Diagnosis and treatment of monoclonal gammopathy of renal significance

INTRODUCTION — Monoclonal gammopathy of renal significance (MGRS) represents a group of disorders in which a monoclonal immunoglobulin secreted by a nonmalignant or premalignant B cell or plasma cell clone causes kidney damage [1-3]. By definition, these disorders do not meet diagnostic criteria for overt, symptomatic multiple myeloma or a lymphoproliferative disorder. The term MGRS was proposed in 2012 by the International Kidney and Monoclonal Gammopathy Research Group to collectively describe patients who would otherwise meet the criteria for monoclonal gammopathy of undetermined significance (MGUS) but demonstrate kidney injury attributable to the underlying monoclonal protein [1]. The goal was to differentiate patients with MGUS, who have no evidence of end-organ damage, from those with MGRS, who are at risk of developing progressive kidney disease. MGRS can also be associated with other hematologic disorders, including smoldering multiple myeloma [4,5], smoldering Waldenström macroglobulinemia [6], and monoclonal B cell lymphocytosis (MBL) [7].

MGRS-associated kidney diseases encompass a wide spectrum of kidney pathology and include such lesions as immunoglobulin-associated amyloidosis, the monoclonal immunoglobulin deposition diseases (MIDDs; light chain deposition disease, heavy chain deposition disease, and light and heavy chain deposition disease), proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), C3 glomerulopathy with monoclonal gammopathy, light chain proximal tubulopathy, and several others.

This topic will review the diagnosis and treatment of MGRS. The diagnosis and management of patients with MGUS and the etiology, pathogenesis, clinical manifestations, diagnosis, and treatment of kidney diseases associated with multiple myeloma and other malignant monoclonal gammopathies are presented separately:

●(See "Diagnosis of monoclonal gammopathy of undetermined significance".)

●(See "Clinical course and management of monoclonal gammopathy of undetermined significance".)

●(See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation".)

●(See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Treatment and prognosis".)

EPIDEMIOLOGY AND PROGNOSIS — Kidney disease is a common complication of multiple myeloma and other malignant conditions with monoclonal gammopathy. However, most of the kidney diseases that are associated with dysproteinemia, with the exception of light chain cast nephropathy, acute kidney injury caused by hypercalcemia, and intracapillary "thrombi" of immunoglobulin M (IgM) in Waldenström macroglobulinemia, can occur in the absence of overt multiple myeloma or other hematologic malignancy. These kidney disorders that are caused by the interaction of monoclonal immunoglobulins or their components meet criteria for the diagnosis of monoclonal gammopathy of renal significance (MGRS). The following studies illustrate the range of findings [8-15]:

●In a study of 474 patients with immunoglobulin light chain (AL) amyloidosis, only 8 percent had evidence of overt multiple myeloma [9]. The majority of patients with AL amyloidosis have smaller clonal plasma cell populations that do not meet criteria for multiple myeloma.

●In two independent series of patients with monoclonal immunoglobulin deposition disease (MIDD), 59 to 65 percent of patients had >10 percent plasma cells in the bone marrow, and approximately 3 percent had evidence of a lymphoproliferative disorder [10,12]. Data on myeloma-defining events were provided by only one of these studies, and only 20 percent had lytic bone lesions. A third study of 255 patients with MIDD reported a diagnosis of multiple myeloma in 34 percent, and only 18 percent of pure light chain deposition disease cases, when myeloma-defining events were used to establish the diagnosis of myeloma [16].

●In the largest series of patients with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), only 1 of 37 patients (3 percent) had multiple myeloma [15].

●Low rates of multiple myeloma have also been reported among patients with fibrillary glomerulonephritis (<1 percent), immunotactoid glomerulopathy (13 percent), and light chain proximal tubulopathy (31 percent) [13,14,17,18].

