Review

Continuing Medical EducationNature Reviews Nephrology 5, 621-628 (November 2009) | doi:10.1038/nrneph.2009.151

Subject Category: Other

Serum free light chain assessment in monoclonal gammopathy and kidney disease

Colin A. Hutchison1, Kolitha Basnayake1 & Paul Cockwell1  About the authors

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Learning objectives

Upon completion of this activity, participants should be able to:

  1. Compare different laboratory assessments for free light chains.
  2. Describe the physiology of free light chains.
  3. Identify the prognosis of monoclonal gammopathy of undetermined significance.
  4. Describe the diagnosis of amyloidosis.

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Abnormalities of immunoglobulin free light chains (FLCs) are frequently present in patients with monoclonal gammopathies and can cause kidney disease. The recent introduction of highly sensitive immunoassays that measure FLCs to levels below those present in normal individuals has provided a new tool for diagnosis and management in this setting. Here, we review the biology of FLC production in health and disease, and the utility of FLC immunoassays in the assessment of monoclonal gammopathies in kidney disease.

Key points

  • Serum free light chain (FLC) immunoassays can identify monoclonal FLCs with high sensitivity and specificity
  • The screening of serum alone using serum protein electrophoresis and measuring serum kappa and lambda FLC levels will identify all patients with multiple myeloma and 99% of patients with AL amyloidosis
  • Concentrations of serum polyclonal FLCs are GFR dependent and increase with increasing renal impairment
  • The monitoring of serum FLCs provides an insight into the response to treatment of patients with acute kidney injury and myeloma
  • Renal recovery from cast nephropathy is associated with a significant reduction in serum FLC levels

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Introduction

Monoclonal gammopathies such as multiple myeloma, AL amyloidosis and light chain deposition disease (LCDD) often involve the kidney. These diseases are caused by an abnormal clone that has developed from a single cell of B-cell lineage, usually a plasma cell. The monoclonal proteins released by the clone can be: intact immunoglobulin, frequently associated with a kappa (kappa) or lambda (lambda) immunoglobulin free light chain (FLC); FLC in isolation; or, rarely, immunoglobulin heavy chain, either with associated FLC production, or in isolation.

Most kidney disease associated with monoclonal gammopathies is caused by monoclonal FLCs. This fact is a consequence of the kinetics of FLC clearance from the serum by the kidneys, so that any structural and functional abnormalities in the kidneys and/or excess production of FLCs can lead to deposition or precipitation in situ. Kidney disease can either present as the first manifestation of a monoclonal gammopathy or develop in the context of known monoclonal disease.

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Assays for measuring FLCs in serum and urine

Serum protein electrophoresis (SPE) is the main screening tool for the assessment of intact monoclonal immunoglobulins, but it has limited utility for serum FLC detection, with a lower limit of sensitivity of between 500 mg/l and 2,000 mg/l.1 At best, these levels are 50-fold higher than the concentrations of kappa or lambda FLC present in normal serum.2 Serum immunofixation electrophoresis (IFE) is more sensitive for FLC detection (lower limit of sensitivity 150–500 mg/l) but it does not allow quantification of the FLCs because of the presence of the precipitating antibody. Furthermore, IFE is more laborious than SPE and is not used as a routine first-line test for the assessment of monoclonal gammopathies.3

Owing to the limited utility of SPE and serum IFE for FLC detection, and because FLCs are cleared by the kidneys, urinary protein electrophoresis (UPE) has been the longstanding method of choice for FLC detection. Monoclonal urinary FLCs are also known as Bence-Jones proteins.4 As urine is relatively deficient in total protein compared with plasma it can be concentrated many times, which provides much increased sensitivity for the detection of FLCs: most laboratories can work to a detection limit of 10–40 mg/l. However, because of the high reabsorptive capacity of proximal tubular epithelium for light chains,5 some patients with a monoclonal gammopathy will have undetectable levels of urinary FLCs. Also, the process of concentrating the urine can result in both loss of protein6 and false positive bands.7, 8

Additional practical considerations exist for UPE because random specimens of urine are unsuitable and the collection of 24-h urine specimens can be challenging in clinical practice.9 In a recent screening study, urine samples were lacking for more than half of the population.10 In a separate study, urine samples for analysis were only provided for 60% of patients subsequently diagnosed with myeloma.11

