Serine Protease HTRA1 Membranous Nephropathy With Polytypic IgG Concurrent With Plasma Cell Dyscrasia

A growing number of target antigens have been identified in membranous nephropathy (MN) in recent years. Clinical correlations exist for some MN antigens, whereas others remain poorly characterized because of their rarity. High-temperature requirement A serine peptidase 1 (HTRA1) is the target antigen in approximately 1%-2% of MN cases without any established disease associations. Recent studies suggest HTRA1-MN may associate with malignancies in approximately 12% of cases, mostly solid tumors. To date, only 2 cases of HTRA1-MN have been reported in the setting of atypical hematopoietic disorders, including chronic lymphocytic lymphoma and monoclonal gammopathy of uncertain significance. Here, we present a case of HTRA1-MN with polytypic IgG deposits in a 62-year-old man with a plasma cell dyscrasia (IgA monoclonal gammopathy and 20% bone marrow involvement by a λ-restricted plasma cell neoplasm) who presented with nephrotic syndrome. A limited initial kidney biopsy suggested early MN. Daratumumab-based induction therapy resulted in a partial renal response (urinary protein-creatinine ratio of 0.7 g/g). However, proteinuria subsequently recurred (∼6.7 g/g), prompting a repeat biopsy that demonstrated HTRA1-MN with polytypic IgG staining. Proteinuria has progressively worsened (12 g/g), with persistent minimal residual plasma cell disease despite ongoing daratumumab maintenance therapy. To our knowledge, this case represents only the second reported case of HTRA1-MN occurring in the setting of monoclonal gammopathy, the first in multiple myeloma, and a rare example of a nonmonotypic MN in this context. Temporal proximity and partial response to anti-plasma cell therapy suggest a possible paraneoplastic relationship, although a causal relationship remains unproven.