K. Noguchi et al.

500 nmFig. 4. Immunoelectron micrographsfor λ (a) and κ (b). λ-Light chain protein is demonstrated in these crystals bypresence of electron-dense gold particles(a). κ-Light chain protein is not seen incrystals (b).

500 nmTo demonstrate that these crystals were
λ-light chains, we performed immunoelectron
microscopic examination using anti-λ- or antiκ-chain antibody as the primary antibody followedby the gold-labeled secondary antibody, and detected numerous λ-chains in the crystals, indicatingthat λ-chains were the main component of the crystals (Fig. 4a). No κ-chains were detected (Fig. 4b).

its association with myeloma (Matsuyama et al.,1994). Fanconi syndrome has been reported tobe caused by κ-chains in a majority of patients(Costanza et al., 1963; Maldonado et al., 1975; Truong et al., 1989; Uchida et al., 1990; Yonemura etal., 1997; Isobe et al., 1998; Minemura et al., 2001)
and by λ-chains in only 2 patients (Matsuyama etal., 1994; Marlowitz et al., 2000). Although theratio of κ- to λ-light chains involved in the onset ofmultiple myeloma is 1.5:1, κ-chains cause Fanconi
syndrome in an overwhelmingly large number ofpatients. To explain this observation, it has recently
been postulated that changes in the V-domains oflight chains are closely involved in their deposition in renal tubules, and that κ-chains frequently
belong to a subgroup that is easily aggregated andDiscussion
Sirota and Hamerman (1954) first reported thatFanconi syndrome complicated multiple myeloma.
Although Fanconi syndrome occurs as an inherited or acquired disorder, few studies have reported94Fanconi syndrome

deposited (Aucoutrier et al., 1993; Matsuyama etal., 1994).
Some studies have reported that electron microscopic observation of proximal renal tubules
demonstrates the presence of rhomboid- or needleshaped crystals (Costanza et al., 1963; Maldonado
et al., 1975; Thorner et al., 1983; Chan et al., 1987;
Truong et al., 1989; Uchida et al., 1990; Yonemuraet al., 1997; Marlowitz et al., 2000; Minemura etal., 2001). Also, a few studies have detected similar
crystals in renal glomeruli or bone marrow plasma
cells (Silva et al., 1983; Thorner et al., 1983). The
shape of the crystals observed in the present patient
was similar to that seen in κ-light chain myeloma,
suggesting that there is no difference between theκ- and λ-light chains in the process of crystal formation or the mechanism of renal tubular damage.
Also, immunohistochemical studies havedemonstrated the deposition of light chains in theproximal renal tubular epithelial cells (Uchida etal., 1990; Marlowitz et al., 2000; Minemura et al.,2001). However, since it was difficult to identify
the light chains in the crystals by light microscopy,
Truong et al. (1989) observed these crystals immunoelectron-microscopically, and showed that they
were mainly composed of κ-light chains (Costanzaand Smoller, 1963). Subsequently, Lajoie et al.
(2000) made a similar report. We first demonstrated with immunoelectron microscopy that the main
component of the crystals was λ-light chains. Because of the paucity of patients with λ-chain myeloma-associated Fanconi syndrome, only 1 such patient has been analyzed immunohistochemically(Marlowitz et al., 2000); thus, the present patientrepresents a valuable case.
Physical injury due to light-chain deposition,
the toxicity of light chains themselves or chemical
damage to renal tubules by lysosome enzymes during the catabolism of light chains in the proximal
renal tubules has been implicated in the mechanism
for the development of Fanconi syndrome as a complication of multiple myeloma (Orfila et al., 1991;
Lajoie et al., 2000; Gu et al., 2003). In the electron
microscopic images in this patient, the normal
structure was so markedly destroyed by crystals
composed of λ-chains that the crystals appeared tocause direct physical injury, leading to tubular dysfunction. Further studies are necesary to find out
whether these morphological changes are related tothe clinical severity of the condition, and whether
treatment can improve the tissue structure.
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Received September 17; accepted November 8, 2004
Corresponding author: Chishio Munemura, MD

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