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. Author manuscript; available in PMC: 2016 May 11.
Published in final edited form as: Kidney Int. 2014 Oct 8;87(4):692–697. doi: 10.1038/ki.2014.333

The use of immunoglobulin light chain assays in the diagnosis of paraprotein-related kidney disease

Punit Yadav 1,2, Nelson Leung 3,4, Paul W Sanders 5, Paul Cockwell 1,2
PMCID: PMC4863638  NIHMSID: NIHMS783398  PMID: 25296094

Abstract

Kidney involvement is common in paraprotein-related diseases. A diversity of clinical presentations and histopathological features can occur secondary to tissue injury caused by precipitation or deposition of a clonal immunoglobulin, usually an immunoglobulin light chain. The paraprotein is either produced by multiple myeloma or by a clone of B-cell lineage that does not fulfill diagnostic criteria for multiple myeloma. The recent introduction of serum immunoglobulin free light chain assays, which accurately quantify both light chain isotypes to produce a ratio that indicates the presence or absence of a light chain paraprotein, is a major clinical development. However, as the interpretation of the assay can be challenging, the aim of this review is to clarify the role of serum and urinary light chain assays in the screening and diagnosis of paraprotein-related kidney disease.

Keywords: monoclonal gammopathy, monoclonal gammopathy of renal significance, multiple myeloma, serum free light chains

MONOCLONAL GAMMOPATHY AND PARAPROTEIN-RELATED KIDNEY DISEASE

Monoclonal gammopathy occurs as a consequence of a clonal proliferation of cells of B-cell lineage, particularly plasma cells, and it affects as many as 5% of the population by the age of 70 years.1 The large majority of individuals with monoclonal gammopathy have monoclonal gammopathy of undetermined significance (MGUS), a condition that is characterized by the presence of a paraprotein (M protein) with <10% bone marrow plasma cells and importantly without end-organ damage. Recently, serum free light chain (FLC) immunoassays have been used to identify light chain only monoclonal gammopathy, with a reported prevalence of around 20% of all MGUS. Approximately 1%/yr of individuals with intact MGUS and 0.3%/yr with light chain MGUS develop a paraprotein-related disease.1,2 Paraprotein-related disease refers to progressive proliferation of the clonal cell and/or the presence of tissue injury associated with the monoclonal gammopathy.

Kidney involvement in paraprotein-related diseases is very common and is associated with high morbidity and mortality. These poor outcomes occur both in patients with multiple myeloma and in patients who do not fulfill diagnostic criteria for multiple myeloma (Table 1). These latter patients no longer have MGUS, as the significance of the monoclonal gammopathy is now identified by the presence of an associated end-organ injury. The term ‘monoclonal gammopathy of renal significance (MGRS)’ has recently been proposed to emphasize the significance of a renal lesion that is directly attributable to a monoclonal immunoglobulin even though the diagnostic criteria for multiple myeloma are not met.3

Table 1.

Renal disorders related to deposition or precipitation of monoclonal immunoglobulin

Renal disorder
Tubulointerstitial
disease		 Myeloma cast nephropathy
Light chain proximal tubulopathy (with or
without Fanconi syndrome)
Glomerular disease
 Organized deposits		 Light chain (AL) amyloidosis
Type I and II cryoglobulinemic glomerulo-
nephritis
Nonamyloid fibrillary glomerulonephritis
GOMMID (or immunotactoid glomerulopathy)
 Nonorganized
 deposits		 Randall-type (MIDD)

LCDD
HCDD
LHCDD
Proliferative glomerulonephritis with
monoclonal Ig deposits
Waldenstrom macroglobulinemia
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Abbreviations: GOMMID, glomerulonephritis with organized microtubular monoclonal Ig deposits; HCDD, heavy-chain deposition disease; Ig, immunoglobulin; LCDD, light chain deposition disease; LHCDD, light and heavy chain deposition disease; MIDD, monoclonal Ig deposition disease.

