Heavy chain deposition disease in kidney biopsies Alenka Vizjak, Jerica Mraz, Jelka Lindič, Dušan Ferluga Institute of Pathology, Faculty of Medicine University of Ljubljana, Slovenia Disclosures: no conflicts of interest Heavy chain deposition disease (HCDD) • HCDD - a rare monoclonal immunoglobulinrelated disorder of not yet fully explored pathogenesis • Characterized by production and systemic deposition of structurally abnormal immunoglobulin heavy chains, while light chains absent in the deposits • First described by Aucouturier et al (N Engl J Med 1993; 329: 1389-93) Monoclonal immunoglobulin deposits in the kidney Amyloid deposits Non-amyloid monoclonal immunoglobulin deposits Amyloidosis MIDD Randall-type GN with monoclonal LC LCDD Igs dps mimicking IC-GN HC (very LHCDD rare) Cryoglobulinemic-GN HCDD Immunotactoid GP / fibrillary GN Patients and methods • 4 biopsy cases of HCDD (5 kidney biopsies; 1 autopsy), representing 0.09% prevalence among 5481 native kidney biopsies • All 4 female patients, age range 62 – 79 yrs, mean age 73.0 yrs • Standard light microscopy • Immunofluorescence microscopy IgA, IgG, IgM, κ, λ, C3, C1q, fibrin/fibrinogen, albumin IgG1, IgG2, IgG3, IgG4, γCH1, γCH2, γCH3 • Electron microscopy Clinical presentation / diagnosis in 4 patients with HCDD Pts At kidney biopsy After kidney biopsy PM - 1st CKD, prot, compl↓ no dysproteinemia PM - 2nd CKD, NS, compl↓ no dysproteinemia JA CKD, prot, compl↓ plasmocytoma BŠ RPGN, NS, compl↓ plasmocytoma RM CKD, nephr prot, compl norm no dysproteinemia CKD – chronic kidney disease, NS – nephrotic syndrome Immunofluorescence microscopy in 4 cases of HCDD γCH1 γCH2 subclass γCH3 κ/λ C3 C1q n.d. 2+ / ± 2+ 4+ 0 4+ 0/0 2+ 4+ IgG3 0 3+ 0/0 4+ 3+ 4+ IgG3 0 4+ 0/0 3+ 4+ 4+ IgG1 0 4+ 0/0 4+ 3+ Pts IgG (γ) IgG PM - 1st 4+ n.d. n.d. PM - 2nd 4+ IgG3 JA 3+ BŠ RM Light and electron microscopy in 4 cases with HCDD Light microscopy •Diffuse nodular glomerulosclerosis •Glomerular capillary aneurysms •Mesangial proliferation, with segm endo-, membranoprol pattern •Extracapillary crescents (few) 4/4 4/4 4/4 3/4 2/4 Electron microscopy •Punctate and powdery electron dense deposits 3/4 IgG (γ heavy chain) κ, λ light chains IgG (γ heavy chain) IgG1 IgG2 C3 C1q γCH1 γCH2 SMA+CD31 CD68 Conclusions of our study • Immunofluorescence examination of kidney biopsy, including testing for Igs heavy and light chains, as well as IgG subclasses, is crucial for the diagnosis of HCDD. • Our study showed that HCDD is peculiar among MIDD because of uniform pattern of nodular glomerulosclerosis with pronounced capillary aneurysms and significant proliferation due to complement activation. • Constant deletion of the gamma heavy chain CH1 domain and its significance in the pathogenesis of HCDD was confirmed.