An immunoassay for serum FLC

The Freelite™ test (The Binding Site Group Ltd, Birmingham, UK) is a nephelometric serum FLC assay that uses kappa and lambda polyclonal antibodies (raised in sheep) against specific epitopes that are hidden in intact immunoglobulins but exposed on FLCs (Figure 1). The test accurately measures FLCs to very low levels and has been used to quantify FLCs in the serum of normal individuals,1 which was not possible before the development of the assay. As well as independently quantifying the two isotypes, monoclonality can be identified by the demonstration of an abnormal ratio of kappa:lambda FLCs (Figure 2), which is a consequence of excess production of a single FLC isotype by a clone of B-cell lineage.2

Figure 1 | An antibody molecule showing heavy and light chain structure, together with free kappa and lambda light chains.
Figure 1 : An antibody molecule showing heavy and light chain structure, together with free |[kappa]| and |[lambda]| light chains. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.comSpecific epitopes that are hidden when the light chains are bound to the heavy chains become visible when the light chains are free. When lambda free light chains form dimers these epitopes are still visible as the bonds created are different to those formed in the intact antibody molecule. Permission obtained from The Binding Site © Bradwell, A. R. Serum free light chain analysis. 4th edn (2006).

Figure 2 | Serum kappa:lambda FLC ratios to identify patients with kappa or lambda light-chain-only multiple myeloma.
Figure 2 : Serum |[kappa]|:|[lambda]| FLC ratios to identify patients with |[kappa]| or |[lambda]| light-chain-only multiple myeloma. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.comThe squares (high kappa:lambda ratio) indicate kappa light-chain-only multiple myeloma and the triangles (low kappa:lambda ratio) indicate lambda light-chain-only multiple myeloma. The area between the two horizontal lines represents the normal range. Permission obtained from The Binding Site © Bradwell, A. R. Serum free light chain analysis. 4th edn (2006). Data obtained from Marien, G. et al. Detection of monoclonal proteins in sera by capillary zone electrophoresis and free light chain measurements. Clin. Chem. 48, 1600–1601 (2002). Abbreviation: FLC, free light chain.

The serum FLC assay has become an established component of the laboratory assessment of monoclonal gammopathies.12 Consensus guidelines have been produced that recommend patients in whom this assay should be used.13 In kidney disease, the assay has been used to accurately identify the relationship between serum FLCs and chronic kidney disease (CKD),14 and has also been used in refining the diagnosis and assessing disease response in patients with monoclonal disease and renal involvement.11, 15, 16, 17, 18, 19, 20

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The biology of FLC production

Any intact immunoglobulin molecule has two identical light chains of the same isotype; either kappa or lambda, but never both. The correct conformation of normal immunoglobulin requires the production rate of FLCs to be 40% higher than that of heavy chains. The excess FLCs are released into the serum. Although all cells of B-cell lineage can produce FLCs, the dominant production of FLCs is by plasma cells. Nearly twice as many plasma cells produce intact immunoglobulins of kappa isotype than produce lambda isotype. This difference is reflected in variations in serum concentrations of the two isotypes, with a ratio of total kappa immunoglobulin to total lambda immunoglobulin of 1.8:1.2

However, the fact that two-thirds of FLC secretion is of kappa isotype is not reflected by the relative serum concentrations of FLCs (and therefore the ratio of the two isotypes) in people with normal renal function,2 as a result of major differences in the renal clearance of kappa and lambda FLCs.

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Renal clearance of FLCs

kappa FLCs are typically present as monomers in the serum, with a molecular weight of 22.5 kDa, a clearance of 40% and a serum half life of 2–4 h. However, lambda FLCs form dimers and consequently have a molecular weight of 45 kDa, a clearance of 20% and a serum half life of 3–6 h.21, 22 In people with normal kidney function, this results in a ratio of kappa:lambda FLCs in the serum of 0.58 (range 0.26–1.65), with median concentrations of 7.3 mg/l (range 3.3–19.4 mg/l) for kappa and 12.7 mg/l (range 5.7–26.3 mg/l) for lambda.2

Following glomerular filtration, FLCs are reabsorbed by proximal tubular epithelium through nonspecific binding to megalin/cubulin scavenger receptors.23, 24 The reabsorptive capacity of this mechanism is high; the proximal tubules can handle up to 30 g of protein per day.5 Consequently, FLCs are only present in the urine of healthy individuals at very low concentrations.25

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Polyclonal FLCs and renal impairment