As kidney disease associated with multiple myeloma and MGRS is usually caused by precipitation or deposition of light chain, the identification and quantification of a light chain producing clone are of particular importance in the diagnosis and management of paraprotein-related diseases. However, there is significant uncertainty about the best approach to this problem in clinical practice, including the use of serum and urinary assays4 and the impact of kidney impairment on the interpretation of the available assays.5 This review provides a potential systematic approach to this clinically challenging problem.

SCREENING FOR INTACT MONOCLONAL GAMMOPATHY

The most commonly used screening test for an intact immunoglobulin paraprotein is serum protein electrophoresis (SPEP), which through identification of an M-spike is sensitive for the detection of an immunoglobulin clone down to a concentration of 500 mg/l.

Immunofixation electrophoresis (IFE) is more sensitive than SPEP (150 mg/l), and it provides isotype characterization of a monoclonal gammopathy. However, IFE is labor-intensive, and it does not quantify the monoclonal immunoglobulin. Serum IFE is therefore generally used if there is an abnormality on SPEP or if there is a high clinical suspicion of a monoclonal gammopathy. Serum IFE is particularly useful in identifying and monitoring a pathological clone when there is more than one clone present.

SCREENING FOR FLC MONOCLONAL GAMMOPATHY

Although SPEP and IFE can detect a light chain clone at concentrations of >500 mg/l and >150 mg/l, respectively, the sensitivity is inadequate, as a clinically relevant monoclonal light chain may be present in the serum at levels below these thresholds. Additional screening assays are therefore needed and include the following:

(i) Urine assays

Because of the insensitivity of SPEP and IFE, urinary testing for light chain (Bence Jones proteinuria) has been the long-term standard of care for the screening and monitoring of a light chain clone. Light chains are physiologically concentrated into the urine, which can then be mechanically concentrated. Urinary protein electrophoresis (UPEP) and urine IFE (UIFE) are both used and can be sufficiently sensitive to identify an abnormal clone of light chain in the urine to a concentration of 10 mg/l.

The shortfalls in the use of a urine assay in clinical practice include the frequent failure to provide an appropriate 24-hour urine collection or a paired serum sample to accompany a urine collection.6 Other important variables include the degree of urine concentration, the IFE method used, and the affinity of the polyclonal antibodies used in the IFE assay.7 Furthermore, urine light chain concentrations may not necessarily correlate with serum concentrations, and they are therefore not directly related to tumor size and light chain production.8

(ii) Serum FLC assays

The first marketed assay used for quantifying serum FLC is a nephelometric assay (Freelite, Birmingham, UK) that uses rabbit anti-human polyclonal antibodies directed against epitopes that are hidden when the light chain is present in the intact immunoglobulin molecule and exposed when the light chain is present in a free form. The assay measures both isotypes of light chain, kappa and lambda, and the results are provided for both isotypes and the ratio of the isotypes. When interpreting the test, both the ratio and the level of each isotype should be considered. The FLC assay is highly sensitive and can detect both isotypes to levels that are below the normal physiological range.

As each cell of the B-cell lineage produces one isotype of light chain immunoglobulin, an excess production of that light chain will usually occur in clonal proliferation as compared with the other isotype. This excess leads to an abnormal FLC ratio. An elevated ratio indicates the presence of a kappa FLC clone, whereas a low ratio indicates a lambda FLC clone. The levels of clonal light chain can vary from several thousand–fold the upper limit of normal in some cases of multiple myeloma to a very subtle perturbation within the normal range of the ratio or within the measurement uncertainty of the assay in some cases of monoclonal gammopathy (see below).

Elevation of the levels of both serum FLC isotypes can occur as a consequence of immune activation or renal impairment, as the main route of clearance of light chain is through the kidneys (see below). However, in this setting, the ratio of the isotypes is maintained within a normal range. In the absence of clonal proliferation, the ratio of kappa to lambda light chain production is preserved at a constant rate of 2:1.

This nephelometric assay has enhanced the diagnostic accuracy and sensitivity of paraprotein-related disease and has been credited for: (i) the introduction of stringent complete response as a new criterion of multiple myeloma response; (ii) improved risk stratification in monoclonal gammopathy; (iii) the identification and characterization of light chain MGUS; and (iv) response criteria in immunoglobulin light chain amyloidosis.