Although MGRS is considered a nonmalignant or premalignant hematologic condition, its effects on the kidney are not benign, and patients with MGRS frequently develop progressive kidney disease and end-stage kidney disease (ESKD). In a study of 19 patients with MIDD, 12 of whom did not have evidence of myeloma, overall patient survival at five years was 70 percent, but kidney survival was only 37 percent [19]. Similarly, a retrospective study of 37 patients with PGNMID found that 38 percent developed persistent kidney function impairment, and 22 percent progressed to ESKD [15]. It is possible that patients with MGRS, most of whom would have been previously classified as having monoclonal gammopathy of undetermined significance (MGUS), may have generally been undertreated or untreated. The reluctance to treat MGRS with chemotherapy directed against the pathogenic plasma cell or B cell clone is largely due to the fact that these patients do not meet criteria for the diagnosis of multiple myeloma or a lymphoproliferative disorder. As an example, in a study of 63 patients with MIDD (22 of whom did not have multiple myeloma), nearly 30 percent of those without myeloma were not treated with cytotoxic therapy [12]. Among patients who did receive treatment, none received the standard myeloma therapy at the time of the study.

MGRS-related kidney diseases recur in most patients after kidney transplantation and can lead to rapid allograft loss [20-30]. Recurrence rates are as high as 71, 86, and 89 percent among patients with monoclonal membranoproliferative glomerulonephritis, MIDD, and PGNMID, respectively [20,25,26,31]. Achieving a complete hematologic response prior to transplantation may decrease the risk of recurrence in these patients [22,27,29,30,32]. (See 'Patients with end-stage kidney disease' below.)

PATHOGENESIS — In monoclonal gammopathy of renal significance (MGRS), the kidney lesions are primarily caused by the abnormal deposition or activity of monoclonal proteins in the kidney. These monoclonal proteins, which may be light chains, heavy chains, or intact immunoglobulins, are produced by small, nonmalignant or premalignant plasma cell or B cell clones. Deposition of the monoclonal proteins may occur within the glomeruli, tubules, vessels, or interstitium of the kidney, depending upon the specific biochemical characteristics of the pathogenic light and/or heavy chains involved. This is discussed in more detail elsewhere. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation", section on 'Pathogenesis' and "Monoclonal immunoglobulin deposition disease".)

In addition to the deposition of monoclonal proteins within the kidney, other mechanisms for the pathogenesis of MGRS have been described:

●Secretion of high levels of vascular endothelial growth factor may be responsible for the characteristic kidney pathologic findings reported in patients with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes), which includes membranoproliferative glomerulonephritis-like lesions, thrombotic microangiopathy, and mesangiolysis with microcapillary formation [33]. (See "POEMS syndrome", section on 'Kidney disease'.)

●Monoclonal proteins can act as autoantibodies directed against complement components, such as complement factor H, factor I, and complement receptor 1 (CR1), resulting in uncontrolled activation of the alternative complement pathway and causing C3 glomerulopathy with monoclonal gammopathy [34-36]. This can also occur when the monoclonal protein acts as a C3 nephritic factor [28,36,37]. Both of these mechanisms result in the deposition of complement factors (such as C3) without significant immunoglobulin deposits. (See "Acquired disorders of the complement system", section on 'C3 nephritic factor'.)

●Circulating monoclonal immunoglobulin autoantibodies can target the phospholipase A2 receptor and induce a form of membranous nephropathy that can rapidly recur after kidney transplantation [38,39]. Cases of monoclonal anti-glomerular basement membrane (GBM) disease due to circulating monoclonal antibodies targeting type IV collagen have also been reported [40-42].

CLASSIFICATION ACCORDING TO PATHOLOGY — The kidney lesions associated with monoclonal gammopathy of renal significance (MGRS) can be categorized according to the ultrastructural characteristics of the deposits (if present) in the kidney (figure 1) [2,3]. Deposits can be divided into those that are organized (ie, with substructure) and those that are nonorganized (ie, granular, without substructure). In some cases of MGRS, there are no visible deposits within the kidney.

