Randall-type monoclonal immunoglobulin deposition disease: novel insights from a nationwide cohort study

Abstract

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.

Epidemiological and clinical characteristics and outcome of monoclonal gammopathy of renal significance‐related lesions in Latin America

“…We did not observe a direct correlation between renal and haematological responses as described in other studies . Some patients showed haematological responses but not RR.…”

Glomerulosclerosis and kidney failure in a mouse model of monoclonal immunoglobulin light-chain deposition disease

“…Our model also enabled us to analyse the intrinsic toxicity of pathogenic monoclonal LC for plasma cells. Similarly to what was shown in patients with MIDD (52,23,5,10) and in the HCDD model (17), plasma cells producing LCDD LC are highly sensitive to PI. We assume that mouse plasma cells are quite different from dysplasic human plasma cells, in that genomic alterations other than the sole LC production could explain such sensitivity.…”

Light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits is associated with a high detection rate of the pathogenic plasma cell clone

“…This could be due to the higher level of circulating MIg in PGNMID-LC than PGNMID-IgG and/or may also reflect differences in the mechanisms of complement activation and glomerular inflammation induced by the deposition of monoclonal LCs. (iv) In more than two-thirds of PGNMID-IgG patients, no monoclonal gammopathy or bone marrow B-cell clone are detected at diagnosis or on follow up, 2,7,18,26 and it has been suggested that an oligoclonal response with the same IgG light-and heavy-chain isotype could be involved in the development of glomerulonephritis, at least in some cases. 7 Thus, only 9%-32% PGNMID-IgG patients have a detectable nephropathic clone.…”

“…In the 2 patients with molecular studies, pIs of the complete V domains and of the CDRs were low, contrasting with cationic values found in LCDD LCs that may play a role in their interaction with anionic basement membranes in LCDD. 2 However, additional molecular analyses of LCs from patients with PGNMID-LC are needed to characterize the overall pattern of LCs in this disease.…”

“…nephropathy); activation of the alternative pathway of complement (APC) (e.g., C3 glomerulopathy or thrombotic microangiopathy associated with monoclonal gammopathy); autoantibody activity (e.g., C3 glomerulopathy and monoclonal membranous glomerulopathy); and cytokine activation (e.g., POEMS syndrome-polyneuropathy, organomegaly, endocrinopathy, monoclonal plasmaproliferative disorder, skin changes). [1][2][3][4][5][6][7][8][9][10][11][12] Aside from myeloma cast nephropathy and Waldenström's macroglobulinemic glomerulopathy, which result from high tumor mass, 13,14 most MIgassociated renal lesions, which were recently classified as monoclonal gammopathy of renal significance (MGRS) lesions, are governed by the physicochemical properties of the pathogenic MIg rather than the proliferation rate or tumor burden of the clones that produce them. 4,15,16 Due to their small molecular weight, Ig LCs are freely filtered through the glomerular filtration barrier and may produce specific tubular injury (e.g., myeloma cast nephropathy, LC proximal tubulopathy).…”