The serum-free light chain assay cannot replace 24-hour urine protein estimation in patients with plasma cell dyscrasias

The serum-free light chain (SFLC) assay provides useful information in patients with plasma cell dyscrasias who secrete no or small quantities of monoclonal protein.^1,2  Changes in SFLC over a period of time correlate with changes in the amounts of 24-hour urinary monoclonal protein.³  It has been suggested that “serum measurements may provide a logical and feasible alternative to 24-hour urine collections” in patients with myeloma.^{3(p 657)} The 2005 myeloma diagnosis and management guidelines from the British Committee for Standards in Haematology^{4(p 412)} state that “[Q]uantification of serum-free immunoglobulin light chain levels (FLC assay) and κ/λ ratio can be used as an alternative to quantifying urinary light chains.” These statements are open to the interpretation that 24-hour urine collection can be given up in favor of estimating SFLC in myeloma.

The extent of proteinuria is a powerful predictor of the development of renal dysfunction. There is a correlation between the degree of proteinuria and the rate of progression of renal failure. Thus, proteinuria is an independent mediator of progressive renal dysfunction and not just evidence of glomerular dysfunction.^5-7  Proteinuria in patients with myeloma consists not only of light chains, but also of albumin and other normal proteins that are not estimated by the SFLC assay.

We explored the relationship between proteinuria and SFLC in 174 samples from 135 patients with myeloma. Patients were at varying stages of the disease and therapy, ranging from initial presentation to remission after therapy to relapse.

The serum-free κ and λ light chain levels were 0.59 to 2330 mg/L (median, 18.6 mg/L) and 0.85 to 4950 mg/L (median, 19.8 mg/L), respectively. The ratio was normal (0.26-1.65) in 56% of samples, low in 11% of samples, and high in 33% of samples. Total 24-hour proteinuria was 23 to 7378 mg (median, 166 mg), and monoclonal proteinuria, quantified in 39 (23%) patients, was 24 to 2349 mg (median, 171 mg). Serum creatinine levels were 2.652 to 928.2 μM (0.3-10.5 mg/dL) (median, 97.24 μM [1.1 mg/dL]).

As Table 1 shows, higher amounts of total and monoclonal proteinuria were more likely to be associated with abnormal ratio. However, more than 40% of patients with more than 500 mg urine protein per day had normal ratios, suggesting that reliance upon the ratio as a substitute for 24-hour urine collection would have resulted in missing clinically significant proteinuria in a substantial number of patients. In addition, one-third of patients with small amounts of monoclonal protein in the urine had normal ratios. As Table 2 shows, normal and abnormal ratios were uniformly distributed across different serum creatinine ranges, suggesting lack of correlation between renal function and SFLC. On the other hand, the relationship between serum creatinine and proteinuria was very strong.

The correlation between serum creatinine and proteinuria does not imply that serum creatinine is a substitute for measurement of protein excretion. Rather, it suggests a parallel relationship between increasing proteinuria and progressive renal dysfunction. Detection of proteinuria in myeloma, in addition to suggesting disease activity, should also prompt a search for amyloid deposition, treatment-related toxicity, and modification of therapy (eg, modification of the type of bisphosphonate used or the addition of angiotensin-converting enzyme inhibitor therapy).

Our data show that a normal SFLC ratio cannot rule out significant total proteinuria, that SFLC is not 100% sensitive in detecting monoclonal proteinuria, and the extent of proteinuria but not the SFLC ratio correlates with renal function. The SFLC assay cannot replace 24-hour urine protein estimation from a clinical standpoint. Any recommendation to the contrary runs the risk of suboptimal patient management.

Correspondence: Seema Singhal, 676 N St Clair St, Ste 850, Chicago, IL 60611; e-mail: s-singhal@northwestern.edu.

Author contributions: S.S. and J.M. treated the patients, designed the study, analyzed and interpreted the data, and wrote the paper. R.S. collected the data and helped with data interpretation. E.V. helped with patient management and data interpretation.

Conflict-of-interest disclosure: The authors declare no competing financial interests.