Study on the pathogenesis of monoclonal gammopathy of renal significance_West China Medical Journal

Authors：

YANG Linlin ¹ , LIU Gang ² ,  LU Hongxia ¹

1. Blood Purification Department, Chengdu Pidu District Hospital of TCM, Chengdu, Sichuan 611730, P. R. China;
2. Department of Nephrology, Peking University First Hospital, Beijing 100034, P. R. China;

Corresponding author：

LU Hongxia, Email: 956600536@qq.com

Keywords：

Monoclonal gammopathy of renal significance; free light chain; monoclonal immunoglobulin

DOI：

10.7507/1002-0179.202009302

Video：

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Monoclonal gammopathy of renal significance (MGRS) is a group of diseases with different renal damage. It is a new type of renal disease with various types of diseases and complex disease mechanism. In MGRS, due to the clonal proliferation of B lymphoid cells or plasma cells, a large number of monoclonal immunoglobulin (MIg) and/or a large number of free light chain (FLC) appear. Intact MIg can interact with intrinsic cells of glomerulus to change its biology in order to promote the development of renal disease, while monoclonal FLC can potentially alter the function of various cells throughout the nephron. Given the relationship of MIg and monoclonal FLC to MGRS, inhibition of MIg and monoclonal FLC would be a promising approach for the treatment of MGRS. This paper reviews the pathogenesis of MGRS from the sites of renal involvement, including glomerulus, renal tubule-interstitium and renal blood vessel.

Citation： YANG Linlin, LIU Gang, LU Hongxia. Study on the pathogenesis of monoclonal gammopathy of renal significance. West China Medical Journal, 2022, 37(4): 627-631. doi: 10.7507/1002-0179.202009302 Copy

