|Year : 2021 | Volume
| Issue : 2 | Page : 298-306
|Monoclonal gammopathy of renal significance: Spectrum of diseases and approach to a case
Rohit Tewari1, Tathagat Chatterjee1, Satish Mendonca2, Manu Dogra1, Suman Kumar Pramanik3, Uday Yanamandra3
1 Department of Pathology, Army Hospital Research and Referral, Delhi Cantonment, New Delhi, India
2 Department of Nephrology, Command Hospital, Kolkata, West Bengal, India
3 Department of Hematology, Army Hospital Research and Referral, Delhi Cantonment, New Delhi, India
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|Date of Web Publication||11-Jan-2022|
| Abstract|| |
The occurrence of kidney diseases associated with a monoclonal gammopathy in the absence of symptomatic multiple myeloma is increasingly recognized. When the kidney is involved, the monoclonal etiology of these diseases results in clinical and laboratory features distinct from those of other disease, necessitating the nomenclature monoclonal gammopathy of renal significance (MGRS). The detection of these monoclonal diseases involving the kidney is important since they are poorly responsive to conventional immunosuppression and instead require clone-directed therapy. The new International Kidney and Monoclonal research group consensus definition of MGRS includes all proliferative conditions of B cells and/or plasma cells. Renal lesions due to monoclonal immunoglobulins are quite capable of progression with resulting end-stage renal disease development. Hence, these lesions require therapeutic intervention even if they do not satisfy myeloma criteria or the presence of any myeloma defining event. The spectrum of renal lesions that can be observed in a case of MGRS is wide and mirrors the list that may be seen in a case of any plasma cell neoplasm. This includes Ig light chain, heavy chain, and heavy and light chain amyloidosis; immunotactoid glomerulonephritis (GN); monoclonal immunoglobulin deposition disease including light chain, heavy chain, or heavy and light chain disease; light chain proximal tubulopathy; crystal-storing histiocytosis; proliferative GN with monoclonal immunoglobulin deposits; C3 glomerulopathy with monoclonal gammopathy and cast nephropathy. The initial approach after histological assessment is based on presence or absence of monoclonal immunoglobulin deposits. If monoclonality is evident, it is important to distinguish between conditions with deposition of intact immunoglobulin molecule or light chains only. The treatment of MGRS is directed at the underlying neoplastic B-cell or plasma cell clones.
|How to cite this article:|
Tewari R, Chatterjee T, Mendonca S, Dogra M, Pramanik SK, Yanamandra U. Monoclonal gammopathy of renal significance: Spectrum of diseases and approach to a case. Saudi J Kidney Dis Transpl 2021;32:298-306
|How to cite this URL:|
Tewari R, Chatterjee T, Mendonca S, Dogra M, Pramanik SK, Yanamandra U. Monoclonal gammopathy of renal significance: Spectrum of diseases and approach to a case. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 Jan 25];32:298-306. Available from: https://www.sjkdt.org/text.asp?2021/32/2/298/335440
| Introduction|| |
Neoplastic plasma cell proliferations have a wide range of manifestations in terms of pathologic lesions as well clinical features based on the amount and type of monoclonal protein being produced. The classification of multiple myeloma (MM) has undergone several changes with the latest classification from the International Myeloma Working Group 2018 update superseding all previous versions. MM diagnosis is a complicated issue and has multiple requirements including the presence of one or more myeloma defining events (MDE) in addition to the evidence of either 10% or more clonal plasma cells on bone marrow examination or a biopsy-proven plasmacytoma. MDE consists of established CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features as well as three specific biomarkers: clonal bone marrow plasma cells ≥60%, serum free light chain (FLC) ratio ≥100 (if involved FLC level is ≥100 mg/L), and more than one focal lesion on magnetic resonance imaging (MRI). Each of the new biomarkers is associated with an approximately 80% risk of progression to symptomatic end-organ damage. The updated criteria are indicative of a huge shift because taking these into account while evaluating a case allows for early diagnosis and initiation of therapy, much before occurrence of end-organ damage. Renal involvement is common in MM. There are a large number of different manifestations of the disease in the kidney, usually involving damaging effects of the abnormal monoclonal protein to different renal compartments including the glomeruli, tubules, interstitium and vessels, or due to neoplastic plasma cell proliferations. Monoclonal gammopathy of undetermined significance (MGUS) as a concept was first introduced by Robert Kyle as early as in 1978. This is a pre-malignant condition and is characterized by the presence of a serum monoclonal immuno-globulin <30 g/L and <10% monoclonal bone marrow plasma cells in a patient who does not have any organ damage due to the monoclonal immunoglobulin. When MGUS converts to malignancy, it mandates the initiation of appropriate therapy. This conversion is indicated by the development of specific clinical and laboratory features of disease. For example, the occurrence of one or more myeloma-defining events, such as hyper-calcemia, renal impairment, anemia, 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) indicates conversion to MM. Progression to Waldenstrom macroglobulinemia (WM) is indicated by the development of anemia, thrombocytopenia, bulky adenopathy or organomegaly, blood hyperviscosity, severe neuropathy, amyloidosis, cryoglobulinemia, cold agglutinin disease, or malignant transformation. The occurrence of kidney diseases associated with a monoclonal gammopathy in the absence of symptomatic MM, WM, or chronic lymphocytic leukemia (CLL) is increasingly recognized. These cases usually 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, which is invariably caused by the monoclonal immuno-globulin. When the kidney is involved, the monoclonal etiology of these diseases results in clinical and laboratory features distinct from those of other disease like the non-monoclonal immune complex diseases involving the kidney, such as a membranous nephropathy or IgA nephropathy. For example, monoclonal immunoglobulin-related renal diseases are usually progressive and usually do not undergo spontaneous remission. These diseases also show higher rates of recurrence after kidney transplantation (often >80%) than their non-monoclonal counterparts. The detection of these monoclonal diseases involving the kidney is important since they are poorly responsive to conventional immunosuppression and instead require clone-directed therapy.
