Monoclonal (M) proteins are the products of certain clones of the B-cell lineage. A B-cell clone can secrete the entire immunoglobulin (Ig), the Ig with excess free light chain (FLC), FLC only or light (LC) and heavy chain (HC) separately. In a minority of patients, the M-protein appears only transiently. This is most commonly seen in the setting of autoimmune diseases or infections . In a majority of the patients though the M-protein is persistent. The level of these proteins can remain stable over a long period of time in some patients . A rising M-protein level signals the progression of the clonal disorder.
The first M-protein testing was described by Dr. William Macintyre and published by Henry Bence Jones . The M-Ig FLC in the urine reversibly opacified when boiled and having acid added to the solution. In honor of his work, the M-LC was later named the Bence Jones protein (BJP). Advances in electrophoresis technique allowed for the separation of serum proteins into three major bands, α, β, and γ . In 1956, Korngold and Lipari demonstrated that the BJP actually contained two antigenic separate types of 7-S globulin which were later named κ and λ in their honor . Five classes of HC have been identified. These are A, G, M, D, and E. In addition to the HC classes, four subclasses of IgG and two subclasses of IgA exist. Of the five classes of Ig, M-protein is the rarest for IgE.
The detection of M-proteins is vitally important in the diagnosis of plasma cell dyscrasias and B-cell lymphoproliferative disorders . Monoclonal gammopathy of undetermined significance (MGUS) a premalignant condition is differentiated from myeloma based on the size of the M-protein [6–8]. Similarly, reduction of the M-protein is used to gauge response to therapy . While the progression of myeloma and other lymphoproliferative disorders depends on the expansion of the clonal mass, proliferation is not necessary for the development and progression of kidney diseases associated with paraproteins. In these conditions, the pathophysiology is linked directly to the toxic properties of the M-protein. Thus, the presence of M-protein may be as important as the level or rate of change. Indeed, these entities are more likely to be found in patients who do not meet criteria for MM. This recognition prompted the introduction of the term monoclonal gammopathy of renal significance (MGRS) to separate these nephrotoxic M gammopathies from MGUS which is benign . MGRS can be the result of any B-cell or plasma cell proliferative disorders that do not meet the criteria for symptomatic MM or malignant lymphoma. Because of this, LC cast nephropathy is not a MGRS related nephropathy as it always occurs in high tumor burden MM.
MGRS is defined by the presence of a nephrotoxic M-protein . A large variety of renal lesions are associated with MGRS (Table 1) [10–14]. Examples include light chain proximal tubulopathy (LCPT) with or without Fanconi syndrome, proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), Ig-LC amyloidosis (AL) and monoclonal immunoglobulin deposition disease (MIDD). As the hematologic characteristics behave more like MGUS in many of these patients, treatment with cytotoxic agents had been traditionally withheld. Differentiating MGRS from the MGUS opened the door to treating these low tumor burden conditions with cytotoxic agents without the need for a diagnosis of MM . The differences in hematologic characteristics do require a slightly different approach to treatment of MGRS as compared with MM or malignant lymphoma. Aside from AL which is fatal, many of the patients with MGRS-associated nephropathies do not have an immediate risk to their survival. Therefore, the primary goal of treatment in MGRS is often the preservation of renal function rather than improving patient survival. In addition, as MGRS-associated nephropathies recur at a high rate after kidney transplantation, reduction of this risk should be another goal prior to transplant [16, 17]. In AL and MIDD, studies have found that a minimum of a hematologic very good partial response (VGPR) is needed for preservation and improvement of the renal function [18, 19]. Others have found the achievement of a complete response (CR) can minimize the risk of recurrence after kidney transplant in AL, and MIDD [19, 20]. However, it is important to note that the degree of M-protein reduction is disease- and patient-specific as the nephrotoxicity of the M-proteins differ from disease to disease and patient to patient. A prime example of this is seen in cast nephropathy. Some patient develops cast nephropathy with FLC levels of 157 mg/dL (1570 mg/L) while others at 6960 mg/dL (69,600 mg/L) . Similar differences have also been noted in AL and MIDD [22, 23]. The reduction of the M-protein is primarily achieved by cytotoxic therapy such as chemotherapy (low and high dose) and radiation in localized disease. As such, precise tools are needed in order to monitor therapy so sufficient elimination of toxic M-protein is accomplished while minimizing adverse effects. Thus, the accurate assessment of the hematologic response is vital for the successful treatment of the kidney disease or the renal replacement therapy with kidney transplantation.
