Myeloma Light Chain-Induced Renal Injury in Mice

Abstract

We investigated the effects of human light chain (LC) protein-overload in mice kidney to gain further insights into the molecular mechanisms involved in the pathogenesis of myeloma kidney. Intact male C57BL/6, 10- to 12-week-old mice were given daily intraperitoneal (i.p.) injections of 1 ml of human ĸ-LCs (1.5 mg/ml, low dose), or (100 mg/ml, high dose) to uninephrectomized mice for 2 weeks. Intact, sham-operated or uninephrectomized control animals were given the same volume (1 ml/day) of saline, human serum albumin (10 mg/ml) or bovine serum albumin (100 mg/ml) i.p. for 2 weeks in place of LCs. The low-dose LC-treated mice had human LCs in their urine and a significant increase in monocyte chemoattractant protein-1 (MCP-1) mRNA in the kidneys. Uninephrectomized mice treated with high-dose ĸ-LCs showed tubule casts, and foci of intracytoplasmic rhomboid crystals within the proximal tubules, along with cytoskeletal disruptions and alterations in the brush-border membrane, and high concentrations of human ĸ-LC were present in their sera. High-dose LC treatment also led to increases in serum creatinine and tumor necrosis factor-α levels, and marked increases in interleukin-6 and MCP-1 expression as well as cellular apoptosis in the kidneys. These studies demonstrate that myeloma LC overload over a range of LC concentrations in mice causes significant functional and morphological kidney injury. The model should be helpful in investigating pathophysiologic mechanisms and exploring therapeutic interventions for myeloma kidney and other LC-associated renal disorders.

Impaired Lysosomal Function Underlies Monoclonal Light Chain–Associated Renal Fanconi Syndrome

“…20 Immortalized cell systems may be dedifferentiated, with loss of polarity and low levels (if any) of endogenous receptors and endocytic uptake, which is problematic for studies of endolysosomal disorders in PT cells. 3,5 In vivo, PT cell dysfunction was observed after injection of high quantities of LCs (1 mg/ml or more) in rat or mouse, 16,29 a condition that does not reflect the chronic delivery of low doses of LCs during smoldering myeloma or MGUS, which typically underlies hematologic disorders associated with RFS. 9 The use of transgenic mice models producing human monoclonal LCs and differentiated primary cultures of PT cells is, thus, particularly useful to investigate mechanisms of epithelial differentiation in response to monoclonal LCs.…”

The pathogenesis and diagnosis of acute kidney injury in multiple myeloma

“…15–18,28,30,42 Excessive FLC endocytosis can also trigger apoptotic pathways and alter the phenotype of PTCs towards a fibroblastic one through epithelial– mesenchymal transition in vitro 15,16,43 and in vivo . 44 Studies have shown that blocking FLC endo cytosis, either by inhibition of endocytosis 9,17,18 or by silencing the endocytic receptors cubilin and megalin, abrogates cytotoxicity. 14,29 These observations support the principal that endocytosis is a prerequisite for these inflammatory processes and are the basis of three potential therapeutic strategies to prevent tubular injury: first, to eliminate or reduce the FLC burden in myeloma patients with renal involvement; second, to block the inflammatory pathways that are activated as a result of FLC toxicity; and third, to potentially block FLC endocytosis.…”

Mechanisms of Light Chain Injury along the Tubular Nephron

“…17,22,24,[26][27][28] The anticipated outcome might include interstitial fibrosis and phenotypic transformation of proximal tubular cells into fibroblasts through epithelial-mesenchymal transition. 17,[28][29][30][31] Monoclonal FLC-mediated redox signaling also promotes apoptosis. 25 In particular, monoclonal FLCs activate the mitogen-activated protein kinase kinase kinase known as apoptosis signalregulating kinase 1 (ASK1).…”

“…Apoptosis is a feature of experimental monoclonal FLC-induced renal failure in animals. 30 An isolated proximal tubulopathy that promotes clinical manifestations of renal failure associated with monoclonal FLC-induced proximal tubular injury is much less common than cast nephropathy. 14,39 However, the direct cellular effects of FLC may be important in cast nephropathy (discussed below) by not only promoting apoptosis but also generating an intrarenal inflammatory milieu that promotes the rapid tubulointerstitial fibrosis 40 and progressive renal failure that is often observed after a bout of AKI in patients with multiple myeloma.…”