Impact of hypertensive emergency and rare complement variants on the presentation and outcome of atypical hemolytic uremic syndrome

Abstract

A typical hemolytic uremic syndrome (aHUS) is a prototypic thrombotic microangiopathy attributable to complement dysregulation. Hypertensive emergency, characterized by elevation of systolic (>180 mmHg) or diastolic (>120 mmHg) blood pressure together with end-organ damage, can cause thrombotic microangiopathy which may mimic aHUS. We retrospectively evaluated the clinical, biological and complement genetic characteristics of 76 and 61 aHUS patients with and without hypertensive emergency, respectively. Patients with hypertensive emergency-aHUS were more frequently males, with neurological involvement, and a slightly higher hemoglobin level. At least one rare complement variant was identified in 51.3% (39/76) and 67% (41/61) patients with or without hypertensive emergency, respectively (P=0.06). In both groups, renal prognosis was severe with 23% and 40% of patients reaching end-stage renal disease after a 5-year follow-up (P=0.1). The 5-year renal survival was 77% in patients without hypertensive emergency or a complement variant, and below 25% in the three groups of patients with hypertensive emergency and/or a complement variant (P=0.02). Among patients without hypertensive emergency, the 5-year renal survival was 100% vs 40% in those treated or not with eculizumab, respectively (P<0.001). Conversely, the 5-year renal survival of patients with hypertensive emergency was 46% vs 23% in those treated or not with eculizumab, respectively (P=0.18). In conclusion, information on the presence or absence of hypertensive emergency and rare complement variants is essential to stratify the long-term renal prognosis of patients with aHUS.

Figure 1.

Study flow chart. Flow chart for the inclusion criteria of patients within the adult population of the French HUS registry screened for genetic abnormalities (n=405). A total of 137 patients were eligible for enrollment in the study. HUS: hemolytic uremic syndrome; HE: hypertensive emergency; aHUS: atypical hemolytic uremic syndrome.

Figure 2.

Renal survival in patients with atypical hemolytic uremic syndrome, with or without hypertensive emergency, not treated with eculizumab. Analysis of renal survival without end-stage renal disease or death in patients not treated with eculizumab. Log-rank test, P=0.1. Follow-up was not available for two patients with hypertensive emergency and atypical hemolytic uremic syndrome. HE: hypertensive emergency; aHUS: atypical hemolytic uremic syndrome.

Figure 3.

Distribution of rare complement variants observed in the whole cohort. Rare complement genetic variants found in patients with atypical hemolytic uremic syndrome are presented above and below the schematic gene representation for those with or without hypertensive emergency, respectively. The nucleotide and amino acid numbering refer to the translation start site (A in ATG is +1), as recommended by the Human Genome Variation Society. Bold characters indicate mutations identified in two or more unrelated patients, suggesting that they may represent mutational hot spots. CFH: complement factor H; MCP: membrane cofactor protein; CFI: complement factor I; CFB: complement factor B; C3: complement component 3: THBD: thrombomodulin.

Figure 4.

Renal survival of patients treated or not with eculizumab. Analysis of renal survival without end-stage renal disease or death according to use of eculizumab treatment in: (A) the whole cohort, P<0.001; (B) in patients without hypertensive emergency (HE) and atypical hemolytic uremic syndrome, P<0.001; and (C) in HE-aHUS patients, P=0.18. Log-rank test. Follow-up was not available for two patients with HE-aHUS.

Figure 5.

Renal survival of patients with atypical hemolytic uremic syndrome according to the presence or absence of rare complement variants and hypertensive emergency. (A) Analysis of renal survival without end-stage renal disease or death in patients not treated with eculizumab, log-rank test, P=0.02. (B) Analysis of renal survival in the whole cohort, log-rank test, P=0.001. Follow-up was not available for two patients with hypertensive emergency and atypical hemolytic uremic syndrome. HE: hypertensive emergency; aHUS: atypical hemolytic uremic syndrome; C: complement.