MGRS is often detected when monotypic Ig or its fragments (LC and/or HC restriction) is detected on a kidney biopsy. At other times, the MGRS is detected during an evaluation of a kidney disorder. As most MGRS-related nephropathies exhibit proteinuria, often high grade, M-protein testing should be performed on all patients with proteinuria without obvious causes such as diabetes. The one condition that is not associated with high-grade proteinuria is vascular limited renal AL which presents with progressive renal impairment . Both high-grade proteinuria and progressive renal impairment are clear indications for renal biopsy so this is similar to non-MGRS renal diseases. It is important to note that MGUS patients outnumber patients with glomerular disease and that not all patients with renal dysfunction and a M-protein have a MGRS-related nephropathy [6, 25]. On the other hand, the threshold for a renal biopsy should be lowered by the presence of a M gammopathy even in the setting of low-grade proteinuria (1–3 g/day) in order to avoid missing the diagnosis of a MGRS-related nephropathy.
The diagnosis and the assessment of response in MGRS rely heavily on the precise measurement of the M gammopathy. It is therefore important for clinicians dealing with these patients to have a good understanding of the tests currently available. The following is a summary of the current clinical tests available for detection and monitoring of M-protein and those that are in development. One must also keep in mind that currently no single test can provide all of the information necessary to the clinician. Furthermore, depending on the disease, reduction of the toxic component (i.e. FLC) is sometimes more important than reduction of the entire M-protein . A thorough understanding of the capabilities and limitations of the tests will lead to better patient care.
Serum protein electrophoresis
The most common method used for detection of M-protein is electrophoresis. Serum protein electrophoresis (SPEP) is a rapid and inexpensive test that is commonly used for screening. SPEP is traditionally performed on agarose gel . Electric current separates proteins loaded on the gel by charge and size. Five zones or fractions are seen in the serum (Figure 1). These are albumin, α1, α2, β, and γ . It is not uncommon for the β-fraction to have two peaks. In normal serum, albumin is the most abundant protein. A sharp band appears when an M-protein is present. This often occurs in the γ region; however, M-proteins can also migrate in the β or even in the α-fractions. M-IgA and FLC are the most common M-proteins that are found outside of the γ region. In some cases, a decrease in the γ peak is noted. This is the characteristic of hypogammaglobulinemia which is the result of immunoparesis from the M-protein .
SPEP is the most frequently used test for the detection of M-proteins around the world. Fully automated systems are available for both agarose gel and capillary electrophoresis. Capillary tube systems have higher reproducibility and are more efficient and cost effective . However, if immunofixation (see below) is required, a gel is required. An automated reader scans and measures the size of the zones and peaks. Because it is quantitative, SPEP is used for diagnostic and response assessment in MM. Despite the benefits, SPEP does have a number of drawbacks. First, its high detection limit is not sensitive enough for low burden diseases such as MGRS. The detection limit is 0.3–0.5 g/dL (3–5 g/L) in the γ region and as high as 0.7 g/dL (7 g/L) in α or β region . As a result, SPEP is positive in 87.6% of MM, but only 73.8% of AL and 55.6% of light chain deposition disease (LCDD) . Secondly, it is purely quantitative. It cannot identify the type of M-protein in the band. For this, immunofixation electrophoresis (IFE) is required.
