26th June 2023

Thrombotic microangiopathies and the kidney

Haemolytic uraemic syndrome

Haemolytic uraemic syndrome (HUS) is characterised by a thrombotic microangiopathy which causes damage to the endothelial cells of blood vessels. It causes anaemia and thrombocytopenia due to intravascular haemolysis.

The common features of HUS are:

• Anaemia
• Thrombocytopenia
• Raised unconjugated bilirubin
• Raised lactate dehydrogenase (LDH)
• Decreased circulating levels of haptoglobin
• Reticulocytosis

The microvasculature of the kidney is most affected in HUS, with the involvement of other organs only occurring in more severe cases. The most common cause of classical HUS is infection with E coli O 157 and its enterotoxin. This typically causes a diarrhoeal illness and is the most common cause of AKI in children in the developed world. This is referred to as D+HUS. The severe diarrhoea associated with HUS often leads to intravascular depletion due to dehydration and, therefore, a pre-renal acute kidney injury. There is good spontaneous recovery in most patients, but sometimes renal replacement therapy is required. In 10% of cases, no infective cause is identified, and this is called atypical HUS. Atypical HUS is subclassified into familial and sporadic subtypes and is associated with dysregulation of the complement system leading to thrombotic microangiopathy.

Thrombotic thrombocytopenic purpura

Like HUS, thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by damage to endothelial cells of small blood vessels and subsequent intravascular thrombosis. The key contrast from HUS is that the brain is more commonly involved in TTP and neurological symptoms such as reduced GCS or seizures are often present.

TTP is an autoimmune disorder caused by antibodies against ADAMTS-13, an enzyme involved in regulating platelet aggregation. This enzyme normally cleaves von Willebrand factors (vWF) and its deficiency results in large multimers which crosslink platelets.

Higher circulating levels of vWF lead to the formation of multiple thrombi as well as the depletion of platelets which in turn can cause bleeding. Red blood cells passing these microthrombi in the capillary circulation are subject to shear stress and trauma, which in turn leads to microangiopathic haemolytic anaemia and schistocyte formation. The small thrombi cause reduced blood flow and cell death; the kidney is particularly susceptible to damage as a result, due to its microcirculation and high blood flow.

TTP is characterised by a pentad of clinical features:

1. Thrombocytopenia
2. Microangiopathic haemolytic anaemia
3. Fever
4. Renal impairment
5. Neurological involvement

Untreated, mortality rates are 90% within ten days. The gold standard of treatment is emergency plasma exchange, however, corticosteroids, aspirin, and rituximab all have a role in management.