●Organized deposits – MGRS lesions with organized deposits can be further subdivided into those with fibrillar deposits, microtubular deposits, or crystal inclusions (picture 1):

•Fibrillary deposits – MGRS lesions with fibrillar deposits include immunoglobulin-associated amyloidosis (light chain, heavy chain, heavy and light chain amyloidosis) and extremely rare cases of fibrillary glomerulonephritis with monotypic deposits. The fibrillar deposits in amyloidosis are Congo red positive, whereas those in fibrillary glomerulonephritis are typically Congo red negative with rare exceptions [43]. Staining for DnaJ heat shock protein family (Hsp40) member B9 (DNAJB9) in this setting can be used to distinguish fibrillary glomerulonephritis, which is positive, from amyloid, which is negative [44]. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis" and "Glomerular diseases due to nonamyloid fibrillar deposits".)

•Microtubular deposits – MGRS lesions with microtubular deposits include monoclonal (type 1 and some type 2) cryoglobulinemia [45] and monotypic immunotactoid glomerulopathy. Microtubules, in contrast with fibrils, are usually larger and have hollow centers. (See "Overview of cryoglobulins and cryoglobulinemia" and "Glomerular diseases due to nonamyloid fibrillar deposits".)

•Crystal inclusions – MGRS lesions with crystal inclusions include light chain proximal tubulopathy, light chain crystalline podocytopathy, crystal-storing histiocytosis, and cryocrystalglobulinemia. In light chain proximal tubulopathy, rod- or rhomboid-shaped light chain crystals are localized within proximal tubular cells. A form of this disorder with noncrystalline inclusions also exists [18,46]. In light chain crystalline podocytopathy, crystalline inclusions are found mostly within podocytes but may also be seen in proximal and distal tubular cells, endothelial cells, interstitial histiocytes, and mesangial cells [47]. In crystal-storing histiocytosis, intracytoplasmic light chain crystalline inclusions are found within interstitial histiocytes and occasionally within proximal tubular cells and podocytes [48,49]. The crystal deposits in cryocrystalglobulinemia, composed of an entire monoclonal immunoglobulin, are present within glomerular endothelial and mesangial cells and/or within the glomerular subendothelial space or vascular lumens [50,51]. Extrarenal deposits can be observed in all three entities. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation", section on 'Light chain proximal tubulopathy' and "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation", section on 'Less common causes of AKI' and "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation", section on 'Less common causes of albuminuria'.)

●Nonorganized deposits – MGRS lesions with nonorganized deposits include the monoclonal immunoglobulin deposition diseases (MIDDs; light chain, heavy chain, or light and heavy chain deposition disease) and monoclonal gammopathy-associated proliferative glomerulonephritis [52], involving monoclonal immunoglobulin G (IgG), and rarely immunoglobulin A (IgA)-, immunoglobulin M (IgM)-, or light chain-only deposits. Membranoproliferative glomerulonephritis is the most common pattern of injury produced by monoclonal gammopathy-associated proliferative glomerulonephritis, which includes disorders such as proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) [8,15,53] and C3 glomerulopathy with monoclonal gammopathy [28,37,54-57]. In C3 glomerulopathy, the deposits are predominately composed of C3 complement. This category also encompasses rare cases of MGRS that histologically mimic polyclonal immunoglobulin-mediated kidney diseases, such as cases of membranous nephropathy and anti-glomerular basement membrane (GBM) antibody (Goodpasture's) disease with monotypic staining on immunofluorescence microscopy [38,58,59].

•(See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Other forms of systemic monoclonal immunoglobulin deposition disease'.)

•(See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation", section on 'Proliferative glomerulonephritis with monoclonal immunoglobulin deposits'.)

•(See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation", section on 'C3 glomerulopathy with monoclonal gammopathy'.)

•(See "Membranous nephropathy: Pathogenesis and etiology", section on 'Membranous-like nephropathy with masked IgG-kappa'.)

●No deposits – MGRS lesions without deposits include thrombotic microangiopathy associated with monoclonal gammopathy (eg, in POEMS syndrome [polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes]) [33,60,61]. (See "POEMS syndrome", section on 'Kidney disease'.)

