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Atypical hemolytic uremic syndrome: What you need to know
Atypical hemolytic uremic syndrome is a rare condition caused by the uncontrolled activation of complement, and subsequently leads to complement-mediated thrombotic microangiopathy. The condition affects both adults and children, with a genetic basis documented in at least 70% of cases.
Atypical hemolytic uremic syndrome (aHUS) progressively attacks the body’s organs and can lead to stroke, heart attack, kidney failure and premature death if diagnosis is delayed.
HemOnc Today spoke with Jeffrey Laurence, MD, professor of medicine in the division of hematology–oncology at Weill Cornell Medicine and attending physician at NewYork-Presbyterian Hospital, about how clinicians can keep aHUS in their differential diagnosis and identify the most appropriate treatments for patients in a timely manner.
Question: How common is aHUS?
Answer: The disease incidence for two of the major thrombotic microangiopathies, aHUS and thrombotic thrombocytopenic purpura (TTP), is said to be between two and four per 1 million in the general population. I personally think this is an underestimate of aHUS because there are multiple conditions that are referred to as complement-activating conditions, including malignant hypertension, systemic lupus, certain immune suppressive and cancer chemotherapy medications, and pregnancy that can unmask aHUS in a genetically susceptible person.
Q: What are common symptoms like?
A: Symptoms of aHUS are identical to the other major thrombotic microangiopathies (TMAs). They include, but are not limited to, fatigue, low-grade fevers and petechiae. More than one organ system often is involved. Patients may have oliguria, symptoms related to the respiratory, cardiac or gastrointestinal tract, or visual symptoms, if those organs are involved.
Q: How might clinicians keep aHUS in their differential diagnosis?
A: Diagnosis is the most difficult part. When a clinician sees a person who has evidence of a microangiopathic hemolytic anemia — including low haptoglobin, elevated LDH, elevated indirect bilirubin, thrombocytopenia and shistocytes, or fragmented red blood cells, on a peripheral blood smear — this is a diagnosis of microangiopathic hemolytic anemia. Then it is the clinician’s task to distinguish among the TMAs, because the four major types — HUS, aHUS, disseminated intravascular coagulation (DIC) and TTP — all can present with these findings. First, one must rule out DIC. If the international normalized ratio and activated partial thromboplastin time are elevated, this coagulopathy needs to be resolved. For example, treat the infection or malignancy or whatever else is the basis for the DIC. It is impossible to make a diagnosis of aHUS or TTP in the presence of active DIC. Next, if there is diarrhea, whether or not it is bloody, there is concern for Shiga toxin-producing E. coli (STEC)-HUS infection. A culture needs to be performed and a PCR for Shiga toxin. The major way in which we distinguish between the remaining two TMAs, aHUS and TTP, is by evaluating the activity of the von Willebrand factor (vWF)-cleaving protease known as ADAMTS13. A test should be drawn for this enzyme activity and for the presence of an enzyme inhibitor before starting any plasma therapy. If the ADAMTS13 is less than 5%, and an autoantibody inhibitor is present, then the patient has acquired TTP. There are rare instances of congenital TTP first manifesting in an adult; in this case, the ADAMTS13 activity would be less than 5%, but an inhibitor would not be present. If the ADAMTS13 is more than 5%, then the diagnosis is aHUS. In children, and in instances where the reticulocyte count is low despite an active hemolytic anemia, one should also rule out cobalamin C deficiency, manifested by elevated plasma levels of homocysteine and methylmalonic acid.
Q: What treatments are available for these patients?
A: Until an exact diagnosis of the TMA involved is made, all patients will receive plasma. The treatment for TTP is plasma exchange (PEx). We do plasma exchange in TTP for three reasons. One reason is because fresh frozen plasma has ADAMTS13 in it, which is the enzyme that is missing, so we are delivering the enzyme; second, to create more space to get more plasma in; and finally, we do plasma exchange to try to remove the autoantibody inhibitor and some of the ultra-large vWF complexes formed in this disease. The latter is the least important reason because most of those autoantibodies are IgGs and plasmapheresis is inefficient at depleting IgGs. For aHUS, PEx is not an appropriate long-term strategy. However, until the ADAMTS13 testing results are back, and a definitive treatment for aHUS can be instituted, this is an appropriate temporizing measure. Of note, it is important to be careful, as its use also raises a critical issue in TMA diagnosis. Depending upon the exact complement mutation underlying susceptibility to aHUS in a particular patient, up to 70% to 80% of the time one can normalize the hemoglobin, haptoglobin and platelet count, and dramatically decrease the LDH with PEx alone, but you have done nothing for the underlying disease. The majority of these patients will go on to develop end-stage renal disease or die, but they may do so with normal hematologic lab values. Fresh frozen plasma contains sufficient quantities of two soluble complement regulatory proteins, CFH and CFI, the two most commonly mutated factors underlying aHUS, to correct those lab values, and yet organ dysfunction continues. In the patient with aHUS, there is only one FDA–approved therapy, eculizumab (Soliris, Alexion), a humanized monoclonal antibody against complement protein C5. This treatment prevents the breakdown of C5 to form C5a, a pro-inflammatory anaphylatoxin, and C5b, which joins with other complement proteins to form the membrane attack complex C5b-9 and causes damage to endothelial cells and red blood cells. The only FDA–approved treatment is a 30-minute infusion of this monoclonal antibody, once weekly for 4 weeks, and then every other week for an extended period of time.
