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Bence Jones Cast Nephropathy
Arthur H. Cohen
Clinical Presentation
Patients with Bence Jones cast nephropathy usually present with acute renal failure (less commonly with chronic renal failure) and Bence Jones proteinuria. It has been known for many years that intravenous radiocon- trast media, dehydration, infections, and the use of nonsteroidal antiin- fl ammatory drugs may induce the precipitation of renal tubular light chain casts and result in acute renal failure, which is reversible in only a small percent of affected patients. A less common manner of presentation is the acquired Fanconi syndrome. This is most often associated with intracellu- lar crystals in plasma cells and tubular cells; the crystals represent the abnormal light chain (2,3).
Pathologic Findings Light Microscopy
Bence Jones cast nephropathy is characterized by prominent casts in renal tubules; the casts are usually large and “brittle,” have fracture lines or are broken into many fragments often with geometric shapes, and are sur- rounded by tubular epithelium, neutrophils, and typically and diagnosti- cally by multinucleated giant cells of foreign-body type (Fig. 16.1). While they are more common in distal tubules, the casts may be formed in any segment of the nephron, including Bowman’s space. The casts have reason- ably typical tinctorial properties: periodic acid-Schiff (PAS) negative, brightly eosinophilic, fuchsinophilic with Masson’s trichrome and, infre- quently, Congo red positive. The staining is not always uniform within the same cast or among all casts in the same kidney, but the above colors are most typical. The casts may be lamellated, contain crystals of a variety of shapes, and, rarely at the periphery have a spicular appearance. There are reasonably constant abnormalities in tubular epithelium; proximal cells often contain numerous uniform cytoplasmic vacuoles. Cells of all tubular
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segments may be necrotic and sloughed into lumina, where they may be adherent to the edges of the casts. Tubular basement membranes are dis- continuous, thereby allowing free communication between the interstitium and the tubular lumina; it is through these gaps that monocytes and other inflammatory cells migrate from the interstitium. The adjacent interstitium is edematous and often infiltrated by monocytes and lymphocyte (1–4).
This constellation of light microscopic abnormalities, especially the mor- phology and tinctorial properties of the casts and the surrounding giant cells, is sufficiently distinctive to be diagnostic of multiple myeloma. Indeed, it is not unusual for the renal biopsy to be the first test indicative of myeloma in a patient who presents with acute renal failure of seemingly unknown origin (5).
Immunohistochemistry
The composition of the casts has been determined by immunohistochem- istry. Most investigators have documented that they consist exclusively or primarily of the abnormal light chain (1,2). Depending on many factors, Tamm-Horsfall protein and the other light chain may also be part of the casts. Many other plasma proteins may also be present. When the other proteins are present, they are usually in a staining intensity less than the abnormal light chain. By immunofluorescence, it is possible to detect Tamm-Horsfall protein in glomerular urinary spaces, a finding that is indicative of obstruction (either intrarenal or extrarenal) of urine with retrograde flow in the nephron. The ultrastructural appearance of the casts is quite variable, although the basic structure is of a mass of deeply electron-dense material. The casts may be homogeneous, finely or coarsely granular, and may incorporate cytoplasmic debris (4).
Figure 16.1. Bence Jones (light chain)cast nephropathy with a tubule containing a pale-staining cast surrounded by a multinucleated giant cell. In contrast, casts composed primarily of Tamm-Horsfall protein are periodic acid-Schiff (PAS) positive (PAS stain).
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Etiology/Pathogenesis
The pathogenesis of cast nephropathy has been partially elucidated, although there are still many unanswered questions. The free abnormal light chain is freely filtered by the glomerulus and, for unclear reasons either because of quantity or quality, it is toxic to tubular epithelium (proxi- mal and distal). Furthermore, in the distal nephron (thick ascending limb of Henle), Bence Jones protein coprecipitates with Tamm-Horsfall protein, thus forming casts (6). It is likely that Bence Jones protein alone can also precipitate in tubules, thereby explaining the presence of the casts in the proximal nephron. It is also likely that a combination of direct damage to tubular cells (tubular necrosis), which is associated with tubular basement membrane breaks, and the physical effects of the geometrically shaped casts leads to tubular wall disruption and migration of monocytes into tubules to surround casts and form multinucleated giant cells. Because of the large size of the casts, they likely obstruct the nephron in which they are formed. Thus, it appears that renal impairment in Bence Jones cast nephropathy is the result of tubular necrosis, interstitial inflammation, and nephron obstruction (1,4).
Investigators during the last decade or so have sought to identify that which confers “nephrotoxicity” on light chains; in addition, as there are several light chain–induced renal lesions, investigations to ascertain why a particular light chain will produce one lesion rather than another are underway. It is likely that host factors are not of prime importance; the intrinsic physical or chemical properties of light chains are thought to be of greatest significance. However, despite initial evidence linking light chain isoelectric point, molecular weight, degree of polymerization, and size, among others, to the development of this or the other light chain–
induced renal lesions, at the present time no property of monoclonal light chains has been identified to explain their nephrotoxic potential (2,3). It is of interest to note, however, that monoclonal light chains from humans with specific light chain–induced lesions (cast nephropathy, light chain deposit disease, amyloid), when injected into mice, induced the same renal abnormality as in humans as elegantly documented by Solomon and col- leagues (7) in 1991.
References
1. Cohen AH. The kidney in plasma cell dyscrasias: Bence Jones cast nephropathy 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.
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4. Cohen AH, Border WA. Myeloma kidney; an immunomorphogenetic study of renal biopsies. Lab Invest 42:248, 1980.
5. Border WA, Cohen AH. Renal biopsy diagnosis of clinically silent multiple myeloma. Ann Intern Med 93:43–46, 1980.
6. Huang ZQ, Sanders PW. Localization of a single binding site for immunoglobu- lin light chains on human Tamm-Horsfall glycoprotein. J Clin Invest 99:732–
736, 1997.
7. Solomon A, Weiss DT, Kattine AA. Nephrotoxic potentials of Bence Jones proteins. N Engl J Med 324:1845–1851, 1991.