1.	Leung N, Bridoux F, Hutchison CA, et al. Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant. Blood, 2012, 120(22): 4292-4295.
2.	Sethi S, Fervenza FC, Rajkumar SV. Spectrum of manifestations of monoclonal gammopathy-associated renal lesions. Curr Opin Nephrol Hypertens, 2016, 25(2): 127-137.
3.	Bridoux F, Leung N, Hutchison CA, et al. Diagnosis of monoclonal gammopathy of renal significance. Kidney Int, 2015, 87(4): 698-711.
4.	Ramirez-Alvarado M, Barnidge DR, Murray DL, et al. Assessment of renal response with urinary exosomes in patients with AL amyloidosis: a proof of concept. Am J Hematol, 2017, 92(6): 536-541.
5.	Herrera GA, Teng J, Turbat-Herrera EA, et al. Understanding mesangial pathobiology in AL-amyloidosis and monoclonal Ig light chain deposition disease. Kidney Int Rep, 2020, 5(11): 1870-1893.
6.	Teng J, Turbat-Herrera EA, Herrera GA. Extrusion of amyloid fibrils to the extracellular space in experimental mesangial AL-amyloidosis: transmission and scanning electron microscopy studies and correlation with renal biopsy observations. Ultrastruct Pathol, 2014, 38(2): 104-115.
7.	Sirac C, Bridoux F. Mesangial cells as amyloid factory: a unique contribution of animal models. Kidney Int, 2014, 86(4): 669-671.
8.	Teng J, Turbat-Herrera EA, Herrera GA. An animal model of glomerular light-chain-associated amyloidogenesis depicts the crucial role of lysosomes. Kidney Int, 2014, 86(4): 738-746.
9.	Muchtar E, Dispenzieri A, Magen H, et al. Systemic amyloidosis from A (AA) to T (ATTR): a review. J Intern Med, 2020, 289(3): 268-292.
10.	Wechalekar AD, Gillmore JD, Hawkins PN. Systemic amyloidosis. Lancet, 2016, 387(10038): 2641-2654.
11.	Vora M, Kevil CG, Herrera GA. Contribution of human smooth muscle cells to amyloid angiopathy in AL (light-chain) amyloidosis. Ultrastruct Pathol, 2017, 41(5): 358-368.
12.	Leo A, Kreft H, Hack H, et al. Restriction in the repertoire of the immunoglobulin light chain subgroup in pathological cold agglutinins with anti-prspecificity. Vox Sang, 2014, 86(2): 141-147.
13.	James LC, Jones PC, McCoy A, et al. Beta-edge interactions in a pentadecameric human antibody V kappa domain. J Mol Biol, 2007, 367(3): 603-608.
14.	Taylor EB, Ryan MJ. Freedom isn’t always free: immunoglobulin free light chains promote renal fibrosis. J Clin Invest, 2019, 129(7): 2660-2662.
15.	Herrera GA, Del Pozo-Yauner L, Teng J, et al. Glomerulopathic light chain-mesangial cell interactions: sortilin-related receptor (SORL1) and signaling. Kidney Int Rep, 2021, 6(5): 1379-1396.
16.	Vidal R, Goñi F, Stevens F, et al. Somatic mutations of the L12a gene in V-kappa (1) light chain deposition disease: potential effects on aberrant protein conformation and deposition. Am J Pathol, 1999, 155(6): 2009-2017.
17.	Keeling J, Herrera GA. Matrix metalloproteinases and mesangial remodeling in light chain-related glomerular damage. Kidney Int, 2015, 68(4): 1590-1603.
18.	Herrera GA, Turbat-Herrera EA, Teng J. Animal models of light chain deposition disease provide a better understanding of nodular glomerulosclerosis. Nephron, 2016, 132(2): 119-136.
