Monoclonal Gammopathy of Renal Significance

A 33-year-old African American man presented to the emergency department with chest tightness. He gave a history of worsening swelling in his legs in the past year. Laboratory tests revealed a creatinine level of 5.17 mg/dL (normal range, 0.6-1.2 mg/dL), albumin of 2.4 g/dL (normal range, 3.5-5.5 g/dL), hemoglobin of 9.9 g/dL (normal range, 13.5-17.5 g/dL) with normal white blood cell count with differential and normal platelet count. He was admitted to the hospital for further treatment. A 24-hour urine protein test revealed 13,335 mg/d of urinary protein, predominantly albumin, confirming a diagnosis of nephrotic syndrome. Further workup included serologies and a kidney biopsy. Serum protein electrophoresis with immunofixation showed IgG λ 0.17 g/dL. Free light chain analysis revealed κ 180.3 mg/L (normal range, 3.30-19.4 mg/L), λ 325 mg/L (normal range, 5.71-26.3 mg/L), with a κ/λ ratio of 0.55 (normal range, 0.26-1.65). Kidney biopsy showed a diffuse proliferative glomerulonephritis on light microscopy. Immunofluorescence studies were positive for intense granular staining for IgG, λ, and C3. Electron microscopy revealed global electron dense immune-type eosinophilic deposits in the peripheral glomerular subendothelial position. A bone marrow biopsy revealed 3 percent plasma cells with λ light chain restriction.

What is your approach to the diagnosis and management of monoclonal gammopathy of renal significance (MGRS)?

MGRS is defined as a renal disease caused by a B-cell or plasma cell clone resulting in the deposition of the secreted monoclonal immunoglobulin, or a fragment thereof, without evidence for overt lymphoma or myeloma.¹  This is a fairly recently described clinical entity and warrants recognition and differentiation from the more common clinical plasma cell disorders, monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). The diagnosis of MGUS requires the monoclonal protein in serum to be less than 3 g/dL, bone marrow plasma cells to be lower than 10 percent, and for an absence of end-organ damage (eg. anemia, hypercalcemia, lytic bone lesions, renal failure) attributable to plasma cell proliferation.²  Patients with MGUS have a 1 percent-per-year risk of progression to malignancy, which includes blood cancers such as MM, light chain amyloidosis and lymphoproliferative disorders. While renal failure is a defining feature of MM, this is driven by cast nephropathy or hypercalcemia, which is secondary to a high tumor burden. This is not MGRS.

The underlying pathologic lesion in MGRS is due to deposition of the monoclonal immunoglobulin fragment, with distinct localization and pattern of ultrastructural organization.³  Histologic features vary between MGRS subdisorders, but all of the entities are linked by the presence of monoclonal immunoglobulin in the kidney, indicating the presence of any underlying clone of the pathologic immunoglobulin-producing lymphocytes or plasma cells.⁴ 

The suspicion of MGRS is usually based on finding a monoclonal gammopathy in conjunction with renal symptoms. It is imperative to rapidly assess the characteristics of the monoclonal gammopathy, carefully search for extrarenal manifestations (which can be common and critical in patients with light chain amyloidosis who frequently have multiorgan involvement, and where early diagnosis is critical for good outcomes), and gauge the type of nephropathy. In most cases, a kidney biopsy with immunofluorescence, and electron microscopic studies to identify the deposit composition and pattern of organization are needed. The spectrum of MGRS encompasses a variety of renal lesions and may be associated with extrarenal manifestations (Table).

Laboratory Diagnosis of MGRS

Following a diagnosis of MGRS, a search for the underlying clonal disorder needs to be undertaken. These tests include a serum protein electrophoresis, urine electrophoresis, serum and urine immunofixation, and the free light chain assay. A peripheral blood flow cytometry can be helpful in identifying a B-cell clone. Further, a bone marrow aspirate and biopsy helps direct detection of the underlying clone. Lastly, a whole-body scan using computed tomography (CT) scan or 18-fluorodeoxyglucose positron emission tomography/CT is helpful in cases where the bone marrow is negative, and there is high suspicion for lymphoma to identify lymphadenopathy. In this setting, a lymph node biopsy may be warranted to identify the underlying clonal pathology. While among most cases the underlying clone is associated with the same light chain restriction as the renal pathology, in rare cases there may be a discordance between the clonal type in the bone marrow and the renal pathologic deposits.

Treatment of MGRS

Recent years have seen the development and approval of many therapies to treat B-cell and plasma cell cancers. These clone-directed therapies are also effective in eradicating the underlying clone of MGRS, but clinicians must still pay attention to the toxicity profile of agents, particularly toward the kidneys, and any dose reductions that may be warranted.

Proteasome Inhibitors

Bortezomib, carfilzomib and ixazomib are U.S. Food and Drug Administration (FDA)-approved proteasome inhibitors used in MM. Bortezomib is also approved in some subtypes of lymphomas. It is the preferred agent in MGRS as it has 1) no renal toxicity, 2) does not need dose adjustments for renal insufficiency, and 3) has a good tolerance profile. Recently, there has been concern for drug-induced thrombotic microangiopathy with proteasome inhibitor therapy,^5,6  which should be recognized and considered in the right setting.

Monoclonal Antibodies

Rituximab, a monoclonal antibody directed at CD20, is effective in B-cell clones. It has a favorable toxicity profile and can be given at full dose in renal failure. Daratumumab is a monoclonal antibody directed at CD38 and is approved for treatment of relapsed MM. There is an ongoing clinical trial testing daratumumab in the treatment of MGRS (NCT03095118).

Cytotoxic Chemotherapy

Alkylating agents such as cyclophosphamide, bendamustine, and melphalan can target both B-cells and plasma cells. Cyclophosphamide and bendamustine have a safe renal profile. Purine analogs such as fludarabine and pentostatin also have excellent activity against B cells and may be used in combination with other drugs such as antibodies or alkylators; however they can have more toxicities related to myelosuppression and are not recommended in the setting of an estimated glomerular filtration rate lower than 30 mL/min.

Immunomodulatory Agents

These agents, which include thalidomide, lenalidomide, and pomalidomide, are active against plasma cells as well as B cells. However, they need dose reductions when used in renal insufficiency and may be associated with more adverse effects. Consequently, these agents are not the first choice to treat MGRS.

Stem Cell Transplant

High-dose melphalan with autologous hematopoietic cell infusion allows achievement of a deep hematologic response.^7,8  In a series of four patients with dialysis-dependent monoclonal immunoglobulin deposition disease, all underwent kidney transplant at a median of 2.6 years after stem cell transplantation (2 in complete response and 2 in partial hematologic response).⁸ 

Other Agents

Ibrutinib is FDA-approved for CLL and multiple lymphoma subtypes. It is orally administered and has a generally favorable safety profile. There is no existing data supporting the use of ibrutinib in MGRS. Corticosteroids are typically combined with other clone-directed therapies described here in most commonly used regimens.

Patient Follow-Up

This patient was discharged and referred to hematology to start treatment. He was started on cyclophosphamide with bortezomib and dexamethasone therapy with a response in his monoclonal protein. At completion of treatment, his κ was 29.85 mg/L, λ 25.34 mg/L, and had resolution of the IgG λ M-spike. His renal function had improved with creatinine of 1.5 mg/dL and 24-hour urine protein level at last follow-up had decreased to 436 mg/d.