Case 1 -

Heavy Chain (g) Deposition Disease Guillermo A. Herrera St. Louis University St. Louis, MO

Case History: 32 year old female presented with hypertension, microhematuria, nephrotic-range proteinuria (5 gm/24 hours) and an increase in serum creatinine (1.6 mg/dL). No anemia or back pain was present. Peripheral blood count was normal. No lymphadenopathy, hepatomegaly or splenomegaly was noted on physical examination which was essentially normal, except for a diastolic blood pressure of 100 mmHg. Serum protein electrophoresis revealed an abnormal band in the neighborhood of the IgG region which did not display full diagnostic criteria for a monoclonal protein. However, immunofixation confirmed the monoclonal nature of this protein. Urine protein electrophoresis and immunofixation were negative. No free light chains were found in the serum. C3 and C4 were within normal limits. A renal biopsy was performed. Renal Biopsy Data: Case 1 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Light Microscopy: Ten glomeruli were identified in the specimen submitted for light microscopic evaluation. One glomerulus was globally sclerosed and the remaining glomeruli showed prominent mesangial expansion associated with formation of mesangial nodules containing abundant extracellular matrix material, highlighted in the PAS and silver methenamine stained sections. Mesangial hypercellularity was noted in some of the expanded mesangial areas accompanying the increase in mesangial matrix. Some thickening of peripheral capillary walls was present on the PAS and silver methenamine stains. A single epithelial crescent was identified. Trichrome stain showed focal moderate interstitial fibrosis associated with tubular atrophy and drop-out. Ribbon-like thickening of some tubular and collecting ducts basement membranes was present. Arterioles showed significantly thickened walls. Immunofluorescence: An additional ten glomeruli were identified in the specimen submitted for immunofluorescence evaluation. Striking linear staining along glomerular and tubular basement membranes was noted for IgG (3+). No staining was present for IgA, IgM, C3, C1q, albumin, fibrinogen, kappa or lambda light chains or in the auto-control section. No staining was appreciated for the CH1 heavy chain epitope along glomerular basement membranes. Electron Microscopy: Two glomeruli were present in the specimen submitted for ultrastructural evaluation. Segmental fusion of the foot processes of the visceral epithelial cells was identified. Fluffy and punctate electron dense material was noted in subendothelial and mesangial locations. Interstitial fibrosis was observed. Similar electron dense material was identified along the tubular basement membranes and in some vessel walls. Diagnosis: Heavy Chain (g) Deposition Disease Discussion Heavy chain disease represents a lymphoproliferative disorder with free heavy chain secretion into the circulation but no tissue deposition. In heavy chain deposition disease (HCDD) the variable regions contain some unusual amino acids substitutions in the complementary-determining regions (CDR) and framework regions (FR), but no major structural alterations or deletions of the variable domain. These changes in the heavy chain molecule alter the physicochemical properties of the heavy chains causing a propensity for tissue deposition. Failure of tissue deposition of the heavy chains in heavy chain disease is a consequence of the partial or complete deletion of the variable region. Clinical and Pathologic Features HCDD is a rare entity with predominant renal involvement. Less than 100 cases have been reported in the literature. It was first fully documented in the literature by Aucouturier et al. in 1993. The age at presentation is quite variable (mean=57.4 years) but a significant number of these patients present in the 3rd or 4th decade of life. Some patients have been diagnosed in their 20s. Signs and symptoms include anemia, proteinuria (often nephrotic-range), sometimes associated with other manifestations of full blown nephrotic syndrome, hematuria, hypertension, and in some cases hypocomplementemia (low C3 and/or C4). Renal insufficiency is usually present at the time of diagnosis. Indeed, the patient presented here had a rather classical presentation for this condition, but the signs and symptoms are also overall quite non-specific. The abnormalities on serum protein electrophoresis when present reflect the migration of the abnormal heavy chain, but in a number of these cases a definitive monoclonal spike can not be confirmed. Immunofixation is usually a better diagnostic tool to support the diagnosis. Currently, there is no test to detect abnormal circulating heavy chains, as is the case with free light chains. Therefore, renal biopsy is required to establish a final diagnosis of HCDD. Nodular glomerulosclerosis represents the recognized and documented renal morphologic pattern in HCDD (as was the case in this patient). Crescents have been found in the renal biopsies from a number of these patients. In contrast to light chain deposition disease, other morphologic glomerular patterns have not been documented in the literature but this is likely due to the fact that our experience with this disease is still quite limited. The definitive diagnosis is based on the finding of linear deposition of IgG along peripheral capillary walls in glomeruli and along tubular basement membranes. All 4 types of g heavy chains have been detected in renal biopsies of patients with this disease. Complement activation by the classical pathway accompanied by detection of C1q in renal biopsies has been shown to occur in g 1 and 3-but not in g 2 and 4 HCDD