Diagnosis and treatment of monoclonal gammopathy of renal significance
- Nelson Leung, MD
Nelson Leung, MD
- Professor of Medicine
- Mayo Clinic College of Medicine
- S Vincent Rajkumar, MD
S Vincent Rajkumar, MD
- Edward W. and Betty Knight Scripps Professor of Medicine
- Mayo Clinic
Monoclonal gammopathy of renal significance (MGRS) represents a group of kidney disorders caused by a monoclonal immunoglobulin that is secreted by a nonmalignant or premalignant B cell or plasma cell clone [1,2]. By definition, these disorders do not meet diagnostic criteria for overt, symptomatic multiple myeloma or a lymphoproliferative disorder. The term MGRS was proposed in 2012 by the International Kidney and Monoclonal Gammopathy Research Group to collectively describe patients who would otherwise meet the criteria for monoclonal gammopathy of undetermined significance (MGUS) but demonstrate renal insufficiency and monoclonal immunoglobulin deposition in the kidney . The goal was to differentiate patients with MGUS, who have no evidence of end-organ damage, from those with MGRS, who are at risk of developing progressive renal disease. MGRS can also be associated with other hematologic disorders, including smoldering multiple myeloma [3,4], smoldering Waldenström macroglobulinemia , and monoclonal B cell lymphocytosis (MBL) .
MGRS-associated kidney diseases encompass a wide spectrum of renal pathology and include such lesions as immunoglobulin-associated amyloidosis, monoclonal immunoglobulin deposition disease (MIDD), proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), C3 glomerulopathy with monoclonal gammopathy, light chain proximal tubulopathy (Fanconi syndrome), and several others.
This topic will review the diagnosis and treatment of MGRS. The diagnosis and management of patients with MGUS and the etiology, pathogenesis, clinical manifestations, diagnosis, and treatment of kidney diseases associated with multiple myeloma and other malignant monoclonal gammopathies are presented separately. (See "Diagnosis of monoclonal gammopathy of undetermined significance" and "Clinical course and management of monoclonal gammopathy of undetermined significance" and "Epidemiology, pathogenesis, and etiology of kidney disease in multiple myeloma and other monoclonal gammopathies" and "Clinical features, evaluation, and diagnosis of kidney disease in multiple myeloma and other monoclonal gammopathies" and "Treatment and prognosis of kidney disease in multiple myeloma and other monoclonal gammopathies".)
EPIDEMIOLOGY AND PROGNOSIS
Kidney disease is a common complication of multiple myeloma and other malignant conditions with monoclonal gammopathy. However, most of the kidney diseases that are associated with multiple myeloma, with the exception of light chain cast nephropathy and acute kidney injury caused by hypercalcemia, can occur in the absence of multiple myeloma or other hematologic malignancy. These renal disorders that are caused by the deposition of monoclonal immunoglobulins or their components meet criteria for the diagnosis of MGRS. The following studies illustrate the range of findings [7-14]:
●In a study of 474 patients with immunoglobulin light chain (AL) amyloidosis, only 8 percent had evidence of multiple myeloma .
- Leung N, Bridoux F, Hutchison CA, et al. Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant. Blood 2012; 120:4292.
- Bridoux F, Leung N, Hutchison CA, et al. Diagnosis of monoclonal gammopathy of renal significance. Kidney Int 2015; 87:698.
- Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med 1980; 302:1347.
- Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 2007; 356:2582.
- Kyle RA, Benson JT, Larson DR, et al. Progression in smoldering Waldenstrom macroglobulinemia: long-term results. Blood 2012; 119:4462.
- Strati P, Nasr SH, Leung N, et al. Renal complications in chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis: the Mayo Clinic experience. Haematologica 2015; 100:1180.
- Bhutani G, Nasr SH, Said SM, et al. Hematologic characteristics of proliferative glomerulonephritides with nonorganized monoclonal immunoglobulin deposits. Mayo Clin Proc 2015; 90:587.
- Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995; 32:45.
- Nasr SH, Valeri AM, Cornell LD, et al. Renal monoclonal immunoglobulin deposition disease: a report of 64 patients from a single institution. Clin J Am Soc Nephrol 2012; 7:231.
- Cohen C, Royer B, Javaugue V, et al. Bortezomib produces high hematological response rates with prolonged renal survival in monoclonal immunoglobulin deposition disease. Kidney Int 2015; 88:1135.
- Pozzi C, D'Amico M, Fogazzi GB, et al. Light chain deposition disease with renal involvement: clinical characteristics and prognostic factors. Am J Kidney Dis 2003; 42:1154.
- Bridoux F, Hugue V, Coldefy O, et al. Fibrillary glomerulonephritis and immunotactoid (microtubular) glomerulopathy are associated with distinct immunologic features. Kidney Int 2002; 62:1764.
- Nasr SH, Fidler ME, Cornell LD, et al. Immunotactoid glomerulopathy: clinicopathologic and proteomic study. Nephrol Dial Transplant 2012; 27:4137.