| Terminology|| |
Earlier, monoclonal gammopathy of renal significance (MGRS) is an entity encompassed clinical situations with production of a monoclonal protein by any small clone of B cells/plasma cells. This definition raised some with issues with regard to therapeutic management, especially with regard to cases of CLL or small lymphocytic lymphomas (SLL) who are cases of malignancy by nomenclature but may or may not need therapy. The new definition includes all B cell and plasma cell clonal proliferative disorders that by themselves and by current treatment guidelines, do not require immediate therapy for the monoclonal disease. In addition, the toxic monoclonal protein is now specified to be nephrotoxic. The new International Kidney and Monoclonal Gammopathy (IKMG) research group consensus definition of MGRS includes all proliferative conditions of B cells and/or or plasma cells (such as SMM, SWM, and monoclonal B cell lymphocytosis). These conditions are associated with the production of a monoclonal immunoglobulin that is toxic to kidneys. Hence, low-grade lymphomas like SLL and mucosa associated lymphoid tissue lymphomas (MALTOMAS), when associated with kidney lesions may also be theoretically considered to be MGRS.
Renal lesions due to monoclonal immuno-globulins are quite capable of progression with resulting end-stage renal disease development. Hence, these lesions require therapeutic intervention even if they do not satisfy myeloma criteria or the presence of any MDE. In the event of the hematological disorder progressing and subsequently satisfying the criteria of a myeloma, Waldenstroms, or CLL, then these conditions are not considered to be MGRS any longer. A variety of renal diseases have now been described in association with MGRS. According to the IKMG recommendations, all these conditions should be called MGRS-associated lesions, conditions, or disorders. Thus, for instance, classic AL amyloidosis might be considered as an MGRS-associated condition when renal involvement is seen. On the other hand, the term MM-associated AL amyloidosis would be used when the same kidney disease is associated with a manifest and symptomatic high tumor mass as well as at least one classic myeloma-defining event.
The type of lesion that develops in the kidney in response to the nephrotoxic monoclonal protein is dictated by the structural characteristics, physicochemical properties of the protein and also on the state of hydration of the patient. The features of the clone that produced it do not appear to play a role. Almost all lesions of MGRS show deposition of either the whole or a part of the immuno- globulin molecule or a product of aggregation. Exceptions to this are C3 glomerulopathy and thrombotic microangiopathy. In situations where the entire immunoglobulin is deposited, demonstration of both heavy-chain and light-chain restrictions is needed to provide evidence of monoclonality of the heavy and the light chain separately.
Diagnosis of renal diseases is usually done with a combination of technologies including light microscopy (LM) with special stains, immunofluorescence (IF) microscopy, and electron microscopy (EM). The same is applicable to MGRS lesions. Considering the lack of availability of EM in many situations, the IKMG does not make the requirement of EM mandatory. However, LM with special stains and fluorescence microscopy with a full complement of antibodies is invariably required. The renal deposits are initially categorized as organized, nonorganized, and nonimmuno-globulin.
| Spectrum of Lesions|| |
The spectrum of renal lesions that can be observed in a case of MGRS is wide and mirrors the list that may be seen in a case of any plasma cell neoplasm. This includes Ig light chain, heavy chain, and heavy and light chain amyloidosis; immunotactoid glomerulonephritis (GN); monoclonal immunoglobulin deposition disease (MIDD) including light chain [Figure 1], heavy chain, or heavy and light chain disease; Type 1 cryoglobulinemic glomerulonephritis (GN); light chain proxymal tubulopathy; crystal-storing histiocytosis; proliferative GN with monoclonal immuno-globulin deposits (PGNMID); C3 glomerulopathy with monoclonal gammopathy and cast nephropathy [Table 1].
