Abstract

The typical hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia and acute renal impairment that usually occur within a  week after prodromal hemorrhagic enterocolitis. Anemia is severe, with increased fragmented red blood cell (schistocytes) in the peripheral blood smear, high serum lactate dehydrogenase (LDH), circulating free hemoglobin, and increased reticulocytes. Platelet count is usually < 60,000/mcL  and in children the disease is most commonly triggered by Shiga toxin-producing Escherichia coli (STEC) infections and less frequently from Shigella dysenteriae type 1 infection and manifests with diarrhea often bloody. (1) Journal of the American Society of Nephrology 2005 vol. 16 pp. 1035-1050)  Also infection caused by streptococcus pneumoniae has been reported as a cause of childhood HUS in 5 to 15% of cases (2) (www.uptodate.com 2014) It is one of the main causes of acute renal failure in children that manifests in 55 to 70% of cases. However renal function recovers in most of them (up to 70% in various series) (1) Journal of the American Society of Nephrology 2005 vol. 16 pp. 1035-1050)  Severe cases can also be presented by acute respiratory distress syndrome (ARDS), toxic megacolon with ileus, pancreatitis, central nervous system (CNS) disorders and multiple organ failure (MOF). (3) (F1000Research 2014,  3: 79 doi: 10.12688/f1000research.2546.2)
The hemolytic uremic syndrome (HUS) caused by Shiga toxin producing Escherichia coli is the cause in 90% of cases of HUS in pediatric age and primarily affects children under the age of five years. The incidence of this disease is estimated to be 2.1 cases per 100,000 persons/year, with a peak incidence in children who are younger than 5 years (6.1 per 100,000/year), and the lowest rate in adults who are 50 to 59 years of age (0.5 per 100,000/year). (1) Journal of the American Society of Nephrology 2005 vol. 16 pp. 1035-1050) The remaining cases of childhood HUS are primary HUS, caused by complement dysregulation, with an estimated prevalence of 7 cases per 1,000,000/year in Europe (4) (British Journal of Haematology 2010 vol. 148 pp. 37-47) and secondary HUS caused by pneumococcal infection (5) (The Journal of Pediatrics 2007 vol. 151 pp. 140-144)
The disease process is initiated and perpetuated by direct interactions between the pathogen or its virulence factors and host cells, as well as the host response. (see section on pathogenesis) Microvascular endothelial cell injury is the principal cause of HUS symptoms. HUS is characterized by widespread thrombotic microangiopathy (TMA) in renal glomeruli, the gastrointestinal tract, the brain and the pancreas. The vessel wall is thickened, usually at the arteriolar-capillary junction, with the swelling or detachment of the endothelial cells from the basement membrane, accumulation of amorphous material in the subendothelial space, intraluminal thrombosis, and partial or complete obstruction of the vessel lumen. (6) (Seminars in Thrombosis and Hemostasis 2010 vol. 36 pp. 575-585)
The main treatment considered effective at the moment in patients with typical HUS is supportive care for the following symptoms :
1) Anemia
2) Thrombocytopenia
3) Fluid and electrolyte disorders
4) Acute renal failure
5) Hypertension
6) Neurologic disorders
7) Disorders involving other organs such as heart, colon, pancreas, and lung (2) (www.uptodate.com 2014)
The atypical hemolytic uremic syndrome, differently from typical hemolytic uremic syndrome is caused by complement dysregulation :
1) Complement gene mutations :
a) Complement factor H  (20 to 30%)
b) CD46, previously known as membrane cofactor protein (MCP) (5 to 15%)
c) Complement factor  I  (4 to 10%)
d) Complement factor 3  (2 to 10%)
e) Complement factor B  (1 to 4%)
2) Antibodies to complement factor B
and by :
3) Thrombomodulin gene mutations  (3 to 5%) (2) (www.uptodate.com 2014)
Complement plays a role in endothelial cell activation, as C5a and C5b result in upregulation of gene expression for cell adhesion molecules such as P-selectin, E-selectin, ICAM-1 and VCAM-1, and cytokines such as IL-6, IL-8 and MCP-1. (7) (Seminars in Thrombosis and Hemostasis 2014 vol. 40 pp. 444-464)
In vitro, thrombomodulin binds to C3b and factor H (CFH) and negatively regulates complement by accelerating factor I-mediated inactivation of C3b in the presence of cofactors,CFH or C4b binding proteins. By promoting activation of the plasma procarboxypeptidase B, thrombomodulin also accelerates the inactivation of anaphylatoxins C3a and C5a. (8) (New England Journal of Medicine 2009 vol. 361 pp. 345-357)
Other genetic defects include mutations in DGKE gene, which encodes diacylglicerol kinase, and mutations in PLG gene which encodes plasminogen. The first defect results in a prothrombotic state due to loss of DGKE function, because DGKE inactivates arachidonic acid-containing diacylglycerols (DAG), an activator of protein kinase C, which promotes thrombosis.  (9) Nature Genetics 2013 vol. 45 pp. 531-536) The second defect leads to a plasminogen deficiency which results in decreased degradation of thrombi and therefore promoting thrombosis. It is suggested that thrombi in small vessels cause a mechanical damage to erythrocytes, releasing peptides (such as eme) that activate complement system leading to endothelial damage and HUS (10) Journal of the American Society of Nephrology 2014 vol. 25 pp. 55-64)
Plasma exchange must be started as soon as possible in patients with atypical HUS, and daily plasma exchanges are performed until hemoglobin level has stabilized, platelet count has normalized, and renal function has improved. In patients refractory to plasma exchange, we can use eculizumab, a monoclonal antibody that binds complement protein C5, blocks its cleavage, and prevents the production of the terminal complement components C5a and the membrane attack complex
C5b-9. (2) (www.uptodate.com 2014) . It is effective in these refractory patients. At the moment eculizumab has been started as first line treatment in patients with aHUS and Scully et al. recommend that also patients who are still on plasma exchange (PEX) must start eculizumab and PEX withdrawn. Patients with aHUS who are on dialysis and who are listed for a kidney transplant, must receive eculizumab immediately prior to transplantation and for a long period to prevent recurrent disease. Whether it will be safe to withdraw eculizumab in these patients at a later stage is not known. (11) (British Journal of Haematology 2014; 164 : 759-766) A recent paper strongly suggest that in DGKE-associated aHUS patients, thrombotic microangiopathy results from impaired endothelial cell (EC) proliferation and angiogenesis rather than complement-mediated  EC lesions, supporting the concept that aHUS caused by DGKE mutations can be classified into coagulation-mediated thrombotic microangiopathy. (12) (Blood 2015 vol. 125 (6) pp. 1038-1046) (see
section on "Pathogenesis of Atypical Hemolytic Uremic Syndrome, part two")
 
