In an article recently published in the American Journal of Kidney Diseases, Zand et al discuss a series of patients with C3 glomerulopathy and monoclonal gammopathy. This is an interesting association at a time when the classification of MPGN is drastically changing. The classic definition of MPGN is based on electron microscopy (EM), with classifications of primary (idiopathic) MPGN type I (MPGN I), type II (MPGN II), or type III (MPGN III) or secondary MPGN. MPGN I, the most common form, is characterized by subendothelial deposits, and MPGN III has both subepithelial and subendothelial deposits. MPGN II is characterized by dense deposits in the glomerular basement membrane (“dense deposit disease”). A novel classification system of MPGN is dependent on the immunofluoresnce (IF) staining. Given recent advances in our understanding of the role of the alternative pathway of complement in MPGN, a practical approach is to view MPGN as immune-complex–mediated or complement-mediated. Thus, immune-complex–mediated MPGN may occur when there are increased levels of circulating immune complexes, while complement-mediated MPGN may occur with disorders of dysregulation of the alternative pathway of complement. If neither of these two exists, chronic thrombotic microangiopathy may be the cause. Of the immune-complex–mediated MPGN, the three most common causes are infections (Hep C, B), autoimmune diseases (SLE, RA), and paraproteinemias.
While prior reports had mentioned paraproteinemias as a major cause of MPGN, it was not until recently when Sethi et al described the major association of monoclonal gammopathy of undetermined significance (MGUS) and MPGN. Traditionally, these entities were thought to be benign and less likely to progress to myeloma. Hematologically, perhaps MGUS may not progress to myeloma and or amyloidosis, but in certain cases may be damaging to the kidney. A small plasma cell clones may be responsible for this MGUS, leading to the MPGN pattern of injury. Classically, all of these cases had monoclonal deposition on kidney biopsy (IF). Some of the cases were associated with low grade B cell lymphoma and/or lymphoplasmacytic lymphoma or chronic lymphocytic leukemia. Interesting, while C3 glomerulopathy has no immune complexes or monoclonal deposits in this series, there might be a causal association of MGUS and C3 GN. Why some patients get immune-complex–mediated and some get complement-mediated MPGN with MGUS is unclear. Regardless, two patients that were treated for their underlying hematologic clonal disorder went into renal remission. This suggests a striking causal relationship. I think the above group of disorders comprise a larger group of Monoclonal Gammopathy of Renal Significance (MGRS). Similar suggestions have been made recently of combining these disorders in a separate class to alert the hematologists and oncologists to be aggressive in the treatment of these patients. The figure summarizes the above associations.
Kenar Jhaveri, MD
eAJKD Blog Editor