Immunoglobulin light chains generate proinflammatory and profibrotic kidney injury
Wei-Zhong Ying, … , Lisa M. Curtis, Paul W. Sanders
Wei-Zhong Ying, … , Lisa M. Curtis, Paul W. Sanders
Published April 16, 2019
Citation Information: J Clin Invest. 2019;129(7):2792-2806. https://doi.org/10.1172/JCI125517.
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Research Article Hematology Nephrology

Immunoglobulin light chains generate proinflammatory and profibrotic kidney injury

Abstract

Because of the less-than-robust response to therapy and impact on choice of optimal chemotherapy and prognosis, chronic kidney disease has drawn attention in the treatment of multiple myeloma, a malignant hematologic disorder that can produce significant amounts of monoclonal immunoglobulin free light chains (FLCs). These low-molecular-weight proteins are relatively freely filtered through the glomerulus and are reabsorbed by the proximal tubule. The present study demonstrated that during the process of metabolism of immunoglobulin FLCs, ROS activated the STAT1 pathway in proximal tubule epithelium. STAT1 activation served as the seminal signaling molecule that produced the proinflammatory molecule IL-1β, as well as the profibrotic agent TGF-β by this portion of the nephron. These effects occurred in vivo and were produced specifically by the generation of hydrogen peroxide by the VL domain of the light chain. To the extent that the experiments reflect the human condition, these studies offer insights into the pathogenesis of progressive kidney failure in the setting of lymphoproliferative disorders, such as multiple myeloma, that feature increased circulating levels of monoclonal immunoglobulin fragments that require metabolism by the kidney.

Authors

Wei-Zhong Ying, Xingsheng Li, Sunil Rangarajan, Wenguang Feng, Lisa M. Curtis, Paul W. Sanders

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Figure 8

Effect of the 2 doses of κ2 FLCs on renal pathophysiology in Stat1–/– and Stat1+/+ mice.

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Effect of the 2 doses of κ2 FLCs on renal pathophysiology in Stat1–/– an...
(A) Mean serum creatinine concentrations (n = 9–10 mice per group) did not differ among the 6 groups on day 10. (B) Compared with the other 3 groups (n = 6–9 mice per group), the mean serum creatinine concentration increased specifically in the κ2-d2 group of Stat1+/+ mice by day 30 of treatment. *P < 0.0001 compared with the other 4 groups (ANOVA). (C) Mean urinary albumin to creatinine ratios (n = 6–8 samples per group) and (D) mean urinary KIM-1 to creatinine ratios (n = 4–7 samples per group) were increased in the κ2-d2 group. *P < 0.01 compared with the other 4 groups (ANOVA). (E) Representative image of kidney cortex (n = 8–10 animals in each group) from a Stat1–/– mouse shows uptake of κ FLC into the proximal tubule (red label) but no expression of KIM-1 (green fluorescence label). (F) In contrast, a representative image of kidney cortex from a Stat1+/+ mouse shows colocalization (yellow) of the κ FLC with KIM-1. G, glomerulus. (G) Blinded analysis of H&E-stained kidney tissues (n = 8–10 animals in each group) revealed an increase in injury markers: apoptotic body or pyknotic nucleus, brush border disruption or breaks in the epithelial barrier, the presence of cells in the tubular lumen, and the composite score — specifically in Stat1+/+ mice treated with the higher dose of κ2 FLC. Stat1–/– mice treated with the higher dose of κ2 FLC showed a higher frequency of apoptosis markers, perhaps related to activation of other redox-sensitive pathways (19). *P < 0.0001 compared with the other 4 groups; **P < 0.0005 compared with the other 5 groups (ANOVA). Scale bars: 50 μm. All data are expressed as the mean ± SEM.