Urine protein electrophoresis
As mentioned earlier, the first person to describe the special properties of M-protein in the urine was Dr. William MacIntyre . BJP, as it was later called, was identified as Ig-FLC. In the urine, M-proteins are usually just FLC or fragments of Ig as intact Igs are usually too large to get through the slit diaphragm of a healthy glomerulus. Urine protein electrophoresis (UPEP) is performed similarly to SPEP. It also has the same basic advantages and disadvantages. The urine M-protein is used for diagnosis and response determination in MM. However, there are also some differences. UPEP is much less sensitive than SPEP because M-proteins are not always present in the urine of patients with M gammopathies . Therefore, the sensitivity of UPEP is the lowest of all the tests. Thus, UPEP should never be used as a screening test by itself. In a study with 2799 patients where 4.4% had a plasma cell dyscrasia, UPEP was positive in only 37.7% of cases as compared to 94.4% for SPEP .
The low sensitivity has led to the suggestion of replacing UPEP with the sFLC assay for screening. Despite the low sensitivity, UPEP does provide information that other tests cannot. First, the electrophoretic pattern is helpful in distinguishing the type of renal injury in patients with M gammopathy or MM. Patients with cast nephropathy have predominately M-Ig FLC in the urine while patients with AL or LCDD have high concentration of albumin . UPEP accurate differentiates cast nephropathy from AL or MIDD. In addition, the presence of M-LC in the urine is associated with increased risk of renal injury in MM. Thus myeloma patients with positive UPEP should be followed more closely for the potential renal threat. Finally, reduction of urine M-protein is one of the response criteria in MM . So, in spite of its shortcomings, UPEP remains a useful supplemental test in patients with paraproteinemia.
Serum and urine immunofixation
The principle of IFE is similar to that of the Western blot. Samples are loaded in parallel lanes and undergo electrophoresis. Unlike in Western blot where the proteins are transferred to paper, antibodies against the HC and LCs of the Ig are directly applied to each lane separately on the gel. The formation of a sharp band indicates the presence of M-Ig component (Figure 1). A M-Ig would be positive for both a HC and a LC while LC only M-protein would only be positive for a single LC. M gammopathy involving HC only often are either negative or demonstrate LC only as these HCs are truncated and may not be detected by the antibodies.
IFE increases the sensitivity to a detection limit of ~0.1 g/dL (~1 g/L) of M-protein . Studies have shown that serum IFE can detect 94.4% of MM cases by itself. IFE also detects 73.8% of AL vs. 65.9% with SPEP . IFE is most helpful in the typing of M-protein and assessment of CR. This could be important especially in cases where more than one M-protein is present. The extra reagents and time add significantly to the cost making IFE more expensive than PEP. However, a recent study suggests that immunofixation is more sensitive at detecting the M-protein in PGNMID than other tests including sFLC assay . This may be due to the fact that the M-protein deposits in PGNMID are always an intact Ig rather than a M-FLC [37, 38].
Nearly 150 years after Dr. Bence Jones first described M-FLCs in the urine, their measurement in the serum became part of routine clinical care for patients with plasma cell dyscrasias. This breakthrough, in 2001, came following many years of work trying to solve the seemingly simple problem of how to measure LCs in the serum which were “free” but not those included in the intact Igs which are typically present at concentrations hundreds-of-fold higher . In the 1970s, size-separation chromatography had been used with accurate results to quantify FLCs in the serum but this technique would not prove to be practical outside of research laboratories.
The routine measurement of FLCs became possible with the development of immunoassays specific to epitopes which are hidden when the LCs are bound but exposed when they are free. The first of these assays to be developed utilized polyclonal antibodies raised in sheep (Freelite®, The Binding Site, Birmingham, UK). The assays provide sensitive measurement of the individual FLC isotype down to normal concentrations seen in health. Monoclonality of a FLC is identified by measuring both FLC isotypes and comparing the ratio of κ to λ. In 2002, Katzman et al. described the diagnostic range for the κ/λ ratio in 282 healthy blood donors . The 100% range of 0.26–1.65 was chosen for clinical practice to avoid a high number of false positives which may have occurred if a 95% range had been used. A M-FLC is therefore identified when a FLC ratio falls outside of this range due to the overproduction of one FLC isotype. This comparison of the two FLC isotypes by a ratio is required as elevation of both FLC isotypes can occur when there is increased polyclonal production of Igs, as seen in infections, or reduced clearance of FLCs occurs as in renal impairment.
