Crescentic nodular glomerulosclerosis secondary to truncated immunoglobulin α heavy chain deposition

Nodular glomerulosclerosis secondary to deposition of monoclonal immunoglobulin (Ig) light chains with or without heavy chains is a recognized clinicopathological entity. Recent reports have demonstrated that an identical glomerular lesion may also occur as a result of truncated τ Ig heavy chain deposition. We investigated the nature of Ig deposits in a patient who presented with rapidly progressive renal failure secondary to crescentic nodular glomerulosclerosis. This patient had a relapsing clinical course responsive to treatment with steroid and cyclophosphamide therapy. In this case, both the glomeruli and tubular basement membrane contained granular immune deposits that were reactive to polyclonal antibodies against α but not τ or μ Ig heavy chains and nonreactive to anti-κ and anti-λ light chain reagents. A monoclonal population of plasma cells secreting α and κ chains was present in the patient's marrow despite the finding of a normal percentage of plasma cells. Serum immunoelectrophoresis was normal, but immunofixation demonstrated the presence of a monoclonal α/κ band. Immunoblot under dissociating and nondissociating conditions showed that both the patient's urine and serum contained Ig fragments that comprised dimer or monomer of an abnormally short α Ig heavy chain (approximately 26 kd) with or without associated κ light chain. The identity of the abnormal serum α Ig heavy chain with that of the glomerular Ig deposits was supported by the finding that both were nonreactive against α1 and α2 subclass-specific monoclonal antibodies despite their reactivity to polyclonal antibodies. Because these monoclonal antibodies would react with structural determinants, which differ between α1 and α2 Ig heavy chains but not those common between them, and because the differences in amino acid sequence between the two largely lie in the CH1 and CH2 domains of the α Ig heavy chain, it is hypothesized that the abnormally short α Ig heavy chain produced by plasma cells in this patient contains deleted CH1 and CH2 domains similar to the findings in patients with τ Ig heavy chain deposition disease.link_to_subscribed_fulltex