The monoclonal gammopathies of renal significance are hematologic disorders defined by monoclonal gammopathy-mediated kidney damage in patients who do not have systemic lymphoma or multiple myeloma. Diagnosis is usually made by a kidney biopsy showing direct paraprotein-mediated kidney damage on immunofluorescence microscopy. A specific challenge exists in patients with monoclonal gammopathies whose kidney biopsies exhibit patterns of injury without visualization of the monoclonal immunoglobulin. Case reports and case series have been published recently describing monoclonal gammopathy–associated C3 glomerulopathy and monoclonal gammopathy–associated thrombotic microangiopathy, with mechanistic hypotheses including paraprotein-mediated activation of the alternative complement pathway. Here, we evaluate the level of evidence supporting the hypothesis that the monoclonal gammopathy is in the causal pathway of monoclonal gammopathy–associated C3 glomerulopathy and monoclonal gammopathy–associated thrombotic microangiopathy and identify gaps in knowledge required to further support these diagnoses.
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