Clearance kinetics and fate of macromolecular IgA in patients with IgA nephropathy

Abstract

IgA glomerulonephritis is associated with macromolecules of polymeric IgA in the circulation and mesangial deposits. An impairment in the reticulophagocytic function of patients with IgA nephropathy has been postulated as the potential cause for persistence of IgA immune complexes in the circulation and their eventual glomerular deposition. Since the fate and removal mechanisms of circulating macromolecular IgA are unknown in humans, we examined the blood clearance and organ uptake of purified IgA polymers and macromolecules in patients with IgA nephropathy and normal controls. The IgA macromolecules were prepared by covalent cross-linking of purified human polymeric IgA with a heterobifunctional reagent, N-succinimidyl 3-(2-pyridyldithio) propionate. After intravenous injection, large IgA molecules were removed rapidly from the circulation of patients (t1/2 = 3.8 +/- 1.0 minutes) and controls (t1/2 = 4.9 +/- 1.5 minutes). Dynamic gamma camera scintigraphy revealed the liver as the major organ that mediated the removal of the macromolecular IgA with no significant difference in the rate of hepatic uptake for patients (t1/2 = 3.4 +/- 0.6 minutes) and controls (t1/2 = 3.3 +/- 0.9 minutes). No significant amount of radioactivity could be detected in the lungs, kidneys, and spleen. The small polymers had a slower and similar clearance rates for patients (t1/2 = 29.3 +/- 7.9 h) and controls (t1/2 = 29.0 +/- 8.6 h). These findings have general significance in showing the liver as a major organ for removal of macromolecular IgA. In addition, the results have specific importance in showing that patients with IgA nephropathy do not suffer from an IgA removal dysfunction.