In addition to Freelite, two other assays have been developed to date for FLC testing.

  • (1)

    An N-latex monoclonal antibody based nephelometric FLC assay (Siemens, Marburg, Germany):9 The Siemens assay and Freelite assay are concordant for the majority of patients; however, clinicians should be aware that some patients may be misclassified by either assay. Recent reports on patients with AL amyloidosis showed that the two assays had similar diagnostic sensitivity but did not correlate sufficiently to be interchangeable for hematological response criteria10 (abstract; Palladini G et al. Hematol Oncol 31 (Supplementary 1): 151–200, 2013). These studies showed that in combination with serum and urine immunofixation both tests had 98% diagnostic sensitivity.

  • (2)

    A luminex assay (Seralite, York, UK): It uses bead-immobilized mouse anti-human monoclonal antibodies. The initial results from this assay are encouraging and it may become commercially available for clinical practice in the near future.11

Because inter-assay differences may be present, it is important to know which assay was used to derive the serum FLC levels.

(iii) What is the relative sensitivity of serum FLC testing compared with urine tests for monoclonal proteins?

At many centers, UPEP or UIFE remains the test of choice for screening for light chain monoclonal gammopathy; however, serum FLC assay is being increasingly used both for screening and for assessment of disease response. The International Myeloma Working Group has recommended that SPEP, IFE, and serum FLC assay is a sufficient screening panel for monoclonal gammopathy except for AL amyloidosis, where it is recommended that screening should also include urine IFE.12

The most pragmatic approach is to use a serum or urine test for diagnostic purposes, but if the test is negative and the diagnosis of MGRS is possible then the alternative test should also be used. This approach recognizes that a false negative test by either serum or urine is possible in patients with a low-level light chain clone.

The following studies presented data that included a direct comparison between serum FLC assay and urinary testing. Although these studies have limitations, they all show that serum FLC testing is more sensitive.

  • (a)

    Nowrousian et al.13 reported 82 patients with multiple myeloma who were followed up through the course of their disease with paired samples that used serum FLC assay and UIFE; the sensitivity of the urine test to identify a monoclonal light chain was 51% for kappa FLC and 35% for lambda FLC. Five percent of samples were negative by serum FLC assay but positive by UIFE.

  • (b)

    In 428 patients with monoclonal gammopathy, Katzmann et al.14 compared UPEP and UIFE with serum studies alone (SPEP, serum IFE, and serum FLC assay). In this study, serum measurements alone were able to detect all but two cases of monoclonal gammopathy where there was a monoclonal component in urine, and those two patients required no further treatment.

  • (c)

    Piehler et al.15 assessed serum FLC measurement combined with SPEP and identified 38 of 40 cases of patients with monoclonal gammopathy. The two patients who were not diagnosed also had negative urine light chain testing.15

  • (d)

    In a study of 890 consecutive serum samples tested for serum FLC, the assay detected monoclonal light chain in 12% more samples than UPEP and UIFE. Furthermore, the SPEP and serum FLC assay combination detected monoclonal protein in 6% more samples than were detected by the combined performance of SPEP, serum IFE, UPEP, and UIFE.16

  • (e)

    In a series of 110 patients with AL amyloidosis, a serum FLC assay was more sensitive (91%) than a UIFE assay (83%). By serum IFE and FLC assays, 99% of patients had an abnormal result in at least 1 of the 2 tests, and using UIFE did not add any information.17

THE IMPACT OF KIDNEY FUNCTION ON FLC RATIO AND LEVELS

Katzmann et al.18 used the serum FLC assay (Freelite) to produce a normal serum ratio and range for FLCs. The recommended FLC ratio of 0.58 with a range of 0.26–1.65 was based on a group of healthy individuals without monoclonal gammopathy and used a 100% confidence interval (CI); this was done because a 95% CI (the range used as normal in most laboratory assays) would lead to a failure to exclude a light chain monoclonal gammopathy in around 5% of the population.

