AMSTERDAM — Eculizumab leads to clinically meaningful improvements in thrombotic microangiopathy and reverses renal damage in adults with atypical hemolytic uremic syndrome (aHUS), regardless of transplant history, new research shows.

After the introduction of eculizumab, most patients were able to discontinue dialysis, and most remained dialysis-free at week 26, said Fadi Fakhouri, MD, PhD, from the University Hospital Centre of Nancy in France.

Clinically meaningful improvements in renal function and significant improvements in platelet count were seen in patients who had undergone kidney transplantation and in those who had not.

"We did not know beforehand if response to eculizumab was going to be different in these 2 cohorts, which is why we compared them," Dr. Fakhouri told Medscape Medical News.

"The most important treatment effect was that we were able to wean most patients off dialysis," he explained.

Dr. Fakhouri presented the study results here at the European Renal Association-European Dialysis and Transplant Association 51st Congress.

Dialysis at Baseline

Although this was not a randomized trial, it is the largest study ever done in adults with aHUS, Dr. Fakhouri reported.

The study involved 9 patients who had undergone kidney transplantation and 32 patients who had not. All were treated with eculizumab, a first-in-class terminal complement inhibitor.

All had a baseline platelet count below 150 × 10⁹/L, a level of lactic acid dehydrogenase at least 1.5 times the upper limit of normal, and a level of serum creatinine above the upper limit of normal.

At baseline, 3 patients in the transplant group and 21 in the nontransplant group were on dialysis. By week 26, dialysis was discontinued in 67% (2 of 3) of the transplant group and 86% (18 of 21) of the nontransplant group.

The mean increase from baseline in platelet count was 146.2 × 10⁹/L in the transplant group (P = .0810) and 132.6 × 10⁹/L in the nontransplant group (P < .0001).

Mean gain from baseline in estimated glomerular filtration rate (GFR) was 19.0 mL/min per 1.73 m² in the transplant group (P = .1940) and 31.5 mL/min per 1.73 m² in those the nontransplant group (P < .0001).

Improvement of at least 1 stage of chronic kidney disease was achieved by 56% of the transplant group and 66% of the nontransplant group. This suggests that eculizumab treatment results in a "substantial recovery" in kidney function in both groups, the investigators conclude.

Plasma Exchange

Historically, although there was no clear evidence of efficacy or improvement in renal function, aHUS has been treated with plasma exchange, Dr. Fakhouri explained.

But "two-thirds of patients ended up in end-stage renal disease despite plasma exchanges," he told Medscape Medical News.

Kidney transplantation has also been used to treat aHUS, but even that does not prevent recurrence; many of these aHUS patients lose their graft when the disease recurs.

Concern that response to eculizumab might be compromised in patients who had undergone transplantation was primarily related to 2 factors.

First, patients who reach end-stage renal disease and require a donor kidney by definition have more severe disease because aHUS has already destroyed their native kidney, Dr. Fakhouri explained.

Second, after transplantation, "ischemia reperfusion is a tremendous trigger for complement activation," he pointed out. "So in patients who have already lost their native kidney to aHUS, which in itself is linked to complement activation, ischemia reperfusion can very easily trigger recurrence," he said.

Significant Study

This study was significant for a number of reasons, said Sanjeev Shah, MD, assistant professor of medicine at the University of Pennsylvania in Philadelphia.

"From a clinical perspective, I think it adds a lot to the basic science data that have come out in the past decade, showing us that aHUS is a disease process that is based on abnormal complement biology and one that deserves targeted treatment because of this," he told Medscape Medical News.

In addition, the fact that the investigators were able to show an improvement in hard end points — namely, improvement in standardized GFR and discontinuation of dialysis — is "very promising," he said.

Dr. Shah pointed out that the study is important for nephrology as a whole because the investigators were able to show improvement in kidney function in a transplant population that is "primed to relapse" after transplantation.

"When you have ischemia reperfusion injury, complement activation is usually profound," he explained. "The fact that the investigators were able to show an improvement in estimated GFR in transplant patients is a huge boon to the treatment of aHUS, where otherwise there is a substantial degree of graft loss."

The study was funded by Alexion Pharmaceuticals. Dr. Fakhouri is a consultant for Alexion Pharmaceuticals. Dr. Shah has disclosed no relevant financial relationships.

European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) 51st Congress: Abstract MO013. Presented June 2, 2014.

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