Increased levels of serum polyclonal FLCs can result from either increased production or reduced clearance. Increased polyclonal FLC production can occur in both infective and inflammatory conditions,26 where serum concentrations can increase several-fold above normal. In CKD, increasing levels of polyclonal kappa and lambda FLCs correlate strongly with declining kidney function, with a stepwise increase in serum concentration with each increase in CKD stage (Figure 3).14 In patients with stage 4 CKD, the concentrations of polyclonal FLCs are more than five-fold higher than those present in individuals with normal renal function.14

Figure 3 | Serum FLC concentrations in patients with CKD.
Figure 3 : Serum FLC concentrations in patients with CKD. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.comBoth kappa (gray) and lambda (white) FLC increase progressively with each CKD stage (both P <0.0001). Data presented as box plots with whiskers; solid lines denote median values. Permission obtained from The American Society of Nephrology © Hutchison, C. A., et al. Quantitative assessment of serum and urinary polyclonal free light chains in patients with chronic kidney disease. Clin. J. Am. Soc. Nephrol. 3, 1684–1690 (2008).14 Abbreviation: FLC, free light chain.

As renal clearance decreases, reticuloendothelial removal of FLCs by pinocytosis becomes increasingly important. As this process is not affected by the different molecular weights of the two FLC isotypes, their serum ratio moves progressively towards the underlying production rates. As a result, a progressive increase occurs in the median kappa:lambda FLC ratio from 0.58 (healthy) to 1.19 in stage 5 CKD (pre-dialysis). The 100% reference range for the kappa:lambda FLC ratio for the whole CKD population is 0.37–3.1.14

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Identification of monoclonal FLCs by kappa:lambda ratio

The monoclonal production of FLCs by a plasma cell clone results in an abnormal serum FLC ratio. A monoclonal kappa FLC produces a high kappa:lambda ratio and a monoclonal lambda FLC produces a low kappa:lambda ratio (Figure 2). The presence of monoclonal FLCs will usually produce a grossly abnormal ratio; however, care is required when the ratio is just outside the standard reference range, as the reference range was derived from a population with normal renal function. If this range is used as a reference in patients with CKD, some individuals with a ratio outside the upper limit of this range will be inappropriately diagnosed with an FLC monoclonal gammopathy. A recent screening study of nearly 1,000 unselected patients identified a false positive rate of 5% for FLC monoclonality because of renal impairment.10 Furthermore, a separate study demonstrated a stepwise increase in false positives with decreasing eGFR: the false positive rates were 2.9%, 3.6% and 4.9% with eGFRs of >60 ml/min/1.73m2, <60 ml/min/1.73m2 and <30 ml/min/1.73m2, respectively.27

To address this problem, we validated a renal FLC ratio reference range (0.37–3.17) against the standard ratio reference range (0.26–1.65) in a population of patients with (dialysis-dependent) renal failure and monoclonal gammopathies.11 This alternative range increased the specificity of the Freelite™ assay for diagnosing monoclonal gammopathies in this setting from 93% to 99%, with 100% sensitivity in both groups.

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Screening for monoclonal FLCs

The use of serum alone for the investigation of monoclonal gammopathies by electrophoresis for intact monoclonal proteins and the Freelite™ assay for light-chain quantification is clearly an attractive option, but is important pathology missed by not assessing the urine? Several studies have now addressed this question.10, 28, 29, 30, 31, 32 The majority of these studies concluded that the assessment of serum alone would not overlook patients who required treatment. However, in a study of patients with AL amyloidosis, Palladini et al.31 found that 4% of cases would have been missed if the assessment had been performed by serum IFE and serum FLC assays without UPE. The largest study to date to address the question was reported by Katzmann and colleagues.32 The authors assessed the utility of SPE and serum FLC assessment alone in 1,877 patients with monoclonal gammopathies. The combination of tests, excluding urine assessment, missed 1% of patients with AL amyloidosis and 0.5% of patients with smoldering multiple myeloma; no patients with multiple myeloma, macroglobulinemia and light chain deposition disease were missed.

The most significant advantage of a diagnostic algorithm based on assessment of serum alone relates to the difficulty of obtaining paired urine and serum samples in the routine clinical setting. Where reported, laboratories did not receive paired samples in 48–83% of patients.10, 30, 33 By using serum assays to quantify FLCs, the risk of a delayed or missed diagnosis by deferred or non-provision of a 24-h urine sample can therefore be avoided.

