2 Figure 1: Renal biopsy showing cast nephropathy: distal tubular casts and interstitial inﬂammation and ﬁbrosis. normal renal function [4]. This directly relates to the severity of AKI at time of presentation, such that those who require and receive dialysis treatment have a median survival of less than 12 months [5]. There are a number of factors that can contribute to the development of AKI in MM; these include dehydration, hypercalcaemia, and the ingestion of nephrotoxic drugs [6]. It is important to note that cast nephropathy may not be the sole pathology in patients with MM and AKI; for example, there may be concomitant amyloid or another renal pathology unrelated to MM. All these factors have the potential to trigger the development of cast nephropathy, which is the commonest cause of severe AKI. Severe AKI in MM is a major medical emergency, as it is associated with a high risk of early death. Historically, less that 20% of people with MM require dialysis at or shortly after presentation recover independent kidney function [5]. As a consequence, there is a major focus on understanding the biological basis for the development of AKI in MM. In addition, the eﬃcacy of novel chemotherapies for promoting better outcomes is under evaluation. Finally, with the introduction of protein- permeable dialysers into clinical practice, there is continuing interest in the clinical utility of extracorporeal removal of light chains to improve renal recovery. 3. The Pathogenic Basis of Cast Nephropathy in Multiple Myeloma Cast nephropathy is characterised by the presence of frac- tured, waxy casts formed of FLC and uromodulin (Figure 1) [7, 8]. These casts precipitate out in the distal tubules resulting in tubular obstruction; there is also associated tubulointerstitial inﬂammation, which may in part be related to a direct proinﬂammatory eﬀect of FLC on proximal tubular epithelial cells (PTEC) [7, 8]. To fully understand the pathogenesis of cast formation it is necessary to understand the renal handling of FLC (Figure 2). Serum FLCs are relatively freely ﬁltered at the Bone Marrow Research glomerulus because of their size (22.5 kD for Kappa (κ) and 45 kD for Lambda (λ)) and cationic net charge; the glomeru- lar sieving coeﬃcient for free Kappa LC has been calculated at 0.09 [9]. As there are detectable levels of polyclonal FLC in the serum of normal individuals (κ at 3.3 to 19.4 mg/L; λ at 5.7 to 26.3 mg/L), it can be extrapolated that in health between 100–600 mg/24 hr of FLC are presented at the renal tubule; as there are minimal levels of FLC present in the urine this indicates a high capacity for reabsorption of FLC by the tubules [10]. This process of FLC reabsorption takes place at PTEC through receptor-mediated interactions, and free LCs in tubular ultraﬁltrate are taken up by the tandem receptors cubilin/megalin, with subsequent endocytosis via the endosomal/lysosomal pathway; some FLC clones bind preferentially to megalin and some to cubilin [11–13]. After endocytosis the FLCs undergo vesicular traﬃcking, which is dependent upon acidiﬁcation of the vesicle. However not all FLC digestion is conﬁned to lysosome, and there may be some degradation of FLC bound to the PTEC membrane [12]. There is no evidence to date that endocytosis of poly- clonal FLC activates PTEC; however there is substantial data that show a profound proinﬂammatory and cytotoxic potential of monoclonal FLC. There is a diﬀerential capacity of any given clone of FLC to activate PTEC to produce proinﬂammatory cytokines through activation of NFκB; this may contribute to the inﬂammatory cell inﬁltration and accelerated ﬁbrosis that is seen in cast nephropathy [14]. The production of these cytokines also involves mitogen- activated protein kinases (MAPKs) ERK 1/2, JNK 1/2, and p38 [11]. A central component of the pathogenicity of monoclonal FLC towards PTEC is mediated through the formation of hydrogen peroxide (H2O2,); in vitro this is generated after FLC endocytosis and indicates a high level of oxidative stress [15]. It has subsequently been established that H2O2 production by monoclonal FLC mediates the oxidation and activation of c-Src (a redox sensitive, nonreceptor tyrosine kinase), an obligate step in this setting for the production of MCP-1/CCL2 [16]. These and other studies show that monoclonal FLCs have a greater inﬂammatory eﬀect on PTECs than other freely ﬁltered proteins [14, 17]. The dynamics of serum FLC (sFLC) levels and renal clearance is important for the interrelationship between FLC processing by PTEC and the development of cast nephropathy. As MM evolves, the amount of clonal FLC that is present in glomerular ultraﬁltrate progressively increases, ultimately to levels that overwhelm the reabsorptive capacity of PTEC. Therefore increasing amounts of FLC are present in ﬁltrate in the loop of Henle and the distal tubule. There is then a diﬀerential capacity of any given clone of FLC to aggregate with uromodulin (Tam-Horsfall protein) to form casts [18]. One of the key determinants of cast formation is the isoelectric point (pI) of the protein. When the ambient pH of tubular ﬁltrate is close to the FLC pI, the protein carries no net charge and will tend to precipitate out of solution; proteins with a pI of 5.6– 7.3 tend to precipitate in the ascending limb of the loop of Henle or early distal tubule while those with a pI < 5.1