Nephrotoxic Light Chains Research Articles

Outcomes of Newly Diagnosed Myeloma Patients Requiring Dialysis: Dialysis Independence Is Associated with Rapid Myeloma Response and Predicts for Longer Survival

Outcomes of Newly Diagnosed Myeloma Patients Requiring Dialysis: Dialysis Independence Is Associated with Rapid Myeloma Response and Predicts for Longer Survival

Receptor-Mediated Endocytosis Is a Trojan Horse in Light-Chain Nephrotoxicity

Receptor-Mediated Endocytosis Is a Trojan Horse in Light-Chain Nephrotoxicity

Immunoglobulin Light Chains Activate Tubular Epithelial Cells through Redox Signaling

The renal proximal tubule metabolizes circulating low-molecular-weight proteins such as Ig free light chains. In the setting of plasma cell dyscrasias, the burden of filtered protein can be very high. Endocytosis of certain nephrotoxic light chains induces H(2)O(2) production and monocyte chemoattractant protein-1 (MCP-1) release, leading to recruitment of inflammatory cells and interstitial fibrosis, but how these processes are linked mechanistically is not well understood. This study investigated the relationship between H(2)O(2) generated after light chain endocytosis by human proximal tubular (HK-2) cells and activation of c-Src, a redox-sensitive tyrosine kinase. HK-2 cells exposed to two different light chains upregulated c-Src activity, which increased the production of MCP-1. In parallel, we observed a time-dependent oxidation of c-Src. Inhibition of c-Src activity and silencing c-Src expression abrogated the light chain-induced MCP-1 response, but had no effect on H(2)O(2), indicating that production of H(2)O(2) is upstream of c-Src in the signaling cascade. Silencing megalin and cubilin expression inhibited the MCP-1 response, whereas extracellular catalase did not, indicating that endocytosis is required and that intracellular generation of reactive oxygen species activates c-Src. These data show that intracellular H(2)O(2) induced by endocytosis of monoclonal free light chains oxidizes and activates c-Src, which promotes release of MCP-1.

A Randomised Controlled Trail of Plasma Exchange in Rapidly Progressive Renal Failure of Myeloma.

In myeloma, plasma exchange (PE) has been suggested to prevent rapidly progressive kidney failure by reducing exposure to nephrotoxic light chains. We carried out a randomized controlled multi-centre trial comparing PE or no PE in 104 patients of whom 101 met the inclusion, exclusion criteria and 4 were lost to follow-up. We compared baseline characteristics as well as renal outcomes and performed a futility analysis to determine the sample size necessary for potential statistical significance for the changes noted. Thirty-nine patients were randomized to the control group and 58 to the PE group with a 6-month follow-up. The baseline characteristics of these 2 groups were similar including serum creatinine, dialysis dependence, age, gender, serum calcium, serum albumin, 24 -hour urine for protein levels and Durie-Salmon myeloma staging. Thirteen (33.3%) of the control group and 19 (33.3%) of the PE group died within 6 months of follow up. Ten patients (31%) in the control and 10 patients (21%) in the PE arm were dialysis dependent at 6 months. Seven patients (47%) came off dialysis in the control and 13 patients (59%) in the PE arm with the mean number of dialysis days from 0–6 months being 45.7±67.6 in the control versus 29.2±56.1 in the PE arm at 6 months. The mean serum creatinine in the control group was 314.6±256.1 μmol/L versus 215.4±215.3 μmol/L in the PE group and the composite end point of death, dialysis or serum creatinine >254 μmol/L occurred in 12 (30.8%) in the control and 11 (19.3%) in the PE arm. The futility analysis to indicate the per group sample size necessary to achieve statistical significance at 6 months for the difference we observed was infinite for cumulative mortality, 805 for dialysis dependence, 2418 for coming off dialysis, 321 for number of dialysis days, 132 for creatinine difference of 100 μmol/L and for the composite outcome of death, dialysis or creatinine>354 μmol/L, 737. We did not observe a statistically significant difference in mortality or renal morbidity for PE versus no PE in patients with myeloma and rapidly progressive kidney failure.

