The term monoclonal gammopathy of renal significance (MGRS) was introduced by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. The IKMG met in April 2017 to refine the definition of MGRS and to update the diagnostic criteria for MGRS-related diseases. Accordingly, in this Expert Consensus Document, the IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy. The diagnosis of MGRS-related disease is established by kidney biopsy and immunofluorescence studies to identify the monotypic immunoglobulin deposits (although these deposits are minimal in patients with either C3 glomerulopathy or thrombotic microangiopathy). Accordingly, the IKMG recommends a kidney biopsy in patients suspected of having MGRS to maximize the chance of correct diagnosis. Serum and urine protein electrophoresis and immunofixation, as well as analyses of serum free light chains, should also be performed to identify the monoclonal immunoglobulin, which helps to establish the diagnosis of MGRS and might also be useful for assessing responses to treatment. Finally, bone marrow aspiration and biopsy should be conducted to identify the lymphoproliferative clone. Flow cytometry can be helpful in identifying small clones. Additional genetic tests and fluorescent in situ hybridization studies are helpful for clonal identification and for generating treatment recommendations. Treatment of MGRS was not addressed at the 2017 IKMG meeting; consequently, this Expert Consensus Document does not include any recommendations for the treatment of patients with MGRS.
The concept of monoclonal gammopathy of undetermined significance (MGUS) was first introduced in 1978 by Robert Kyle1. This premalignant condition is characterized by the presence of a serum monoclonal immunoglobulin <30 g/l and <10% monoclonal bone marrow plasma cells in a patient who does not have any organ damage attributable to the monoclonal immunoglobulin. Conversion of MGUS to malignancy, which mandates the initiation of appropriate treatment, is indicated by the development of disease-specific features. For example, conversion to multiple myeloma (MM) is indicated by the occurrence of one or more myeloma-defining events, such as hypercalcaemia, renal impairment, anaemia, lytic bone lesions or an event suggestive of impending myeloma (such as a serum involved:uninvolved free light-chain ratio >100, >60% bone marrow plasma cells or ≥1 bone lesions on MRI)2. Progression to Waldenström macroglobulinaemia (WM) is indicated by the development of anaemia, thrombocytopenia, bulky adenopathy or organomegaly, blood hyperviscosity, severe neuropathy, amyloidosis, cryoglobulinaemia, cold agglutinin disease or malignant transformation3. Similarly, treatment for chronic lymphocytic leukaemia (CLL) is initiated when a patient with MGUS develops cytopenias, progressive or symptomatic lymphadenopathy, organomegaly or constitutional symptoms4. Patients with MGUS who do not yet exhibit any of these disease-specific features do not require treatment but should undergo careful monitoring2,5,6,7,8,9.
The kidney is commonly involved in these haematological malignancies. Light-chain cast nephropathy is now considered a myeloma-defining event, although it is not exclusive to MM10. In addition to cryoglobulinaemic glomerulonephritis, a variety of other kidney diseases have been observed in patients with WM, including immunoglobulin light-chain (AL) amyloidosis, monoclonal immunoglobulin deposition disease (MIDD), light-chain proximal tubulopathy (LCPT) and, on rare occasions, cast nephropathy11,12,13. Similar renal lesions have also been described in patients with CLL14. Importantly, however, these kidney diseases have also been described in patients with a low clonal burden (defined as monoclonal immunoglobulin <30 g/l and <10% monoclonal bone marrow plasma cells) who therefore do not meet the diagnostic criteria for MM or other malignancies. In the past, these patients were categorized as having ‘idiopathic’ light-chain disposition disease or ‘primary’ amyloidosis15,16. The fact that these kidney lesions have been replicated in animal models by Bence Jones protein injections alone further supports the notion that the presence of MM is not required17,18. For this reason, the International Myeloma Working Group does not consider patients with plasma cell dyscrasia and kidney diseases other than cast nephropathy to have MM unless they also exhibit other myeloma-defining events2.
The occurrence of kidney diseases associated with a monoclonal gammopathy in the absence of symptomatic MM, WM or CLL is increasingly recognized10. Most of these patients have a small, low-grade clonal disorder that is similar to MGUS, although (unlike MGUS) these clones do cause vital organ damage — including neuropathy, cardiomyopathy, hepatic dysfunction and dermopathy — mediated by the monoclonal immunoglobulin2,19,20. The clonal aetiology of these diseases results in clinical features that differ from those of non-monoclonal gammopathies, such as membranous nephropathy or IgA nephropathy. For example, monoclonal immunoglobulin-related diseases tend to be progressive and are unlikely to undergo spontaneous remission21,22,23,24,25. Monoclonal immunoglobulin-related diseases also show higher rates of recurrence after kidney transplantation (often >80%) than their non-monoclonal counterparts26,27,28. Monoclonal diseases are poorly responsive to conventional immunosuppression and instead require clone-directed therapy25,29,30,31,32.
