Immunoglobulin light chains activate nuclear factor-κB in renal epithelial cells through a Src-dependent mechanism

Abstract

IntroductionMultiple myeloma, a malignant plasma cell disorder, has an incidence rate of approximately 1.1% among all malignancies and constitutes 12%-13% of hematologic malignancies in the United States. 1 In a study examining newly diagnosed patients with multiple myeloma, the incidence of renal dysfunction, determined by serum creatinine elevation Ն 1.3 mg/dL, was 48%. These same investigators showed that an increase in the serum creatinine concentration to Ն 2.0 mg/dL portended a poor prognosis, with a 35% reduction in median survival compared with patients with normal serum creatinine concentrations. 2 Mortality was accentuated if patients developed end-stage kidney disease in the setting of multiple myeloma. In one study that examined outcomes in 3298 patients, the 2-year all-cause mortality was 58% compared with 31% for patients with end-stage kidney disease from other causes. 3 The immunoglobulin free light chain (FLC) is the culprit in most of these renal lesions, and the majority of patients with renal failure from monoclonal FLCs in this setting have tubulointerstitial renal disease. 4 These studies place importance on maintaining or improving renal function and emphasize the need to focus not only on the reduction of FLCs during treatment, but also on understanding the underlying renal pathophysiology.A major function of the kidney is to reclaim low-molecularweight proteins that appear in the glomerular ultrafiltrate. FLCs are low-molecular-weight proteins that readily undergo glomerular filtration and are processed by the proximal tubule epithelium. Specifically, FLCs are absorbed into the proximal tubule by a receptormediated complex that consists of megalin and cubilin. [5][6][7][8] Once endocytosed, proximal tubule epithelial cells hydrolyze the proteins and return the amino acid residues to the circulation. Under normal conditions, total serum FLC concentration is typically Ͻ 30 mg/L, and approximately 500 mg of FLCs are cleared daily by the kidney; however, in pathologic states such as multiple myeloma, serum levels exceeding 100 000 mg/L have been observed. 9,10 In addition, unlike other proteins, this renal reclamation process is complicated by intracellular oxidative stress due to the production of hydrogen peroxide, which promotes cytotoxicity and also initiates signaling cascades that produce a pro-inflammatory state with elaboration of monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6). 11,12 As is true for most progressive forms of renal disease regardless of underlying etiology, tubulointerstitial injury and fibrosis are invariant findings that contribute to a progressive loss of renal function. 13 Thus, receptor-mediated endocytosis and metabolism of monoclonal FLCs generates an intrarenal pro-inflammatory environment that exacerbates ongoing renal injury and tubulointerstitial fibrosis, promoting functional progression of the kidney disease.The intracellular signaling process is known to be mediated through oxidative activation of c-Src, the 60-kDa product of c-src, a...

Bortezomib‐based therapy combined with high cut‐off hemodialysis is highly effective in newly diagnosed multiple myeloma patients with severe renal impairment

“…The excess of FLC causes direct injury to proximal tubular cells through the induction of pro-inflammatory cytokines (IL-6, IL-8, TNF) and the activation of the NF-kB pathway, leading to tubular cell death [20,21].…”

“…Renal response was defined as complete (CR renal ), partial (PR renal ), or minor (MR renal ), according to the criteria formulated by the IMWG. In particular, CR renal was defined as an increase in eGFR from < 50 to 60 mL min 21 or better; PR renal was an increase from <15 to 30-59 mL min 21 and MR renal was an increase from <15 to 15-29 mL min…”

“…Between November 2009 and January 2014, all consecutive patients who received at the Units of Hematology and Nephrology in Bologna a diagnosis of MM and RI secondary to tubular-interstitial damage were enrolled in a prospective study of bortezomib-based induction therapy combined with HCOD. Patients could be enrolled provided that their involved serum FLC (sFLC) concentration at baseline was above 1,000 mg L 21 . Additional inclusion criteria were an upper age limit below 85 years and an Eastern Cooperative Oncology Group (ECOG) performance status 2 [15].…”

“…The most frequent adverse event was peripheral neuropathy (PN), grade 1-2 in 57% of patients, grade 3 in 2 patients (9%). Three patients required bortezomib dose reductions from 1.3 to 1 mg sm 21 due to PN and in 1 of them a further dose reduction from 1 to 0.7 mg sm 21 was needed.…”

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

“…These LCs can overwhelm the endocytic capacity of PT cells, being then lost in urine, 6 whereas their intracellular accumulation leads to tubulointerstitial inflammation and fibrosis through different pathways that include oxidative stress, activation of NF-kB, and release of inflammatory mediators. 3,7 In high-mass myeloma, massive quantities of LCs in distal tubular segments may trigger the formation of casts that obstruct the lumen, also leading to tubulointerstitial fibrosis. 6 Alternatively, monoclonal LCs may cause renal Fanconi syndrome (RFS), a general dysfunction of PT cells leading to the urinary leak of LMW proteins, phosphate, uric acid, glucose, and amino acids often associated with osteomalacia and progressive renal failure.…”