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Assessment of monoclonal gammopathy

An underlying monoclonal gammopathy should be considered in the differential diagnosis of new presentation kidney disease, particularly in individuals with acute kidney injury (AKI) or proteinuric kidney disease. Following a diagnostic algorithm provides excellent discriminatory value for excluding the likelihood of monoclonal disease without knowledge of renal pathology. In cases where the renal histology is known and is consistent with injury associated with monoclonal disease, the underlying nature of the monoclonality is required to be established to substantiate the diagnosis; specialist hematology advice is important in obtaining this information and to direct disease-specific management.

The standard assessment of monoclonal gammopathy uses the combination of SPE (with or without IFE) and UPE (with or without IFE) using a concentrated 24-h urine sample. International guidelines recommend that IFE should be included in the initial assessment of serum samples, but clinical practice3, 10 and national guidelines34 indicate that this does not usually occur. Rather, serum IFE is used as a confirmatory test for the presence of a suspected monoclonal protein shown by SPE. Recently, the measurement of serum FLCs by immunoassays has been adopted into hematological guidelines as an alternative to the assessment of the urine for monoclonal FLCs.13, 34 A diagnostic algorithm that incorporates recommendations from both expert hematology consensus groups and 'real-world' practice is shown in Figure 4.

Figure 4 | Screening algorithm for suspected monoclonal gammopathies.
Figure 4 : Screening algorithm for suspected monoclonal gammopathies. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.comScreening for monoclonal proteins should always include assessment for both intact Ig and for FLCs. Intact monoclonal Igs are identified in the serum by SPE or IFE. Many centers undertake SPE as the first screening assessment for intact Igs; others would recommend IFE first. Monoclonal FLCs can either be identified in the serum using serum FLC immunoassays or in the urine using UPE (24-h collection). If all of these assessments are negative, the presence of a monoclonal protein is highly unlikely, but a tissue biopsy (*) should be considered in cases where there is a high index of suspicion of AL amyloidosis. ‡In cases where SPE, serum FLC assays or UPE are positive, IFE is usually performed. §In cases where UPE is negative, serum FLC analysis should be considered as an alternative to UPE to exclude clones that produce only low concentrations of monoclonal FLCs (previously classified as non-secretory multiple myeloma but can now be correctly identified as light-chain-only myeloma). When a monoclonal protein is identified, further diagnostic assessment is normally undertaken (including skeletal survey and bone marrow examination). Abbreviations: FLC, free light chain; IFE, immunofixation electrophoresis; Igs, immunoglobulins; SPE, serum protein electrophoresis; UPE, urinary protein electrophoresis.

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Disease-specific considerations

Monoclonal gammopathies can produce a range of renal injuries (Table 1) as defined by histological, immunohistochemical and electron microscopy assessment. The specific underlying disease is then diagnosed by specialist assessment including bone marrow studies, skeletal surveys and evaluation for monoclonal proteins.


MGUS

Monoclonal gammopathy of undetermined significance (MGUS) is the most common monoclonal gammopathy, with a prevalence of 3.2% in individuals over 50 years of age.35 The prevalence of MGUS increases with age and varies with ethnicity. By definition, MGUS is not associated with end-organ damage, but it does progress to clinically significant disease (such as myeloma or amyloidosis) at a rate of 1% per year.35 Previously identified risk factors for the progression of MGUS were the size and type of the M-spike (monoclonal protein spike).36 More recently, serum FLCs were shown to be an independent risk factor for progression of MGUS in a study carried out by the Mayo Clinic.37 Furthermore, when an abnormal FLC ratio is defined as a risk factor and is combined with an IgM or IgA type intact monoclonal gammopathy and an M-spike >15 g/l (which are other known independent risk factors for progression), 58% of patients with all three risk factors will progress to a disease phenotype over a period of 20 years, compared with a 5% risk of progression for individuals with no risk factors. Although the incidence of MGUS in patients with CKD is several-fold that of the general population,38 the significance of this finding is uncertain and current long-term follow-up strategies in this group are the same as those recommended for the general population with MGUS.39, 40

Myeloma

Myeloma has an incidence of around 40 per million population per year. Depending on the definition used, renal impairment is present in up to 50% of patients at presentation of their myeloma and is associated with increased morbidity and mortality.41 However, patients who recover renal function have clinical outcomes that are comparable to those of individuals with normal renal function.41 No published studies of renal histology exist in the area of myeloma and kidney disease that relate renal damage and function with serum FLC levels at diagnosis. In animal models, cast nephropathy develops with monoclonal FLCs at different concentrations, depending on the individual FLC and the presence or absence of other variable factors (for example, hydration, furosemide and calcium concentrations).42