|Figure 1: Flowchart showing evaluation of suspected monoclonal gammopathy of renal significance cases with and without monoclonal immunoglobulin deposits.|
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|Table 1: Spectrum of lesions of monoclonal gammopathy of renal significance.|
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| Approach to a Suspected Case of Monoclonal Gammopathy of Renal Significance|| |
Therapeutic management of renal lesions related to MGRS and other kidney diseases is quite different, and hence, this distinction is extremely important. The process usually begins with a renal biopsy in view of a nephrotic/nephritic/rapidly progressive renal failure (RPRF) or acute kidney injury (AKI) presentation. In the eventuality of the biopsy showing an MGRS-associated lesion, hematological evaluation is indicated.
The clinical differentials considered are based on the clinical renal syndrome. Cases presenting with nephrotic syndrome may have an overlap with any cause of the nephrotic syndrome such as minimal change disease, focal segmental glomerulosclerosis or membranous nephropathy. Cases presenting with AKI or RPRF like picture may have clinical overlap with acute interstitial nephritis or the thrombotic microangiopathies. Cases presenting with renal tubular defects may have clinical overlap with Fanconi syndrome. Further evaluation with serological markers and a kidney biopsy would help in evaluation.
Just like any other renal disease, the diagnosis of MGRS needs close correlation between findings of clinical presentation in terms of renal syndrome, findings on LM with special stains including Periodic acid–Schiff, Masson Trichrome and Congo red, direct IF findings with antibodies to immunoglobulins, complement and light chains as well as electron microscopic structure of the deposits. In a subset of patients, further ancillary techniques are needed to establish the diagnosis, including direct IF on paraffin embedded tissue after proteinase digestion to pick up masked deposits, immunogoldon EM and laser micro dissection followed by liquid chromatography and mass spectrometry (LC–MS).
The initial approach after histological assessment is based on presence or absence of monoclonal immunoglobulin deposits [Figure 2]. If monoclonality is evident, it is important to distinguish between conditions with deposition of intact immunoglobulin molecule or light chains only [Figure 3]. Disorders that are associated with deposition of intact immunoglobulin molecules like PGNMID and immunotactoid glomerulopathy need demonstration of monoclonality for heavy chain (achieved by staining of subtypes of IgG, i.e., IgG1, IgG2, IgG3 and IgG4 as well as kappa, lambda immunostaining to establish monoclonality of the light chain.
|Figure 2: Flow chart showing interpretation of findings on direct immunofluorescence with respect to nature of deposit.|
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|Figure 3: Case of monoclonal immunoglobulin deposition disease in a monoclonal gammopathy of renal significance setting. 3a: Section showing enlarged glomeruli with thickened capillary walls and mesangial nodule formation with deposition of PAS positive material (PAS, ×40); 3b: The mesangial nodules and capillary walls do not show any Congophilic material (Congo Red, ×40); 3c: Tubular basement membranes are thickened (PAS, ×40); 3d: Tubular basement membranes are thickened (PASM, ×40); 3e: DIF for Kappa is negative in glomerular capillary walls and mesangial nodules (DIF for Kappa, ×40); 3f: DIF for Lambda is positive in glomerular capillary walls and mesangial nodules (DIF for Lambda, ×40).|
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It is important to note that IgG heavy chain restriction is not in itself enough to establish monoclonality, since some non-MGRS glome- rular diseases like a phospholipase A2 receptor associated polyclonal membranous nephropathy and nonmonoclonal fibrillary GN commonly show staining restricted to one IgG heavy chain subclass but positive staining for both kappa and lambda light chains. Some MGRS diseases like PGNMID and C3 GN are associated with hypocomplementemia. In these cases, identification of C3 and C1q in the monoclonal deposits by DIF helps in explaining the hypocomplementemia.
EM is sometimes, though not always, needed to identify the specific MGRS-associated lesion. In usual circumstances, EM should be performed on 2%–3% glutaraldehyde-fixed tissue. In the case of nonavailablility of glutaraldehyde-fixed adequate tissue, paraffin- embedded tissue can be reprocessed for EM. This procedure of reprocessing is associated with development of artifacts; however, the light chain/immune deposits do remain intact for reasonably accurate assessment of structure/ substructure for categorization. Representativeness of the sample is important in these situations since there are conditions where the disease may not be identifiable in a single glomerulus, hence sampling of at least two glomeruli is advisable. For example, the microtubular substructure of deposits that is useful in establishing the diagnosis of cryoglobulinemic GN may be seen in only few glomeruli. MIDD shows characteristic powdery deposits along the tubular basement membranes usually. In some cases, these deposits are not present universally, but only along few places in the tubular basement membranes. Hence, a thorough evaluation on EM is needed to pick up these deposits and to distinguish classic MIDD from MIDD which shows IF positivity only. Intratubular epithelial cell crystals are an important finding, especially in the proximal light chain tubulopathies. Occasionally, LM and DIF may miss the detection of these crystals. EM examination plays a vital role in this setting. Ultrastructural immunogold labeling 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 available.
