Title: Monoclonal Gammopathy of Renal Significance (MGRS)
In this GlomCon Conference Dr. Kate Robson led a Case-based Discussion in which she reviewed the evaluation and management of Monoclonal Gammopathy of Renal Significance. Our
Moderator’s Notes is derived from her live presentation which you can watch here: https://glomcon.org/monoclonal-gammopathy/a-case-based-discussion-5
Author: Dr. Jessica Lapasia
Editors: Dr. Kate Robson, Dr. Ali Poyan Mehr
• MGUS = <10% clonal plasma cells in the bone marrow, with approximately 1%/year progression to myeloma.
• Smoldering myeloma = 10-60% clonal plasma cells in the bone marrow, with approximately 10%/year progression to myeloma.
• Active multiple myeloma = >10% clonal plasma cells in the bone marrow, with at least one myeloma-defining event (Calcium elevation, Renal impairment, Anemia, Bone disease.)
• As the burden of clone increases, patients may progress over time from MGUS to smoldering myeloma to active myeloma.
• Monoclonal gammopathy can also cause end-organ effect independent of the size of the clone (as in AL amyloidosis, MIDD, immunotactoid GN, Fanconi syndrome.)
• Several factors can contribute to disease characteristics/burden:
o Rate of immunoglobulin/FLC production
o Structural/chemical properties of immunoglobulin/FLCs
o Host micro-environment (pH, tissue factors)
• SPEP can be negative in patients with clinically significant paraproteinemia. Checking serum immunofixation and serum free light chains should accompany SPEP, whenever paraprotein related kidney disease is suspected.
o Approximately 15% of myeloma cases only produce light chains and SPEP alone may not be sufficient screening for myeloma.
• MGUS plus renal disease does not necessarily equal MGRS and it is important to think of other unrelated conditions (such as DM) contributing to decline in renal impairment. Biopsy is currently our gold standard for diagnosis of MGRS.
Testing for MGUS/MGRS
• Protein electrophoresis separates proteins by size. This test has limited detection of low level of paraprotein or small size proteins (such as light chains.)
• Immunofixation is more specific and can help identify heavy and light chains as well as help confirm a monoclonal population.
• Kappa light chain is produced at twice the rate of lambda light chain and is cleared more effectively by the kidney; thus, a normal ratio of k/l is <1. In renal impairment, the kappa becomes proportionately elevated due to reduced clearance, and the k/l is more reflective of the rate of production.
• A suggested normal range of free light chain ratio (FLC) in patients with renal impairment is 0.37-3.1. Consider discussion with hematology for cases with a FLC above a ratio of 4-5.
• In normal physiology, small amounts of FLC are reabsorbed at the proximal tubule and then lead to endosomal intake and lysosomal degradation.
• In cast nephropathy, a large FLC burden overwhelms the proximal tubule reabsorption capacity and an excess of light chains in the distal tubule bind to Tamm-Horsfall protein and lead to cast formation.
• In light chain proximal tubulopathy, light chains are resistant to proteolysis and are prone to aggregation in the proximal tubule and lead to crystal formation – light chain proximal tubulopathy can be the first clinical presentation of renal disease (and indication for biopsy) in patients with MGUS.
• Consider Fanconi Syndrome in patients with normoglycemic glycosuria, hypophosphatemia, and amino aciduria.
Monoclonal Ig Deposition Disease (MIDD)
• Can be light chain (LC), heavy chain (HC), or both (LHC).
• Light chain is the most common, 80% of these are kappa, likely due to its unique physical properties that make it more likely to aggregate.
• Almost all patients have evidence of a dysproteinemia (100% with abnormal FLC, 73% with abnormal SPEP) and more than 50% of patients have multiple myeloma.
• Detectable circulating dysproteinemia can precede or succeed the presentation of kidney disease.
• Significant proportion of patients (>30%) progress to ESKD at 25m follow up, despite targeted treatment.
• Patients who achieve a hematologic response have a much better renal survival.
