A 78-Year-Old Man with Anasarca and Chronic Kidney Disease

A 78-year-old man with a medical history of gastroesophageal reflux disease (GERD) and essential hypertension presented to his primary care physician for evaluation of lower extremity edema and weight gain of one month’s duration. His complete blood count showed a white blood count of 10.8 × 10/µL, hemoglobin of 12 g/dL, and platelets of 249 × 10⁹/µL. His basic metabolic panel (BMP) showed creatinine of 2.37 mg/dL (baseline creatinine, 1.02 mg/dL), albumin of 1.7 g/dL, and normal BMP otherwise. A serum protein electrophoresis demonstrated a monoclonal protein present in the gamma region, with a concentration of 1.8 g/dL. Immunofixation demonstrated an IgM κ monoclonal protein with elevated concentration of 2,917 mg/dL. A skeletal survey showed no lytic lesions. On physical exam, he was noted to have 7 kg weight gain and non-pitting edema of lower extremities extending to thighs.

A kidney biopsy was obtained, and pathology demonstrated a “fluffy,” finely granular electron–dense material in the periphery of glomerular basement and focally along the subendothelial aspect with widespread foot effacement. Immunofluorescence demonstrated a κ-restricted staining consistent with IgM κ monoclonal gammopathy.

He underwent a bone marrow biopsy, which showed normocellular bone marrow with trilineage hematopoiesis and no increase in plasma cells. Fluorescence in situ hybridization (FISH) and karyotype were normal.

What is the most likely diagnosis?

Answer: C

MGRS is a heterogeneous group of pathologic renal conditions attributed to a clonal plasma cell disorder. MGRS does not meet the criteria for overt MM or a B-cell lymphoproliferative disorder, and the hematologic component of the disorder is generally consistent with MGUS (Table). However, there is a need to distinguish MGRS from MGUS and unrelated renal abnormalities, as the clonal protein in MGRS plays a direct role in kidney damage and requires treatment of the underlying clone.

There are two main categories of renal disorders associated with monoclonal gammopathies.1 The first group of renal disorders requires the secretion of large amounts of all or part of the monoclonal immunoglobulin (MIg). This is typically illustrated by the massive precipitation of light chain (LC) in the lumen of distal tubules, which characterizes LC-cast nephropathy (this the most common cause of acute kidney injury in MM). The other group is renal diseases associated with low-grade lymphoproliferative disorders. In this setting, structural peculiarities of the MIg, particularly the variable domain and not the rate of production, are the main determinants of renal lesions. For this reason, the spectrum of renal diseases in MGRS is extensive. Kidney disorders that are caused by the interaction of MIgs or their components may meet criteria for the diagnosis of MGRS. These include well-established entities such as AL amyloidosis and more recently described pathology, particularly proliferative glomerulonephritis with MIg deposits and C3 glomerulopathy with monoclonal gammopathy.

When should we suspect MGRS? Patients with a nonmalignant or premalignant monoclonal gammopathy (e.g., MGUS, smoldering MM, smoldering Waldenström macroglobulinemia, or monoclonal B-cell lymphocytosis) who present with unexplained kidney function impairment and/or proteinuria.²

Kidney biopsy is indicated in most cases to determine the exact lesion associated with MGRS and to evaluate its severity. Diagnosis requires integration of morphologic alterations by light microscopy, immunofluorescence (IF), electron microscopy, and immunoelectron microscopy, and in some cases by IF staining for Ig isotypes. Factors associated with MGRS included proteinuria of at least 1.5 g/day, hematuria, and abnormal serum-free LC ratio.²

Since patients with MGRS do not meet diagnostic criteria for MM or a lymphoproliferative disorder, clinicians have previously been reluctant to treat these patients with chemotherapy.³ Therapy is tailored based on characteristics of monoclonal gammopathy, particularly its isotype, and whether it corresponds to an overt lymphoid and/or plasmacytic disorder.

Early recognition of MGRS is crucial, and our understanding of the spectrum of MGRS is evolving. MGRS is also very likely to progress to MM. To date, no strategy is available to inhibit MIg tissue deposition or to remove the already deposited material.³ Suppression of MIg secretion by chemotherapy often improves outcomes, thus preserving kidney function. The choice of chemotherapeutic agents should consider the patient’s renal metabolism and potential renal and extrarenal toxicity.2

Table. Differentiation between MGUS, MGRS, and MM.

	MGUS	MGRS	MM
Clonal burden	Low Monoclonal protein spike <3 g/dL Plasma cells <10% of bone marrow	Low Monoclonal protein spike <3 g/dL Plasma cells <10% of bone marrow	High Monoclonal protein spike >3 g/dL Plasma cells >10% of bone marrow
Organ damage	No	Yes	Yes (CRAB)
Kidney disease	No (or unrelated)	Yes	Yes (common 50%)
Kidney biopsy	No	Yes (biopsy and immunofluorescence studies to identify the monotypic immunoglobulin deposits)	No (most cases do not need a kidney biopsy)
Treatment	No (only surveillance)	Yes	Yes

As summarized in “Diagnosis of monoclonal gammopathy of renal significance” by Bridoux et al, 2015.

Khera A, Panitsas F, Djebbari F, et al. Long term outcomes in monoclonal gammopathy of renal significance. Br J Haematol. 2019;186:706-716.
Bridoux F, Leung N, Hutchison CA, et al. Diagnosis of monoclonal gammopathy of renal significance. Kidney Int. 2015;87:698-711.
Fermand JP, Bridoux F, Kyle RA, et al. How I treat monoclonal gammopathy of renal significance (MGRS). Blood. 2013;122:3583-3590.