which is consistent with the fact that IgG 1 and 3 are strong activators of the complement cascade by the classical pathway. Ultrastructurally the heavy chain deposits in the various renal compartments appear identical to those composed of light chains and can be found in similar locations (i.e. glomeruli, along tubular basement membranes and in the vasculature). These deposits are variably electron dense, punctate to powdery in appearance. In some instances they are markedly electron dense and clearly detectable while in other cases they are subtle and can be easily missed. Therefore, differentiation of light from HCDD requires immunofluorescence evaluation. LHCDD can be combined in the same patient; accurate diagnosis of these combined pathological processes may be quite challenging. Obviously concomitant light and heavy chain deposition must be established by immunofluorescence in the renal biopsy. Pathogenesis Evaluation of the constant domain of the heavy chain molecule using immunofluorescence techniques shows a deletion of the CH1 domain in the majority of the cases with the CH2 epitope missing in a few cases. Rarely the mutations in the heavy chain molecule are mapped to the hinge region. The missing domains in the heavy chains result in the premature secretion of the heavy chain into the circulation. Normal heavy chains associate post-translationally with heavy chain binding protein (BiP) in the endoplasmic reticulum. Light chains assemble with heavy chains and the complex is transferred to the Golgi apparatus for further processing and secretion. When a mutant heavy chain lacks key epitopes, it fails to associate with BiP and is then prematurely secreted into the circulation. Treatment, Prognosis and Future Expectations The clinical presentation, pathological findings and sequence of events to progression to end stage renal disease are quite similar in all cases with HCDD. Proteinuria and renal insufficiency are the typical presenting features generally evolving to a fully developed nephrotic syndrome with subsequent progression to end stage renal disease. Although in some cases bone marrow evaluation may show clear cut evidence of a neoplastic clone of plasma cells, it is quite often non-diagnostic of myeloma. The treatment of HCDD is similar to that of light chain deposition disease. A number of chemotherapeutic protocols have been used aimed at eradicating or controlling the neoplastic plasma cell clone to reduce or abolish the circulating heavy chains. Because of the small number of patients that have been diagnosed with this condition, therapeutic protocols are still been debated. The majority of the patients with HCDD progress to renal failure in spite of treatment. Some patients have advanced to end stage renal disease in less than a year. As expected, the prognosis is better in patients who present with a serum creatinine of 4 mg/dL or less, similar to what has been documented in light chain deposition disease. Systemic complication associated with deposition of heavy chains in various organs has not been reported, as has been the case with light chain deposition disease. However, this is likely due to the difficulties associated with the diagnosis and the fact that the knowledge about HCDD is limited. A very unusual patient developed lambda light chain-related amyloidosis ten years after the original diagnosis of HCDD which was missed in the initial renal biopsy. In general, a high rate of recurrence of monoclonal immunoglobulin deposition diseases after renal transplantation has been shown in the literature. Although renal transplantation has only occurred in very few HCDD cases,recurrence of this disease has been documented. One reported case was associated with recurrence two and a half years after transplantation. A case of recurrent LHCDD after renal transplantation has also been documented in the literature. As more cases of HCDD are studied our understanding of this disease will undoubtedly increase. There is a need to develop an in-vitro and/or in-vivo model to study the pathogenesis of renal damage in this condition. References Alchi, B., Nishi, S., Iguchi, S., et al. Recurrent light and HCDD after renal transplantation. Nephrol Dial Transpl 20:1487-1491, 2005 Buxbaum, JN, Chuba, JV, Hellman, GC et al. Monoclonal immunoglobulin deposition disease: Light chain and light and HCDDs and their relationship to light chain amyloidosis. Clinical features, immunopathology and molecular analysis. Annals Int Med 112:455-464, 1990 Buxbaum, JN, Gallo, G. Nonamyloidotic monoclonal immunoglobulin deposition disease. Light-chain, heavy-chain and light and HCDDs. In: Monoclonal Gammopathies and Related Disorders. Hematol Oncol Clin North Amer 13:1235-1248, 1999 Herzenberg, AM, Kiaii, M, and Magil, AB. HCDD: Recurrence in a renal transplant and report of IgG2 subtype. Am J Kidney Dis 35:1-5, 2000 Herzenberg, AM, Lien J, Magil AB. Monoclonal heavy chain (Immunoglobulin G3) Deposition disease: Report of a Case. Am J Kidney Dis 28:128-131, 2000 Kambham, N, Markowitz, GS, Appel, GG, Kleiner, MJ et al. Heavy chain deposition disease: The disease spectrum. Am J Kidney Dis 33:954-962, 1999 Katz, A, Zent, R, Bargman, M. IgG Heavy-chain deposition disease. Mod Pathol 7:874-878, 1994 Komatsuda, A., Nobuki, M., Wakui, H., et al. Development of systemic l-light chain amyloidosis in a patient with gamma-heavy chain deposition disease during long-term follow-up. Nephrol Dial Transpl 20:434-437, 2005 Lin, J, Markowitz, GS, Valeri, AM et al. Renal monoclonal immunoglobulin deposition disease: the disease spectrum. J Am Soc Nephrol 12:1482-1492, 2001. Markowitz, GS. Dysproteinemias and the kidney. Adv Anat Pathol 11:49-63, 2004.