Bone Marrow Research 3 Excess LCs Freely ﬁltered at glomerulus Light chains pass to proximal tubule Light chains pass to distal tubule LCs precipitate out in acidic tubular ﬂuid LCs combine with uromodulin Cast formation Tubular obstruction Scavenged by proximal tubular cubilin/megalin Endocytosis Vesicular traﬃcking H2O2 production Inﬂammation via chemokine and cytokine production Accelerated ﬁbrosis Figure 2: Renal handling of LCs. precipitate more distally (the pI of FLC has been shown to range from 3.5 to 9.9) [18, 19]. This reﬂects the progressive acidiﬁcation of tubular ﬂuid as it ﬂows through the distal nephron; this consequently facilitates the precipitation of proteins with progressively lower pIs. This may have direct clinical relevance in the management of the acid-base status of the individual patient which is supported by disease model studies, where the alkalinisation of the urine ameliorated the eﬀects of FLC on inulin clearance in rats [20]. After precipitation of FLC, cast formation occurs when uromodulin traps the FLC and a gel-like cast is formed. Uromodulin is secreted at the thick ascending limb of the loop of Henle; it is the main urinary protein in healthy individuals and has the ability to self-aggregate into a gel like substance and bind with many low molecular weight proteins [21, 22]. Uromodulin has been shown to have a speciﬁc binding site for FLC; this has been shown in animal models to be a peptide sequence [23]. When a monoclonal antibody against this peptide sequence was utilised there was a reduction in FLC binding to uromodulin, and there is great interest therefore in the potential for small molecule blockers to reduce cast formation [23, 24]. Uromodulin may also have an immunomodulatory role via the induction of inﬂammatory cytokines such as TNF-α and IL-6 from monocyte/macrophages and neutrophils [25, 26]. In conclusion, current concepts around the pathogenesis of AKI in MM can be summarised as follows: (i) cast nephropathy may be precipitated by dehydration, hyper- calaemia, or nephrotoxic drugs; (ii) the precipitating factors for cast nephropathy may themselves cause AKI in the absence of cast formation; (iii) the direct pathogenicity of monoclonal FLC on PTEC may also precipitate AKI; this may occur in combination with cast nephropathy or (less commonly) through causing acute tubular necrosis (ATN) in the absence of cast formation. Renal impairment is more likely to be reversible with supportive measures alone when it is not related to cast formation [3].