MH Rosner, A Edeani, M Yanagita, IG Glezerman and N Leung,
Clinical journal of the American Society of Nephrology : CJASN, 2016 12 07
Paraprotein-related kidney disease represents a complex group of diseases caused by an abnormal paraprotein secreted by a clone of B cells. The disease manifestations range from tubulopathies, such as the Fanconi syndrome, to a spectrum of glomerular diseases that can present with varying degrees of proteinuria and renal dysfunction. Diagnosis of these diseases can be challenging because of the wide range of manifestations as well as the relatively common finding of a serum paraprotein, especially in elderly patients. Thus, renal biopsy along with detailed hematologic workup is essential to link the presence of the paraprotein to the associated renal disease. Recent advances in treatment with more effective and targeted chemotherapies, as well as stem cell transplantation, have improved the renal and overall prognosis for many of these disorders.
MA Perazella and KW Finkel,
Clinical journal of the American Society of Nephrology : CJASN, 2016 12 07
Paraproteins are monoclonal Igs or their components (light or heavy chains) that are produced by a clonal population of mature B cells, most commonly plasma cells. These paraproteins or monoclonal proteins are secreted into the blood and subsequently filtered by the glomerulus before entering into urine, where they can cause various types of kidney disease, including both glomerular and tubulointerstitial injuries. Furthermore, a monoclonal protein that causes a specific glomerular or tubulointerstitial lesion in a human can reproducibly cause the same pathology when injected into an animal, supporting unique paraprotein characteristics. This Moving Points in Nephrology will provide an update for the Clinical Journal of the American Society of Nephrology readership on some of the clinically relevant kidney lesions associated with monoclonal paraprotein production and the pathophysiology underlying these kidney lesions.
JJ Hogan and BM Weiss,
Clinical journal of the American Society of Nephrology : CJASN, 2016 09 07
The monoclonal gammopathies of renal significance (MGRS) are a group of disorders characterized by monoclonal Ig deposition in the kidney, but are not associated with systemic lymphoma or overt multiple myeloma. The prevailing hypothesis is that the pathogenic paraproteins in MGRS are produced by underlying B cell or plasma cell clones. However, in the MGRS literature, the yield of detecting a clone has been variable, and progression to ESRD is common. Here, we present an "onco-nephrologic" approach to the MGRS disorders by highlighting recent advances in lymphoma and multiple myeloma that can be used in the evaluation and management of these patients.
F Bridoux, N Leung, CA Hutchison, G Touchard, S Sethi, JP Fermand, MM Picken, GA Herrera, E Kastritis, G Merlini, M Roussel, FC Fervenza, A Dispenzieri, RA Kyle and SH Nasr,
Kidney international, Apr 2015
Monoclonal gammopathy of renal significance (MGRS) regroups all renal disorders caused by a monoclonal immunoglobulin (MIg) secreted by a nonmalignant B-cell clone. By definition, patients with MGRS do not meet the criteria for overt multiple myeloma/B-cell proliferation, and the hematologic disorder is generally consistent with monoclonal gammopathy of undetermined significance (MGUS). However, MGRS is associated with high morbidity due to the severity of renal and sometimes systemic lesions induced by the MIg. Early recognition is crucial, as suppression of MIg secretion by chemotherapy often improves outcomes. The spectrum of renal diseases in MGRS is wide, including old entities such as AL amyloidosis and newly described lesions, particularly proliferative glomerulonephritis with monoclonal Ig deposits and C3 glomerulopathy with monoclonal gammopathy. Kidney biopsy is indicated in most cases to determine the exact lesion associated with MGRS and evaluate its severity. Diagnosis requires integration of morphologic alterations by light microscopy, immunofluorescence (IF), electron microscopy, and in some cases by IF staining for Ig isotypes, immunoelectron microscopy, and proteomic analysis. Complete hematologic workup with serum and urine protein electrophoresis, immunofixation, and serum-free light-chain assay is required. This review addresses the pathologic and clinical features of MGRS lesions, indications of renal biopsy, and a proposed algorithm for the hematologic workup.
