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Monoclonal Immunoglobulin Deposition Disease
Arthur H. Cohen
Introduction/Clinical Setting
Patients with plasma cell dyscrasias may have other forms of renal disease than light chain cast nephropathy. These include the closely related systemic disorders amyloidosis (AL type) and light chain deposit disease (1–7). In the kidneys, although both of these conditions clinically and pathologically affect primarily glomeruli, there is important and often constant involvement of tubular basement membranes, interstitium, and arteries. On rare occasions, the intact monoclonal protein (light and heavy chains) or heavy chain alone may deposit in renal basement membranes and systemically. Consequently, these disorders, originally considered solely of abnormal light chain pathogenesis and termed by some as light chain deposit diseases or nephropathies, are more correctly termed and thought of as monoclonal immunoglobulin deposition diseases (5). Evalu- ation of immunoglobulin synthesis by bone marrow cells has determined incomplete light chains and/or heavy chain fragments (8).
Light Chain Deposition Disease/Heavy Chain Deposition Disease
Light chain deposit disease is characterized by the nonimmune deposition of a monoclonal light chain in all renal basement membranes as well as the glomerular mesangium. Renal involvement is part of a systemic disease, for virtually all other organs and tissues are also the sites of light chain deposits. The kidneys are the most important organs involved in terms of clinical manifestations, although some patients can develop significant and fatal cardiac lesions (1–3,5).
as a nodular glomerulopathy with features virtually indistinguishable from nodular diabetic glomerulosclerosis (Fig. 17.1); however, it has become apparent that there is a large spectrum of glomerular morphologies includ- ing normal glomeruli, diffuse widening of mesangium, crescents, etc. The tubular basement membrane deposits often result in the light microscopic appreciation of thickened tubular basement membranes. Careful high magnification examination of periodic acid-Schiff (PAS)-stained sections may indicate a slightly lighter staining band external to the normal base- ment membrane (1).
Heavy chain deposition disease is characterized by the nonimmunologic binding of an abnormal heavy chain, most commonly immunoglobulin G (IgG), to all basement membranes (8,10). The morphologic aspects differ from light chain deposit disease in that the glomerular structure is almost always nodular. However, glomerular hypercellularity mimicking membra- noproliferative or other proliferative glomerulonephritis may be the domi- nant morphology (11,12).
Figure 17.1. Light chain deposition disease with glomerulus with nodular mesan- gium. This appearance is similar to diabetic nodular glomerulosclerosis (Jones silver stain).
Immunofluorescence Microscopy
These disorders require immunofluorescence evaluation of tissue sections, for the diagnosis rests on documenting a single light and/or heavy chain in the tissue basement membranes. Thus, the diagnosis of this deposition disease can be made only with the routine use of immunofluorescence; one cannot rely on the glomerular morphology to dictate when to evaluate the biopsy with antibodies to the light chains. Immunofluorescence shows monoclonal prominent staining along the tubular and glomerular base- ment membranes (Fig. 17.2). In the absence of tissue for immunofluores- cence, documentation of ultrastructurally defined deposits when present (see below) should serve as a strong indication of light chains. In heavy chain deposition disease, when IgG3 is the paraprotein, complement is also deposited with associated hypocomplementemia (13).
Electron Microscopy
The ultrastructural manifestations of the light chain deposits are of clus- tered punctate dense deposits external to tubular and within vascular basement membranes (2,3). Deposits in the glomerular basement mem- branes are similar (Fig. 17.3), whereas they are variably evident in the mesangium. However, there may be no electron microscopic counterpart of the immunofluorescence deposition (1).
Figure 17.2. Light chain deposition disease with linear staining of all renal basement membranes and mesangial regions of the glomeruli (kappa immunofluorescence).
Etiology/Pathogenesis
Clinically, this renal lesion presents with heavy proteinuria (both light chain and larger plasma proteins), renal insufficiency, and sometimes hypertension. Approximately 50% of the patients have overt myeloma; the rest have either plasmacytosis or no evidence of increased plasma cells (1–3,7). In this last instance, there is increased immunoglobulin synthesis with excess light chain production. Therapy may result in the disappear- ance of nodules and improvement of renal function (14).
References
1. Cohen AH. The kidney in plasma cell dyscrasias: Bence Jones cast nephro- pathy and light chain deposit disease. Am J Kidney Dis 32:529–532, 1998.
2. Schwartz MM. The dysproteinemias and amyloidosis. In: Jennette JC, Olson JL, Schwartz MM, Silva FG, eds. Heptinstall’s Pathology of the Kidney, 5th ed. Philadelphia: Lippincott-Raven, 1998:1321.
3. Striker LJM-M, Preudhomme JL, D’Amico G, Striker GE. Monoclonal gam- mopathies, mixed cryoglobulinemias, and lymphomas. In: Tisher CC, Brenner BM, eds. Renal Pathology with Clinical and Functional Correlations, 2nd ed.
Philadelphia: JB Lippincott, 1994:1442.
Figure 17.3. Light chain deposition disease with continuous granular density in glomerular basement membrane (arrow) (electron microscopy).
4. Solomon A, Weiss DT, Kattine AA. Nephrotoxic potentials of Bence Jones proteins. N Engl J Med 324:1845–1851, 1991.
5. Buxbaum JN, Chuba JV, Hellman GC, Solomon A, Gallo GR. Monoclonal immunoglobulin deposition disease: light chain and light and heavy chain deposition diseases and their relationship to light chain amyloidosis: clinical features, immunopathology, and molecular analysis. Ann Intern Med 112:455–
464, 1990.
6. Montseny JJ, Kleinknecht D, Meyrier A, et al. Long-term outcome according to renal histological lesions in 118 patients with monoclonal gammopathies.
Nephrol Dial Transplant 13:1438–1445, 1998.
7. Preudhomme J-L, Aucouturier P, Touchard G, et al. Monoclonal immuno- globulin deposition disease (Randall type): relationship with structural abnor- malities of immunoglobulin chains. Kidney Int 46:965–972, 1994.
8. Buxbaum JN. Abnormal immunoglobulin synthesis in monoclonal immuno- globulin light chain and light and heavy chain deposition disease. Amyloid 8:84–93, 2001.
9. Sinniah R, Cohen AH. Glomerular capillary aneurysms in light chain nephrop- athy: an ultrastructural proposal of pathogenesis. Am J Pathol 118:298–305, 1985.
10. Lin J, Markowitz GS, Valeri AM, et al. Renal monoclonal immunoglobulin deposition disease: the disease spectrum. J Am Soc Nephrol 12:1482–1492, 2001.
11. Nasr SH, Markowitz GS, Stokes MB, et al. Proliferative glomerulonephritis with monoclonal IgG deposits: a distinct entity mimicking immune-complex glomerulonephritis. Kidney Int 65:85–96, 2004.
12. Vedder AC, Weening JJ, Krediet RT. Intracapillary proliferative glomerulo- nephritis due to heavy chain deposition disease. Nephrol Dial Transplant 19:1302–1304, 2004.
13. Soma J, Sato K, Sakuma T, et al. Immunoglobulin gamma-3-heavy-chain deposition disease: report of a case and relationship with hypocomplemente- mia. Am J Kidney Dis 43:E10–16, 2004.
14. Komatsuda A, Wakui H, Ohtani H, et al. Disappearance of nodular mesangial lesions in a patient with light chain nephropathy after long-term chemotherapy.
Am J Kidney Dis 35:E9, 2000.
