Physiology of serum free light chains

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Monoclonal gammopathies generally arise from an abnormal clone that has developed from a single cell of B-cell lineage. The monoclonal protein can be intact immunoglogulin (often associated with free light chain), free light chain (FLC) in isolation, or more rarely immunoglobulin heavy chain, either in isolation or with associated free light chain.

Intact immunoglogulin molecules have two light chains of identical subtype, either kappa or lambda. In order to acheive the correct assembly of intact immunoglobulin, the production rate of FLCs is approximately 40% higher than that of heavy chains. The FLCs which are not incorporated into immunoglobulin molecules are released into the serum.

Around twice as many plasma cell produce kappa than produce lambda, but this is not reflected in their relative serum concentrations:
kappa FLCs

  • Typically circulate as monomers
  • Molecular weight of 22.5 kDa
  • Renal clearance of 40%
  • Serum half life of 2-4 hours

Lamba FLCs

  • Circulate as dimers
  • Molecular weight 45 kDa
  • Renal clearance of 20%
  • Serum half life of 3-6 hours

Note that the proximal tubules can reabsorb up to 30g of filtered protein per day, ensuring FLCs are present only in minute concentrations in healthy individuals.

Therefore, the measurable kappa/lamba ratio depends on the integrity of renal function. In people with normal kidney function, the kappa/lambda ratio is around 0.6, primarily due to the baseline higher clearance of kappa chains. As renal function declines, the role of the reticuloendothelial system in FLC removal takes on increasing importance. This process is not influenced by the molecular weight and so results in a progressive increase in the kappa/lambda ratio from 0.6 to 1.2 in patients with CKD 5.

The presence of monoclonal production of free light chain will result in an abnormal kappa/lambda ratio, with a monoclonal kappa producing a high ratio and a monoclonal lambda producing a low ratio. However, it’s important to remember that the reference range was developed from a population with normal renal function.

These are important principles to be aware of to allow proper interpretation of these tests in clinical practice.

Posted by Finnian McCausland MD

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