The Proximal Tubule Toxicity of Immunoglobulin Light Chains

Abstract

Plasma and B cells dyscrasias that overproduce monoclonal immunoglobulin free light chains (FLCs) affect the kidney frequently in various ways. The hematologic dyscrasia responsible for the production of FLCs may or may not meet the criteria for cancer, such as multiple myeloma (MM) or lymphoma, or may remain subclinical. If there is overt malignancy, the accompanying kidney disorder is called myeloma- or lymphoma-associated. If the dyscrasia is subclinical, the associated kidney disorders are grouped as monoclonal gammopathy of renal significance. Glomeruli and tubules may both be involved. The proximal tubule disorders comprise a spectrum of interesting syndromes, which range in severity. This review focuses on the recent insights gained into the patterns and the mechanisms of proximal tubule toxicity of FLCs, including subtle transport disorders, such as proximal tubule acidosis, partial or complete Fanconi syndrome, or severe acute or chronic renal failure. Histologically, there may be crystal deposition in the proximal tubule cells, acute tubule injury, interstitial inflammation, fibrosis, and tubule atrophy. Specific structural alterations in the V domain of FLCs caused by somatic hypermutations are responsible for crystal formation as well as partial or complete Fanconi syndrome. Besides crystal formation, tubulointerstitial inflammation and proximal tubulopathy can be mediated by direct activation of inflammatory pathways through cytokines and Toll-like receptors due to cell stress responses induced by excessive FLC endocytosis into the proximal tubule cells. Therapy directed against the clonal source of the toxic light chain can prevent progression to more severe lesions and may help preserve kidney function.

Keywords: Fanconi syndrome; chronic kidney disease; light chains; proximal tubule; proximal tubule crystallopathy; proximal tubulopathy.

Figure 1

Proximal tubule toxicity of immunoglobulin free light chains (FLC). Once certain monoclonal FLCs with specific V region sequences^,, , , , are endocytosed through the megalin/cubilin complex on the luminal surface of the proximal tubule, they are concentrated in the endolysosomal (L) system and promote cell injury. A large variety of FLCs produce proximal tubulopathy from the generation of oxidative stress and direct cytotoxicity (red arrows at left indicate proximal tubule segments with significant cellular injury). FLCs with κ restriction can specifically undergo homotypic polymerization to form crystals (red arrows at right), producing proximal tubule crystallopathy. Direct toxicity of these FLCs leads to lysosomal dysfunction and the clinical manifestations of Fanconi syndrome. The natural history of both conditions includes the clinical manifestations of progressive chronic kidney disease from tubule atrophy, interstitial inflammation, and interstitial fibrosis.