JP Fermand, F Bridoux, RA Kyle, E Kastritis, BM Weiss, MA Cook, MT Drayson, A Dispenzieri and N Leung,
Blood, Nov 21 2013
Recently, the term monoclonal gammopathy of renal significance (MGRS) was introduced to distinguish monoclonal gammopathies that result in the development of kidney disease from those that are benign. By definition, patients with MGRS have B-cell clones that do not meet the definition of multiple myeloma or lymphoma. Nevertheless, these clones produce monoclonal proteins that are capable of injuring the kidney resulting in permanent damage. Except for immunoglobulin light chain amyloidosis with heart involvement in which death can be rapid, treatment of MGRS is often indicated more to preserve kidney function and prevent recurrence after kidney transplantation rather than the prolongation of life. Clinical trials are rare for MGRS-related kidney diseases, except in immunoglobulin light chain amyloidosis. Treatment recommendations are therefore based on the clinical data obtained from treatment of the clonal disorder in its malignant state. The establishment of these treatment recommendations is important until data can be obtained by clinical trials of MGRS-related kidney diseases.
CA Hutchison, S Harding, P Hewins, GP Mead, J Townsend, AR Bradwell and P Cockwell,
Clinical journal of the American Society of Nephrology : CJASN, Nov 2008
Monoclonal free light chains (FLC) frequently cause kidney disease in patients with plasma cell dyscrasias. Polyclonal FLC, however, have not been assessed in patients with chronic kidney disease (CKD) yet could potentially play an important pathologic role. This study describes for the first time polyclonal FLC in patients with CKD.A sensitive, quantitative immunoassay was used to analyze serum and urinary polyclonal FLC in 688 patients with CKD of various causes.Serum kappa and lambda FLC concentrations increased progressively with CKD stage (both P < 0.001) and strongly correlated with markers of renal function, including cystatin-C (kappa: R = 0.8, P < 0.01; and lambda: R = 0.79, P < 0.01). Urinary FLC concentrations varied significantly between disease groups (kappa: P < 0.001; lambda: P < 0.005) and also rose significantly with increasing CKD stage (both FLC P < 0.0001). Urinary FLC concentrations were positively correlated with their corresponding serum concentration (kappa: R = 0.63; lambda: R = 0.65; both P < 0.001) and urinary albumin creatinine ratio (kappa: R = 0.58; lambda: R = 0.65; both P < 0.001). The proportion of patients with abnormally high urinary FLC concentrations rose with both the CKD stage and the severity of albuminuria.This study demonstrates significant abnormalities of serum and urinary polyclonal FLC in patients with CKD. These data provide the basis for studies that assess the contribution of polyclonal FLC to progressive renal injury and systemic inflammation in patients with kidney disease.
MB Stokes, AM Valeri, L Herlitz, AM Khan, DS Siegel, GS Markowitz and VD D'Agati,
Journal of the American Society of Nephrology : JASN, 2016 05
Light chain proximal tubulopathy (LCPT) is characterized by cytoplasmic inclusions of monoclonal LC within proximal tubular cells. The significance of crystalline versus noncrystalline LCPT and the effect of modern therapies are unknown. We reported the clinical-pathologic features of 40 crystalline and six noncrystalline LCPT patients diagnosed between 2000 and 2014. All crystalline LCPTs were κ-restricted and displayed acute tubular injury. One-third of noncrystalline LCPT patients displayed λ-restriction or acute tubular injury. Only crystalline LCPT frequently required antigen retrieval to demonstrate monoclonal LC by immunofluorescence. In five of 38 patients, crystals were not detectable by light microscopy, but they were visible by electron microscopy. Hematolymphoid neoplasms, known before biopsy in only 15% of patients, included 21 monoclonal gammopathies of renal significance; 15 multiple myelomas; seven smoldering multiple myelomas; and three other neoplasms. Biopsy indications included Fanconi syndrome (38%; all with crystalline LCPT), renal insufficiency (83%), and proteinuria (98%). Follow-up was available for 30 (75%) patients with crystalline LCPT and all six patients with noncrystalline LCPT, of whom 11 underwent stem cell transplant, 16 received chemotherapy only, and nine were untreated. Complete or very good partial hematologic remissions occurred in six of 22 treated crystalline LCPT patients. By multivariable analysis, the only independent predictor of final eGFR was initial eGFR, highlighting the importance of early detection. All patients with crystalline LCPT treated with stem cell transplant had stable or improved kidney function, indicating the effectiveness of aggressive therapy in selected patients.