19.	Ahmad SB, Bomback AS. C3 glomerulopathy: pathogenesis and treatment. Adv Chronic Kidney Dis, 2020, 27(2): 104-110.
20.	Imamura H, Konomoto T, Tanaka E, et al. Familial C3 glomerulonephritis associated with mutations in the gene for complement factor B. Nephrol Dial Transplant, 2015, 30(5): 862-864.
21.	Zipfel PF, Wiech T, Stea ED, et al. CFHR gene variations provide insights in the pathogenesis of the kidney diseases atypical hemolytic uremic syndrome and C3 glomerulopathy. J Am Soc Nephrol, 2020, 31(2): 241-256.
22.	Iatropoulos P, Noris M, Mele C, et al. Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome. Mol Immunol, 2016, 71: 131-142.
23.	Bhutani G, Nasr SH, Said SM, et al. Hematologic characteristics of proliferative glomerulonephritides with nonorganized monoclonal immunoglobulin deposits. Mayo Clin Proc, 2015, 90(5): 587-596.
24.	Kousios A, Duncan N, Tam FWK, et al. Proliferative glomerulonephritis with monoclonal Ig deposits (PGNMID): diagnostic and treatment challenges for the nephrologist!. Kidney Int, 2019, 95(2): 467-468.
25.	Fogo AB, Lusco MA, Najafian B, et al. AJKD atlas of renal pathology: immunotactoid glomerulopathy. Am J Kidney Dis, 2015, 66(4): e29-e30.
26.	Nasr SH, Kudose SS, Said SM, et al. Immunotactoid glomerulopathy is a rare entity with monoclonal and polyclonal variants. Kidney Int, 2021, 99(2): 410-420.
27.	Herrera GA. Proximal tubulopathies associated with monoclonal light chains: the spectrum of clinicopathologic manifestations and molecular pathogenesis. Arch Pathol Lab Med, 2014, 138(10): 1365-1380.
28.	Yu XJ, Zhou XJ, Wang SX, et al. Monoclonal light chain crystalline podocytopathy and tubulopathy associated with monoclonal gammopathy of renal significance: a case report and literature review. BMC Nephrol, 2018, 19(1): 322.
29.	Ecotière L, Thierry A, Debiais-Delpech C, et al. Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients. Nephrol Dial Transplant, 2016, 31(1): 64-72.
30.	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(5): 1555-1565.
31.	Sengul S, Erturk S, Khan AM, et al. Receptor-associated protein blocks internalization and cytotoxicity of myeloma light chain in cultured human proximal tubular cells. PLoS One, 2013, 8(7): e70276.
32.	Lusco MA, Fogo AB, Najafian B, et al. AJKD atlas of renal pathology: light chain cast nephropathy. Am J Kidney Dis, 2016, 67(3): e17-e18.
33.	Weiss JH, Williams RH, Galla JH, et al. Pathophysiology of acute Bence-Jones protein nephrotoxicity in the rat. Kidney Int, 1981, 20(2): 198-210.
34.	Walther C, Podoll AS, Finkel KW. Treatment of acute kidney injury with cast nephropathy. Clin Nephrol, 2014, 82(1): 1-6.
35.	Manohar S, Nasr SH, Leung N. Light chain cast nephropathy: practical considerations in the management of myeloma kidney-what we know and what the future may hold. Curr Hematol Malig Rep, 2018, 13(3): 220-226.
36.	Yoshida Y, Kato H, Ikeda Y, et al. Pathogenesis of atypical hemolytic uremic syndrome. J Atheroscler Thromb, 2019, 26(2): 99-110.
37.	Rigothier C, Delmas Y, Roumenina LT, et al. Distal angiopathy and atypical hemolytic uremic syndrome: clinical and functional properties of an anti-factor H IgAλ antibody. Am J Kidney Dis, 2015, 66(2): 331-336.

