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PRIORITY PRESS - Annual Meeting of the Canadian Society of Nephrology

St. John’s, Newfoundland and Labrador / April 25-30, 2012

St. John’s - Thrombotic microangiopathies are microvascular occlusive disorders characterized by systemic aggregation of platelets, thrombocytopenia and mechanical injury to red blood cells. In the more common hemolytic uremic syndrome (HUS), toxins from bacteria initiate the pathogenic thrombotic cascade. Atypical disease (aHUS)is triggered by uncontrolled complement activation leading to systemic thrombotic microangiopathy. It is associated with a high mortality rate and many patients progress to end-stage renal disease within a year of their diagnosis. The recommended treatment strategies for aHUS are plasma infusion and exchange. However, these have limited effectiveness in many patients, as not all etiological defects giving rise to the disease can be removed or replaced by plasma therapy. A novel complement C5 inhibitor that interrupts the final step of the pathophysiologic cascade leading to aHUS has the potential to completely reverse the overactivated complement system and restore plasma to normal.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Atypical hemolytic uremic syndrome (aHUS) is part of a family of vascular disorders referred to as thrombotic microangiopathies (TMAs). These include aHUS, typical HUS (more recently called Shiga toxin Escherichia coli or STEC-HUS) and thrombotic thrombocytopenic purpura (TTP). The core pathology driving this group of diseases is a defect in the integrity of endothelial cells lining the small blood vessels. As endothelial cells become damaged, “a cascade of shared downstream events is triggered that includes activation of the clotting cascade, where clots form, thrombi occlude small vessels downstream and then tissues no longer supported by blood or oxygen either die or quit functioning,” explained Dr. Christoph Licht, Associate Professor of Pediatrics, University of Toronto, Ontario, in an interview here during the meeting.

Pathophysiology

Red blood cells are also damaged in the process and there is a loss in platelet counts. As Dr. Licht noted, damage to these endothelial cells is multifactorial. In the case of STEC-HUS, it may start with bacteria from cows or cow products (E. coli), which gain access to the circulatory system via the gastrointestinal (GI) tract. Once circulating in the bloodstream, toxins, notably Shiga toxin (Stx), are released into the blood where they damage endothelial cells, triggering the downstream cascade of uncontrolled thrombotic events. In the case of aHUS, current thought is that it arises from a defect in the complement system, especially in the alternative pathway of the complement system.

“This system is constantly on the go, so no triggers are required, it is constantly auto-activating,” Dr. Licht observed. Normally, regulatory proteins serve as negative controls and protect the system from over-activation or inappropriate activation at the wrong time or at the wrong site. However, if these regulatory proteins are missing or are impaired by the presence of mutations, “then the cascade runs too fast and since this occurs on the surface of endothelial cells, these cells are damaged and you enter this cascade of final events culminating in aHUS,” Dr. Licht explained.

A severe deficiency of von Willebrand factor-cleaving protease (ADAMTS13) activity (<5% than in normal plasma) has been observed in most patients with TTP. ADAMTS13 deficiency results in the formation of platelet thrombi, causing TTP; unlike patients with TTP, ADAMTS13 is usually normal in patients with aHUS. TTP may also be triggered by certain stimuli that possibly cause autoimmune reactivity to ADAMTS13.

Potential Role in STEC-HUS

Somewhat contrary to expectations, eculizumab proved to be highly effective when used to treat 3 children with severe STEC-HUS. As reported by Dr. Anne-Laure Lapeyraque, CHU Ste-Justine, Montréal, Quebec, and colleagues (N Engl J Med 2011;364:2561-3), progressive involvement of the central nervous system occurred in all 3 patients despite repeated cycles of plasma exchange. Following the first eculizumab infusion, neurologic status in all 3 patients improved dramatically within 24 hours.

This experience and recently reported results of in vitro studies supports the concept that Stx may activate complement directly, providing a rationale for therapeutic complement blockade in STEC-HUS with severe complications. Dr. Martin Bitzan, McGill University Health Centre, Montréal, agreed that patients with severe STEC-HUS with progressive central nervous system involvement may benefit from anti-C5 monoclonal antibody therapy.

During a STEC-HUS outbreak, “the majority of patients will do well, it’s only the minority who may end up with kidney failure or on dialysis. So we need to figure out if this is an effective treatment [in this disease] and then what are the criteria to justify treatment,” Dr. Bitzan told delegates. Importantly, there are currently no criteria by which to judge which patients with STEC-HUS would be candidates for eculizumab therapy.