While this classification system provides an organizational framework for approaching the diagnosis of MGRS-associated kidney diseases, it does not provide any information about the clinical course or prognosis of these different diseases.

CLINICAL MANIFESTATIONS — Kidney disease in patients with monoclonal gammopathy of renal significance (MGRS) can present as a complication of a previously diagnosed nonmalignant or premalignant hematologic disorder (eg, monoclonal gammopathy of undetermined significance [MGUS], smoldering multiple myeloma) or as the initial clinical manifestation of a monoclonal gammopathy. Similar to the kidney diseases associated with multiple myeloma and other malignant monoclonal gammopathies, those associated with MGRS can present with acute or subacute kidney injury, chronic kidney disease, proteinuria and/or nephrotic syndrome, or electrolyte abnormalities. The most common presenting symptoms are kidney function impairment and proteinuria, with or without hematuria. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation".)

MGRS can also mimic kidney diseases that are not normally associated with monoclonal gammopathy, such as membranous nephropathy and anti-glomerular basement membrane (GBM) antibody (Goodpasture's) disease [38,58,59]. This may occur when the monoclonal immunoglobulin targets the same antigen that is normally targeted by polyclonal antibodies in these diseases.

DIAGNOSIS

When to suspect MGRS — The diagnosis of monoclonal gammopathy of renal significance (MGRS) should be suspected in the following patients:

●All patients with a nonmalignant or premalignant monoclonal gammopathy (eg, monoclonal gammopathy of undetermined significance [MGUS], smoldering multiple myeloma, smoldering Waldenström macroglobulinemia, or monoclonal B cell lymphocytosis [MBL]) who present with unexplained kidney function impairment and/or proteinuria. The general approach to evaluating such patients is presented elsewhere. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation", section on 'Evaluation'.)

●All patients who present with unexplained kidney function impairment and/or proteinuria and are found to have a monoclonal gammopathy (ie, by serum or urine protein electrophoresis or immunofixation or by serum free light chain assay) during their evaluation of kidney disease. The urine free light chain assay does not have any known value at this time with regards to these disorders.

In a study of 160 patients with monoclonal gammopathy who underwent a kidney biopsy, an MGRS-related lesion was identified in 40 percent [62]. Factors associated with MGRS included proteinuria ≥1.5 g/day, hematuria, and abnormal serum free light chain ratio.

Establishing the diagnosis — In most patients suspected of having MGRS, we perform a kidney biopsy, unless contraindicated. The presence of monoclonal immunoglobulin deposits in the kidney establishes the diagnosis of MGRS. These monoclonal deposits must be restricted to a single class of light and/or heavy chain based on immunofluorescence. A kidney biopsy is the only means of demonstrating the nephrotoxicity of the monoclonal protein. This is important because the existence of a serum or urine monoclonal protein by itself does not prove that a monoclonal protein is responsible for the kidney disease. However, a kidney biopsy can be deferred in the following clinical circumstances:

●Patients presenting with albuminuria or nephrotic syndrome who already have an established diagnosis of immunoglobulin light chain (AL) amyloidosis based upon biopsies of non-kidney tissues. A presumptive diagnosis of renal AL amyloidosis can be made in these patients without a kidney biopsy.

●Patients with monoclonal gammopathy who present with laboratory abnormalities consistent with Fanconi syndrome (eg, aminoaciduria, normoglycemic glycosuria, hypophosphatemia, hypouricemia, subnephrotic-range proteinuria). Such patients have a presumptive diagnosis of light chain proximal tubulopathy.

In some patients with biopsy findings consistent with C3 glomerulonephritis, monoclonal immunoglobulin deposits may not be detectable using standard immunofluorescence techniques. In such patients, paraffin immunofluorescence after protease digestion should be performed to "unmask" hidden immunoglobulin deposits [59,63]. Failure to identify these "masked" monoclonal immunoglobulins can result in missing the diagnosis of MGRS and incorrectly diagnosing these patients as having only C3 glomerulonephritis. If no monoclonal immunoglobulins are detected by paraffin immunofluorescence, documentation of a circulating monoclonal protein by serum or urine protein electrophoresis, immunofixation, and/or serum free light chain assay is necessary to establish a diagnosis of C3 glomerulopathy with monoclonal gammopathy. In addition, an evaluation of the alternative complement pathway, including testing for the presence of C3 nephritic factor and autoantibodies against complement factor H, should be performed to identify the cause of complement dysregulation. (See "Overview and clinical assessment of the complement system".)