Increasing recognition of the relationship between monoclonal gammopathies and kidney disease generated the need for more-accurate classification of these disorders, which were previously often misdiagnosed or categorized as unclassifiable by existing disease criteria. Moreover, as the use of cytotoxic therapy is typically limited to patients with MM, WM or CLL, patients with monoclonal gammopathy-related kidney diseases (who do not meet the criteria for these malignancies) were left without access to these essential drugs2. Accordingly, a series of meetings was organized by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) with the aim of designating these clonal disorders as pathologies distinct from MGUS and thereby enabling government agencies to allocate resources for their treatment. In 2012, the IKMG introduced the term monoclonal gammopathy of renal significance (MGRS) to describe haematological conditions that produce a monoclonal immunoglobulin associated with kidney injury33. Since then, the IKMG has published recommendations for the treatment of MGRS34 and a classification scheme for MGRS-related renal lesions35. The IKMG met again in New Orleans, Louisiana, United States, in 2017 to update the classification of MGRS-associated renal lesions as well as to refine the definition of MGRS. The present Expert Consensus Document is derived from these discussions, which occurred both face to face and in e-mail exchanges that incorporated the views of IKMG members who could not be present. The treatment of MGRS was not discussed at the meeting; therefore, this topic is not updated in this consensus document.
Updated definition of MGRS
The original definition of MGRS included all small B cell clones that produced a toxic monoclonal protein33. Although this definition was based on the dangerous small B cell clones concept19, the nature of the clonal disease was not well defined. Specific questions arose regarding whether patients with smouldering (indolent) MM (SMM) or smouldering (indolent) WM (SWM) should be considered to have MGRS. Similar confusion existed with regard to the inclusion of patients with low-grade CLL or lymphoma, who do have a diagnosis of a malignancy but do not require treatment. The new definition includes all B cell and plasma cell clonal proliferative disorders that do not require immediate treatment for the clonal disease. In addition, the toxic monoclonal protein is now specified to be a nephrotoxic monoclonal immunoglobulin33.
The new IKMG consensus definition of MGRS (Box 1) includes all B cell or plasma cell proliferative disorders (such as SMM, SWM and monoclonal B cell lymphocytosis (MBL; a diagnosis that is the equivalent of MGUS for clones of the CLL lineage)) that produce a nephrotoxic monoclonal immunoglobulin1,4,36,37. Low-grade CLL and low-grade B cell non-Hodgkin lymphomas, such as marginal zone lymphoma, mantle-cell lymphoma or mucosa-associated lymphoid tissue (MALT) lymphoma are also considered to be MGRS when they are associated with renal lesions38,39,40,41 (Table 1). These low-grade proliferative disorders would be classified as MGUS, and affected patients would be monitored for progression but not offered treatment if not for the renal injury19. In patients who develop renal lesions as a result of the monoclonal immunoglobulin, therapeutic intervention is required to prevent further damage resulting in end-stage renal disease. Accordingly, the diagnosis of MGRS does not require the presence of any defining features of an overt lymphoplasmacytic malignancy and particularly not the presence of any myeloma-defining event.
Once the haematological condition progresses to overt MM, WM, advanced stage CLL or malignant lymphoma (as defined by their respective established disease criteria), these diseases are no longer considered MGRS and affected patients are managed according to disease-specific protocols.
Updated classification system
A variety of renal diseases have now been described in association with MGRS35 (Fig. 1). The IKMG recommends that these should be referred to as MGRS-associated lesions, conditions or disorders. Thus, for instance, classic AL amyloidosis might be considered an MGRS-associated condition when renal involvement is present. By contrast, the term MM-associated AL amyloidosis would be used when the same renal condition is associated with a symptomatic high tumour mass accompanied by at least one classic myeloma-defining event.