In patients with severe AKI, a delayed diagnosis and/or delayed commencement of treatment can lead to the rapid development of in situ scarring.43 Monoclonal light chains have profound toxicity in this setting44 and prompt treatment is required.45 The rate of dialysis-dependent AKI in patients with myeloma has been estimated at 4–6 cases per million population per year; 90% of these patients have renal failure secondary to cast nephropathy and recovery to independent renal function occurred in less than 25% of published cases with this histology.46

We recently reported that treatment with chemotherapy and a serum FLC removal strategy using a high cut-off (protein-permeable) dialyzer resulted in renal recovery in 74% (14/19)46 of patients with cast nephropathy, high serum FLC levels and dialysis-dependent AKI. Renal recovery occurred in patients who had an early and sustained fall in serum FLC concentrations. A separate study in a cohort of patients undergoing plasma exchange as part of their treatment showed that renal recovery occurred when FLC levels dropped to 50% or less.18 On an individual case basis, therefore, serum FLCs might be a useful indicator of renal recovery. No assessments of the utility of serial monitoring of UFE as a determinant of renal recovery have been published. One major confounder when relating historic data with more recent outcomes is that the treatment of myeloma has evolved considerably over the past decade and newer agents, such as thalidomide and bortezomib, might be associated with improved renal outcomes.47, 48, 49

Finally, over two-thirds of patients with non-secretory myeloma—who had no detectable monoclonal protein by IFE and UPE—had detectable monoclonal FLCs by the Freelite™ immunoassay.50 Presumably UPE was normal in these patients because the monoclonal FLCs were completely reabsorbed by the proximal tubules.

Primary (AL) amyloidosis

Amyloidosis can be caused by a number of precursor proteins. This disorder is defined by the deposition, at a range of tissue sites, of an extracellular fibril protein that is characterized by 9–11 nm fibrils and, after Congo red staining, shows green birefringence under polarized light. The most common type of amyloidosis is primary or AL amyloidosis and the causative proteins in these cases are FLCs. AL amyloidosis has an incidence of around 10 per million population per year. Most cases of AL amyloidosis (98%) are associated with a mature plasma cell clone, but this disease can also occur with underlying B-cell lymphoproliferative disorders.51 The kidneys are the organ most commonly affected (74%); the majority of patients with kidney involvement present with nephrotic syndrome and normal renal function. If the amyloid deposits occur mainly in the vessels, however, the renal impairment can precede the proteinuria.52

In a study of 262 patients with AL amyloidosis, Lachmann et al.53 combined assessment of serum and urine by SPE and IFE and identified a monoclonal protein in 79% of patients. However, when the serum FLC immunoassays were used in combination with IFE, a monoclonal protein was identified in 98% of patients. As the serum FLC assay directly measures the circulating level of the precursor protein, it represents an important advance in the diagnosis and monitoring of the disease. Reduction in FLC level is associated with survival benefits, irrespective of the chemotherapy regimen used.53, 54

Particular care is required in the interpretation of a renal biopsy being assessed for AL amyloidosis. The renal diagnosis will be made with Congo red staining and electron microscopy to identify fibrils. However, the specific demonstration of clonal FLCs in situ by immunofluorescence is shown in only two-thirds of cases of AL amyloidosis.55 An assessment of monoclonal gammopathy, including the quantification of serum FLCs, should be performed in all cases where primary amyloidosis is suspected, including those cases that are positive for amyloid by Congo red and electron microscopy, but negative for immunochemical assessments of FLCs.

