Treating myeloma cast nephropathy without treating myeloma

Abstract

Cast nephropathy is the result of coprecipitation of immunoglobulin free light chains (FLCs) with Tamm-Horsfall glycoprotein (THP). It is a hallmark of multiple myeloma that has significant consequences. Treatment strategies in the past focused on reduction of serum FLC by control of the myeloma. In this issue, Ying et al. report on their successful synthesis of a cyclized competitor peptide that blocks the binding of FLC to THP. In animal studies, this cyclized peptide was capable of reducing cast formation and kidney injury, representing a novel treatment strategy for cast nephropathy that does not depend on the responsiveness of the myeloma to chemotherapy.

Figure 1. Light microscopy of a kidney with cast nephropathy stained with PAS stain.

Multiple distal tubules are filled with PAS-negative casts (asterisks). Some of the cast have a fractured appearance. An inflammatory cellular reaction is seen surrounding the casts (single-headed arrows). Inflammatory infiltrates (single-headed arrows) are seen in the interstitium of the kidney, usually near obstructed tubules. All of these are characteristic features of cast nephropathy. Increased spacing (double-headed arrows) between tubules throughout the biopsy indicates either edema (acute) or tubular atrophy (chronic) and is the result of the injury from the casts. Normally tubules should be lined back to back with each other.

Figure 2. Treatment of cast nephropathy by targeting THP and FLC interaction.

(A) Excessive monoclonal FLC is filtered and binds with THP in the ascending limb of the loop of Henle, resulting in obstruction and cast nephropathy. (B) In the presence of cyclized competitor peptide (CCP), the binding site of THP is blocked, thus preventing FLC from binding and coprecipitation with it. FLC and THP both pass freely through the nephron.