Sequential BTK inhibitor therapy maintains hematological and renal stability in Waldenström macroglobulinemia with renal dysfunctionNew treatment approach shows promise for rare blood cancer patients

Light-chain proximal tubulopathy (LCPT) is a rare renal manifestation of monoclonal gammopathy that is exceptionally uncommon in Waldenström macroglobulinemia (WM). We report a case of crystalline κ-LCPT in WM and conduct a literature review of WM-associated LCPT and crystal-storing histiocytosis (CSH). A 65-year-old man with a 4-year history of intermittent hematuria and proteinuria developed progressive renal dysfunction. Before admission, myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA) was strongly positive by qualitative immunoblotting, initially raising concern for ANCA-associated vasculitis. After admission, repeat testing on a separate sample showed only modest MPO-ANCA elevation by chemiluminescence, whereas proteinase 3 (PR3)-ANCA and both P-ANCA and C-ANCA by indirect immunofluorescence were negative; serum immunoglobulin M (IgM) was markedly elevated, and monoclonal IgM-κ was identified in serum and urine. Kidney biopsy demonstrated crystalline κ-LCPT, with κ-predominant light-chain staining in proximal tubular epithelial cells and organized intracytoplasmic crystals on electron microscopy. Concurrent glomerular findings showed an immunoglobulin A (IgA) nephropathy pattern, characterized by strong mesangial IgA/C3 deposition, polytypic glomerular κ and λ staining without light-chain restriction, and corresponding electron-dense deposits. The biopsy showed no active pauci-immune necrotizing or cellular crescentic glomerulonephritis, arguing against ANCA-mediated renal injury. Crystalline material was also identified ultrastructurally within interstitial mononuclear cells, raising but not confirming CSH because histiocytic lineage was not verified by CD68/CD163. Bone marrow examination established WM/LPL with MYD88-L265P positivity. MYD88-L265P places the underlying lymphoplasmacytic clone within the canonical MYD88–interleukin-1 receptor-associated kinase (IRAK)–Bruton tyrosine kinase (BTK)–nuclear factor κB (NF-κB) signaling axis of WM. The discordant MPO-ANCA serology was considered more likely to represent non-specific/paraprotein-associated assay reactivity. Sequential BTK inhibitor therapy (ibrutinib followed by zanubrutinib, with the temporary addition of bortezomib–dexamethasone) achieved sustained hematological response and stable renal function over 49 months of follow-up. Our literature review identified seven eligible published WM-associated LCPT and/or CSH cases, yielding eight cases including the present patient. This case expands the spectrum of WM-associated renal disease by highlighting crystalline κ-LCPT as a rare clone-related tubular lesion and underscores the importance of integrated renal pathological and hematological evaluation in distinguishing clone-related injury from coexisting renal lesions.