For unknown reasons, the majority (70 to 80 percent) of patients with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) do not have a detectable circulating monoclonal gammopathy by serum and urine monoclonal protein testing and do not have detectable plasma cell or B cell clones on bone marrow aspirate and biopsy. In these patients, the monoclonal protein is only found in the kidney, and the diagnosis of MGRS is usually established when these patients undergo kidney biopsy for evaluation of unexplained kidney function impairment and/or proteinuria or kidney allograft dysfunction.

Kidney biopsies are generally safe among patients with monoclonal gammopathy. In one study of 1993 patients who underwent either native or transplant kidney biopsies, the rate of major hemorrhagic complications was similar between those with and without monoclonal gammopathy [64].

Subsequent evaluation of patients with confirmed MGRS — The presence of monoclonal immunoglobulin deposits in the kidney indicates the existence of a plasma cell, B cell, or lymphoplasmacytic clone that is responsible for the production of the monoclonal protein. In patients with a confirmed diagnosis of MGRS, the subsequent evaluation focuses on characterizing this clone in order to guide appropriate therapy. (See 'Treatment of proliferative glomerulonephritis' below.)

In all patients with MGRS, we perform the following hematologic evaluation, if such an evaluation has not been previously completed:

●Monoclonal protein testing – We perform a serum protein electrophoresis and immunofixation, 24-hour urine protein electrophoresis and immunofixation, and serum free light chain assay. The urine free light chain assay provides no additional information, and we do not recommend ordering this test. The combination of these studies maximizes the sensitivity of detecting a monoclonal protein, particularly among patients with small clones that may produce low levels of circulating monoclonal protein [8,65,66]. The circulating monoclonal protein, if detected, must match the type of monoclonal protein present within the kidney deposits. Identification of a serum or urine monoclonal protein, if present, is also important in monitoring the response to therapy. (See "Laboratory methods for analyzing monoclonal proteins" and 'Monitoring the response to therapy' below.)

●Bone marrow aspirate and biopsy – Analysis of the bone marrow should include immunohistochemistry and flow cytometry (for B cells and plasma cells) for surface and intracellular markers of plasma cells and B cells. In addition, staining for kappa and lambda light chains should be performed to demonstrate that an identified clone exhibits the same light chain restriction as the monoclonal deposits in the kidney. Cytogenetic and fluorescence in situ hybridization analysis are increasingly used to help direct therapy and may be helpful in some cases.

In patients who do not have a detectable clone with the above testing or who have an IgM monoclonal protein (who are more likely to have a B cell or lymphoplasmacytic clone), additional imaging studies (such as a computed tomography of the chest, abdomen, and pelvis, combined with positive emission tomography [PET], if available) to search for a B cell clone may be required, since most IgM molecules are produced by B cells. In addition, we perform flow cytometry of peripheral blood lymphocytes, which can detect small, low-grade clones, such as those in chronic lymphocytic leukemia and MBL.

Among patients with MGRS, the ability to detect a pathogenic clone varies by disorder. As an example, in two separate studies of patients with light chain deposition disease, bone marrow biopsy revealed a plasma cell clone in 65 to nearly 100 percent of cases [32]. By contrast, the rate of clonal detection among patients with PGNMID is significantly lower, ranging from 25 to 30 percent [8,67]. Overall, when all major case series of patients with MGRS are considered, approximately 40 percent of cases have no identifiable clone [68].

