When Does MGUS Become MGRS?

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Monoclonal gammopathy of unknown significance (MGUS), commonly considered a benign condition, is characterized by a low level of detectable monoclonal immunoglobulin (Ig) in the serum (<30 g/L) and <10% monoclonal plasma cells on bone marrow biopsy. Assuming these low levels of circulating Igs do not cause any end organ damage, treatment is usually not recommended for MGUS. However, in some patients with MGUS, these low levels of Ig or kappa/lambda light chains can cause direct kidney deposition or activation of complements leading to kidney diseases. Because of this, in 2012, the term “monoclonal gammopathy of renal significance” (MGRS) was coined to recognize the spectrum of kidney diseases from MGUS and to treat accordingly (1).

In a recently published retrospective study in the Clinical Journal of the American Society of Nephrology, Yong and colleagues (2) describe the histopathological and clinical features of this entity. In this single-center study (performed in China), approximately 700 patients with monoclonal gammopathy who underwent single kidney biopsy were retrospectively examined over a period of 21 years (1999−2020). Thirty-eight percent of patients were classified as having a MGRS-related lesion, whereas the rest (62%) did not have MGRS.

Ig monoclonal protein-related amyloidosis was the predominant kidney lesion seen in most patients (63%), followed by monoclonal immune deposition disease (9%) and thrombotic microangiopathy (8%). In the non-MGRS group, membranous nephropathy (40%) was the most common, followed by IgA nephropathy (14%) and diabetic nephropathy (9%).

In the MGRS group, a higher percentage of patients had proteinuria >1.5 g/d (81% vs. 70%) and a higher prevalence of hypoalbuminemia <3 g/dL (61% vs. 52%) compared with the patients with a non-MGRS lesion. The prevalence of hypertension, diabetes, and hematuria was less in the MGRS group. A free light-chain ratio (normal range 0.2−2.9) was significantly abnormal (odds ratio, 5.57; 95% confidence interval, 2.90−10.69; P = 0.001) in the MGRS subgroup, which had been verified by a previous study done at the Mayo Clinic (3). The authors also compared clinical data for patients with Ig amyloidosis and non-amyloidosis MGRS. Patients with amyloidosis were significantly older and more likely to have hypoalbuminemia and nephrotic-range proteinuria than the non-amyloidosis group.

The authors concluded that the presence of abnormal free light chains, advanced age, and proteinuria >1.5 g/dL is the potential clinical indicator and can point toward the diagnosis of MGRS.

Yong et al. (2) reported similar findings as the Mayo Clinic, except that the hematuria was also significantly associated with MGRS in the Mayo Clinic study (3). This is contrary to the study by Yong et al. (2), where incidence of hematuria was less in the MGRS group than in the non-MGRS group. One possible explanation for such a difference could be a higher incidence of glomerulonephritis and IgA nephropathy in the Chinese population, leading to more hematuria in the non-MGRS group.

The Yong et al. (2) study found a high incidence of an MGRS-related lesion (approximately 40% vs. 60% non-MGRS) in patients with monoclonal gammopathy and kidney diseases, thus necessitating the need for kidney biopsy to diagnose otherwise missed cases of MGRS. We cannot rule out the possibility of diagnostic bias, since all patients with MGRS underwent kidney biopsies in the study. The salient clinical characteristics differentiating MGRS from non-MGRS kidney biopsy lesions include older age, greater proteinuria (>1.5 g/d), and an abnormal free light-chain ratio among the MGRS group. Nephrologists should be aware of these clinical associations to help in the diagnosis and management of MGRS with kidney disease.