- Nasr SH, Satoskar A, Markowitz GS, et al. Proliferative glomerulonephritis with monoclonal IgG deposits. J Am Soc Nephrol 2009; 20:2055.
- Ma CX, Lacy MQ, Rompala JF, et al. Acquired Fanconi syndrome is an indolent disorder in the absence of overt multiple myeloma. Blood 2004; 104:40.
- Stokes MB, Valeri AM, Herlitz L, et al. Light Chain Proximal Tubulopathy: Clinical and Pathologic Characteristics in the Modern Treatment Era. J Am Soc Nephrol 2016; 27:1555.
- Heilman RL, Velosa JA, Holley KE, et al. Long-term follow-up and response to chemotherapy in patients with light-chain deposition disease. Am J Kidney Dis 1992; 20:34.
- Leung N, Lager DJ, Gertz MA, et al. Long-term outcome of renal transplantation in light-chain deposition disease. Am J Kidney Dis 2004; 43:147.
- Nasr SH, Sethi S, Cornell LD, et al. Proliferative glomerulonephritis with monoclonal IgG deposits recurs in the allograft. Clin J Am Soc Nephrol 2011; 6:122.
- Czarnecki PG, Lager DJ, Leung N, et al. Long-term outcome of kidney transplantation in patients with fibrillary glomerulonephritis or monoclonal gammopathy with fibrillary deposits. Kidney Int 2009; 75:420.
- Pinney JH, Lachmann HJ, Sattianayagam PT, et al. Renal transplantation in systemic amyloidosis-importance of amyloid fibril type and precursor protein abundance. Am J Transplant 2013; 13:433.
- Zand L, Lorenz EC, Cosio FG, et al. Clinical findings, pathology, and outcomes of C3GN after kidney transplantation. J Am Soc Nephrol 2014; 25:1110.
- Lorenz EC, Sethi S, Leung N, et al. Recurrent membranoproliferative glomerulonephritis after kidney transplantation. Kidney Int 2010; 77:721.
- Short AK, O'Donoghue DJ, Riad HN, et al. Recurrence of light chain nephropathy in a renal allograft. A case report and review of the literature. Am J Nephrol 2001; 21:237.
- Herrmann SM, Gertz MA, Stegall MD, et al. Long-term outcomes of patients with light chain amyloidosis (AL) after renal transplantation with or without stem cell transplantation. Nephrol Dial Transplant 2011; 26:2032.
- Chauvet S, Frémeaux-Bacchi V, Petitprez F, et al. Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy. Blood 2017; 129:1437.
- Sayed RH, Wechalekar AD, Gilbertson JA, et al. Natural history and outcome of light chain deposition disease. Blood 2015; 126:2805.
- Sanada S, Ookawara S, Karube H, et al. Marked recovery of severe renal lesions in POEMS syndrome with high-dose melphalan therapy supported by autologous blood stem cell transplantation. Am J Kidney Dis 2006; 47:672.
- Meri S, Koistinen V, Miettinen A, et al. Activation of the alternative pathway of complement by monoclonal lambda light chains in membranoproliferative glomerulonephritis. J Exp Med 1992; 175:939.
- Jokiranta TS, Solomon A, Pangburn MK, et al. Nephritogenic lambda light chain dimer: a unique human miniautoantibody against complement factor H. J Immunol 1999; 163:4590.
- Zand L, Kattah A, Fervenza FC, et al. C3 glomerulonephritis associated with monoclonal gammopathy: a case series. Am J Kidney Dis 2013; 62:506.
- Debiec H, Hanoy M, Francois A, et al. Recurrent membranous nephropathy in an allograft caused by IgG3κ targeting the PLA2 receptor. J Am Soc Nephrol 2012; 23:1949.
- Terrier B, Karras A, Kahn JE, et al. The spectrum of type I cryoglobulinemia vasculitis: new insights based on 64 cases. Medicine (Baltimore) 2013; 92:61.
- Larsen CP, Bell JM, Harris AA, et al. The morphologic spectrum and clinical significance of light chain proximal tubulopathy with and without crystal formation. Mod Pathol 2011; 24:1462.
- El Hamel C, Thierry A, Trouillas P, et al. Crystal-storing histiocytosis with renal Fanconi syndrome: pathological and molecular characteristics compared with classical myeloma-associated Fanconi syndrome. Nephrol Dial Transplant 2010; 25:2982.
- Sethi S, Cuiffo BP, Pinkus GS, Rennke HG. Crystal-storing histiocytosis involving the kidney in a low-grade B-cell lymphoproliferative disorder. Am J Kidney Dis 2002; 39:183.
- Leung N, Buadi FK, Song KW, et al. A case of bilateral renal arterial thrombosis associated with cryocrystalglobulinaemia. NDT Plus 2010; 3:74.
