Crescentic nodular glomerulosclerosis secondary to truncated immunoglobulin alpha 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 tau 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 alpha but not tau or mu Ig heavy chains and nonreactive to anti-kappa and anti-lambda light chain reagents. A monoclonal population of plasma cells secreting alpha and kappa 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 alpha/kappa 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 alpha Ig heavy chain (approximately 26 kd) with or without associated kappa light chain. The identity of the abnormal serum alpha Ig heavy chain with that of the glomerular Ig deposits was supported by the finding that both were nonreactive against alpha 1 and alpha 2 subclass-specific monoclonal antibodies despite their reactivity to polyclonal antibodies. Because these monoclonal antibodies would react with structural determinants, which differ between alpha 1 and alpha 2 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 alpha Ig heavy chain, it is hypothesized that the abnormally short alpha Ig heavy chain produced by plasma cells in this patient contains deleted CH1 and CH2 domains similar to the findings in patients with tau Ig heavy chain deposition disease.