Patients who are diagnosed with a form of MGRS that can be associated with extrarenal manifestations (eg, AL amyloidosis, monoclonal immunoglobulin deposition disease [MIDD], monoclonal [type I] cryoglobulinemia) should undergo a disease-specific evaluation for such manifestations. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

TREATMENT — The primary goal in the treatment of monoclonal gammopathy of renal significance (MGRS) is to preserve kidney function and avoid progression of extrarenal manifestations if present. Although most cases of MGRS are caused by monoclonal immunoglobulin deposition in the kidney, there are no available therapies to inhibit this tissue deposition or to remove existing deposited material.

The treatment of kidney disease that is associated with multiple myeloma and other malignant monoclonal gammopathies is discussed elsewhere. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Treatment and prognosis".)

Overview of our approach — The treatment of MGRS is determined primarily by the pathologic type of kidney injury, the nature of the clone (either plasma cell, B cell, or lymphoplasmacytic) that is producing the nephrotoxic monoclonal immunoglobulin, and the likelihood of reversing existing kidney damage or preventing further kidney injury [52]. Because patients with MGRS do not meet diagnostic criteria for multiple myeloma or a lymphoproliferative disorder, clinicians have previously been reluctant to treat these patients with chemotherapy. However, several studies of patients with MGRS have shown that kidney outcomes are closely associated with the hematologic response to chemotherapy [11,22,27,32]. Given this evidence, once the specific kidney lesion has been identified by kidney biopsy, we prefer a treatment approach that employs chemotherapy directed against the pathologic clone, with the primary goal of preserving kidney function.

In general, the chemotherapeutic agents used to treat MGRS are those that target plasma cell or other B cell neoplasms. Such agents include proteasome inhibitors (eg, bortezomib, carfilzomib, ixazomib), monoclonal antibodies (eg, rituximab, daratumumab), alkylating agents (eg, cyclophosphamide, bendamustine, melphalan), immunomodulatory drugs (eg, thalidomide, lenalidomide, pomalidomide), and glucocorticoids (eg, prednisone, dexamethasone). In some patients (such as those with amyloidosis or monoclonal immunoglobulin deposition disease [MIDD]), the treatment strategy may also involve autologous hematopoietic cell transplantation. Chemotherapeutic agents that do not require dose modification for kidney function are preferred, to limit the occurrence of adverse events (particularly cytopenias). The treatment of MGRS should be selected and administered in consultation with a hematologist or oncologist who is experienced in the use of antimyeloma and antilymphoma agents.

Our approach to the treatment of monoclonal gammopathy-associated proliferative glomerulonephritis (proliferative glomerulonephritis with monoclonal immunoglobulin deposits [PGNMID], C3 glomerulopathy with monoclonal gammopathy) is presented below. The specific treatment of the following MGRS-associated kidney diseases is discussed in more detail elsewhere:

●Immunoglobulin-associated amyloidosis (see "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis")

●MIDD (see "Monoclonal immunoglobulin deposition disease")

●Fibrillary glomerulonephritis and immunotactoid glomerulopathy (see "Glomerular diseases due to nonamyloid fibrillar deposits", section on 'Treatment')

●Monoclonal (type 1) cryoglobulinemia (see "Treatment protocols for multiple myeloma" and "Treatment and prognosis of Waldenström macroglobulinemia" and "Treatment protocols for lymphoma")

●Thrombotic microangiopathy associated with monoclonal gammopathy (as in POEMS syndrome) (see "POEMS syndrome", section on 'Management')

Treatment of proliferative glomerulonephritis — Patients with monoclonal gammopathy-associated proliferative glomerulonephritis (PGNMID or C3 glomerulopathy with monoclonal gammopathy) are at risk for progressive kidney disease and should be treated to prevent further kidney injury and deterioration of kidney function. In general, the treatment focuses upon eradication of the pathologic clone in these patients [52].

Patients with PGNMID — The treatment of patients with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) depends upon the presence or absence of a detectable B or plasma cell clone or detectable monoclonal protein in the serum or urine (algorithm 1).

