Cast nephropathy

Polyclonal free light chains and bence-jones proteins

About 500 mg of polyclonal FLCs are produced daily by the normal lymphoid system and catabolized by the proximal tubule. This system is highly efficient and only 1 to 10 mg of polyclonal FLCs normally appear in the urine each day. However, in the setting of a plasma cell dyscrasia, FLC production increases considerably, producing circulating levels of monoclonal FLCs that can be hundreds of fold higher than normal. When this increase occurs, the capacity of the multiligand endocytic receptor complex of the proximal tubule is quickly exceeded, and high concentrations of FLCs appear in the tubular fluid and finally in the urine. The FLCs that appear in the urine are traditionally termed Bence-Jones proteins (BJP) . Before the advent of serum assays for the measurement of monoclonal FLCs, the identification of BJP was a critical element of the workup of patients with suspect myeloma.

Mechanisms of injury

Monoclonal FLCs are known to induce isolated proximal tubular injury, cast nephropathy, or a combination of both. FLC interaction with proximal tubule cells (PTCs) can activate inflammatory cascades that lead to tubulointerstitial fibrosis, a major feature of myeloma kidney. Similarly, FLC interaction with Tamm-Horsfall proteins (THPs; also known as uromodulin ) and cast formation in the distal tubule can block glomerular flow and produce tubular atrophy and contribute to interstitial fibrosis.

Cast nephropathy

In addition to this proximal tubule injury, the major mechanism of FLC-mediated tubule damage is intratubular obstruction from precipitation of FLCs in the lumen of the distal nephron ( Figs 7.1 A and B), which leads to interstitial inflammation and fibrosis. The clinical relevance of cast formation was initially revealed by an eloquent series of studies that infused nephrotoxic human FLCs in rats. These studies demonstrated that infusion of these FLCs resulted in increased proximal tubule pressure and simultaneously decreased single-nephron glomerular filtration rate. Intraluminal protein casts were identified in these rat kidneys. Persistence of intraluminal casts in vivo reduces single-nephron glomerular blood flow to the obstructed nephron and results in atrophy of the nephron proximal to the obstruction. ^, When infused directly into the rat nephron in vivo, monoclonal FLCs from patients with cast nephropathy produced dose-dependent intraluminal obstruction by precipitating in the distal nephron; casts were not observed before the tip of the loop of Henle. Obstruction was accelerated by the presence of furosemide. Pretreatment of rats with colchicine decreased urinary levels of THP and prevented intraluminal cast formation and obstruction. Additional studies demonstrated an integral relationship between monoclonal FLCs and THPs in cast formation and the associated kidney injury. In humans, casts are generally observed in the distal portion of the nephron, although they have also been found in proximal tubular segments and even in glomeruli in renal biopsy specimens. However, these casts also contained THP, suggesting intraluminal reflux of coprecipitated THP and FLC into the proximal nephron.

Cast formation in vivo is a complex process that is dictated by multiple variables, including the ionic composition of the tubule fluid, tubule fluid flow rates, the concentration of THP and FLC, the strength of binding interaction between THP and FLC, and the presence of furosemide. These observations have direct clinical relevance as many of these factors (except the intrinsic binding interaction between THP and FLC) can be modified with current treatment modalities.

Identifying nephrotoxic light chains

Not all monoclonal FLCs are nephrotoxic. Although the risk of AKI in patients with MM is increased when FLC proteinuria reaches 2 g per day, some patients do not develop kidney disease despite high FLC urine concentrations. Because no tool to predict toxicity of a given FLC is currently available, preventive measures and removal of precipitating factors are mandatory.

The mechanisms involved in the renal pathogenic effects of individual monoclonal FLCs remain incompletely understood. Nephrotoxicity appears to be an intrinsic property of some FLCs, as indicated by the recurrence of similar renal lesions after kidney transplantation, and by animal studies that have specifically reproduced human FLC-related nephropathies using injections of purified human FLCs, intraperitoneal injections of transfected plasmacytomas secreting a pathogenic human FLC, ^, or gene-targeted insertion. Growing evidence shows that the pattern of renal injury is governed by both structural peculiarities of monoclonal FLCs, particularly of the variable (V) domain, and is influenced by environmental factors, such as pH, urea concentration, or local tissue proteolysis. In addition, intrinsic host factors are likely to have an important role in determining both the type and severity of any renal response to a given FLC.

Pathogenic FLCs purified from patients’ urine are characterized by their propensity to form high-order aggregates or polymers in vitro, which differ according to the sequence variability of the V domain. The peculiarities of the V domain are observed in many types of renal disease induced by light chains. Myeloma-associated Fanconi syndrome, for example, is characterized by proximal tubule dysfunction secondary to FLC reabsorption and crystallization within the lysosomal compartment of PTCs. FLCs associated with Fanconi syndrome are nearly always of the Vκ1 subgroup and are derived from only two germ line genes, immunoglobulin kappa variable (IGKV)1-39 and IGKV1-33 . In immunoglobulin light chain (AL) amyloidosis and light chain deposition disease, the pathogenic role of V regions is suggested by overrepresentation of the Vλ6 and Vκ462 subgroups, respectively, N-glycosylation of the V region, and substitutions of key amino acids induced by somatic mutations that might account for the propensity of certain FLCs to aggregate and influence tropism of deposition. FLCs associated with light chain deposition disease are characterized by cationic isoelectric points, whereas the isoelectric point profile of FLCs involved in AL amyloidosis is heterogeneous. This observation suggests that fibrillar amyloid deposits form by electrostatic interaction between oppositely charged polypeptides, whereas granular deposits in light chain deposition disease result from the binding of cationic polypeptides to anionic basement membranes.

The role of the molecular characteristics of FLCs in myeloma kidney is less clear. In high-mass myeloma, the capacity of the proximal tubule to reabsorb and degrade FLCs is rapidly overwhelmed by the dramatic increase in the burden of filtered FLCs. Large amounts of FLCs reach the distal tubule lumen where they interact with THP. Huang and Sanders identified a binding domain for FLCs on THP, which consisted of nine amino acids and was termed light chain binding domain . Importantly, all FLCs tested bound to this FLC-binding domain. In turn, the CDR3 domain in the variable region of both κ and λ FLCs interacted with THP. The binding affinities of FLCs for THP are related to the amino acid composition of the CDR3 domain.

Despite our growing understanding of the pathogenic mechanisms by which immunoglobulin (Ig) FLCs induce renal injury, there are currently no clinically relevant tools for identifying the potential nephrotoxicity of a specific monoclonal FLC.