Myeloma Cast Nephropathy: New treatment possibilities

There are a laundry list of renal complications in multiple myeloma that have been previous reviewed on RFN.  Myeloma cast nephropathy is one of the most frequent, being found in approximately a third of patients in autopsy series.  Acute kidney injury is a common presentation of myeloma cast nephropathy with a variable amount of proteinuria.  As a tubular interstitial lesion with intact filtration barrier lower levels of albuminuria are typically present however large amounts of serum free light chains can be present leading to the classic findings of a negative urine dipstick (which detects albumin) with high levels of proteinuria by quantitative evaluation (stay frosty medical students, your intern is just itching to pimp you on this one).

On light microscopy diffuse tubular damage resembling ATN is seen along with distinctive distal tubular casts (in contrast to light chain fanconi syndrome where intracellular proximal tubular deposits are seen).  These casts often have sharp edges, a tendency to fracture (image on the left) and frequently have adherent neutrophils, monocytes or multinucleated giant cells around their periphery (image on the right).

Two papers from a group in Alabama shed light on the mechanism of formation of these casts and new potential treatment strategies.  It has long been known that the casts are composed of light chains bound to Tamm-Horsfall protein.  What the group first showed is that the CDR3 region on free light chains is the critical determinant of the binding with Tamm-Horsfall protein.

In their more recent paper, they report the development of a competitive inhibitor of the light chain Tamm-Horsfall protein interaction by blocking the Tamm-Horsfall protein binding site.  In a rodent model, in which human serum from patients with multiple myeloma was used to induce myeloma cast nephropathy they demonstrate the ability of the inhibitor to prevent both the histologic changes of myeloma cast nephropathy as well as AKI.

The inhibitor was infused just four hours after the serum containing light chains so future studies will need to examine situations that more closely mimic human disease in which presentation to care is delayed for much longer periods of time.  Despite this, the study adds to our understanding of the mechanisms on AKI in patients with myeloma casts nephropathy and provides a new avenue for investigation of treatment of renal disease in patients with myeloma casts nephropathy independent of chemotherapy.

Images from the recent NephSap Pathology edition.