OVERVIEW
Atypical haemolytic uraemic syndrome (aHUS) is a syndrome characterized by a triad of microangiopathic haemolytic anemia, acute kidney injury and thrombocytopenia. Unlike typical HUS caused by Shiga toxin-producing Escherichia coli (STEC) infection, the main pathogenic mechanism in patients with aHUS is abnormal activation of the complement bypass pathway. aHUS has an incidence rate of approximately 7/1,000,000, and the prognosis of aHUS can be improved by symptomatic support, drugs, and plasma exchange, The prognosis can be improved by symptomatic support, drugs, plasma exchange, and renal transplantation.
Causes
Congenital or acquired abnormal activation of the complement bypass pathway is the main pathogenic mechanism of aHUS. Most patients have mutations in the genes of complement-related factors, and some of them are caused by infections, drugs, autoimmune diseases, and hereditary cobalamin C metabolism defects.
Symptoms
The classic triad of microvascular hemolytic anemia, acute kidney injury, and thrombocytopenia. Severe hypertension is often present. 20% of patients may have extra-renal manifestations such as neurologic, cardiac and gastrointestinal involvement.
1.Microangiopathic hemolytic anemia
Patients with markedly decreased hemoglobin, markedly increased reticulocyte count, red blood cell fragments visible on blood smear, negative anti-human globulin test (Coomb’s test), and elevated lactate dehydrogenase.
2 Acute kidney injury
Acute kidney injury occurs almost simultaneously with anemia, manifesting as oliguria or anuria, edema, anorexia, nausea, vomiting, dyspnea, etc., often with increased blood pressure. Some patients need dialysis.
3. Thrombocytopenia
About 90% of patients have thrombocytopenia, but skin purpura and active bleeding in other areas are less common.
Examination
1. Blood count
Hemoglobin is obviously reduced, often lower than 80g/L; reticulocyte count is obviously increased; platelet reduction, mostly lower than 50×109/L; white blood cell count is mostly increased, up to (20-30)×109/L. Blood smear can see abnormal red blood cell morphology. Anti-human globulin test is negative.
2. Urine routine
Urine routine can see varying degrees of hematuria, severe hemolysis can have hemoglobinuria, can also see proteinuria, leukocytes and tubular pattern.
3. Plasma complement measurement
Most of the patients may have decreased complement C3 level, C4 level is mostly normal, but normal plasma C3 level can not exclude atypical hemolytic uremic syndrome; some patients may have decreased level of factor H or factor I, and positive factor H antibody.
4. Liver function tests
Liver function tests show that serum total bilirubin is increased, lactate dehydrogenase and its isoenzymes are elevated.
5.Renal function test
Blood urea nitrogen and creatinine can be seen increased in oliguric stage of acute kidney injury; some patients’ renal function will not be restored, or gradually progress to end-stage renal disease.
6.Electrolyte measurement
Electrolyte measurement can find increased blood potassium and metabolic acidosis.
7 Coagulation function examination
Early fibrinogen is slightly decreased, fibrin degradation products are increased, coagulation factors II, VIII, IX and X are decreased, and prothrombin time is prolonged, which usually returns to normal within a few days.
8 Renal biopsy
Renal biopsy shows renal microangiopathy and microvascular embolism, which is one of the bases for confirming the diagnosis and estimating the prognosis.
9 Genetic testing
Most patients with atypical hemolytic uremic syndrome have genetic factors. Genetic testing to find pathogenic mutations in relevant genes can help diagnose, understand the cause of the disease and evaluate the prognosis.
Diagnosis
1. The classic triad of microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury is the clinical basis for the diagnosis of HUS. If there is no evidence of STEC infection, consider aHUS.
2. Renal biopsy reveals renal microangiopathy, embolism, etc. can clarify the diagnosis.
3. Plasma complement assay reveals decreased complement C3, decreased levels of factor H or factor I, and positive factor H antibody to support the diagnosis of aHUS. Genetic testing can help to diagnose, understand the cause and determine the prognosis of aHUS, such as finding mutations in the complement components of the bypass pathway.
Differential diagnosis
1. Typical hemolytic uremic syndrome (aHUS)
Typical hemolytic uremic syndrome (THUS) mainly affects children under 5 years of age, and is rare in infants within 6 months of age. 90% of patients present with fever, abdominal pain, diarrhea, vomiting, and loss of appetite in the first 5-10 days of illness. Evidence of STEC infection can be found, and the prognosis is mostly favorable compared to aHUS.
2. Thrombotic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura is often associated with central nervous system symptoms such as epilepsy, impaired consciousness, cerebrovascular disease, etc. Renal symptoms are less severe.ADAMTS13 activity is reduced.
Treatment
The treatment of atypical hemolytic uremic syndrome mainly includes symptomatic support, drugs, plasma exchange, and renal transplantation.
1. Symptomatic supportive treatment
Symptomatic supportive treatment includes anti-infection, supplemental nutrition, transfusion of red blood cells and platelets, maintenance of water and electrolyte balance, and dialysis if necessary.
(1) Treatment for acute kidney injury
In addition to emphasizing rest, strict control of water intake, active treatment of hypertension, etc., it is advocated to carry out dialysis treatment as early as possible, and peritoneal dialysis is preferred.
(2) Correcting anemia and thrombocytopenia
It is generally advocated to transfuse blood according to the demand, transfuse red blood cells when there is severe anemia; transfuse platelets when there is obvious bleeding manifestation or invasive operation is needed; however, it should be noted that transfusion of platelets may exacerbate the formation of microthrombosis, and transfusion is not recommended in general.
2. Drug therapy
Eculizumab is a humanized C5 monoclonal antibody, which has the effect of reducing endothelial damage, thrombosis and kidney injury.
3. Plasma exchange
Plasma exchange can help to remove defective complement proteins and autoantibodies, replenish normal complement proteins, and improve renal function and blood condition.
4. Kidney transplantation
Kidney transplantation may be considered when the above treatments are ineffective and chronic renal failure develops gradually, but the disease may recur after kidney transplantation.
Prognosis
The prognosis of atypical hemolytic uremic syndrome varies depending on the cause of the disease and is related to the type of mutation in the complement gene. Plasma exchange and the use of eculizumab can help improve the prognosis.
Prevention
The development of atypical hemolytic uremic syndrome is genetically linked, but only about half of patients with genetic risk factors will develop the disease, and triggers such as infections should be avoided as much as possible. Prophylactic treatments to reduce the risk of disease recurrence include eculizumab, plasmapheresis, and liver transplantation; patients at low risk of recurrence do not need to receive prophylactic therapy. Genetic counseling is available if there is a clear family history of the disease; prenatal diagnosis, including genetic testing, is also available after pregnancy.