Serum concentrations of FLCs and intact immunoglobulins reflect the balance between their production and clearance rates. An understanding of immunoglobulin clearance mechanisms in both normal and pathological conditions is important when considering the utility of sFLCs and intact immunoglobulins as tumour markers in monoclonal gammopathies.
3.5.1. Half-life of sFLCs(Figure 3.10), while larger polymers are cleared more slowly . In contrast, IgG has a half-life of approximately 21 days with minimal renal clearance (Section 5.3). Although κ FLC production rates are estimated to be twice that of λ, their faster removal ensures that actual serum concentrations are approximately 50% lower (Chapter 5). The half-life of FLCs is dependent upon kidney function, so that FLC removal may be prolonged to 2 - 3 days in MM patients with complete renal failure . In patients with chronic kidney disease (CKD), κ and λ sFLC concentrations increase due to reduced renal clearance . When renal clearance is reduced, a greater proportion of sFLC are removed through pinocytosis by cells of the reticuloendothelial system . This mechanism removes κ and λ sFLC at the same rate so the relative FLC concentrations change to reflect more closely the higher rate of κ production and there are minor increases in the κ/λ sFLC ratio .
3.5.2. Renal clearance of FLCsFigure 3.11 shows the glomerular filtration and metabolism of FLCs within a kidney nephron. Each nephron contains a glomerulus with basement membrane fenestrations, which allow filtration of serum molecules into the proximal tubules. Pore sizes are variable, with restricted filtration of molecules that are greater than 20 kDa in size, and a molecular weight cut-off of around 60 kDa. Protein molecules that pass through the glomerular pores are bound by the multi-ligand megalin and cubulin receptors on proximal tubule epithelium; these are then absorbed unchanged, degraded in the proximal tubular cells into their constituent amino acids, or excreted as fragments . This megalin/cubulin absorption pathway is designed to prevent loss of large amounts of proteins and peptides into urine. It is very efficient and can process between 10 and 30 g of small molecular weight proteins daily. Therefore, the 500 mg of FLCs produced each day by the normal lymphoid system are filtered by the glomeruli and completely processed in the proximal tubules .
Because of the huge metabolic capacity of the proximal tubule, the amount of FLCs in urine (even when production is considerably increased in a patient with MM), is more dependent upon renal function than synthesis by the tumour. As a consequence, serum and urine FLC concentrations may differ during the evolution of light chain MM (LCMM) (Figure 3.12). From low initial starting concentrations, sFLCs increase steadily with growing tumour mass, while concentrations in the urine show little change until the proximal tubular metabolism is exceeded and overflow proteinuria develops. Hence, early disease and oligo-secretory disease are not identified from urine tests. Subsequently, urine FLCs rise rapidly as overflow occurs, to reach a maximum. Concentrations then decrease as renal impairment occurs, and are low in complete renal failure. By contrast, sFLC levels increase as renal impairment develops due to the lengthening half-life of FLCs that are no longer cleared by the kidneys. Because of the biphasic urine curve, decreasing concentrations may indicate response to treatment or deterioration of renal function. Urine measurements are therefore unreliable during disease monitoring. Serum levels, however, rise or fall in correct relationship to worsening or improving disease status. The merits of serum over urine testing are further discussed in Chapter 24.