SH Nasr, AM Valeri, LD Cornell, ME Fidler, S Sethi, VD D'Agati and N Leung,
Clinical journal of the American Society of Nephrology : CJASN, Feb 2012
To better define the clinical-pathologic spectrum and prognosis of monoclonal immunoglobulin deposition disease (MIDD), this study reports the largest series.Characteristics of 64 MIDD patients who were seen at Mayo Clinic are provided.Of 64 patients with MIDD, 51 had light chain deposition disease, 7 had heavy chain deposition disease, and 6 had light and heavy chain deposition disease. The mean age at diagnosis was 56 years, and 23 patients (36%) were ≤50 years of age. Clinical evidence of dysproteinemia was present in 62 patients (97%), including multiple myeloma in 38 (59%). M-spike was detected on serum protein electrophoresis in 47 (73%). Serum free light chain ratio was abnormal in all 51 patients tested. Presentation included renal insufficiency, proteinuria, hematuria, and hypertension. Nodular mesangial sclerosis was seen in 39 patients (61%). During a median of 25 months of follow-up (range, 1-140) in 56 patients, 32 (57%) had stable/improved renal function, 2 (4%) had worsening renal function, and 22 (39%) progressed to ESRD. The mean renal and patient survivals were 64 and 90 months, respectively. The disease recurred in three of four patients who received a kidney transplant.Patients with MIDD generally present at a younger age than those with light chain amyloidosis or light chain cast nephropathy. Serum free light chain ratio is abnormal in all MIDD patients, whereas only three-quarters have abnormal serum protein electrophoresis. The prognosis for MIDD is improving compared with historical controls, likely reflecting earlier detection and improved therapies.
F Joly, C Cohen, V Javaugue, S Bender, M Belmouaz, B Arnulf, B Knebelmann, M Nouvier, V Audard, F Provot, V Gnemmi, D Nochy, JM Goujon, A Jaccard, G Touchard, JP Fermand, C Sirac and F Bridoux,
Blood, Feb 2019 07
Monoclonal immunoglobulin deposition disease (MIDD) is a rare complication of B-cell clonal disorders, defined by Congo red negative-deposits of monoclonal light chain (LCDD), heavy chain (HCDD), or both (LHCDD). MIDD is a systemic disorder with prominent renal involvement, but little attention has been paid to the description of extrarenal manifestations. Moreover, mechanisms of pathogenic immunoglobulin deposition and factors associated with renal and patient survival are ill defined. We retrospectively studied a nationwide cohort of 255 patients, with biopsy-proven LCDD (n = 212) (including pure LCDD [n = 154], LCDD with cast nephropathy (CN) [n = 58]), HCDD (n = 23), or LHCDD (n = 20). Hematological diagnosis was monoclonal gammopathy of renal significance in 64% and symptomatic myeloma in 34%. Renal presentation was acute kidney injury in patients with LCCD and CN, and chronic glomerular disease in the other types, 35% of whom had symptomatic extrarenal (mostly hepatic and cardiac) involvement. Sequencing of 18 pathogenic LC showed high isoelectric point values of variable domain complementarity determining regions, possibly accounting for tissue deposition. Among 169 patients who received chemotherapy (bortezomib-based in 58%), 67% achieved serum free light chain (FLC) response, including very good partial response (VGPR) or above in 52%. Renal response occurred in 62 patients (36%), all of whom had achieved hematological response. FLC response ≥ VGPR and absence of severe interstitial fibrosis were independent predictors of renal response. This study highlights an unexpected frequency of extrarenal manifestations in MIDD. Rapid diagnosis and achievement of deep FLC response are key factors of prognosis.