Amyloid is an important entity in the MGRS spectrum. Identification of specific types of amyloid is usually dependent on light chain immunostaining on DIF and use of a spectrum of immunohistochemical antibodies. Laser micro dissection followed by LC–MS has recently established its role in this field. Today, this is considered the gold standard for amyloid typing but facilities are available in only a few specialized centers. In renal pathology laboratories that routinely perform IF studies on native kidney biopsy samples, LC–MS is essential for typing renal amyloidosis in about 15% of patients. LC–MS is crucial for the diagnosis of rare hereditary forms of renal amyloidosis that cannot be typed by IF, but it is also important to distinguish AH and AHL amyloidosis from nonimmunoglobulin amyloidosis-associated with nonspecifically entrapped immunoglobulins (particularly AA amyloidosis) and from fibrillary GN.
LC–MS can also be useful in the diagnosis of MGRS-associated lesions other than immunoglobulin amyloidosis when IF 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 IF studies because an IgD antibody is not included in the routine IF panel.
| Monoclonal Immunoglobulin Testing|| |
Monoclonal immunoglobulin testing is indicated after the diagnosis of an MGRS-associated lesion. The approach is the same as for any suspected plasma cell neoplasm. The first step is serum and urine protein electrophoresis. Immunofixation electrophoresis is a more sensitive procedure. Immunofixation is necessary for the identification and typing of monoclonal immunoglobulins, as well as for the determination of a complete response.,
Small amounts of monoclonal protein can also be detected by immunoblotting and this is a sensitive technique for the same. This technique can also 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 amyloidosis.
Serum FLC assay has established itself as an important test in this clinical scenario over the past few years. This test detects unbound free kappa and lambda light chains. Kappa and Lambda FLCs are detected independently and can these values 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. Impaired renal function alters the free light-chain concentrations, since FLCs are cleared by the kidney. 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 clearance.
Identification of the pathogenic monoclonal immunoglobulin has important implications. The monoclonal immunoglobulin that is found in the patients’ blood and/or urine must match that in the immunoglobulin deposits detected in the renal biopsy tissue; if the immuno-globulin found in renal biopsy deposits differs from that found in the circulation, the monoclonality of the putative culprit immuno-globulin is questionable.
| Treatment|| |
By logic, the treatment of MGRS is directed at the underlying neoplastic B-cell or plasma cell clones. For many years, there was a hesitation to treat these conditions due to fears of drug toxicity and the possibility of the patient developing a second malignancy due to use of alkylating agents for a condition that was not “very serious.” Hence, the aim of treatment remains to achieve remission in proteinuria with reduction in serum creatinine levels or delayed/no need for dialysis or independence from dialysis, and reducing the chances of a recurrence after renal transplantation. Considering the etiology of the renal disease process, treatment is based on a combination of chemotherapeutic agents used to treat plasma cell dyscrasia or non-Hodgkin lymphoma. Renal outcomes are based on baseline glomerular filtration rate, as shown in PGNMID, MIDD, and amyloidosis. Therefore, early and quick initiation of treatment is needed to ensure a good renal outcome. Prompt initiation of therapy is recommended before irreversible renal damageoccurs.,
In CKD stage 1-3, early initiation of treatment is needed to achieve good results. Further treatment with ASCT may be undertaken in order to consolidate the hematological and renal remissions. However, in cases with CKD stage 4, chemotherapy is indicated only if a renal transplant is planned, or if there is extrarenal disease. Prior to transplant, achievement of a complete hematological response are important to prevent recurrence of MGRS in the allograft kidney.
| Conclusion|| |
Clonal proliferative diseases that produce a nephrotoxic monoclonal protein are increasingly being recognized. MGRS is a new term to encompass all these lesions under a single umbrella so that they can be correctly addressed. It is important to recognize these lesions as pathological so that appropriate therapy can be instituted. The diagnosis of MGRS cannot be established in the absence of a renal biopsy that will demonstrate presence of monoclonal immunoglobulin deposits (light chains/heavy chains as in MIDD or immune complex type deposits as in PGNMID) or indirectly tells us about the diagnosis and implicating their involvement in the case of C3 GN or thrombotic microangiopathy with a circulating monoclonal immunoglobulin. Hematological evaluation might require peripheral blood flow cytometry, bone marrow biopsy and imaging studies to assess localized disease.
Conflict of interest: None declared.
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Department of Pathology, Army Hospital Research and Referral, Delhi Cantonment, New Delhi
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