Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model
Wei-Zhong Ying, … , Kristal J. Aaron, Paul W. Sanders
Wei-Zhong Ying, … , Kristal J. Aaron, Paul W. Sanders
Published April 9, 2012
Citation Information: J Clin Invest. 2012;122(5):1777-1785. https://doi.org/10.1172/JCI46490.
View: Text | PDF
Research Article

Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model

Abstract

A common renal complication of multiple myeloma is “myeloma kidney,” a condition also known as cast nephropathy. The renal lesions (casts) are directly related to the production of monoclonal immunoglobulin free light chains (FLCs), which coprecipitate with Tamm-Horsfall glycoprotein (THP) in the lumen of the distal nephron, obstructing tubular fluid flow. Here, we report that analysis of the binding interaction between FLCs and THP demonstrates that the secondary structure and key amino acid residues on the complementarity-determining region 3 (CDR3) of FLCs are critically important determinants of the molecular interaction with THP. The findings permitted development of a cyclized competitor peptide that demonstrated strong inhibitory capability in the binding of FLCs to THP in vitro. When used in a rodent model of cast nephropathy, this cyclized peptide construct served as an effective inhibitor of intraluminal cast formation and prevented the functional manifestations of acute kidney injury in vivo. These experiments provide proof of concept that intraluminal cast formation is integrally involved in the pathogenesis of acute kidney injury from cast nephropathy. Further, the data support a clinically relevant approach to the management of renal failure in the setting of multiple myeloma.

Authors

Wei-Zhong Ying, Christopher E. Allen, Lisa M. Curtis, Kristal J. Aaron, Paul W. Sanders

×

Figure 7

Experimental peptide 1 served as an effective inhibitor of cast nephropathy in vivo.

Options: View larger image (or click on image) Download as PowerPoint
Experimental peptide 1 served as an effective inhibitor of cast nephropa...
Changes in (A) mean serum creatinine, determined by tandem mass spectrometry, and (B) medullary cast formation of 3 groups of rats (n = 5–6 per group) were determined in a rescue experiment in which the competitor cyclized experimental (exp.) peptide 1 (AHX-CLSADSSGSYLYVCKK), a control cyclized peptide (AHX-CLSAHSSGSYLYVCKK), or vehicle alone was administered intraperitoneally 4 hours after rats received the nephrotoxic FLC (κ2). Mean serum creatinine increased in the vehicle-treated and control cyclized peptide–treated groups, but rats given competitor cyclized peptide 1 were protected from AKI. Animals that received experimental peptide 1 had fewer casts in the medulla compared with animals that received either vehicle or the control peptide. Rats that received the control peptide also had fewer casts (P < 0.05) than animals that received vehicle alone. *P < 0.05, compared with the other 2 groups. Data are shown as mean ± SEM.