Effects of excess factor D on early- and late-phase activation of the complement cascade

The present study was undertaken to examine the effects of excess factor D build-up in the body of end-stage renal disease (ESRD) patients upon the activation of the alternative pathway and the terminal pathway in the fluid phase. First, to clarify the effect of excess factor D on the alternative pathway, purified factor D from an ESRD patient was added to normal serum and the changes in concentrations of C3a-des-Arg and C5a-des-Arg were investigated. The results showed that once the serum factor D level reached a concentration corresponding to 15 micrograms/ml in the serum of the ESRD patient, the C3a-des-Arg and C5a-des-Arg levels had climbed to about 1.7-fold the concentration in normal serum. Next, in order to clarify the effect of excess factor D on the terminal pathway, purified factor D was added to normal serum, and the changes in C5b6 generation were examined. The results indicated that as the factor D level increased in the serum, the C5b6 level rose gradually also; and when the factor D concentration reached 15 micrograms/ml, the C5b6 generation had risen to approximately 1.5-fold the level in normal serum. The present results therefore suggest that factor D build-up in ESRD patients provides a uremic toxin that can cause abnormal activation of the whole complement cascade.