Proximal tubular injury in myeloma.

Renal involvement is common in multiple myeloma and implies much worse prognosis. Most of the kidney disorders associated with myeloma are caused by the excess production of monoclonal light chains, and renal involvement is almost always accompanied by light chain proteinuria. Light chains have variable effects on the kidney; some are more toxic than others and different light chains affect different structures in the kidney. In normal quantities light chains are filtered relatively unhindered in the glomerulus and endocytosed by the proximal tubule cells through the tandem endocytic receptors megalin/cubilin and targeted to degradative sites. Proximal tubule injury is the most common mode of renal involvement and it can manifest in a variety of ways. When light chains are overproduced the proximal tubular endocytic process is overloaded and cell stress responses that include phosphorylation of MAPKs, prominently, p38 MAPK, and nuclear transcription factors NF-kappaB, AP-1 are activated resulting in production of inflammatory and proinflammatory cytokines, TNF-alpha, interleukin-6, 8, and monocyte chemo-attractant protein-1. In early stages of myeloma, light chain nephrotoxicity often presents with proximal tubular functional abnormalities, such as Fanconi syndrome. These proximal tubule alterations often progress to a severe tubulointerstitial kidney disease, the most common type of kidney involvement responsible for endstage renal failure seen in myeloma patients.