Editors' ChoiceKidney Disease

Help—Plumber Needed

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Science Translational Medicine  06 Jun 2012:
Vol. 4, Issue 137, pp. 137ec98
DOI: 10.1126/scitranslmed.3004396

All plumbing systems are prone to clogs. The first tool to grab when trouble arises is a plunger to dislodge the clog. Sometimes, this does not resolve the problem, and more sophisticated tools are needed. If nothing helps, then the job should be turned over to a specialist. A specialist is also required when protein complexes clog the ascending loop-of-Henle in the kidneys of some patients with multiple myeloma. The result is acute kidney failure or progressive renal insufficiency, contributing to the mortality and morbidity of these patients. The plasma cells of multiple myeloma patients secrete monoclonal immunoglobulin free light chains (FLCs) that bind to Tamm-Horsfall glycoproteins (THPs) produced by the cells of the thick ascending limb of the kidney’s loop-of-Henle, resulting in clogging of the ascending loop with the protein complexes.

Instead of depending on a plunger to bust the clogs, Ying et al. pinned down the binding affinities of the different variable FLCs and the key amino acid residues that are responsible for binding between the FLCs and THPs. This allowed the authors to design a synthetic peptide that inhibited binding between FLCs and THPs in vitro and in vivo. Addition of two cysteine residues at each end of the peptide induced formation of an intramolecular disulfide bond; cyclization of the peptide further increased its blocking capabilities. Ying et al. then showed that intraperitoneal administration of the cyclic peptide restored normal kidney function in rats even when administered 4 hours after the animals were exposed to nephrotoxic FLCs.

Current treatment strategies for patients with multiple myeloma include chemotherapeutic agents to fight the cancer and dialysis or apheresis to reduce the burden of FLCs produced by plasma cells. The study by Ying et al. now offers a new treatment that does not reduce the amount of FLCs but rather blocks their binding to THPs, thus preventing clog formation in the first place. The peptide has only been tested in rodents so far, but it warrants further investigation. Of course, there are still many questions to be addressed—such as whether the peptide will work if FLCs are produced in excess and whether it will be able to reach the ascending loop when the kidney is already damaged—but this is an important first step.

W. Z. Ying et al., Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model. J. Clin. Invest. 122, 1777–1785 (2012). [PubMed]

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