There are no randomized trials to guide the optimal approach to therapy. Evidence in support of a clone-directed approach to the treatment of PGNMID comes primarily from observational studies and one small, uncontrolled trial [67,69]:

●In a retrospective series of 19 patients with PGNMID, of whom seven (37 percent) had a detectable circulating serum or urine monoclonal protein and six (32 percent) had a detectable plasma or B cell clone, treatment was directed at the underlying clone, or for patients without a detectable clone, empirically given to target a hypothesized underlying clone. Clone-directed therapies included rituximab, cyclophosphamide, bortezomib, and glucocorticoids in varying combinations. Among the 16 patients who received treatment, 13 (81 percent) experienced a response to initial therapy, six (38 percent) of whom had a complete renal response (defined as stabilization or improvement in serum creatinine and estimated glomerular filtration rate [eGFR] and reduction in proteinuria to <0.5 g/24 hours) [67]. Among patients who responded, the median time to a partial response and complete response was 5.2 and 12.5 months, respectively. Resolution of paraproteinemia was not necessary to achieve a complete renal response. None of the patients who received treatment developed end-stage kidney disease (ESKD), whereas all three patients who were not treated progressed to ESKD. In this study, response was more likely in patients who received clone-directed therapy as opposed to non-clone-directed therapy.

●An open-label, phase II trial evaluated the efficacy and safety of daratumumab, a monoclonal anti-CD38 antibody used in the treatment of multiple myeloma, in 11 patients with PGNMID [69]. At 12 months, four patients achieved a complete renal remission (defined as proteinuria <500 mg/day and <15 percent decline from baseline eGFR) and six achieved partial renal remission (defined as 50 percent reduction in proteinuria and <30 percent decline from baseline eGFR). Relapse occurred in one patient who had achieved a complete remission and in two who achieved a partial remission. There were five serious adverse events related to daratumumab, including two serious infections, eye chemosis, severe headache, and acute closed-angle glaucoma.

PGNMID with a detectable plasma or B cell clone — In patients with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) who have a detectable pathologic B or plasma cell clone, we treat with clone-directed chemotherapy to eradicate the clone responsible for producing the monoclonal protein (algorithm 1). (See 'Subsequent evaluation of patients with confirmed MGRS' above.)

The selection of chemotherapy is based upon the nature of the detected clone:

●In patients with a detectable plasma cell clone, we administer a treatment regimen similar to that used to treat multiple myeloma. We prefer the combination of bortezomib (subcutaneous injection of 1.3 mg/m² once weekly), cyclophosphamide (an oral dose of 500 mg once weekly adjusted for kidney function), and dexamethasone (an oral dose of 40 mg once weekly) [52]. Daratumumab is an alternative option, although data are limited [69]. Treatment can be continued for up to six months if there is evidence of a hematologic response and no toxicity. Previous studies in other MGRS-associated kidney diseases have found that achievement of a hematologic very good partial response (VGPR) is required for improved kidney outcomes [11,28,32,70]. (See "Multiple myeloma: Initial treatment".)

●In patients with a detectable B cell clone, we administer a treatment regimen similar to that used to treat Waldenström macroglobulinemia. We prefer the use of rituximab (an anti-CD20 monoclonal antibody), either alone or in combination with cyclophosphamide and dexamethasone or with bendamustine, because most IgM-producing cells are CD20 positive [52]. (See "Treatment and prognosis of Waldenström macroglobulinemia", section on 'Initial treatment'.)

PGNMID with no detectable plasma or B cell clone — In patients with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) who do not have a detectable plasma or B cell clone, our approach to treatment depends upon the presence or absence of a detectable monoclonal protein in the serum or urine, as discussed below (algorithm 1).

