Effect of Myeloma Light Chains on Phosphate and Glucose Transport in Renal Proximal Tubule Cells

Abstract

Primary cultures of cells derived from the rat proximal tubule were exposed to up to 200 µM λ- or χ-light chain obtained from myeloma patients. Light chains inhibited the uptake of both phosphate and glucose by the cells while albumin had no effect. The half-maximal inhibitory concentration (IC₅₀) of both the λ-and ĸ-light chains on phosphate transport were similar, 34 and 35 µM respectively. The IC₅₀ of the ĸ-light chain on glucose transport was 360 µM. The inhibitory effect of light chains was dose-dependent (r = 0.90, p < 0.0l for the λ-light chain and r = 0.93, p < 0.001 for the χ-light chain, on phosphate transport; and r = 0.93, p < 0.00l for glucose transport). Dixon and Line-weaver-Burk plot analyses were characteristic for noncompet-itive inhibition. The inhibition constant 89 µMfor phosphate uptake derived from the Dixon plot was similar to the IC₅₀ calculated from the dose-response curves. These findings indicate that light chains, at concentrations found in the tubule fluid of a typical myeloma patient, are potent inhibitors of phosphate and glucose transport in proximal tubular cells, and that direct cell toxicity is a major mechanism of light chain nephrotoxicity.

Role of the monoclonal chain V domain and reversibility of renal damage in a transgenic model of acquired Fanconi syndrome

“…Proximal tubule function was altered, as demonstrated by reduced absorption of water, chloride, and glucose. 38,39 In further in vitro studies, purified human monoclonal LCs were shown to induce inhibition of brush-border membrane sodium cotransporters, 40,41 and to decrease basolateral Na-KATPase expression and activity. 42 Similar mechanisms could be involved in the pathogenesis of monoclonal LC-associated FS.…”

Proximal Tubulopathies Associated With Monoclonal Light Chains: The Spectrum of Clinicopathologic Manifestations and Molecular Pathogenesis

“…The other 2 patterns of proximal tubular damage are characteristically seen in patients with clinical Fanconi syndrome exhibiting type II renal tubular acidosis, phosphaturia, hyperuricemia, aminoaciduria, and glycosuria without hyperglycemia (those associated with cytoplasmic inclusions in proximal tubular cells and those with constipated lysosomes). Batuman et al 47 have demonstrated the direct toxicity of some light chains on proximal tubular cells, inhibiting the transport of phosphate and glucose into tubular cells, providing experimental support for the pathogenesis of these disorders, and activating redoxsensitive pathways that promote apoptosis.…”

Mechanisms of Light Chain Injury along the Tubular Nephron

“…7,17 FLCs may be directly toxic to proximal tubular cells by blocking glucose, amino acid, or phosphate transport. 14,15,[18][19][20][21] Recently, monoclonal FLCs, but not polyclonal FLCs, have been shown to generate intracellular oxidative stress, particularly in the form of hydrogen peroxide. 22 Hydrogen peroxide promotes redox-signaling events that result in the production of chemokines and cytokines as well as apoptosis of the proximal tubular cells.…”