The type of renal lesion is governed by the innate structural characteristics and physicochemical properties of the monoclonal immunoglobulin rather than by the features of the clone that produced it17. Except for C3 glomerulopathy and thrombotic microangiopathy, which are not associated with renal deposition of monoclonal immunoglobulin, most MGRS-associated lesions are caused by the deposition of entire or parts of the monoclonal immunoglobulins or of various products of aggregation. Monoclonal immunoglobulin deposits in the kidney are generally restricted to immunoglobulin light chains (except in diseases that show a monoclonal immunoglobulin heavy-chain restriction, such as heavy-chain deposition disease or immunoglobulin heavy-chain amyloidosis). For example, in AL amyloidosis, the renal deposits are composed of only a single light chain35. In conditions where the entire immunoglobin is deposited, demonstration of both heavy-chain and light-chain restrictions are required to provide evidence of monoclonality.
The classification scheme proposed in 2017 by the IKMG for MGRS-associated lesions (Fig. 2) is based on the findings of immunofluorescence studies and the ultrastructural appearance of the deposits on electron microscopy. However, electron microscopy is not universally available, even in industrialized countries; consequently, the IKMG classification encourages but does not mandate the use of electron microscopy in the assessment of MGRS-associated disorders. By contrast, light microscopy and immunofluorescence studies with a full panel of antibodies are invariably required. The renal deposits are initially categorized as organized, non-organized and non-immunoglobulin. At the 2017 IKMG meeting in New Orleans, two additional subcategories were added to the non-organized and non-immunoglobulin categories of the classification scheme35. Thrombotic microangiopathy associated with monoclonal gammopathy was provisionally added as a subcategory of non-immunoglobulin deposits42, and a miscellaneous subcategory was added to the non-organized deposit category, which applies to pathological entities that are ultrastructurally similar to a non-monoclonal-immunoglobulin-related disease but are only sometimes associated with a monoclonal gammopathy. The MGRS-associated disorders included in this classification are discussed in more detail below.
Lesions with organized deposits
Organized deposits of monoclonal immunoglobulins can be further divided into fibrillar, microtubular or crystalline and/or inclusionary forms (Fig. 3). Immunoglobulin-related amyloidosis, which includes subtypes with light-chain, heavy-chain and both heavy-and-light-chain deposition (AL, AH and AHL, respectively), has traditionally been recognized as the only condition in the fibrillar category43. However, monoclonal fibrillary glomerulonephritis has occasionally also been reported44. Amyloid fibrils stain with Congo red and are solid, non-branching and randomly arranged, with diameters of 7–12 nm (Fig. 3a). Amyloid fibrils involve glomeruli and blood vessels in the vast majority of patients and the interstitium in roughly 60% of patients (Fig. 2). Intratubular cytoplasmic AL amyloidosis occurs rarely45. The randomly arranged fibrils seen in fibrillary glomerulonephritis are on average twice as thick (10–30 nm) as those observed in amyloidosis (Fig. 3b) and generally do not stain with Congo red44. A small subgroup (7–17%) of patients with fibrillary glomerulonephritis demonstrates clinical evidence of a monoclonal gammopathy. In 3–15% of these patients, the IgG deposits exhibit light-chain restriction44,46,47, and this pathology is termed monoclonal fibrillary glomerulonephritis. Glomerular staining for DnaJ homologue subfamily B member 9 (DNAJB9) is a reliable marker for fibrillary glomerulonephritis48. This feature can be used to distinguish monoclonal fibrillary glomerulonephritis from AHL and AH amyloidosis, especially as fibrillary glomerulonephritis can sometimes show Congo red staining49,50.
Immunotactoid glomerulonephritis and cryoglobulinaemic glomerulonephritis are the two diseases that feature microtubular immunoglobulin deposits (Fig. 3c). Microtubules can be distinguished from fibrils by their hollow centres and large diameters (17–52 nm)51. Only type I and II cryoglobulinaemias are considered to be MGRS-associated disorders because type III cryoglobulinaemia is associated solely with polyclonal immunoglobulins. Immunotactoid glomerulonephritis is usually a renal-limited disease, whereas systemic manifestations including vasculitic rashes, peripheral neuropathy and arthralgias are common in patients with cryoglobulinaemia. Moreover, immunotactoid glomerulonephritis is not associated with cryoglobulinaemia and does not display the typical characteristics of cryoglobulinaemic glomerulonephritis (namely, glomerular protein thrombi and arterial or arteriolar vasculitic lesions). The glomerular deposits in immunotactoid glomerulonephritis are uniformly composed of microtubules, typically arranged in parallel arrays, with predominantly subepithelial and subendothelial localization. By contrast, only some of the deposits in cryoglobulinaemic glomerulonephritis are organized, and they usually appear as short, curved or straight microtubules (Fig. 3d) with predominantly intraluminal and subendothelial localization52,53,54. Of note, organized deposits are not always observed in cryoglobulinaemic glomerulonephritis55.