- Papo T, Musset L, Bardin T, et al. Cryocrystalglobulinemia as a cause of systemic vasculopathy and widespread erosive arthropathy. Arthritis Rheum 1996; 39:335.
- Sethi S, Rajkumar SV. Monoclonal gammopathy-associated proliferative glomerulonephritis. Mayo Clin Proc 2013; 88:1284.
- Nasr SH, Markowitz GS, Stokes MB, et al. Proliferative glomerulonephritis with monoclonal IgG deposits: a distinct entity mimicking immune-complex glomerulonephritis. Kidney Int 2004; 65:85.
- Bridoux F, Desport E, Frémeaux-Bacchi V, et al. Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association? Clin J Am Soc Nephrol 2011; 6:2165.
- Sepandj F, Trillo A. Dense deposit disease in association with monoclonal gammopathy of unknown significance. Nephrol Dial Transplant 1996; 11:2309.
- Sethi S, Sukov WR, Zhang Y, et al. Dense deposit disease associated with monoclonal gammopathy of undetermined significance. Am J Kidney Dis 2010; 56:977.
- Lloyd IE, Gallan A, Huston HK, et al. C3 glomerulopathy in adults: a distinct patient subset showing frequent association with monoclonal gammopathy and poor renal outcome. Clin Kidney J 2016; 9:794.
- Borza DB, Chedid MF, Colon S, et al. Recurrent Goodpasture's disease secondary to a monoclonal IgA1-kappa antibody autoreactive with the alpha1/alpha2 chains of type IV collagen. Am J Kidney Dis 2005; 45:397.
- Larsen CP, Ambuzs JM, Bonsib SM, et al. Membranous-like glomerulopathy with masked IgG kappa deposits. Kidney Int 2014; 86:154.
- Ravindran A, Go RS, Fervenza FC, Sethi S. Thrombotic microangiopathy associated with monoclonal gammopathy. Kidney Int 2017; 91:691.
- Larsen CP, Messias NC, Walker PD, et al. Membranoproliferative glomerulonephritis with masked monotypic immunoglobulin deposits. Kidney Int 2015; 88:867.
- Fish R, Pinney J, Jain P, et al. The incidence of major hemorrhagic complications after renal biopsies in patients with monoclonal gammopathies. Clin J Am Soc Nephrol 2010; 5:1977.
- Katzmann JA, Kyle RA, Benson J, et al. Screening panels for detection of monoclonal gammopathies. Clin Chem 2009; 55:1517.
- Palladini G, Russo P, Bosoni T, et al. Identification of amyloidogenic light chains requires the combination of serum-free light chain assay with immunofixation of serum and urine. Clin Chem 2009; 55:499.
- Hogan JJ, Weiss BM. Bridging the Divide: An Onco-Nephrologic Approach to the Monoclonal Gammopathies of Renal Significance. Clin J Am Soc Nephrol 2016; 11:1681.
- Fermand JP, Bridoux F, Kyle RA, et al. How I treat monoclonal gammopathy of renal significance (MGRS). Blood 2013; 122:3583.
- Vignon M, Javaugue V, Alexander MP, et al. Current anti-myeloma therapies in renal manifestations of monoclonal light chain-associated Fanconi syndrome: a retrospective series of 49 patients. Leukemia 2017; 31:123.
- Yamamoto T, Hishida A, Honda N, et al. Crystal-storing histiocytosis and crystalline tissue deposition in multiple myeloma. Arch Pathol Lab Med 1991; 115:351.
- Stokes MB, Aronoff B, Siegel D, D'Agati VD. Dysproteinemia-related nephropathy associated with crystal-storing histiocytosis. Kidney Int 2006; 70:597.
- Farooq U, Bayerl MG, Abendroth CS, et al. Renal crystal storing histiocytosis in a patient with multiple myeloma. Ann Hematol 2009; 88:807.
- DeLyria PA, Avedschmidt SE, Yamada C, Farkash EA. Fatal Cryocrystalglobulinemia With Intravascular and Renal Tubular Crystalline Deposits. Am J Kidney Dis 2016; 67:787.
- Palladini G, Dispenzieri A, Gertz MA, et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol 2012; 30:4541.
- EPIDEMIOLOGY AND PROGNOSIS
- CLASSIFICATION ACCORDING TO PATHOLOGY
- CLINICAL MANIFESTATIONS
- Diagnosis of MGRS
- Evaluation of patients with a confirmed diagnosis of MGRS
- Overview of our approach
- Treatment of proliferative glomerulonephritis
- - Patients with PGNMID
- Patients with a detectable monoclonal protein in the serum or urine
- Patients without a detectable monoclonal protein in the serum or urine
- - Patients with C3 glomerulopathy with monoclonal gammopathy
- Treatment of other MGRS-associated kidney diseases
- - Light chain proximal tubulopathy
- - Less common disorders
- Monitoring the response to therapy
- Patients with end-stage renal disease
- SUMMARY AND RECOMMENDATIONS