Animal models: a pot of gold

Comment on Sirac et al, page 536

The article by Sirac and colleagues in the current issue of Blood is a seminal contribution to the literature.

Significant advances have taken place in the understanding of molecular events that govern light-chain–mediated nephrotoxicity in patients with plasma-cell dyscrasias. However, most of the work has been performed using in vitro systems. Animal models recapitulating the specific human renal diseases have been very difficult to develop.

Using transgenic mice in which the endogenous mouse Jκ cluster was replaced by a human VκJκ1-rearranged gene cloned from a patient with acquired Fanconi syndrome, the authors recapitulated the disease process and then, by deleting the Vκ1 transgene, the proximal tubular abnormalities were dramatically reduced, both morphologically and functionally.

This work elegantly shows and confirms what has already been proposed by investigators: the physicochemical characteristics of the variable regions of the individual circulating light chains from patients with plasma-cell dyscrasias primarily determine whether nephrotoxicity would occur and where the pathologic damage within the various renal compartments is located, as well as the characteristics (morphologic and functional) of the damage produced. In the renal Fanconi syndrome, kappa light chains (type κI predominantly, but also κIII) are the ones involved (only 1 case associated with lambda light chains is reported). The molecular defect when light chains are derived from the O2/O12 germline gene (the most common abnormality in the condition) is almost always characterized by the presence of a hydrophobic residue in the CDR-L1 loop at position 30 in the variable portion of the light chain,¹  which imposes on the pathogenic light chain an intrinsic resistance to digestion by proximal tubular enzymes. As a consequence, the light chains endocytosed into the proximal tubules are converted into crystalline structures, the morphologic hallmark of most cases of plasma-cell dyscrasia–associated Fanconi syndrome.

The transgenic model created provides a perfect milieu to dissect the molecular mechanisms involved in the pathogenicity of this disorder. The acquired renal Fanconi syndrome is most often associated with a smoldering plasma-cell dyscrasia. In one reported case, it took 16 years for plasma-cell dyscrasia to become manifest after renal Fanconi syndrome was diagnosed.²  The light chains associated with this syndrome appear to exhibit a low nephrotoxic potential; this fact highlights the importance of aggressive treatment of the renal manifestations in these patients.

The excitement associated with research accomplishments such as this centers around the potential to develop therapeutic interventions to address molecular events that govern pathologic processes involved, thus reversing the disease process. The authors have shown that reversibility is possible. Although this disease affects a relatively small number of patients, the concept behind deciphering molecular events for a particular disease process to develop therapeutic strategies is sound and the way of the future in medicine. The creation of an animal model for acquired Fanconi syndrome should provide the impetus for developing similar animal models for other monoclonal light- and heavy-chain–associated renal diseases, such as light- and heavy-chain deposition disease and amyloidosis. The challenge is on! ▪