The crystalline and/or inclusions category consists of LCPT, crystal-storing histiocytosis (CSH) and (cryo)crystalglobulinaemic glomerulonephritis56,57. LCPT occurs as crystalline and non-crystalline variants. In the crystalline variant, numerous light-chain crystals of various shapes are seen within proximal tubular cells, inside lysosomes or freely in the cytoplasm (Figs 1, 3e). This variant is associated with κ light-chain deposition and complete or partial Fanconi syndrome56,57,58,59. In the non-crystalline variant, proximal tubular cells are distended and injured by the accumulation of numerous non-crystalline light-chain inclusions within lysosomes. This variant is typically associated with λ rather than κ light-chain deposition, and Fanconi syndrome is uncommon56,57,58,59. Rarely, non-crystalline LCPT can mimic acute tubular necrosis or acute interstitial nephritis57,59. In patients with CSH, light-chain crystals are often seen in renal histiocytes as well as in proximal tubular cells60 (Fig. 3f) and can have a widespread extrarenal distribution, including in bone marrow, lymph nodes, lungs, thyroid, parotid gland, cornea, synovium, skin, subcutaneous fat, stomach, liver and brain61,62,63,64. Finally, (cryo)crystalglobulinaemic glomerulonephritis is a rare monoclonal gammopathy characterized by immunoglobulin thrombi in the arterioles and glomerular capillaries. These thrombi exhibit a crystalline structure or periodicity on electron microscopy65. In some patients, the crystallization process in the periphery is precipitated by cold exposure, termed cryocrystalglobulinaemia66. Mesangial and endocapillary hypercellularity is often absent65,66. As in cryoglobulinaemia, intravascular crystal deposition results in small-vessel occlusion, thrombosis and/or inflammatory vasculitis65,67. Renal biopsy samples in patients with (cryo)crystalglobulinaemia reveal large extracellular crystals within glomerular capillaries and arterioles, which are frequently associated with fibrin thrombi and inflammation. Intracellular crystals can also be seen in patients with cryocrystalglobulinaemia (Fig. 3g).
Lesions with non-organized deposits
Non-organized monoclonal immunoglobulin deposits are seen in patients with MIDD and those with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID). MIDD comprises a group of diseases characterized by deposition of light chains, heavy chains or both light and heavy chains68,69,70. In MIDD (Figs 1, 3h), linear punctate deposits are seen along both the glomerular basement membrane (GBM) and the tubular basement membrane (and occasionally extrarenally). By contrast, in PGNMID, deposits are confined to the glomeruli, where they are present in the mesangium and subendothelial space and occasionally in the subepithelial space (Figs 1, 3i). In addition, the deposits seen in PGNMID contain only intact immunoglobulins24,71, whereas those seen in heavy-chain MIDD or light-and-heavy-chain MIDD typically lack the first constant domain of the immunoglobulin24,70,71. In most patients, PGNMID is IgG3-driven, whereas truncated IgG1 is the most frequent immunoglobulin deposited in heavy-chain MIDD70,72. However, PGNMID can also be IgA-driven or (rarely) IgM-driven72,73.
Lesions without deposits
Not all MGRS-associated renal lesions include monoclonal immunoglobulin deposits. The best example of an MGRS-associated disorder lacking such deposits is C3 glomerulopathy with monoclonal gammopathy, which includes both C3 glomerulonephritis and the rare entity of dense deposit disease. By definition, substantial renal immunoglobulin deposits will be absent in patients with C3 glomerulopathy, although 60–80% of patients aged >50 years with C3 glomerulopathy have a monoclonal gammopathy at the time of diagnosis74,75,76. This proportion far exceeds the expected rate in the general population75,76,77. Thus, although renal disease related to the monoclonal immunoglobulin can be demonstrated in only about 30% of patients affected by C3 glomerulopathy (in whom the monoclonal immunoglobulin acts as a C3 nephritic factor or anti-factor-H antibody), it should still be considered an MGRS-associated disorder25,75.
