Atypical hemolytic uremic syndrome(aHUS)
Hemolytic-uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia, and renal failure caused by platelet thrombi in the microcirculation of the kidney and other organs. Typical (acquired) HUS is triggered by infectious agents such as strains of E. coli (Stx-E. coli) that produce powerful Shiga-like exotoxins, whereas atypical HUS ( aHUS ) can be genetic, acquired, or idiopathic (of unknown cause). Onset of atypical HUS ranges from prenatal to adulthood. Individuals with genetic atypical HUS frequently experience relapse even after complete recovery following the presenting episode. Relapsing HUS is more likely to be genetic. In most cases it is caused by chronic, uncontrolled activation of the complement system , a branch of the body’s immune system that destroys and removes foreign particles.Sixty percent of genetic aHUS progresses to end-stage renal disease (ESRD). The final outcome of aHUS is usually death or permanent renal or neurologic impairment.
- Atypical HUS is considered genetic in the following situations:
- Two or more members of the same family are affected by the disease at least six months apart and exposure to a common triggering infectious agent has been excluded;
- Disease-causing mutation (s) are identified in one of the ten genes known to be associated with aHUS, irrespective of familial history.
Genetic atypical HUS can be multiplex (i.e., familial; two or more affected family members) or simplex (i.e., a single occurrence in a family).
- Atypical HUS is considered acquired when an underlying environmental factor such as drugs, systemic disease, viral agents, or bacterial agents that do not result in Shiga-like exotoxins (Stx) can be identified.
- Atypical HUS is considered idiopathic when no trigger (genetic or environmental) is evident.
(Atypical Hemolytic-Uremic Syndrome, 2013)
Signs and Symptoms
Both children and young adults with aHUS have* nonspecific symptoms* of illness: pallor, poor feeding, vomiting, fatigue, and drowsiness. Anuria or oligoanuria with or without peripheral edema may be present. Marked hypertension may also be present either from the acute kidney injury or from the ischemia caused by the TMAs . Hypertension may be severe enough to provoke posterior reversible encephalopathy or cardiac failure. Half of children and the majority of adults need dialysis at admission. Extrarenal manifestations are observed in 20% of patients. The most frequent extra renal manifestation is CNS involvement (10% of patients) with diverse presentations: irritability, drowsiness, seizures, diplopia, cortical blindness, hemiparesis or hemiplegia, stupor, and coma. Myocardial infarction due to cardiac microangiopathy has been reported in approximately 3% of patients and is presumed to be the cause of reported episodes of sudden death.
Five percent of patients present with a life-threatening multiorgan failure due to diffuse TMA. Less commonly, aHUS patients have more of an insidious onset, with subclinical anemia and fluctuating thrombocytopenia for weeks or months and apparent normal renal function at diagnosis.
Unusual presentations of aHUS are possible. Some patients have little or no anemia or thrombocytopenia and the only manifestation of an active TMA is hypertension and proteinuria with or without an overtly abnormal creatinine.
( Atypical hemolytic uremic syndrome: what is it, how is it diagnosed, and how is it treated?,2012)
Diagnosis
aHUS is clinically characterized by microangiopathic hemolytic anaemia (low hemoglobin, high lactic acid dehydrogenase, undetectable or low haptoglobin, presence of schistocytes in the peripheral blood smear, and negative Coombs test), thrombocytopenia (platelets < 150000/mm3 or a documented rapid decrease), and acute kidney injury (AKI) (hematuria, proteinuria, and/or reduced renal function). However, as a systemic disease, aHUS can affect the endothelia of any organ, and extrarenal manifestations including involvement of the central nervous system, liver, heart, pancreas, and skin, are observed in as many as 20% of patients. These additional sites of involvement can blur the distinction between aHUS and other primary thrombotic microangiopathies (TMAs), such as STEC-associated HUS, thrombotic thrombocytopenic purpura(TTP), HELLP syndrome (hemolytic anemia, elevated liver enzymes, and low platelets), and transcyanocobalamin deficiency, or TMAs secondary to malignant hypertension, catastrophic antiphospholipid syndrome, or disseminated intravascular coagulation. (Familial Atypical Hemolytic Uremic Syndrome: A Review of Its Genetic and Clinical Aspects, 2012.)