References  :

1 ) Noris Marina, Remuzzi Giuseppe :  Hemolytic uremic syndrome. Journal of the American Society of Nephrology 2005; 16 : 1035-1050
2 ) Niaudet Patrick, Mattoo Tej K., Kim Melanie S.  :  Overview of hemolytic uremic syndrome in children. www.uptodate.com  2014
3 ) Mljatovic D.,  Blagalc A., Zupan Z.  : Case Report : Severe form of hemolytic-uremic syndrome with multiple organ failure in a child : a case report.F1000Research 2014, 3:79 doi:26887/f1000research.2546.2
4 ) Taylor C.M., Machin S., Wigmore S.J. et al.  : Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. British Journal of Haematology 2010; 148 : 37- 47
5 ) Waters A.M., Kerecuk L., Luk D. et al.  : Hemolytic uremic syndrome associated with invasive pneumococcal disease : the United Kingdom experience. The Journal of Pediatrics 2007; 151 : 140-144
6 ) Karpman Diana, Sartz Lisa, Johnson Sally  : Pathophysiology of Typical Hemolytic Uremic Syndrome 2010; 36 : 575-585
7 ) Riedl Magdalena, Fakhouri Fadi, Le Quintrec Moglie et al.  : Spectrum of complement-mediated thrombotic microangiopathies : Pathogenic insights identifyng novel treatment approaches. Seminars of Thrombosis and Hemostasis 2014; 40 : 444-464
8 ) Delvaeye Mieke,Noris Maina,De Vries Astrid et al. :Thrombomodulin mutations in atypical hemolytic-uremic syndrome.New England Journal of Medicine 2009; 361 : 345-357
9 ) Lemaire M., Frémeaux-Bacchi V., Schaefer F. et al. : Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nature Genetics 2013; 45 : 531-536
10 ) Bu F., Maga T., Meyer N.C. et al.  : Comprehensive genetic analysis of complement and coagulation genes in atypical uremic syndrome. Journal of the American Society of Nephrology 2014; 25 : 55-64 
11 ) Scully Marie and Goodship Tim : How I treat thrombotic thrombocytopenic purpura and atypical haemolytic uraemic syndrome. British Journal of Haematology 2014; 164 : 759-766
12 ) Bruneau Sarah, Néel Mélanie, Roumenina Lubka T.  : Loss of DGKε induces endothelial cell activation and death independently of complement activation. Blood 2015; 125 (6) : 1038-1046

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