1. Leung N, Bridoux F, Hutchison CA, et al. Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant. Blood, 2012, 120(22): 4292-4295.
2. Sethi S, Fervenza FC, Rajkumar SV. Spectrum of manifestations of monoclonal gammopathy-associated renal lesions. Curr Opin Nephrol Hypertens, 2016, 25(2): 127-137.
3. Bridoux F, Leung N, Hutchison CA, et al. Diagnosis of monoclonal gammopathy of renal significance. Kidney Int, 2015, 87(4): 698-711.
4. Ramirez-Alvarado M, Barnidge DR, Murray DL, et al. Assessment of renal response with urinary exosomes in patients with AL amyloidosis: a proof of concept. Am J Hematol, 2017, 92(6): 536-541.
5. Herrera GA, Teng J, Turbat-Herrera EA, et al. Understanding mesangial pathobiology in AL-amyloidosis and monoclonal Ig light chain deposition disease. Kidney Int Rep, 2020, 5(11): 1870-1893.
6. Teng J, Turbat-Herrera EA, Herrera GA. Extrusion of amyloid fibrils to the extracellular space in experimental mesangial AL-amyloidosis: transmission and scanning electron microscopy studies and correlation with renal biopsy observations. Ultrastruct Pathol, 2014, 38(2): 104-115.
7. Sirac C, Bridoux F. Mesangial cells as amyloid factory: a unique contribution of animal models. Kidney Int, 2014, 86(4): 669-671.
8. Teng J, Turbat-Herrera EA, Herrera GA. An animal model of glomerular light-chain-associated amyloidogenesis depicts the crucial role of lysosomes. Kidney Int, 2014, 86(4): 738-746.
9. Muchtar E, Dispenzieri A, Magen H, et al. Systemic amyloidosis from A (AA) to T (ATTR): a review. J Intern Med, 2020, 289(3): 268-292.
10. Wechalekar AD, Gillmore JD, Hawkins PN. Systemic amyloidosis. Lancet, 2016, 387(10038): 2641-2654.
11. Vora M, Kevil CG, Herrera GA. Contribution of human smooth muscle cells to amyloid angiopathy in AL (light-chain) amyloidosis. Ultrastruct Pathol, 2017, 41(5): 358-368.
12. Leo A, Kreft H, Hack H, et al. Restriction in the repertoire of the immunoglobulin light chain subgroup in pathological cold agglutinins with anti-prspecificity. Vox Sang, 2014, 86(2): 141-147.
13. James LC, Jones PC, McCoy A, et al. Beta-edge interactions in a pentadecameric human antibody V kappa domain. J Mol Biol, 2007, 367(3): 603-608.
14. Taylor EB, Ryan MJ. Freedom isn’t always free: immunoglobulin free light chains promote renal fibrosis. J Clin Invest, 2019, 129(7): 2660-2662.
15. Herrera GA, Del Pozo-Yauner L, Teng J, et al. Glomerulopathic light chain-mesangial cell interactions: sortilin-related receptor (SORL1) and signaling. Kidney Int Rep, 2021, 6(5): 1379-1396.
16. Vidal R, Goñi F, Stevens F, et al. Somatic mutations of the L12a gene in V-kappa (1) light chain deposition disease: potential effects on aberrant protein conformation and deposition. Am J Pathol, 1999, 155(6): 2009-2017.
17. Keeling J, Herrera GA. Matrix metalloproteinases and mesangial remodeling in light chain-related glomerular damage. Kidney Int, 2015, 68(4): 1590-1603.
18. Herrera GA, Turbat-Herrera EA, Teng J. Animal models of light chain deposition disease provide a better understanding of nodular glomerulosclerosis. Nephron, 2016, 132(2): 119-136.
19. Ahmad SB, Bomback AS. C3 glomerulopathy: pathogenesis and treatment. Adv Chronic Kidney Dis, 2020, 27(2): 104-110.
20. Imamura H, Konomoto T, Tanaka E, et al. Familial C3 glomerulonephritis associated with mutations in the gene for complement factor B. Nephrol Dial Transplant, 2015, 30(5): 862-864.
21. Zipfel PF, Wiech T, Stea ED, et al. CFHR gene variations provide insights in the pathogenesis of the kidney diseases atypical hemolytic uremic syndrome and C3 glomerulopathy. J Am Soc Nephrol, 2020, 31(2): 241-256.
22. Iatropoulos P, Noris M, Mele C, et al. Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome. Mol Immunol, 2016, 71: 131-142.
23. Bhutani G, Nasr SH, Said SM, et al. Hematologic characteristics of proliferative glomerulonephritides with nonorganized monoclonal immunoglobulin deposits. Mayo Clin Proc, 2015, 90(5): 587-596.
24. Kousios A, Duncan N, Tam FWK, et al. Proliferative glomerulonephritis with monoclonal Ig deposits (PGNMID): diagnostic and treatment challenges for the nephrologist!. Kidney Int, 2019, 95(2): 467-468.
25. Fogo AB, Lusco MA, Najafian B, et al. AJKD atlas of renal pathology: immunotactoid glomerulopathy. Am J Kidney Dis, 2015, 66(4): e29-e30.
26. Nasr SH, Kudose SS, Said SM, et al. Immunotactoid glomerulopathy is a rare entity with monoclonal and polyclonal variants. Kidney Int, 2021, 99(2): 410-420.
27. Herrera GA. Proximal tubulopathies associated with monoclonal light chains: the spectrum of clinicopathologic manifestations and molecular pathogenesis. Arch Pathol Lab Med, 2014, 138(10): 1365-1380.
28. Yu XJ, Zhou XJ, Wang SX, et al. Monoclonal light chain crystalline podocytopathy and tubulopathy associated with monoclonal gammopathy of renal significance: a case report and literature review. BMC Nephrol, 2018, 19(1): 322.
29. Ecotière L, Thierry A, Debiais-Delpech C, et al. Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients. Nephrol Dial Transplant, 2016, 31(1): 64-72.
30. 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(5): 1555-1565.
31. Sengul S, Erturk S, Khan AM, et al. Receptor-associated protein blocks internalization and cytotoxicity of myeloma light chain in cultured human proximal tubular cells. PLoS One, 2013, 8(7): e70276.
32. Lusco MA, Fogo AB, Najafian B, et al. AJKD atlas of renal pathology: light chain cast nephropathy. Am J Kidney Dis, 2016, 67(3): e17-e18.
33. Weiss JH, Williams RH, Galla JH, et al. Pathophysiology of acute Bence-Jones protein nephrotoxicity in the rat. Kidney Int, 1981, 20(2): 198-210.
34. Walther C, Podoll AS, Finkel KW. Treatment of acute kidney injury with cast nephropathy. Clin Nephrol, 2014, 82(1): 1-6.
35. Manohar S, Nasr SH, Leung N. Light chain cast nephropathy: practical considerations in the management of myeloma kidney-what we know and what the future may hold. Curr Hematol Malig Rep, 2018, 13(3): 220-226.
36. Yoshida Y, Kato H, Ikeda Y, et al. Pathogenesis of atypical hemolytic uremic syndrome. J Atheroscler Thromb, 2019, 26(2): 99-110.
37. Rigothier C, Delmas Y, Roumenina LT, et al. Distal angiopathy and atypical hemolytic uremic syndrome: clinical and functional properties of an anti-factor H IgAλ antibody. Am J Kidney Dis, 2015, 66(2): 331-336.

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