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Multiple myeloma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Renal impairment is also common in myeloma patients.65 Approximately one-third of the patients present with significant renal impairment67 and it will affect approximately half at some point during the course of the illness.65,68 A small number of patients (3%–12%) present with renal failure severe enough to require dialysis.69 The main cause of renal failure in myeloma is deposition of BJP in the renal tubules. The classic histological features of ‘myeloma kidney’ are of fractured distal tubular casts with a surrounding chronic inflammatory infiltrate including giant cells. The physicochemical properties of individual immunoglobulin light chains result in differing degrees of renal impairment. Less frequently, light-chain deposition may produce a form of glomerulonephritis (light-chain deposition disease). Many other factors may contribute to renal failure and these include hypercalcaemia, infection, dehydration, hyperuricaemia, amyloid deposition and non-steroidal anti-inflammatory drugs.
Mechanisms of Fibril Formation and Cellular Response
Published in Martha Skinner, John L. Berk, Lawreen H. Connors, David C. Seldin, XIth International Symposium on Amyloidosis, 2007
Martha Skinner, John L. Berk, Lawreen H. Connors, David C. Seldin
AL amyloidosis is the most common systemic amyloidosis, and is believed to be significantly underdiagnosed. It is characterized by the accumulation of monoclonal light chains (or fragments thereof) as amyloid deposits, most frequently in the kidney and heart. Light chain deposition disease is a related disorder in which the deposits are amorphous, rather than fibrillar. In rare cases, the same light chain is found deposited as both fibrillar and amorphous deposits. In both AL amyloidosis and LCDD, the deposits are most commonly found associated with the basement membranes of the extracellular matrix (ECM). The underlying basis of these diseases is poorly understood: for example, for AL amyloidosis, although the depositions are extracellular, it is unclear whether fibrillation is triggered intra-cellularly (e. g. in lysosomes) or extra-cellularly; also, it is unclear whether fibrils or other aggregated forms, such as soluble oligomers, may contribute to toxicity and disease. A number of observations suggest that surfaces, particularly membranes, may be important in the development of AL amyloidosis. For example, amyloidogenic light chains have been shown to preferentially interact with caveolae in the membranes of cells (1). Caveolae are specialized membrane domains enriched in specific lipids and characteristic proteins, and have similar lipid composition to lipid rafts (high in cholesterol, sphingolipids). In addition, as noted, the fibrillar deposits in AL amyloidosis are usually found associated with the basement membranes of the extracellular matrix, and in vitro the kinetics of light chain fibril formation are very dependent on surfaces (e. g. glass vs. plastic). We have been investigating a pair of “matched” k IV light chain variable domains: SMA is an amyloidogenic VL obtained from a patient who had AL amyloidosis; LEN is a homologous light chain variable domain, which is “benign”, from a patient with no evidence of amyloidosis. Their sequences differ predominantly in the CDR loops. Several attempts have been made to discover a correlation between the properties of light chains and their propensities for fibrillation. The only significant correlation found is that of thermodynamic stability; thus, the amyloidogenic SMA is much less stable than the benign LEN (2). In prior studies, we have shown that SMA fibrillation involves two partially folded intermediates: one more native-like, IN, leading preferentially to amorphous deposits; one more unfolded, Iu, leading preferentially to fibrils. Factors that increase the concentration of such intermediates will favor aggregation. The kinetics of fibrillation of SMA and LEN increase with decreasing pH, and there is a kinetic competition between fibrillation and amorphous deposition, which favors amorphous deposits at higher pHs. This could, in part, explain the difference between AL and LCDD deposits. More destabilizing conditions (pH, denaturant) for SMA favor fibrillation.
A case of light chain deposition disease involving the kidney with a normal serum free kappa/lambda light chain ratio
Published in Renal Failure, 2022
Suojian Zhang, Haifeng Ni, Qin Xu, Xiaoqin Cai, Haitao Li, Zhiqiang Wei, Juan Cao
Light chain deposition disease (LCDD) is a monoclonal gammopathy-related disease, which can cause damage to many organs, including the liver, heart, lung, and kidney. The kidney is one of the most commonly affected organs [1–3]. Patients with LCDD involving the kidney may present with proteinuria, hematuria, nephrotic syndrome, and renal impairment [4]. LCDD can be secondary to multiple myeloma and plasma cell disease, or it may not be associated with any other disease. In 2012, the International Kidney and Monoclonal Gammopathy Research Group named the condition of monoclonal gammopathy without plasma cell disease or B lymphocyte proliferative disease, but with renal damage, as monoclonal gammopathy of renal significance (MGRS) [5]. LCDD is a rare disease and previously reported cases have had significantly increased or decreased serum free kappa/lambda ratios [1,6,7]. Here, we report a case of LCDD involving the kidney with a normal serum-free kappa/lambda ratio.
Management of multiple myeloma bone disease: impact of treatment on renal function
Published in Expert Review of Hematology, 2018
Nikolaos Kanellias, Maria Gavriatopoulou, Evangelos Terpos, Meletios Athanasios Dimopoulos
In a small group of six patients with MM who started treatment at the recommended dose of 90mg/month, the dose was raised later on the course of the disease to 180mg/month and in some cases in 360mg/month. None of the patients had serum creatinine >1.2 mg/dL before the administration of PAM, and all developed renal insufficiency (mean creatinine, 3.6 mg/dL; range, 1.6–5.0 mg/dL) and nephrotic syndrome. The mean value of 24-h urine protein was 12.4 g/d (range, 5.4–26 g/d) [32]. Kidney biopsies revealed glomerulosclerosis with focal and segmental collapse, and severe tubular degenerative changes, including the formation of tubular microcysts. Electron microscopy studies revealed diffuse loss of podocytes highly differentiated cytoarchitecture, including the disappearance of primary processes and extensive effacement of foot process. There was no evidence suggestive of cast nephropathy, light chain deposition disease or amyloidosis. A possible mechanism for renal damage resembles the effect of PAM in osteoclasts. PAM may play a crucial role in podocytes via inhibition of the assembly of actin rings, in the same way, that modifies the cytoskeleton in osteoclasts. Additionally, the toxic effects of PAM might be favored by the high drug concentrations that reach the kidney [32].
Acute kidney injury on chronic kidney disease: from congestive heart failure to light chain deposition disease and cast nephropathy in multiple myeloma
Published in Journal of Community Hospital Internal Medicine Perspectives, 2019
Sana Shaikh, Christian Nwankwo, Alexandre Lacasse, Steven Cheng
Free light chains (FLCs) are overproduced by abnormal B-cells in plasma cell dyscrasias and other lymphoproliferative disorders [1]. They are filtered by the glomeruli, reabsorbed in the proximal tubules and degraded in the tubular cells, making the kidney a prominent deposition target [2]. Light chain (LC) deposition contributes to renal insufficiency in multiple myeloma (MM) by causing three main patterns of injury: cast nephropathy (CN), monoclonal immunoglobulin deposition disease (MIDD) and amyloidosis [3]. Light chain deposition disease (LCDD) is the most prevalent variant of MIDD. Lesions in combination are scarcely observed, with LCDD-CN being relatively more frequent and LCDD-amyloid being rare [1,3,4].