Immunoglobulin deposition disease

LCDD is most frequently associated with monoclonal kappa FLCs (types I and IV).56 These deposits are, by definition, non-amyloidotic, predominately localized to the kidney basement membranes (glomerular and tubular), amorphous and electron-dense. In addition to the glomerulopathy, FLCs promote mesangial cell transformation to a myofibroblastic phenotype with active production of extracellular matrix mediated by the increased production of transforming growth factor-beta.57 Light chain deposition disease is associated with multiple myeloma in 65% of cases, and the kidney is the organ most frequently involved, with kidney involvement affecting nearly all patients (96%).58 In one series, LCDD accounted for 19% of 118 renal biopsies from patients with multiple myeloma.59

Renal impairment is common at presentation and can progress rapidly; it is often associated with a heavy proteinuria. To date, no evaluations of the diagnostic utility of serum FLC immunoassays have been performed in patients with LCDD and the diagnosis of LCDD remains a histological one. Anecdotal evidence, however, suggests a utility for these assays in the monitoring of patients' responses to treatment.20

In addition to LCDD, the deposition of immunoglobulin heavy chains can occur independently of light chains (heavy chain deposition disease) or together with light chains (light/heavy chain deposition disease). Both of these conditions are considerably rarer than LCDD and only one large case series has described them in the literature.60 No significant differences in the presenting features or outcomes of these three patterns of immunoglobulin deposition disease seem to exist. However, Lin et al.60 clearly demonstrated that patients with LCDD who have co-existing cast nephropathy have a significantly worse prognosis, both in terms of progression to end-stage renal failure and overall patient survival, compared with those without cast nephropathy.

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Conclusions

As a consequence of their structure and size, free light chains have an intimate relationship with renal function and with the development of kidney disease. Serum FLC immunoassays have been adopted into hematology guidelines for the diagnosis and monitoring of patients with monoclonal gammopathies. The high sensitivity of these assays provides broad applicability for patients with kidney disease, but an awareness of the different reference range for FLCs in patients with renal impairment is important.

Review criteria

The PubMed and MEDLINE databases were searched using the following terms: monoclonal proteins, monoclonal gammopathies or plasma cell dyscrasias, free light chains, renal or kidney. C. A. Hutchison and K. Basnayake screened all of these manuscripts for relevance to the review area. P. Cockwell performed a secondary review of the manuscripts screened by C. A. Hutchison and K. Basnayake. No limitations were placed on publication dates or languages.

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Acknowledgments

Charles P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.

Competing interests statement

The authors declare no competing interests.

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References

  1. Bradwell, A. R. et al. Highly sensitive automated immunoassay for immunoglobulin FLCs in serum and urine. Clin. Chem. 47, 673–680 (2001).

  2. Katzmann, J. A. et al. Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. Clin. Chem. 48, 1437–1444 (2002).

  3. Doyle, A., Soutar, R. & Geddes, C. C. Multiple myeloma in chronic kidney disease. Nephron Clin. Pract. 111, c7–c11 (2009).

  4. Jones, H. B. Papers on chemical pathology, Lecture III. Lancet II, 88–92 (1847).

  5. Solomon, A., Waldmann, T. A., Fahey, J. L. & McFarlane, A. S. Metabolism of Bence Jones proteins. J. Clin. Invest. 43, 103–117 (1964).

  6. Lindstedt, G. & Lungberg, P. Loss of tubular proteinuria pattern during urine concentration with a commerical membrane filter cell. Clin. Chem. Acta 56, 125–126 (1974).

  7. Harrison, H. H. The "Ladder Light Chain" or "Pseudo-Oligoclonal" pattern in urinary immunofixation electrophoresis (IFE) studies: a distinct IFE pattern and an explanation hypothesis relating it to free polyclonal light chains. Clin. Chem. 37, 1559–1564 (1991).

  8. Hess, P. P., Mastropaolo, W., Thompson, G. D. & Levinson, S. S. Interference of polyclonal free light chains with identification of Bence-Jones proteins. Clin. Chem. 39, 1734–1738 (1993).

  9. Bridgen, M. L., Neal, E. D., McNeely, N. D. & Hoag, G. N. The optimal urine collection for detection and monitoring of Bence Jones proteinuria. Am. J. Clin. Path. 93, 689–693 (1990).

  10. Hill, P. G., Forsyth, J. M., Rai, B. & Mayne, S. Serum free light chains: an alternative to the urine Bence Jones proteins screening test for monoclonal gammopathies. Clin. Chem. 52, 1743–1748 (2006).

  11. Hutchison, C. A. et al. Serum free light chain measurement aids the diagnosis of myeloma in patients with severe renal failure. BMC Nephrol. 22, 11 (2008).

  12. Pratt, G. The evolving use of serum free light chain assays in haematology. Br. J. Haematol. 141, 413–422 (2008).

  13. Dispenzieri, A. et al. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia 23, 215–224 (2009).

  14. Hutchison, C. A. et al. Quantitative assessment of serum and urinary polyclonal free light chains in patients with chronic kidney disease. Clin. J. Am. Soc. Nephrol. 3, 1684–1690 (2008).