Q: What are typical outcomes like for these patients? How long must specific treatments for the TMAs be continued?
A: In terms of acquired TTP, a complete response is usually achieved after five to nine plasma exchanges in about 80% of patients, but relapses may occur in half of those individuals. In those not initially responding to PEx, or suffering frequent relapses, a variety of immune suppressive regimens have been effectively utilized. In terms of aHUS, the ability to stop eculizumab therapy once a complete response has been achieved is unclear. I tell my patients that they should remain on treatment for an extended period of time, with possible modification of that statement in the future based upon ongoing research. In ASH’s guidelines, published in 2016, the section on TMAs states that treatment with eculizumab for aHUS is indefinite.
Q: What do you think the clinical community needs to understand the most about aHUS?
A: If you do not consider aHUS in your differential diagnosis of a TMA, particularly if the TMA occurs in the setting of a complement activating condition such as infection, autoimmune disease, malignant hypertension, pregnancy, etc., and it does not resolve once that complement activating condition has been treated, then you will never find it. Two-thirds of patients with aHUS have such an identifiable complement activating condition. As a general rule, if a patient presents with a microangiopathy, rule out DIC and STEC-HUS, and order the ADAMTS13 activity and inhibitor tests. If the ADAMTS13 comes back suggesting TTP, with an activity less than 5%, then treat it. If the ADAMTS13 comes back greater than 5% to 10% — the exact cut-off varies by lab — consider aHUS and treat it appropriately. If there is a complement-activating condition accompanying the TMA, and TTP, STEC-HUS and DIC have been ruled out or treated, then treat that condition. If the TMA persists, consider that complement activation has unmasked aHUS, and treat for that. It is also important to recognize time to response to a specific therapy in the TMAs. As noted above, most TTP patients will have a complete hematologic remission and a decrease of more than 25% in creatinine, if elevated, following five to nine plasma exchanges. In aHUS, platelet response to eculizumab is usually seen within 7 days, but the range for an acute episode is between 1 and 84 days. In terms of creatinine, a decrease is usually seen within three to four weekly doses, but studies have shown no plateau in a steady increase in estimated GFR after 2 years. Some clinicians feel that if a response to eculizumab is not seen after one or two doses, they should go back to PEx, but that is incorrect.
Q: What are current areas of research? Is there any hope for breakthroughs in the near future?
A: For aHUS, there are many strategies in early stage development to attack the complement system. These include other monoclonal antibodies and small interfering RNAs directed at C5, or components higher up in the complement cascade, including C3. One treatment in clinical trials is directed at MASP2, part of the lectin pathway of complement. Eculizumab itself has been genetically modified to extend its half-life, and that agent is in clinical trials. In terms of TTP, the focus of current research is on better immunosuppressive therapies, and possible use of recombinant ADAMTS13 enzyme.
Q: Is there anything else that you would like to mention?
A: Two clinical pearls. One is that all of the thrombotic microangiopathies might be expected to cause microvascular thrombosis and, thus, affect any organ, but this not true for the lung. The lung is never structurally involved in TTP; however, it is frequently involved, clinically and pathologically, in aHUS. The second is to know the meaning of ‘thrombocytopenia’ in the setting of TTP vs. aHUS. TTP is a platelet consumptive disorder. Clots are predominantly platelet-rich white clots and the mean platelet count is less than 20,000. aHUS is not primarily a platelet consumptive disorder. Microvascular clots are typical fibrin-based and, in the absence of a complicating complement activating condition, the mean platelet count is greater than 30,000 to 40,000. – by Jennifer Southall
For more information:
Jeffrey Laurence, MD, can be reached at Weill Cornell Medical College, 1300 York Ave., New York, NY 10065; email: jlaurenc@med.cornell.edu.
Disclosure: Laurence reports research funding and speaking honoraria from Alexion, the manufacturer of eculizumab.