The FLC assay quickly caught the interest of the international hematology community when Drayson et al. identified that over half of the patients classified as having a non-secretory MM had M-FLCs present when assessed with these new assays. These patients could therefore be reclassified as having FLC only MM . From this early clinical study these assays have been evaluated across numerous clinical scenarios and are now included in international clinical guidelines for the diagnosis of plasma cell dyscrasia; for the monitoring of patients with MM, for the risk stratification of MGUS, and to define stringent CR . When combined with SPEP and IFE in a serum only screening algorithm the FLC assays identified 100% of patients with MM, 97% of AL, and 90% of patients with plasmacytoma . In the renal field the Freelite assays have been shown to identify 100% of patients with myeloma causing acute kidney injury, and they provide a marker of early disease response and sensitive predictor of renal outcomes [42–44].
Interpretation of Freelite assays in renal impairment
FLCs are middle molecular weight proteins. κ-FLCs are typically present in the serum as a monomer and λ as a dimer, with corresponding molecular weights of 22.5 and 45 kDa, respectively. Both molecules are therefore filtered relatively free at the glomerulus and in health FLC are almost entirely reabsorbed from the filtrate by the megalin/cubulin receptors in the proximal tubules . The quantities of polyclonal FLCs entering the urine are therefore low when the tubules are functioning normally.
In the context of renal impairment the serum half-lives and therefore absolute serum concentrations of both molecules increase as the GFR falls . As renal impairment progresses the serum half-lives of FLCs becomes increasingly influenced by the slower reticuloendothelial clearance. Clearance of FLCs by pinocytosis in the reticuloendothelial system does not discriminate between the two isotypes based on size, in comparison with renal clearance which preferentially clears the smaller κ molecules. Therefore as renal failure progresses the serum concentrations of FLCs become more representative of the underlying production rate, which is approximately 1.8:1 (κ:λ). This translates through to a change in the normal reference range for the FLC ratio in renal impairment to 0.37–3.1 from that used in the general population of 0.26–1.65 . When used in clinical practice this “renal range” increased the specificity of the Freelite assays for identifying myeloma causing acute kidney injury from 93% to 98% without reducing the sensitivity of the assays .
New FLC assays
As the advent of the original Freelite assays, two further FLC assays have been developed. The first is an N-latex nephelometric assay which utilizes several M antibodies for both κ and λ reagents (Siemens, Marburg, Germany). Multiple M antibodies are used in each reagent to increase the ability of the assay to identify all M-FLCs. The Siemens assay has been adopted quickly into clinical practice predominately through the routine laboratories already using Siemens platforms. Data supporting the utility of these assays in clinical practice is lagging behind their uptake in clinics and to date no international guidelines support their use.
Direct comparison of the N-latex assays with the Freelite assays has identified two principal issues: First, the absolute values reported by the two assays are significantly different, resulting in correlations below the international standard of equivalence, R2>0.95 [47–50]. Second, in head-to-head studies of patients with FLC only myeloma the N-latex assays have not identified, all patients identified as abnormal by Freelite and vice versa [47, 49, 51]. In AL, N-latex was normal in 21% vs. 15% with Freelite. While this was not statistically significant (p=0.3), the study was quite small with only 62 patients. When combined with serum and urine IFE, N-latex assays identified 98% of the patients similar to Freelite assays. On the other hand, the median reduction of difference in FLC (dFLC) as measured by the assays was different (N-latex=68% vs. Freelite 77%, p=0.04). This means that no mathematical relationship exists between the results of the two assays. It also means that neither assay was able to detect all of the patients. Thus, the two assays cannot be used interchangeably but may be useful as complementary tests. Significant debate as to how the N-latex assays should be incorporated into clinical practice and future guidelines is now required. To date, the assay is still awaiting FDA approval in the US but is currently in use in Europe and Australia.