  15. Hutchison, C. A. et al. Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: in vitro and in vivo studies. J. Am. Soc. Nephrol. 18, 886–895 (2007).

  16. Cserti, C., Haspel, R., Stowell, C. & Dzik, W. Light-chain removal by plasmapheresis in myeloma-associated renal failure. Transfusion 47, 511–514 (2007).

  17. Pillon, L. et al. Approach to acute renal failure in biopsy proven myeloma cast nephropathy: is there still a role for plasmapharesis? Kidney Int. 74, 956–961 (2008).

  18. Leung, N. et al. Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains. Kidney Int. 73, 1282–1288 (2008).

  19. Ritz, E. Plasma exchange for acute renal failure of myeloma—logical, yet ineffective. J. Am. Soc. Nephrol. 17, 914–916 (2006).

  20. Brockhurst, I., Harris, K. P. & Chapman, C. S. Diagnosis and monitoring a case of light-chain deposition disease in the kidney using a new, sensitive immunoassay. Nephrol. Dial. Transplant. 20, 1251–1253 (2005).

  21. Miettinen, T. A. & Kekki, M. Effect of impaired hepatic and renal function on Bence Jones protein catabolism in human subjects. Clin. Chim. Acta 18, 395–407 (1967).

  22. Wochner, R. D., Strober, W. & Waldmann, T. A. The role of the kidney in the catabolism of Bence Jones proteins and immunoglobulin fragments. J. Exp. Med. 126, 207–221 (1967).

  23. Klassen, R. et al. Light chains are a ligand for megalin. J. Appl. Physiol. 98, 257–263 (2005).

  24. Batuman, V. et al. Myeloma light chains are ligands for cubilin (gp280). Am. J. Physiol. Renal Physiol. 275, F246–F254 (1998).

  25. Hutchison, C. A. et al. Quantitative assessment of serum and urinary polyclonal free light chains in patients with type II diabetes: an early marker of diabetic kidney disease? Expert Opin. Ther. Targets 12, 667–676 (2008).

  26. Hoffman, U. et al. Free immunoglobulin light chains in patients with rheumatic diseases. Z. Rheumatol. 62 (Suppl. 1), 1051 (2003).

  27. Vermeersch, P., Van Hoovels, L., Delforge, M., Godelieve, M. & Bossuyt, X. Diagnostic performance of serum free light chain measurement in patients suspected of a monoclonal B-cell disorder. Br. J. Haematol. 143, 496–502 (2008).

  28. Katzmann, J. A. et al. Elimination of the need for urine studies in the screening algorithm for monoclonal gammopathies by using serum immunofixation and free light chain assays. Mayo Clin. Proc. 81, 1575–1578 (2006).

  29. Hofman, W., Garbrecht, M., Bradwell, A. R. & Guder, W. G. A new concept for detection of Bence Jones proteinuria in patients with monoclonal gammopathy. Clin. Lab. 50, 181–185 (2004).

  30. Beetham, R., Wassell, J., Wallage, M. J., Whiteway, A. J. & James, J. A. Can serum free light chains replace urine electrophoresis in the detection of monoclonal gammopathies? Ann. Clin. Biochem. 44, 516–522 (2007).

  31. Palladini, G. et al. Identification of amyloidogenic light chains requires the combination of serum free light chain assay with immunofixation of serum and urine. Clin. Chem. 55, 499–504 (2009).

  32. Katzmann, J. A. et al. Screening panels for detection of monoclonal gammopathies. Clin. Chem. 55, 1517–1522 (2009).

  33. Holding, S. et al. Combination of serum free light chain analysis with capillary zone electrophoresis improves screening for monoclonal gammopathies [abstract]. Blood 110, 1497 (2007).

  34. Smith, A., Wisloff, F. & Samson, D. On behalf of the UK Myeloma Forum, Nordic Myeloma Study Group and British Committee for Standards in Haematology. Br. J. Haematol. 132, 410–451 (2005).

  35. Kyle, R. A. et al. Prevalence of monoclonal gammopathy of undetermined significance. N. Engl. J. Med. 354, 1362–1369 (2006).

  36. Kyle, R. A. & Rajkumar, S. V. Monoclonal gammopathy of undetermined significance. Br. J. Haematol. 134, 573–589 (2006).