C3 glomerulonephritis and dense deposit disease are distinguished by their ultrastructural appearance: ill-defined, moderately electron-dense mesangial, subepithelial and subendothelial deposits are seen in C3 glomerulonephritis (Fig. 3j), whereas highly electron-dense ‘sausage-like’ intramembranous deposits and mesangial rounded nodular deposits are seen in dense deposit disease (Fig. 3k). Large ‘hump-shaped’ subepithelial deposits might be seen in either lesion25 (Fig. 3j). C3 glomerulonephritis is the most common form of C3 glomerulopathy with monoclonal gammopathy. Importantly, roughly 5–10% of patients with monoclonal gammopathy and findings on standard immunofluorescence (that is, conducted on frozen tissue) consistent with C3 glomerulonephritis will actually have a membranoproliferative glomerulonephritis with masked monoclonal deposits. These patients require additional immunofluorescence studies to be performed on protease-digested, paraffin-embedded tissue for identification of the monoclonal immunoglobulin in the deposits78,79.
Lesions with provisional status
Thrombotic microangiopathy is the endothelial injury seen most commonly in microangiopathy with haemolytic anaemia (MAHA). Thrombotic microangiopathy and MAHA can occur concurrently in patients with monoclonal gammopathies, including MM and WM13,42,80,81. The pathophysiology of these disorders is not entirely understood but might be related to the monoclonal immunoglobulin acting as an autoantibody against a complement regulatory protein82. The other lesion in this category is glomerular microangiopathy associated with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome83,84. The glomerular microangiopathy seen in POEMS syndrome is associated with a monoclonal gammopathy, which is nearly always λ light-chain type. However, the λ light chain itself is usually absent from kidney biopsy samples. Instead, the lesion is a subacute to chronic glomerular thrombotic microangiopathy characterized by mesangial and endothelial cell proliferation, mesangiolysis, widening of the subendothelial zone and double contouring85. Interestingly, these patients show no evidence of MAHA. The renal lesions in POEMS syndrome are thought to be secondary to a cytokine-mediated endothelial cell injury, similar to that seen in myeloproliferative neoplasm-related glomerulopathy86.
Lesions classed as miscellaneous
The ‘miscellaneous’ subcategory of MGRS-associated lesions includes kidney diseases that are typically not associated with MGRS, such as anti-GBM disease secondary to a monoclonal gammopathy. The anti-GBM monoclonal antibody can be IgG or IgA87,88,89. In most patients with this disease, the anti-GBM antibody is not detectable in serum by commercially available enzyme-linked immunosorbent assay (ELISA) or multiplex flow immunoassays, which are designed to detect antibodies against only α3NC1. These patients experience frequent relapses and the disease recurs after kidney transplantation, which is not typical in patients with non-MGRS-associated anti-GBM disease87,88,89. A pattern of membranous nephropathy that is visually indistinguishable from that associated with polyclonal immunoglobulin-mediated membranous lesions on light microscopy and electron microscopy has been described in patients with monoclonal IgG deposits90,91. Although the phospholipase A2 receptor (PLA2R) was identified as the target of the monoclonal IgG in a single patient included in a small study, a larger study found that only 26% of patients showed evidence of antibodies to PLA2R and that none of those patients had a lymphoproliferative disorder90,91. Finally, Henoch–Schönlein purpura with IgA nephropathy has very occasionally been reported in patients with IgA monoclonal gammopathy or MM92,93.
Evaluation of suspected MGRS
Owing to differences in clinical characteristics and therapy, it is essential to distinguish MGRS-associated disorders from kidney diseases that are unrelated to monoclonal immunoglobins10,12,24,28,94,95. In patients suspected of having MGRS, the evaluation starts with a kidney biopsy. If analysis of the biopsy sample identifies an MGRS-associated lesion, a haematological evaluation (including monoclonal immunoglobulin studies, clonal determination and cytogenetic analysis) should be performed. These steps are discussed in greater detail below.
When to perform a renal biopsy
As MGRS is a haematological condition defined by its renal manifestations, a kidney biopsy is essential for its diagnosis. However, not every patient with a monoclonal gammopathy and kidney disease has MGRS. The frequency of MGUS is 3% in people aged >50 years, 5% in persons aged >70 years and as high as 8% in men aged >80 years77. The prevalence of MGUS is two to three times higher in African Americans than in white individuals of the same population96. The incidence of chronic kidney disease (CKD) also increases after age 60 years97. Therefore, the same patient could have both MGUS and CKD that are unrelated to each other. Studies from the same county in the United States found that the annual incidence of glomerular disease was approximately 1 per 100,000 individuals in the general population and that the prevalence of MGUS in people aged >50 years was 3.2%77,98. A renal biopsy study of patients with clinically suspected MGUS found that 45% of these patients did not have an MGRS-associated kidney disorder; however, as additional disease entities related to monoclonal gammopathies have been identified after the publication of this article, the true value might be lower10.
