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PRIORITY PRESS - Kidney Week - American Society of Nephrology (ASN)

Atlanta, Georgia / November 5-10, 2013

Atlanta - Atypical hemolytic uremic syndrome (aHUS) affects both children and adults, is characterized by systemic thrombotic microangiopathy, which can lead to stroke, heart attack, kidney failure, and death. Despite plasma exchange/infusion, approximately 65% of patients have died or have developed end stage renal disease within 1 year of diagnosis. Poorly prevented in the past, the complications of aHUS can now be managed when complement activation is inhibited in advance of extensive organ damage. The persistent clinical hurdle is rapid diagnosis for a disease with a non-specific presentation, however, progress in understanding this disease continues. Inhibition of complement turns off the pathology, but it does not cure aHUS and this disease continues to be a chronic systemic genetic condition with catastrophic consequence when left uncontrolled. Rapid diagnosis and clinical intervention is critical to achieve optimal outcomes.

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

Uncontrolled activation of complement is the key pathogenic event in atypical hemolytic uremic syndrome (aHUS). Complement is central to the recruitment of platelets, leukocytes, and inflammatory mediators that result in thrombotic microoangiopathy (TMA). It has long been understood that complement drives the TMA characteristic of aHUS, but the development of an effective inhibitor of complement confirms that it is the final common pathway.

“AHUS is a genetic, life-threatening, progressive disease resulting from chronic uncontrolled complement activation. If complement activation is controlled, the process can be aborted,” reported Dr. A. Osama Gaber, Director of Organ Transplantation, Methodist Hospital, Houston, Texas. The most vivid evidence of this has been the unprecedented responses achieved with the monoclonal antibody eculizumab, which is directed at the C5 complement protein. Dr. Gaber presented one of several sets of data with this agent. The studies uniformly associated this agent with rapid normalization of hematological markers of aHUS as well as with sustained protection from disease complications.

Monoclonal Antibody Targets Complement

By inhibiting complement-mediated TMA, eculizumab has been shown to improve outcomes in patients with aHUS but the disease continues to pose many challenges.

“Why is the kidney the most common target of this upregulation of complement? The truth is that we do not know, but we can make some educated guesses,” reported Dr. Joshua M. Thurman, Division of Renal Diseases and Hypertension, University of Colorado, Denver. One of the hypotheses articulated by Dr. Thurman involves factor H, which is a potent inhibitor of complement, and for which genetic mutations associated with aHUS are common. However, identification of a genetic mutation is not necessary to diagnose aHUS.

The signs and symptoms of aHUS, typical or infection-producing hemolytic-uremic syndrome (HUS), such as Shiga-toxin-producing Escherichia coli HUS (STEC-HUS), and thrombotic thrombocytopenic purpura (TTP) are overlapping and non-specific. Patients with aHUS often present with an abrupt onset of systemic disease which may include the kidney, heart, lung, blood vessels, brain and gastro-intestinal organs. Laboratory tests in patients with aHUS reveal low levels of platelets, elevated lactate dehydrogenase, decreased haptoglobin, anemia and schistocytes, as well as, elevated creatinine and proteinuria. In addition to laboratory results, clinical symptoms of complement-mediated TMA such as abdominal pain, confusion, fatigue, edema, nausea, vomiting and diarrhea, can also point to underlying disease. One key and practical clinical point made by Dr. Thurman is to not overlook aHUS in adults.

aHUS Can Occur at Any Age

“Patients with genetic susceptibility may never develop aHUS or they may live healthy lives for decades before some stressor trips the trigger that sets this disease in motion,” Dr. Thurman reported. “I think this is underappreciated. Clinicians think of aHUS in children, but typically diagnose TTP in adults with TMA, overlooking aHUS when it is the actual cause.”

