Dysregulation of Complement in aHUS

Dysregulation of Complement in aHUS

 

Abnormalities that result in dysregulation of complement are associated with ~50% of cases of aHUS. These abnormalities may be genetic or acquired.

 

Genetic Risk Factors

These are most commonly rare genetic variants in the genes (CFH, CFI and CD46) encoding regulatory proteins. Many of these variants are known to be pathogenic and cause loss of function, either due to abnormal protein expression leading to low protein levels or the expression of a defective protein. Less frequently, there are rare genetic variants in the genes (C3 and CFB) encoding proteins involved in complement activation. Functional studies of some of these have demonstrated gain of function resulting in complement overactivation.

The consequences of all rare genetic variants identified in patients with aHUS has not yet been established .Where there is uncertainty that a rare genetic variant is pathogenic, the term variant of uncertain significance (VUS) should be used.

Acquired Risk Factors

Autoantibodies have been reported to complement regulators in aHUS. These are most commonly identified against FH and can be found in ~10% of patients with aHUS. These autoantibodies are inhibitory, and block the regulatory role of FH resulting in loss of complement regulation.

Prognosis of aHUS – Stratification by Complement Abnormality

Stratification of patient risk of progression to end-stage renal disease and recurrent disease in the renal transplant has been possible depending upon the complement abnormality identified and is summarised below.

 

Gene or subgroup

Risk of death or ESRD at 1st episode or within 1 year prior to Eculizumab

CFH

50-70%

CFI

50%

CD46

0-6%

C3

60%

CFB

50%

Autoantibodies to FH

30-40%

Risk of ESRD
 

Gene or subgroup

Risk of recurrence after renal transplant without prophylactic Eculizumab

CFH

75-90%

CFI

45-80%

CD46

<20%

C3

40-70%

CFB

100%

Autoantibodies to FH

Yes, if high antibody titre

Risk of disease recurrence following renal transplantation

Penetrance / Triggers

The penetrance of disease in individuals carrying a pathogenic variant is ~ 70% by the age of 70. This can be explained by the need for additional disease risk modifiers (genetic) and a trigger (environmental).

Triggering events include respiratory tract infections, other infections, malignancy and pregnancy.

Screening for Complement Risk Factors

We offer screening for genetic and acquired abnormalities of complement dysregulation to help establish a diagnosis of aHUS at our combined aHUS lab diagnostic services in Newcastle upon Tyne Hospitals NHS Foundation Trust.

The results of this screening (including patients in whom no abnormality is identified) do not influence the initial decision to commence eculizumab. However, they are important during patient review and help inform the National aHUS service in the ongoing care of the patient.