Hemolytic uremic syndrome

Although HUS can be seen in a variety of clinical scenarios, the common feature in all forms of HUS is damage to the endothelium of the glomerular capillary bed and resulting thrombotic microangiopathy. In the epidemic form, this is caused by infection with Shiga toxin-producing strains of Escherichia coli.[9] Infectious HUS (non-Shiga toxin-related) is caused by non-E coli organisms, including streptococcal species.[14]

In familial HUS, a defect in one of the proteins involved in the regulation of the complement system may be found.[6] The cause of sporadic, non-Shiga toxin-associated HUS is not known, although some of the cases have been shown to have the same defects that are seen in familial syndromes. It has been established that dysregulation in the complement cascade is a trigger for atypical HUS.[15]

The causes of secondary HUS include exposure to drugs (e.g., cyclosporine, some chemotherapy agents, targeted cancer agents), bone marrow transplant, and pregnancy.[16]

The common feature in all types of HUS is endothelial injury, leading to microvascular thrombosis and resulting microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The central nervous system, and occasionally other organs such as the heart, intestine, retina, liver, and pancreas, may be affected due to microvascular thrombosis.

Epidemic HUS: Shiga toxin produced by Escherichia coli damages renal glomerular endothelial cells, causing cell damage and detachment, exposing the basement membrane with resultant microvascular thrombosis, fragmentation of erythrocytes, and destruction of platelets, and ultimately causing renal insufficiency.[9]

Infectious (non-Shiga toxin-related) HUS: neuraminidase produced by streptococcal species, as well as other organisms, alters the surface of glomerular cells to expose antigens that are recognized by naturally occurring antibodies, triggering an immune reaction and endothelial damage.[14] Other mechanisms through which infectious agents trigger HUS are not known.

Atypical HUS: defects in the production or function of one of the proteins in the alternative complement pathway have been found. These defects are thought to lead to excessive complement activation and result in endothelial damage, causing renal dysfunction, and at times multi-organ involvement.[6]

Secondary HUS: also thought to be caused by endothelial cell damage, although the exact mechanism is not known. More recently, there have been reports of thrombotic microangiopathy associated with the use of targeted cancer agents (e.g., immunotoxins, monoclonal antibodies, and tyrosine kinase inhibitors).[17]

Sporadic HUS: the pathophysiology is unknown but is thought to be related to endothelial cell damage. Some patients without known familial disease are found to have defects in the regulation of complement similar to those found in familial cases (i.e., affecting the structure and/or function of factor H).[15]

There are multiple causes of microangiopathic hemolytic anemia, including:[4]

Shiga toxin-associated HUS
Complement-mediated HUS
Thrombotic thrombocytopenic purpura
Streptococcal/infection-associated HUS
Cobalamin deficiency-associated HUS
Transplant-associated HUS
Coagulation protein-associated HUS
Secondary HUS (due to medications, cancer, and other systemic diseases).

Shiga toxin-producing Escherichia coli (STEC) HUS (typical, D+, epidemic)

Caused by Shiga toxin-producing E coli strains (typically Shiga toxin 1 and/or Shiga toxin 2). STEC HUS has commonly been associated with E coli O157:H7; however, there are a number of emerging strains (e.g., E coli O111, O26, O121, O145, O91, O103, O104, and O080).[5] A history of bloody diarrhea is typically present, but STEC HUS can occur without diarrhea.

Infectious (non-Shiga toxin-related) HUS

Non-E coli-related, caused by neuraminidase produced by streptococcal species as well as other organisms. Not usually associated with diarrhea.

Atypical, D-minus HUS

Inciting factor is not known. However, in many cases there are abnormalities in complement regulatory pathways. Diarrhea is not typically present.

Familial HUS

In 50% of cases, a defect in one of the proteins involved in the regulation of the alternative complement pathway has been found.[6]

Secondary HUS

Causes include the following:

Bone marrow transplant
Drug-induced (cyclosporine, some chemotherapy agents)
Pregnancy-related.

Pathophysiology