The third FLC assay to enter the field is another luminex assay using bead-immobilized mouse anti-human M antibodies (Seralite®, Abingdon Health, York, UK) . This assay is just starting to be evaluated in clinical practice and is being specifically targeted as a point of care test.
With each new test, the sensitivity and specificity for M-proteins improved. The addition of immunofixation increased the sensitivity of protein electrophoresis by about 30 folds . Similarly, the advent of the sFLC assay added another 30-fold sensitivity to immunofixation. The majority of the non-secretory myelomas were found to be Ig-LC only . Two new tests show promising results that lead to higher sensitivity and specificity. Using time-of-flight (TOF) technique, a mass spectrometer can quickly and accurately detect M-proteins based on their mass to charge ratio. As, each M-FLC has a unique mass to charge ratio, only a very small amount of the protein is required for a positive identification (Figure 2A–D). Because proteomic analysis is not required for TOF, this technique is fast and inexpensive. TOF mass spectrometry easily identified the κ-LC in adalimumab (mw=23,412.13 Da) when spiked into normal serum. The detection limit for κ-LC was 0.005 g/dL (0.05 g/L) and 0.025 g/dL (0.25 g/L) for the HC with a coefficient of variation of 6.2% . TOF mass spectrometry identified M LC in patients who were classified as achieving CR by immunofixation and sFLC assay. This higher sensitivity and specificity will be extremely helpful in minimal residue disease (MRD) detection and MGRS-related kidney diseases that have low levels M-Ig . The mass spectrometer can accept multiple types of body fluid. Bound LCs and FLC are separated by preserving the bond between the LC and the HC. Unfortunately, its high sensitivity is also one of its limitations. TOF mass spectrometry can detect oligoclonal bands that IFE cannot. While this is not a problem in MM where the M-LC is the dominate species and easily distinguishable, identification of a ultralow level M-LC such as those found in PGNMID can be difficult if it exists in an oligoclonal milieu. Despite that, mass spectrometry offers a significant improvement in M-protein detection once the technique has been perfected.
Another novel test is the urinary exosomes which are extracellular vesicles secreted by the various cells in the urinary tract. As such they contain both surface bound proteins as well as cytoplasmic proteins presented in the innate orientation of the cell . This makes them an extremely powerful tool for the study of cellular proteomics in the urinary tract. In addition, the process of isolating urinary exosomes automatically enriches the concentrations of urinary proteins. In patients with AL, urinary exosomes were found to contain monotypic LC oligomers attached to the surface of exosomes most often from the glomerular fractions (Figure 3) . Urinary exosomes appear very specific for AL as only monomeric LCs were found in exosomes of patients with MM. Furthermore, the oligomeric LC species disappeared in patients who achieved a CR. This suggests urinary exosomes could be an excellent biomarker for renal response in MGRS-associated nephropathies.
In summary, the ability to accurately detect M-proteins has dramatically changed the way conditions like MM and Waldenstrom macroglobulinemia are diagnosed and managed. SPEP which measures the concentration of M-protein helps determine when treatment may be needed as well as the response to treatment. IFE and FLC assays not only help determine the type of M-protein and the clone, but their higher sensitivity help link M-proteins to the development of kidney diseases in patients who do not have the clonal mass or features to be considered MM or lymphoma. These MGRS clones typically have lower proliferation rates similar to MGUS. Because of that, the M-protein can be difficult to detect due to the low concentration. Newer techniques such as TOF mass spectrometry have the potential of increasing the sensitivity even further than that of FLC assay. Urinary exosomes have the potential of differentiating between nephrotoxic and non-nephrotoxic M-LCs. These techniques will no doubt increase our understanding of the pathophysiology and advance the treatment of these patients.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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About the article
Published Online: 2016-04-23
Published in Print: 2016-06-01