Metabolism of complement factor D in renal failure

Metabolism of complement factor D in renal failure. Factor D is an essential enzyme of the alternative pathway of complement. Its plasma concentration increases approximately tenfold in end-stage renal failure (ESRF). To analyze its metabolism in humans, we injected purified radiolabelled factor D into 5 healthy individuals and 12 patients with various renal diseases or renal failure. Fractional metabolic rates (FMR) and extravascular/intravascular distributions (EV/IV) were calculated using a compartmental model. The FMR was very rapid in normal individuals (mean 59.6 %/hr; range 74.1 to 50.5), significantly diminished in the five patients with ESRF (5.7 %/hr; 7.0 to 2.8; P < 0.004), and correlated well with the creatinine clearance (r = 0.89; P < 0.001). The extrarenal catabolic rate was not modified in renal failure. Despite a significant inverse correlation between plasma levels of factor D and creatinine clearance [r = 0.68; P < 0.002], factor D levels were not a sensitive indicator of renal function because the synthesis rate (SR) varied widely from one individual to another (mean SR: 62.9µg/kg/hr; 14.9 to 136.5). Factor D synthesis was not significantly altered by renal function, and did not correlate with C-reactive protein, suggesting that factor D is not an acute phase protein. The proportion of intact factor D elimination in the urine was increased in patients with tubular dysfunction (up to 15% compared to < 0.2% in normal individuals) confirming that under normal circumstances factor D is filtered through the glomerulus and catabolized by tubular cells. In renal failure the EV/IV ratio was diminished (in normals: 8.5, 10.8 to 7.1; in ESRF: 2.4, 3.1 to 1.9; P < 0.004), indicating that accumulation of factor D was more pronounced intravascularly. These findings suggest that in humans, factor D catabolism is very rapid and essentially renal. In renal failure the several-fold increase in factor D concentration may be responsible for enhanced alternative pathway activation, particularly in the circulation.