Clinicians must balance the risks associated with underdiagnosis of potentially treatable conditions against those of complications from the biopsy procedure. However, patients with MGRS-associated renal lesions (including amyloidosis) do not experience any increase in the risk of bleeding after kidney biopsy (which remains about 4%)99,100. Thus, performing a kidney biopsy in a patient with diabetes and rapidly progressive loss of renal function or increasing proteinuria is reasonable, especially if their diabetes is well controlled and/or evidence of extrarenal microvascular disease is absent. Because MGUS is uncommon in individuals aged <50 years (and is especially rare in those aged <40 years), its presence in people aged <50 years, when accompanied by renal manifestations, deserves a thorough evaluation. Older age (≥70 years) should not discourage biopsy as most MGRS-related renal diseases occur in patients aged >50 years. In young and physically fit patients who are eligible for kidney transplantation, a kidney biopsy should be performed provided the kidneys are not markedly shrunken. Transjugular kidney biopsy is an option in high-risk patients from whom it would otherwise be difficult to obtain kidney tissue101,102.
Renal biopsy evaluation
The diagnosis of MGRS-associated lesions requires the integration of morphological alterations seen on light microscopy with the findings of immunohistochemistry (immunofluorescence or immunoperoxidase) and transmission electron microscopy studies, as well as correlation with the patient’s medical history and laboratory findings. In some patients, ancillary techniques are needed to establish the diagnosis, including protease immunofluorescence, ultrastructural immunogold labelling and laser microdissection followed by liquid chromatography and mass spectrometry (LC–MS). A detailed description of our consensus recommendations for renal biopsy and the indications for ancillary techniques is provided in Table 2. Our recommended approach to renal biopsy analysis in patients suspected to have MGRS is provided in Fig. 4.
To confirm the monotypic nature of the immunoglobulin deposits, immunofluorescence staining for IgG subclasses should be performed in biopsy samples from patients with glomerular disorders related to deposition of an intact monoclonal IgG (such as PGNMID, immunotactoid glomerulopathy, type I cryoglobulinaemic glomerulonephritis and monoclonal membranous nephropathy) or of a truncated monoclonal heavy chain (such as heavy-chain deposition disease, heavy-and-light-chain deposition disease or heavy-chain amyloidosis). Of note, IgG subclass restriction is not sufficient by itself to establish monoclonality, as some non-MGRS glomerular diseases — such as PLA2R-associated polyclonal membranous nephropathy and non-monoclonal fibrillary glomerulonephritis — commonly show staining restricted to one IgG subclass but positive staining for both κ and λ light chains23,103. Identification of complement C1q and/or C3 proteins within the monotypic renal deposits might reveal the cause of hypocomplementaemia in patients with MGRS-associated lesions such as PGNMID, immunotactoid glomerulonephritis, type I cryoglobulinaemic glomerulonephritis, C3 glomerulonephritis and heavy-chain or heavy-and-light-chain deposition disease23,24,51,52,68,103,104.
Electron microscopy is often necessary to identify the specific MGRS-associated lesion. Ideally, electron microscopy should be performed on 2–3% glutaraldehyde-fixed tissue. If glutaraldehyde-fixed tissue is not available or lacks glomeruli, formalin-fixed, paraffin-embedded tissue samples can be reprocessed for electron microscopy. Although reprocessing is usually associated with various artefacts, the immune deposits generally remain sufficiently intact to permit an accurate assessment of their location and structure. Electron microscopy of frozen tissue samples or tissue fixed in Zenker or B5 fixatives is not recommended owing to its generally very poor ultrastructural preservation. In patients with monoclonal gammopathy, at least two glomeruli should be studied ultrastructurally as glomerular deposits can be sparse and only a portion of the deposits show substructural features. For example, in most patients with cryoglobulinaemic glomerulonephritis, only a small number of deposits (most commonly intraluminal ones) exhibit the microtubular substructure that is so useful in establishing the diagnosis53. In patients with monoclonal gammopathy, a directed search for intratubular cytoplasmic crystals or inclusions by electron microscopy is of paramount importance, as these features can be overlooked by light microscopy and standard immunofluorescence studies on frozen tissue. Additionally, in some patients with classic MIDD, the characteristic punctate, powdery, electron-dense deposits can be found only in small sections of the tubular basement membranes. Therefore, a thorough search for tubular basement membrane deposits by electron microscopy is necessary to distinguish classic MIDD from MIDD identified by immunofluorescence only69. Ultrastructural immunogold labelling is a sensitive technique that can assist in the histopathological diagnosis of MGRS-associated lesions, such as AL amyloidosis, MIDD, LCPT and CSH, by confirming the location and composition of monoclonal deposits, but it is not widely available35,60,70,105,106,107.
