Chapter 27

Cast nephropathy, also known as myeloma kidney, is the principal cause of AKI in MM [550]. In this condition, large quantities of monoclonal FLCs are produced by the tumour, and are filtered by the glomeruli, overwhelming the resorptive capacity of the proximal tubules. This leads to proximal tubule injury as a result of excessive endocytosis and large quantities of FLCs entering the distal tubules. In an analysis of 19 MM patients with dialysis-dependent AKI, Besemer et al. [558] noted that their median sFLC concentration was 8580 mg/L (range 1590 - 66100). Patients with higher sFLC concentrations have a higher risk of cast nephropathy and AKI in general [544][247].

FLCs entering distal tubules co-precipitate with Tamm-Horsfall protein (THP, also known as uromodulin) to form waxy casts within the tubule lumen (Figure 27.2A and B). THP is a 105 kDa glycophosphatidylinositol (GPI)-anchored glycoprotein expressed in the thick ascending limb of the loop of Henle. Protease cleavage releases THP into normal urine, where it is found as the dominant high-molecular-weight protein polymer. THP is thought to be important in preventing ascending urinary infections and may have a protective role in AKI [559]. Interestingly, it contains a short peptide motif that has a high affinity for FLCs [560].

The waxy casts in the distal tubules obstruct the tubular flow, resulting in leakage into the interstitium with subsequent inflammation and fibrosis [550]. Increasing concentrations of sFLCs are filtered by the remaining functioning nephrons which in turn become blocked, leading to a vicious cycle of further increases in sFLC concentrations and progressive renal damage. This may explain why some MM patients, without apparent pre-existing renal impairment suddenly develop catastrophic and irreversible renal failure. The process can be aggravated by factors that lower the threshold for cast precipitation such as dehydration, diuretics, hypercalcaemia, infections and nephrotoxic drugs [22].

Until a few years ago only 20% of patients with dialysis-dependent cast nephropathy ever recovered independent kidney function [550]. As early renal recovery has been shown to improve patient survival, attention has focused on providing a rapid diagnosis and ensuring early commencement of therapy directed at light chain reduction [544][561].