Different types of glomerulopathic light chains interact with mesangial cells using a common receptor but exhibit different intracellular trafficking patterns

Patients with plasma cell dyscrasias may have circulating light chains (LCs), some of which are nephrotoxic. Nephrotoxic LCs can affect the various renal compartments. Some of these LCs may produce predominantly proximal tubular damage, while others are associated with distal nephron obstruction (the so-called ‘myeloma kidney'). Both these are considered tubulopathic (T) LCs. A receptor has been found in proximal tubular cells (cubilin/megalin complex), which mediates the absorption of LCs and is involved in the pathogenesis of tubulopathies that occurs in these patients. Another group of nephrotoxic LCs is associated with glomerular damage and these are considered as glomerulopathic (G). These patients with G-LCs may develop AL-amyloidosis (AL-Am) or LC deposition disease (LCDD). Recent evidence indicates that the physicochemical characteristics (amino-acid composition and conformation of the variable region) of a given nephrotoxic LC may be the most significant factor in determining the type and location of renal damage within the nephron. Other factors may also be involved, including yet uncharacterized host factors that may include genetic polymorphism, among others. Interestingly, the amount of LC production by the clone of plasma cells does not correlate directly with the severity of the renal alterations. Understanding the nature of the interactions between G-LCs and mesangial cells (MCs) is crucial to define key steps that may be targeted for therapeutic purposes. Experimental studies have delineated important aspects pertaining to interactions between G-LCs and MCs, indicating that these interactions are receptor mediated. The data presented in the current study support a single receptor present on MCs for both LCDD and AL-LCs, as clearly demonstrated with competition and colocalization immunofluorescence (IF) studies. This receptor resides in caveolae present on the plasma membrane of HMCs and is overexpressed when HMCs are incubated with G-LCs but not TLCs. Caveolae play a fundamental role in receptor-mediated endocytosis, a crucial process in the internalization of AL-LCs and amyloidogenesis. LC internalization is clathrin mediated. The data also indicate that intracellular trafficking in MCs is different for AL-LCs and LCDD-LCs. AL-LCs are delivered to the mature lysosomal compartment where amyloid formation occurs. LCDD-LCs alter mesangial function and phenotype by interacting with the MC surface membranes through similar receptors as the AL-LCs. The data also demonstrated that cubilin and megalin were absent on MCs, so the receptor involved is different from the one already characterized in the proximal tubules.

Renal involvement in plasma cell dyscrasias.

Monoclonal light chain-related renal diseases represent a unique collection of renal disorders with monoclonal light chain deposition underlying the pathogenesis of these disorders. Yet, despite this common pathogenic mechanism, each renal lesion is unique. In addition, these syndromes are unusual in that, unlike many other renal disorders, they are potentially reversible causes of renal failure. This review focuses on the pathogenesis of three light chain-related renal diseases: AL amyloidosis, granular light chain deposition disease, and cast nephropathy ("myeloma kidney"). Management of these renal lesions in relation to the different pathophysiologic mechanisms is also discussed. Treatment should be designed to decrease production of nephrotoxic light chains and to prevent the binding interaction between these light chains and the various structures of the nephron.

Renal disease in multiple myeloma

Multiple myeloma is a malignant tumor of B (plasma) cells that is characterized by monoclonal immunoglobulin production. The incidence of myeloma is increasing worldwide, particularly among individuals of advanced age. Renal impairment at diagnosis is present in approximately 20% of patients with myeloma, and uremia is the cause of death in about 15%. Several renal disorders may be present in myeloma. Bence Jones cast nephropathy (BJCN), acute tubular necrosis, and “nonspecific” tubulointerstitial nephritis are related to nephrotoxic light chains in urine. Hypercalcemia potentiates the toxicity of urinary light chains. The tissue deposition of light chains leads to renal AL-amyloidosis or light chain deposition nephropathy (LCDN). In necropsy series, the incidence of BJCN, renal AL-amyloidosis, and LCDN is about 30%, 10%, and 4%, respectively. Clinically, urinary nephrotoxic light chain-associated disorders and LCDN are usually manifested in chronic or acute renal failure. The nephrotic syndrome is commonly due to renal AL-amyloidosis. Most cases of end-stage renal failure are due to BJCN and LCDN. The basic therapy of renal impairment is hydration, forced diuresis, and initiation of chemotherapy. Diphosphonates are effective new tools for the correction of hypercalcemia, and decrease the incidence of pathological fractures. In acute renal failure, plasma exchange in association with forced diuresis, dialysis, and chemotherapy may improve renal function. End-stage renal failure requires maintenance renal replacement therapy. In myeloma patients with advanced age, the limits of medical intervention should be judged individually. Particular attention should be paid to the supportive care of the patients.