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Abstract: FR-OR064

Ex Vivo Formation of C5b9 on Endothelial Cells Differentiates Complement-Mediated Renal Failure from Hypertensive Nephrosclerosis in Severely Hypertensive Patients

Session Information

Category: Glomerular

  • 1004 Clinical/Diagnostic Renal Pathology and Lab Medicine


  • Timmermans, Sjoerd, Maastricht University Medical Center, Maastricht, Netherlands
  • Reutelingsperger, Chris, Maastricht University, Maastricht, Netherlands
  • Paassen, Pieter Van, Maastricht University Medical Center, Maastricht, Netherlands

Group or Team Name

  • Limburg Renal Registry

Severe hypertension (HTN) can induce renal failure due to hypertensive nephrosclerosis, a diagnosis rarely confirmed by biopsy assuming that the kidney is the victim rather than culprit of HTN. Underlying acute thrombotic microangiopathy (TMA) can therefore be missed, particularly in patients not presenting with microangiopathic hemolysis and thrombocytopenia. Moreover, it is critical to distinguish TMA due to shear stress from TMA dominantly caused by complement dysregulation, having major impact on treatment and prognosis.


To differentiate complement-mediated from shear stress-induced kidney injury in patients with severe HTN (blood pressure >180/120 mmHg) and renal failure, we analyzed serum-induced C5b9 formation on resting and ADP activated human microvascular endothelial cells (HMEC) by using samples from patients with severe HTN either with active TMA or hypertensive nephrosclerosis on kidney biopsy. Serum from patients with atypical hemolytic uremic syndrome (aHUS) and dense deposits disease (DDD) were used as positive and negative controls; all samples were compared with normal human serum run in parallel.


Serum from 12 patients with HTN-associated TMA induced extensive C5b9 formation on resting (293%, P<0.001) and activated HMEC (318%, P<0.001), identical to aHUS samples (n=3; 344% and 394%, respectively). In contrast, samples from 5 patients with hypertensive nephrosclerosis induced scanty C5b9 formation on both resting (98%, P=1.0) and activated HMEC (108%, P=0.7), identical to DDD (n=5; 89% and 90%, respectively). C3c and C5b9 staining on kidney sections linked complement activation to TMA but not to nephrosclerosis. Moreover, genetic analysis confirmed complement defects in 6 (50%) out of 12 patients with HTN-associated TMA.


In conclusion, intrarenal solid phase complement dysregulation and ongoing TMA appears the dominant cause of renal failure in a subset of patients with severe HTN. The HMEC test differentiates complement-mediated TMA from other causes of HTN associated kidney injury, such as shear stress.