The utility of this range was confirmed by analysis of a group of patients with polyclonal hypergammaglobulinemia. This cohort had elevation of both kappa FLC and lambda FLC levels, but the kappa to lambda ratio was within the normal range, indicating the central role of FLC ratio in screening for clonality.18 Other FLC assays have standardized their assay against the normal range reported for Freelite.

Katzmann et al.18 described an increase in serum FLC levels with age and a higher median kappa to lambda ratio (0.70) in normal elderly individuals compared with younger individuals (0.49). However, they showed that this age-related increase in FLC levels and FLC ratio was a function of renal impairment. An incremental increase in FLC with renal dysfunction starts early and can be identified with an estimated glomerular filtration rate consistent with stage 2 chronic kidney disease.19

Subsequently, a larger study more accurately characterized the impact of renal impairment on FLC ratio and levels. This study analyzed a cohort of patients with stages of chronic kidney disease up to and including individuals with end-stage kidney disease.5 The median serum FLC ratio for the cohort was 1.12 (0.37–3.1), with more precise levels and ratios defined by the stage of chronic kidney disease. As with the Katzmann study, a 100% CI was used, with all patients included in the data set following the exclusion of any patient with a monoclonal gammopathy.

The increase in the normal-range ratio in individuals with renal impairment reflects the differential clearance of light chain isotypes. Kappa FLC is a monomeric molecule (molecular weight 22.5 kDa) and is cleared in 2–4 h at 40% of the glomerular filtration rate; lambda FLC is typically a dimeric molecule (molecular weight 45 kDa) and is cleared in 3–6 h at 20% of the glomerular filtration rate. The alternative route of removal of FLC is through pinocytosis by the reticulo-endothelial system; this slow route of clearance (the half-life of FLC in individuals with no kidney function is 4 days) removes both isotypes at the same rate. Therefore, as kidney function declines, along with an increase in the serum levels of both isotypes, the median serum ratio increases, moving closer to the production ratio.

ASSAY VARIABILITY AND THE USE OF A RENAL REFERENCE RANGE

The extended or ‘renal’ reference range (ratio, 0.37–3.1) was used to diagnose monoclonal gammopathy in a group of patients presenting with acute kidney injury and resulted in an improvement in assay specificity in this setting.20 Using the renal reference range in clinical practice may lead to increased diagnostic accuracy.

The light chain assay results by Freelite are within 20% of the specified concentration in matched quality control specimens. However, with repeated measurements, there can be higher intra-assay variation for the individual isotypes, and this will amplify variability in the calculated kappa to lambda ratio so that doubling or halving of the ratio can occur in the absence of a change in the status of the disease.21 This means that a ratio around the limit of the reference range may be misclassified as either normal or abnormal. This has implications for the utility of the assay in clinical practice.22 Results on the N-Latex monoclonal FLC assay (Siemens) reported low inter-assay variation of 5–7% across the measuring range.23

Despite the variability of the assay, clinicians should be aware of the impact of renal impairment on serum FLC levels, because this may affect the interpretation of the results reported. The linear association between the levels of the individual isotypes and declining glomerular filtration rate means that patients with end-stage kidney disease will have serum FLC levels that are several-fold higher (often over 100 mg/l for either isotype) than the upper limit of the range reported for individuals with normal kidney function; in this setting, these high levels of serum FLC are probably physiological. However, care is needed in interpreting the reported serum FLC ratio, as illustrated by the following examples.

(1) For patients with advanced chronic kidney disease and a serum FLC ratio between 1.66 and 3.1, the use of the normal ratio (0.26–1.65) would classify a patient as having a kappa FLC monoclonal gammopathy. A ratio in this range, particularly for patients with advanced kidney disease, should not be overinterpreted; only if there were a significant clinical suspicion of a monoclonal gammopathy would further investigation be indicated.

(2) For individuals with advanced chronic kidney disease and a subtle lambda FLC clone (producing a ratio of 0.26–0.36), the use of the normal ratio (0.26–1.65) would miss evidence of the lambda FLC monoclonal gammopathy; application of the ‘renal’ reference range (0.37–3.1) would, under appropriate clinical circumstances, lead to further investigation for a monoclonal gammopathy.