Laser microdissection followed by LC–MS is currently the gold standard for amyloid typing but is available in only a few specialized centres. In renal pathology laboratories that routinely perform immunofluorescence studies on native kidney biopsy samples, LC–MS is essential for typing renal amyloidosis in about 15% of patients43,108. LC–MS is crucial for the diagnosis of rare hereditary forms of renal amyloidosis that cannot be typed by immunofluorescence, but it is also important to distinguish AH and AHL amyloidoses from non-immunoglobulin amyloidoses associated with nonspecifically entrapped immunoglobulins (particularly AA amyloidosis) and from fibrillary glomerulonephritis49,109. LC–MS can also be useful in the diagnosis of MGRS-associated lesions other than immunoglobulin amyloidosis when immunofluorescence studies are not available or have negative findings. An example of the latter situation is IgD heavy-chain deposition disease, which is generally missed by immunofluorescence studies because an IgD antibody is not included in the routine immunofluorescence panel110.
Monoclonal immunoglobulin testing
Once the diagnosis of an MGRS-associated lesion has been established, a search for the culprit monoclonal immunoglobulin should be undertaken (if it has not been identified already). Protein electrophoresis analyses of serum and urine samples are the first tests performed111. Although its sensitivity is inferior to that of some other tests discussed here, serum protein electrophoresis is quantitative, easy to perform and inexpensive. Urine protein electrophoresis is less sensitive than serum protein electrophoresis but provides the total protein level, urinary albumin level and globular protein (monoclonal immunoglobulin or light chain) component — parameters that are necessary for diagnosis, prognostication and response assessment112,113,114. Immunofixation of a serum sample and of a concentrated urine aliquot from a 24 h collection should also be done because this test is more sensitive than protein electrophoresis. Immunofixation is necessary for the identification and typing of monoclonal immunoglobulins, as well as for the determination of a complete response113,115. Immunoblotting is a highly sensitive technique that can detect small amounts of monoclonal immunoglobulin, characterize the distribution of IgG heavy-chain subclasses and detect deletion of the first constant domain, the hallmark of heavy-chain deposition disease and AH amyloidosis70. However, this technique is not widely available.
Another critical test is the serum free light-chain assay, which detects unbound free light chains113. This assay measures κ and λ free light chains independently and can be used to determine the κ:λ free light-chain ratio. Clonality can be inferred from an abnormal κ:λ free light-chain ratio: a high ratio indicates a κ clone whereas a low ratio indicates a λ clone. Because free light chains are cleared by the kidney, impaired renal function alters the free light-chain concentration. The ‘normal’ free light-chain ratio, 0.26–1.65, can rise to 0.34–3.10 in patients with severe renal impairment (CKD stage 5 or greater), but small declines in renal function can also impair free light-chain clearance116. Knowing which serum free light-chain assay is being used by the laboratory is extremely important, as at least two major assays are currently on the market. Not only are the results of these assays mathematically inconvertible, but the effects of renal impairment differ between these assays; the evidence suggests that the N Latex assay is less affected than the FreeLite assay by impaired renal function117. Thus, the same assay must be used to monitor a particular patient throughout their treatment. Moreover, given that the two assays have different performance characteristics, free light-chain levels might need to be checked using the other assay if the first result is negative. In addition, serum immunofixation might be more helpful than serum free light-chain assays in diseases associated with an intact monoclonal immunoglobulin (such as PGNMID)72. Finally, although antibodies for use in urinary light-chain assays have been developed, these assays have not been validated and should not be used to quantify the amount of light chain (Bence Jones protein) in a 24 h urine specimen (which should instead be measured by urine protein electrophoresis, as previously stated)118.
Identification of the culprit monoclonal immunoglobulin has important diagnostic and prognostic consequences. The monoclonal immunoglobulin detected in serum and/or urine must match that found in immunoglobulin deposits in the kidney35; if the immunoglobulin found in renal deposits differs from that found in the circulation, the monoclonality of the putative culprit immunoglobulin is called into question. Although the serum M-spike concentration and serum free light-chain assay results have both diagnostic and prognostic importance, the correlation between the results of these tests and the severity or type of kidney disease is less well established.