Evaluation of aHUS should include serum C3 and C4 levels as well as serum concentrations
of complement regulators, including CFH, CFI, CFB, anti-CFH antibodies and MCP expression on leucocytes.
Normal levels of C3, C4, CFH, CFI and CFB do not exclude aHUS. Patients should undergo genetic analysis of CFH, CFI, MCP, CFB, THBD, CFHR1–5 and C3. (Complement disorders and hemolytic uremic syndrome Catherine Joseph and Jyothsna Gattineni, 2013.)
Pathogenesis
Various defense mechanisms exist in humans to protect from invading pathogens and the complement system is a key element of innate immunity that aids in rapid recognition and elimination of pathogens. The complement system consists of more than 30 different proteins, most of which are synthesized in the liver and distributed across plasma and cell surfaces. The complement system has three primary functions; cellular lysis by opsonization, generation of inflammatory mediators and modulation of adaptive immune response. Activation of the complement system is crucial and occurs by three different pathways and all of them converge at the formation of C3 convertase.
(Complement disorders and hemolytic uremic syndrome Catherine Joseph and Jyothsna Gattineni, 2013.)
The alternate complement pathway (AP) is constitutively active and functions as an arm of our innate immune system. Tight control of the AP is required to limit unregulated generation of C3 convertase and subsequent generation of the C5 convertase. C5 convertase activity leads to cleavage of C5 and liberation of C5a, an anaphylatoxin. The sequential assembly of C5b and C6-C9 to form the membrane attack complex5 at the vascular endothelial cell surface causes endothelial cell damage, platelet activation, and thrombus formation. The first indication that excessive activation of the AP was associated with aHUS came in 1973 with the report of 5 patients with HUS and low plasma C3 levels. Since that time, several dysregulated complement pathway proteins have been identified in patients with aHUS, both with and without decreased C3 levels, and it is now known that a decreased C3 is not universal in aHUS. It has been shown previously that mutations in genes encoding proteins that regulate the AP or autoantibodies that inhibit complement regulatory proteins can be identified in approximately 60%-70% of aHUS patients. Both mutations that result in a quantitative deficiency of protein and mutations associated with a normal plasma level of functionally ineffective protein have been identified. Therefore, measurement of complement factor levels cannot substitute for mutation screening in patients suspected of aHUS.
Complement factor H (CFH) mutations are the most common and account for 23%-27% of identified mutations in registry patients in the United States and Europe. Membrane cofactor protein (MCP) mutations occur at a frequency of 5%-7%. Complement factor I (CFI) and complement component C3 (C3) occur at 4%-8% and 2%-8%, respectively. Gene mutations in complement factor B (CFB; 1%-4%) and thrombomodulin (3%-5%) have also been noted. The CFH-related (CFHR) proteins have also been associated with aHUS. The role of the CFHR proteins is less well defined than the other complement proteins; however, complement-modulatory activity has been reported. Homozygous deletions in the CFH-related proteins 1 and 3 make up approximately 6% of cases, with homozygous deletions being associated with CFH autoantibody levels for unclear reasons. CFH is in close proximity to the genes CFHR1-CFHR5 encoding the 5 CFHR proteins. The high degree of sequence homology that exists between CFH and the CFHR genes results in deletions and substitutions within the CFH gene through nonallelic homologous recombination. The resulting hybrid proteins are often poorly functioning and may affect the regulatory role of the native CFH protein. These mutations account for 1%-3% of aHUS patients. Up to 12% of patients have mutations in 2 or more genes. Finally, 6%-10% of patients, primarily children, have an acquired risk for aHUS via anti-CFH autoantibodies. Many of these patients appear to also have the homozygous CFHR1-CFHR3 deletions; however, they may also be associated with other aHUS mutations. Despite the genetic advances that have been made in aHUS, 35%-40% of patients with a clinical scenario consistent with aHUS will have no demonstrable genetic mutation using current screening strategies. These patients may have mutations in unscreened regions of known genes. Alternatively, there are likely to be additional genes that cause aHUS that are not yet discovered. To further complicate this scenario, even when genetics are well described in a given family, the penetrance of the disease is only 50%, with half of family members with the same mutation remaining healthy. This may be a consequence of modifier genes or the influence of
environmental factors. (Atypical hemolytic uremic syndrome: what is it, how is it diagnosed, and how is it treated?,2012)
Treatement
Supportive care should be provided to all children with aHUS, which includes management
of hypertension, renal replacement therapy when indicated, and correction of anemia and
electrolyte abnormalities as well as providing adequate nutrition. Platelet transfusions are
generally contraindicated as they worsen the thrombotic microangiopathy and anemia.
