-827. 8- Fitzpatrick MM, Shah V, Trompeter RS, Dillon MJ, Barratt TM.Interleukin-8 and polymorphoneutrophil leucocyte activation in hemolytic uremic syndrome of childhood. Kidney Int 1992, 42:951956. 9-Fitzpatrick MM, Shah V,Filler G, Dillon MJ, Barratt TM. Neutrophil activation in the haemolytic uraemic syndrome: free and complexed elastase in plasma. Pediatric Nephrol 1992; 6:50-53. 10-Fernández GC, Gómez SA, Rubel CJ, Bentancor LV, Barrionuevo P, Alduncín M, Grimoldi I, Exeni R, Isturiz MA, Palermo MS Impaired neutrophils in children with the typical form of hemolytic uremic syndrome. Pediatr Nephrol. 2005; 20(9):1306-14.