Abstract: SA-PO716
Massive Ex Vivo C5b9 Formation on Endothelium Indicates Complement Defects and a Clinical Response to Complement Inhibition in Patients with Thrombotic Microangiopathy
Session Information
- Pathology and Lab Medicine: Clinical
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pathology and Lab Medicine
- 1602 Pathology and Lab Medicine: Clinical
Authors
- Timmermans, Sjoerd, Maastricht University Medical Center, Maastricht, Netherlands
- van Paassen, Pieter, Maastricht University Medical Center/Nephrology and Clinical Immunology, Maastricht, Netherlands
Group or Team Name
- Limburg Renal Registry
Background
The syndromes of thrombotic microangiopathy (TMA) are extraordinarily diverse, some of which have been linked to defects in complement regulation. The correct recognition of such defects in patients with TMA is critical for treatment and prognosis, although challenging in patients with coexisting conditions, i.e., so-called secondary TMAs. We evaluated the clinical value of an ex vivo test to detect complement defects in a well-defined cohort of patients with TMA.
Methods
Sixty-three patients with TMA on kidney biopsy and/or peripheral blood smear were analyzed for serum-induced ex vivo C5b9 formation on microvascular endothelial cells and compared to pooled normal human serum. Patients with TMA also were screened for rare variants in genes linked to complement regulation. In addition, renal survival at 1 year was assessed.
Results
At diagnosis, massive ex vivo C5b9 formation was found in n/N=40/63 (63%) patients with TMA, including n/N=15/15 with atypical hemolytic uremic syndrome, n/N=17/25 with hypertensive emergency, n/N=6/6 with pregnancy, n/N=1/1 with invasive Streptococcus pneumonia infection, and n/N=1/1 after an endovascular aortic repair, but neither in those with coexisting autoimmunity (n=9) nor thrombotic thrombocytopenic purpura (n=6). Patients with massive ex vivo C5b9 formation presented with severe acute kidney injury (median serum creatinine of 538 versus 197 µmol/L, P<0.01) and a high prevalence of rare variants in complement genes (23 [58%] versus 0, P<0.001) as compared to those with normal ex vivo C5b9 formation. Seventeen patients with massive ex vivo C5b9 formation were treated with eculizumab (median number of treatment was 14); renal survival at 1 year was n/N=14/17 (82%) and n/N=9/23 (39%) for treated and untreated patients (P<0.01), respectively. Notably, 3 patients with normal ex vivo C5b9 formation who had been treated with eculizumab progressed to end-stage renal disease.
Conclusion
Massive ex vivo C5b9 formation indicates defects in complement regulation as the dominant cause of TMA, including TMAs that present with coexisting conditions. Patients with TMA and massive ex vivo C5b9 formation may benefit from complement inhibition.