Plasma Therapy
Plasma exchange therapy is the first-line therapy for children with aHUS and should be initiated as soon as the diagnosis is suspected. Although plasma infusion replenishes deficient complement regulators, plasma exchange has the added benefit of removing mutant complement factors and/or autoantibodies. The rate of remission after plasma exchange is variable (30–80%) depending on the genetic mutations. Plasma exchange is of little benefit in patients with a MCP mutation as MCP is not a circulating factor. The duration, dose and frequency of plasma exchange should be adjusted on a case-by-case basis. Immunosuppressive agents are of no benefit in aHUS except in patients with complement factor H autoantibodies, in whom they can be used in conjunction with plasma exchange . In the future, concentrated complement factor H (purified/ recombinant) when available could be used to replenish deficient or mutated complement factor H.
Eculizumab
The generation of terminal complement complex is quintessential for the pathogenesis of aHUS. Eculizumab is a monoclonal antibody to C5 that prevents cleavage of C5 to C5b, preventing the formation of terminal complement complex. Recently, eculizumab has been used in patients with aHUS with good results. There is an increased risk of developing Neisseria meningitis infection with the use of eculizumab and patients need to be vaccinated prior to initiation of therapy with eculizumab.
Renal Transplantation
The majority of children with aHUS will progress to ESRD and become candidates for renal transplantation. Kidney transplantation is associated with a high risk of recurrence (~50%) and approximately 80–90% of the kidney grafts that have recurrence will fail. Recurrence of aHUS is dependent on the genetic mutation, with increased risk in patients with complement factor H, complement factor I and C3 mutations, whereas the risk is significantly less for patients with MCP mutations . Thus, living donor kidney transplantation is contraindicated in children with mutations in CFH, CFB, CFI, C3 or THBD due to the increased risk of recurrence of aHUS. Moreover, there is an increased risk of the donor developing aHUS, as the donor might have disease-causing mutation with
incomplete penetrance of the disease. If living related kidney transplantation is the only option available to the family then the donor and recipient should undergo thorough genetic evaluation of the complement system and the donor should be counseled that even if the genetic testing is negative, the risk of developing aHUS is not completely eliminated. Eculizumab can be used in case of disease recurrence or as a preventive agent in patients with aHUS after renal transplantation. Initial attempts at combined liver–kidney transplantation were disappointing due to complement activation and liver nonfunction; however, four patients who received peri-operative plasma exchange had a favorable outcome. (Complement disorders and hemolytic uremic syndrome Catherine Joseph and Jyothsna Gattineni, 2013.)
Diarrhea-related hemolytic uremic syndrome: unmasking antifactor H antibodies. 2011
Do complement factor H 402Y and C7 M allotypes predispose to (typical) haemolytic uraemic syndrome?, 2011
Lavoro svolto da Elisa Stolaj