The diagnosis of MGRS should generally be established before obtaining a haematological consultation. The focus of the haematologist and/or oncologist and haematopathologists should be clonal identification, which is central to the management of patients with MGRS. The only exception is when the patient has already been diagnosed as having MM, WM or CLL, which eliminates the need for a kidney biopsy (because treatment will be initiated regardless of the kidney lesions present). Clonal identification is essential because the same kidney diseases can occur in different haematological disorders (Table 3). Of note, although a pathological clone can be identified in virtually every patient with AL amyloidosis or MIDD, such clones are often difficult to detect in other diseases. For example, the chance of identifying the pathological clone falls below 17% for patients who do not have a detectable monoclonal immunoglobulin on immunofixation studies72, and only 20–30% of patients with PGNMID have a detectable circulating monoclonal immunoglobulin24,72. As treatment differs according to whether the clone has a plasmacytic or lymphocytic nature, choosing the right agent is challenging if a clone cannot be identified.
Bone marrow aspiration and biopsy should be performed to evaluate MGRS in most patients, although in patients with CLL clones, the diagnosis could be made with peripheral blood flow cytometry. Morphological assessment should include quantification of the percentage of plasma cells (in plasma cell clones) and evaluation for the presence of atypical lymphoid or lymphoplasmacytic aggregates (in lymphoma clones) as well as amyloid deposits. In addition, ancillary studies — in particular, flow cytometry immunophenotyping, detection of minimal residual disease and cytogenetic and genetic evaluation of the clones — are helpful for the identification of small clones as well as for deriving treatment recommendations119,120,121. The myeloma fluorescent in situ hybridization (FISH) panel has shown increasing importance in guiding the treatment of patients with plasma cell dyscrasias. For example, patients with AL amyloidosis featuring translocation t(11;14) have inferior responses to bortezomib-based therapy, whereas those with gain of chromosome 1q21 show poorer responses to melphalan plus dexamethasone99,100,122,123,124 (versus patients without these genetic variants). These findings highlight the importance of performing the myeloma FISH panel on all bone marrow biopsy samples from patients with plasma cell dyscrasia.
If bone marrow evaluation does not reveal a clonal haematological disorder, the next step could be to perform imaging studies (such as CT with or without PET, or whole-body MRI) to look for a localized plasmacytoma or for lymphadenopathy in low-stage, low-grade lymphoma34,35. For patients suspected to have MM, whole-body CT with or without PET (or MRI) should be performed to look for bone disease125,126. Any suspicious lesions should be biopsied and enough material should be obtained to enable diagnostic and prognostic studies. Next-generation flow cytometry has been used in the measurement of minimal residual disease127. This technique might be helpful in patients suspected of having MGRS who have negative findings on traditional cytology or flow cytometry studies of bone marrow samples.
MGRS is a new classification of pathogenic clonal proliferative disorders that produce a nephrotoxic protein. The term MGRS was needed to improve the classification of these diseases for research purposes, and to accurately categorize them as pathological, so that government agencies could allocate the resources necessary for their treatment. The diagnosis of MGRS can be established only by performing a kidney biopsy that either demonstrates the presence of monotypic immunoglobulin deposits or infers their involvement in the case of C3 glomerulonephritis or thrombotic microangiopathy with a circulating monoclonal immunoglobulin. Clinicians will need to balance the risk of missing a diagnosis against those of the complications of renal biopsy; therefore, the judicious use of renal biopsy is important. Detection of a monoclonal immunoglobulin, in addition to helping to establish the diagnosis of MGRS, has diagnostic and prognostic value and is also used to predict treatment responses. Haematological evaluation might require peripheral blood flow cytometry, bone marrow biopsy and imaging studies to assess localized disease.
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N.L. is supported by the generous donations of T. Kirshenbaum and J. Kirshenbaum as well as G. Kohler and A. Drennan. P.W.S. is supported by grants from the US Office of Research and Development, Medical Research Service, Department of Veterans Affairs (grant 1 IP1 BX001595), the US National Institutes of Health George M. O’Brien Kidney and Urological Research Centers Program (P30 DK079337) and the University of Alabama–Birmingham School of Medicine (AMC21 Multi-PI Grant and Anderson Innovation Award).
- Bence Jones protein
Monoclonal immunoglobulin light chains detected in the urine of patients with multiple myeloma and other haematological malignancies.
- Dangerous small B cell clones
Size is not everything — even small B cell-derived clones might synthesize a very toxic monoclonal immunoglobulin that produces devastating systemic damage and a progressive or even fatal clinical course.