The development of a monoclonal antibody against complement C5 has provided a fundamental advance in confirming that aHUS is complement driven, and altering the prognosis. Prior to eculizumab, which is also effective for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) (Hillmen et al. Am J Hematol 2010;85:553-9), approximately 65% of aHUS patients died or developed end stage renal disease within 1 year of diagnosis, despite plasma exchange/infusion. In data from two phase 2 trials published together, eculizumab largely eliminated TMA-related events, and restored kidney function (Legendre et al. N Engl J Med 2013;368:2169-81). In new data presented at Kidney Week, including a prospective study, results were similar.

In the prospective, open-label study of 41 patients, identified as the largest yet conducted, 24 of 41 patients were on dialysis at the time of entry. The response to eculizumab was rapid and dramatic. The improvement in hematological markers began almost immediately after treatment. The average time to normalization of platelets was 8 days. Over the course of 26 weeks of treatment, the mean increase in the estimated glomerular filtration rate (eGFR) was 29.3 mL/min/1.73 m². Of the 24 who started therapy on dialysis, 20 no longer required this support by the end of the study.

Renal Function Restored

“These results demonstrate that eculizumab can normalize hematologic parameters, improve renal function, and inhibit complement-mediated TMA,” reported Dr. Fadi Fakhouri, Department of Nephrology, University of Nantes, France. “Once you stop C5, you block the main actor in this process.”

The benefit is sustained as long as therapy is maintained, according to data presented in two additional studies each following patients for up to 3 years on eculizumab therapy. In one, presented by Dr. Gaber, 17 patients who had progressive TMA were enrolled. The other, presented by Dr. Muriel-Yahsou Delmas, CHU Pellegrin-Bordeaux, Bordeaux, France, followed 20 patients. After an induction regimen, patients were maintained on 1200 mg of the monoclonal antibody administered intravenously every 2 weeks.

The two studies generated very similar results. Rapid improvements over the first 6 months in hematological markers were sustained over 3 years. Incremental benefits in renal function measured by eGFR or serum creatinine levels were observed at 1 year relative to 6 months and at 2 years relative to one year, although there was no further improvement at 3 years relative to 2 years. Consistent with control of symptoms, clinically significant improvement in quality of life was observed in both studies.

“No patients progressed to endstage renal disease or required renal transplant,” reported Dr. Gaber, who concluded that “these data highlight the long-term efficacy of eculizumab and support the benefit from continued therapy.” Summarizing the other set of data, Dr. Delmas emphasized the ability of control of complement to restore renal function.

“These data show that the reversal of renal dysfunction is possible for aHUS patients who receive long-term eculizumab therapy, even for those with a history of chronic kidney damage,” she reported.

Prospective aHUS Study in Children

In a third study, 22 pediatric patients with aHUS were evaluated over 26 weeks. While 73% were newly diagnosed, almost half had been treated with plasma exchange prior to entry. Complete TMA response, the primary endpoint, was achieved in 64% of the patients, while 95% achieved platelet normalization, and 86% had eGFR improvement of at least 15 mL/min/1.73 m². According to the lead investigator, Dr. Larry A. Greenbaum, Emory University, Atlanta, Georgia, the results support a “recommendation that eculizumab be used as first-line treatment for aHUS in pediatric patients.”

Based on the evidence from these trials that complement is the key target in aHUS as well as STEC-HUS, compounds capable of turning off this pathway “will play a major role in treatment,” agreed Dr. Christoph Licht, Hospital for Sick Children, University of Toronto, Toronto, Ontario. He cautioned that there are numerous challenges in the ongoing effort to better understand the pathophysiology of these diseases to achieve prevention or cure, but there is new clarity in the direction research needs to take. 

Conclusion

The development of a therapy that can effectively inhibit complement has been a breakthrough in the control of aHUS. This has confirmed complement as the critical driver of the disease and may spur the next set of research initiatives needed to understand how to prevent the disease process. Eculizumab is the only drug therapy approved for the treatment of this life threatening disease, effectively managing and improving patient outcomes.