More information will be revealed regarding the use of eculizumab in STEC-HUS when final observations from the German STEC-HUS outbreak of 2011 are published.

Diagnosis of Exclusion

As discussed by Dr. Lapeyraque, between 33% and 40% of aHUS patients progress to end-stage renal disease or die with the first manifestation of aHUS; within a year following diagnosis, 65% of all patients have died, require dialysis or develop permanent renal damage despite receiving plasma exchange (PE) or plasma infusion (PI) for the acute event.

The diagnosis of aHUS is essentially one of exclusion. If patients have no evidence of STEC in their stool, it is not STEC-HUS, and if ADAMTS13 is normal (i.e. >5% ADAMTS13 activity), then they have complement-mediated TMA, i.e. aHUS. It is noteworthy that about 50% of aHUS patients carry mutations in genes encoding complement proteins but genetic testing is not required for the diagnosis of aHUS because up to half of them do not have an identifiable mutation.

In a retrospective review of 30 aHUS pediatric patients treated with eculizumab, a complement C5 inhibitor, Dr. Lapeyraque and colleagues noted that 50% of patients who responded to treatment did not have any complement-identified mutations or had no mutations at all. In this review, 17 of 19 evaluable patients achieved normal platelet counts after a median of 28 weeks of therapy including 7 out of 8 patients with abnormal baseline platelet counts.

Improvement in kidney function occurred in 9 patients, with increases in estimated glomerular filtration rates of ≥15 mL/min/1.73 m². Complement inhibition also eliminated the need for dialysis in 4 out of 8 patients and no patient required new dialysis once treatment had been initiated. Overall, 13 patients or 68% of the group achieved a TMA event-free status (a stable platelet count and no PE/PI or dialysis).

The most common adverse event from treatment was pyrexia, and the safety profile of eculizumab was similar to that observed in prospective trials involving adults and adolescents. The complement inhibitor represents a new standard of care for aHUS, not just for pediatric patients, as Dr. Lapeyraque indicated, but for patients of any age.

PE/PI and aHUS

PE/PI are currently recommended for the treatment of aHUS but there are limitations to both treatment strategies. If only soluble proteins in blood were driving the TMA disease process, then replacing a patient’s lack of normal complement control proteins would be sufficient.

In addition to regulatory proteins in the blood, there are also membrane-bound proteins that sit on the surface of endothelial cells and protect them from damage. Patients whose complement-mediated TMA is caused by defects in such membrane-bound proteins are less likely to respond well to PE/PI, as Dr. Licht pointed out. “In addition, many patients with HUS also have impaired renal function and reduced urine output,” he added. This means that they do not tolerate plasma infusion well and are at risk for fluid overload and hypertension. Plasma exchange requires central venous access and has all the clotting and infection risks that are associated with central venous lines. In contrast, eculizumab blocks the final step in the cascade of the complement system, irrespective of what the regulatory defect is.

In his own research, Dr. Licht, for example, have shown that plasma taken from patients with uncontrolled complement activation responds to a certain degree when mixed (“treated”) with normal plasma, but not completely. In contrast, if the same plasma is treated with eculizumab, “you get a complete recovery of this overactivated complement system, the plasma reverts to normal so there is no difference between the patient’s plasma in the presence of eculizumab and controls,” he said.

In the clinical trial program evaluating eculizumab, adult and adolescent patients enrolled in study C08-003 (n=20) had longstanding aHUS (median duration 48 months) and substantial organ damage despite a median duration of 10 months of PE/PI. During treatment with the complement inhibitor, 80% of patients achieved TMA event-free status while platelet counts normalized in 90% of the same group.  The need for PE/PI was eliminated in all patients; kidney function was maintained; and no new dialysis was required during a median treatment interval of 40 weeks.

Very similar findings were seen in study C08-002. This included an adult/adolescent patient population experiencing progressive TMA despite intensive PE/PI. The median duration of aHUS was 10 months. Following initation of eculizumab, significant increases in platelet counts were seen as early as day 7 in most patients and increases were sustained through to study end point. Some 88% of patients (n=17) achieved TMA event-free status during the treatment interval and there was no need for PE/PI or new dialysis. Renal function also improved in over half of patients and treatment was well tolerated in both study groups.

“You can think of aHUS patients who may for very specific reasons not be ideal candidates for treatment with this monoclonal antibody. But in general, my personal opinion is that eculizumab is clearly superior to plasma treatment,” concluded Dr. Licht.