Abstract
Having developed serum free light chain (FLC) assays and initiated many of the early evaluations, we would welcome the opportunity to comment upon some of the issues raised in the November edition of the Annals of Clinical Biochemistry. 1–3
The difficulties of measuring monoclonal proteins are considerable. It is impossible to produce turbidimetric assays that measure monoclonal FLCs with the same accuracy and precision as seen with C3 assays (for example). However, the alternative to quantification of FLCs in serum is urine Bence Jones protein (BJP) measurement and due to the physiological and analytical limitations of urinalysis we maintain that serum analysis offers a number of advantages.
In a healthy kidney, the vast majority of filtered FLCs are reabsorbed and catabolized in the proximal tubules. Only when this reabsorption mechanism is impaired or overwhelmed do significant quantities of FLCs appear in the urine. Concentrations of FLCs in the urine are therefore, controlled by the reabsorption capacity of the kidneys and this accounts for the generally poor correlation between serum and urine FLC quantification. In some patients, low concentrations of monoclonal FLCs may be found in the urine when the serum FLC ratio is still within the normal range. This might be explained by impaired reabsorption in a proportion of nephrons and has been observed in a number of diagnostic studies. 1,4,5 However, in all of these trials a combination of serum electrophoretic analyses and serum FLC measurements has identified every patient with a disease requiring treatment.
Beetham et al. 1 concluded that their results did not support a change from urinalysis but a different conclusion may be drawn from the same data. They reported that a strategy of using serum FLC analysis instead of urine would have missed one patient where the only abnormality was BJP in the urine. Follow-up of this patient indicated monoclonal gammopathy of unknown significance (MGUS), so no significant pathology would have been missed by omitting urinalysis. Conversely, this strategy would have identified five patients where the only abnormalities were the FLC ratio but no follow-up of these patients was reported. The largest published investigation addressing this issue had more than 12 times as many patients with BJP (n = 428) 5 and concluded that serum analysis (immunofixation, electrophoresis and serum FLC measurement) could replace urinary BJP analysis without loss of diagnostic sensitivity.
Irrespective of the debate concerning the relative analytical merits of serum versus urine FLC analysis, it is clear that inclusion of serum FLC measurement in a screening protocol will improve the diagnostic sensitivity because of the number of patients who fail to provide urine. This has already been demonstrated in a number of studies. 4,6,7 Beetham et al. stated that with ‘active follow-up of the requestors’ they were able to obtain paired urine samples with 52% of their sera. From discussions, we know that 20% compliance is relatively common although the need for urinalysis has been recognized for over 25 years. It was noted by Beetham et al. that three of their patients were negative by serum electrophoresis and immunofixation but had clearly abnormal serum k/L ratios and BJP in their urine; such patients could equally have been in the group who failed to provide urine samples.
Rather than debating analytical issues assuming that urinalysis is the ‘gold standard’ we should focus on the realities of not obtaining urine samples and the clinical benefits of serum FLC analysis.