Monoclonal gammopathy of clinical significance: a guide for nephrologists

Monoclonal gammopathy of undetermined significance (MGUS) is commonly encountered in older individuals. MGUS, by definition, is a benign finding where an expanded population of clonal plasma and B-cells produces a monoclonal antibody that is a biologically inactive. Even in patients with overt plasma cell neoplasms such as multiple myeloma, the monoclonal antibody is often a marker of disease burden but not pathogenic except in light chain cast nephropathy. However, there is a growing recognition that, in rare cases, clonal cells and/or monoclonal gammopathy not meeting criteria for hematologic malignancy can be pathogenic drivers of disease. These MGUS syndromes have been termed monoclonal gammopathies of clinical significance (MGCS), a larger umbrella under which sits the monoclonal gammopathies of renal significance (MGRS). In this review, we focus on MGCS entities beyond standard MGRS and provide a mechanism-based classification centered on the pathogenic nature of the paraprotein rather than on clonal disease burden. We highlight MGCS entities of relevance to nephrologists, including POEMS syndrome, TEMPI syndrome, monoclonal gammopathy-associated systemic capillary leak syndrome, and hematologic autoantibody-mediated disorders. Awareness and recognition of these rare processes are ultimately essential for accurate diagnosis and patient management.