  37. Kyle, R. A. et al. A long term study of prognosis in monoclonal gammopathy of undetermined significance. N. Engl. J. Med. 346, 564–569 (2002).

  38. Hutchison, C. A. et al. Free light chain abnormalities in patients with chronic kidney disease [abstract]. J. Am. Soc. Nephrol. 17, 899a (2006).

  39. Rajkumar, S. V. et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 106, 812–817 (2005).

  40. Blade, J. Monoclonal gammopathy of undetermined significance. N. Engl. J. Med. 355, 2765–2770 (2006).

  41. Blade, J. et al. Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution. Arch. Intern. Med. 158, 1889–1893 (1998).

  42. Sanders, P. W. Pathogenesis and treatment of myeloma kidney. J. Lab. Clin. Med. 124, 484–488 (1994).

  43. Basnayake, K. et al. Resolution of cast nephropathy following free light chain removal by haemodialysis in a patient with multiple myeloma: a case report. J. Med. Case Reports 2, 380 (2008).

  44. Wang, P. X. & Sanders P. W. Immunoglobulin light chains generate hydrogen peroxide. J. Am. Soc. Nephrol. 18, 1239–1245 (2007).

  45. Sanders, P. W. Management of paraproteinemic renal disease. Curr. Opin. Nephrol. Hypertens. 14, 97–103 (2005).

  46. Hutchison, C. A. et al. Treatment of acute renal failure secondary to multiple myeloma with chemotherapy and extended high cut-off hemodialysis. Clin. J. Am. Soc. Nephrol. 4, 745–754 (2009).

  47. Chanan-Khan, A. A. et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood 109, 2604–2606 (2007).

  48. Ludwig, H. et al. Reversal of acute renal failure by bortezomib-based chemotherapy in patients with multiple myeloma. Haematologica 92, 1411–1414 (2007).

  49. Kastritis, E. et al. Reversibility of renal failure in newly diagnosed multiple myeloma patients treated with high dose dexamethasone-containing regimes and the impact of novel agents. Haematologica 92, 546–549 (2007).

  50. Drayson, M. et al. Serum free light-chain measurements for identifying and monitoring patients with nonsecretory multiple myeloma. Blood 97, 2900–2902 (2001).

  51. Sanchorawala, V. et al. AL amyloidosis associated with B-cell lymphoproliferative disorders: frequency and treatment outcomes. Am. J. Hematol. 81, 692–695 (2006).

  52. Rysavá, R. AL amyloidosis with renal involvement. Kidney Blood Press. Res. 30, 359–364 (2007).

  53. Lachmann, H. J. et al. Outcome in systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light chains following chemotherapy. Br. J. Haematol. 122, 78–84 (2003).

  54. Matsuda, M. et al. Serum levels of free light chains before and after chemotherapy in primary systemic AL amyloidosis. Intern. Med. 44, 428–433 (2005).

  55. Novak, L., Cook, W. J., Herrera, G. A. & Sanders, P. W. AL-amyloidosis is under-diagnosed in renal biopsies. Nephrol. Dial. Transplant. 19, 3050–3053 (2004).

  56. Deret, S. et al. Molecular modeling of immunoglobulin light chains implicates hydrophobic residues in non-amyloid light chain deposition disease. Prot. Eng. 10, 1191–1197 (1997).

  57. Zhu, L. et al. Pathogenesis of glomerulosclerosis in light chain deposition disease. Role for transforming growth factor-beta. Am. J. Pathol. 147, 375–385 (1995).

  58. Pozzi, C. et al. Light chain deposition disease with renal involvement: clinical characteristics and prognostic factors. Am. J. Kidney Dis. 42, 1154–1163 (2003).

  59. Montseny, J. J. et al. Long-term outcome according to renal histological lesions in 118 patients with monoclonal gammopathies. Nephrol. Dial. Transplant. 13, 1438–1445 (1998).

  60. Lin, J. et al. Renal monoclonal immunoglobulin deposition disease: the disease spectrum. J. Am. Soc. Nephrol. 12, 1482–1492 (2001).

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Author affiliations

Renal Institute of Birmingham, University Hospital Birmingham, and Department of Infection and Immunity, University of Birmingham, Birmingham, UK. (C A Hutchison, K Basnayake, P Cockwell).

Correspondence to: C A Hutchison Email: c.a.hutchison@bham.ac.uk

Published online 29 September 2009

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