SCREENING FOR PARAPROTEIN-RELATED KIDNEY DISEASE

The approach to diagnosis should always include an assessment for light chain clonality to identify light chain isotype abnormalities that are measurable in the serum and/or urine. The clinical presentations are diverse and range from proteinuria to severe acute kidney injury. An algorithm that can be used in screening patients is shown in Figure 1.

Figure 1.

Figure 1

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Screening pathways for paraproteinemia-related kidney disease.

Acute kidney injury

In a patient with acute kidney injury of unknown cause, the serum FLC assay has great utility (see Figure 1). With a clonal serum FLC level <500 mg/l, it is less likely that the patient has cast nephropathy. However, if the clonal serum FLC level is ⩾500 mg/l, an urgent assessment for cast nephropathy is indicated.20 Patients who have a prompt diagnosis of cast nephropathy and rapid commencement of disease-specific therapy have better outcomes.

MGRS

If patients require screening for MGRS, then serum FLC assay is the most sensitive first-line test for screening for a light chain clone. If there is negative serum FLC test and there is clinical suspicion, such as AL-type amyloidosis or monoclonal immunoglobulin deposition disease, then UPEP and UIFE should be performed. If urine testing is used as the first-line test and is negative, then a serum FLC test should also be carried out. If the patient has a light chain clone and clinical and laboratory findings consistent with a differential diagnosis of MGRS, then kidney biopsy is indicated.

Rarely, patients can have MGRS in the absence of a detectable light chain clone by serum FLC assay or urine testing. If the cause of progressive kidney disease is uncertain, then ultimately a tissue diagnosis is required to exclude MGRS. The assessment of a biopsy for the presence of MGRS requires careful pathological evaluation.24 Identification of MGRS should be followed by a prompt hematological assessment including a bone marrow biopsy.

The FLC assay has the following advantages over UPEP or UIFE: (i) additional sensitivity for the identification of a light chain clone; (ii) ease of use; and (iii) ease of quantification. The disadvantages of the serum FLC assay are as follows: (i) it is not fully sensitive to the presence of a pathogenic light chain clone—in a small number of patients a low-level pathogenic light chain clone may only be identifiable from urine testing;25–27 (ii) the measurement uncertainty (intra-patient variability) of the assay; (iii) the cost of the assay; and28 (iv) inaccuracy of the nephelometric assay (Freelite) with antigen excess.

Future directions in serum LC assays in kidney disease

The widespread use of serum FLC assays has transformed the diagnostic pathways for patients with monoclonal gammopathy and led to improvements in clinical care. However, there are shortfalls in the evidence for serum FLC assays, with the large majority of studies being retrospective and from single centers.29

The assays will remain a focus for clinical investigators and guideline groups over the next decade, and this will lead to further clarity in the role of serum FLC in the diagnosis and monitoring of individuals with monoclonal gammopathy.30 The key outstanding issues for light chain testing in kidney disease that require evaluation include the following:

  • (a)

    The relative roles of serum and urine light chain assays in the diagnosis and monitoring of patients with a monoclonal gammopathy

  • (b)

    Does the renal reference range have clinical utility?

  • (c)

    Are there significant clinical differences between serum FLC assays?

  • (d)

    Can serum FLC be used as a prognostic marker for MGRS?

  • (e)

    Can changes in FLC be used to predict a renal response?

CONCLUSION

Serum FLC assays have contributed to major improvements in care for patients with monoclonal gammopathy. The assay can be used as a first-line test in screening pathways for a light chain clone in patients with kidney disease, but it should be interpreted in the context of the clinical case. The use of the assays will continue to increase, and the next stage in their development will focus on more accurate clinical application and integration into treatment pathways to better direct management of patients with paraprotein-related kidney disease.

ACKNOWLEDGMENTS

The following abstract has been cited on page 3 of the manuscript - Palladini G et al. Hematol Oncol 31 (Supplementary 1): 151–200, 2013.

Footnotes

DISCLOSURE

PWS is an advisory board member of ZS Pharma, and has been a consultant to The Binding Site Group, Birmingham, UK. PC is a medical advisor to the Binding Site Group, Birmingham, UK. The remaining authors declared no competing interests.

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