Detectable monoclonal protein in the serum or urine — In patients with PGNMID who do not have a detectable clone but have monoclonal immunoglobulin deposition in the kidney and a monoclonal protein of the same isotype detectable in the serum or urine, there is evidence to support a causal relationship between the circulating monoclonal protein and the lesion on kidney biopsy. Such patients should be treated with chemotherapy to eradicate the "hypothesized clone" responsible for producing the monoclonal protein. As the clone itself in these patients has not been detected, the selection of chemotherapy is based upon the isotype of the monoclonal immunoglobulin identified in the serum (or urine) and kidney:

●In patients who have a non-IgM type (eg, IgG or IgA) monoclonal protein in the serum (or urine) and kidney, we administer a treatment regimen similar to that used to treat multiple myeloma. We prefer the combination of bortezomib (subcutaneous injection of 1.3 mg/m² once weekly), cyclophosphamide (an oral dose of 500 mg once weekly adjusted for kidney function), and dexamethasone (an oral dose of 40 mg once weekly in younger patients and 20 mg weekly for older, more frail patients) [52]. Daratumumab is an alternative option, although data are limited [69,71]. Treatment can be continued for up to six months if there is evidence of a hematologic response and no toxicity. Previous studies in other MGRS-associated kidney diseases have found that achievement of hematologic VGPR is associated with improved kidney outcomes [11,28,32,70]. (See "Multiple myeloma: Initial treatment".)

●In patients who have an IgM monoclonal protein in the serum (or urine) and kidney, we administer a treatment regimen similar to that used to treat Waldenström macroglobulinemia. We prefer the use of rituximab (an anti-CD20 monoclonal antibody), either alone or in combination with cyclophosphamide and dexamethasone or with bendamustine, because most IgM-producing cells are CD20 positive [52]. We typically administer one cycle of therapy and reevaluate the patient over the next few months to determine if there is a hematologic response. Retreatment can be considered if there is evidence of renal and hematologic response. (See "Treatment and prognosis of Waldenström macroglobulinemia", section on 'Initial treatment'.)

No detectable monoclonal protein in the serum or urine — In patients who have monoclonal immunoglobulin deposition in the kidney but no detectable clone and no detectable monoclonal protein in the serum or urine, the decision to aggressively treat with chemotherapy is more controversial since there is no clear evidence that a pathologic clone is responsible for the kidney disease. There is no high-quality evidence to guide the optimal therapy in such patients. Our approach is based primarily upon our clinical experience and data from retrospective case series showing that patients with PGNMID who have neither a detectable clone nor a detectable monoclonal protein in the serum or urine may respond to empiric clone-directed therapy [67]:

●In patients who present with acute or subacute kidney injury and/or significant proteinuria (>1 g/day), we prefer to initiate clone-directed chemotherapy. Our approach to selecting a treatment regimen in such patients is as follows:

•In patients who have non-IgM (eg, IgG or IgA) monoclonal protein deposits in the kidney, it is difficult to infer whether the patient has a hypothetical plasma cell clone or a B cell clone. In such patients, it is reasonable to initiate empiric treatment with either plasma cell- or B cell-directed therapy after discussing the potential risks and benefits of these therapies with the patient. Treatment should be individualized based upon the severity of disease and patient preference. As an example, some experts may take a stepwise approach and start by administering a B cell-directed therapy (eg, rituximab), which may be associated with fewer adverse effects, and switch to a plasma cell-directed therapy for those patients who do not respond to initial therapy. Other experts may choose to begin with plasma cell-directed therapy or combine both plasma cell- and B cell-directed therapy as initial empiric therapy. (See 'PGNMID with a detectable plasma or B cell clone' above.)

•In patients who have IgM monoclonal protein deposits in the kidney, we administer rituximab 375 mg/m² weekly for four weeks. As discussed above, we prefer rituximab in this setting because most IgM-producing cells are CD20 positive [52].

●In patients with normal kidney function and proteinuria <1 g/day, a more conservative approach to treatment is reasonable. We treat these patients with antiproteinuric therapy (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) and blood pressure control for up to three months. We continue to monitor the patient for a monoclonal protein by serum and urine electrophoresis and immunofixation and serum free light chain assay. In patients who show no reduction in proteinuria or improvement in kidney function, a trial of chemotherapy is reasonable. The choice of therapy is similar to that discussed above for patients presenting with acute/subacute kidney injury and/or significant proteinuria.

Patients with C3 glomerulopathy with monoclonal gammopathy — In patients with C3 glomerulopathy with monoclonal gammopathy, we typically treat with chemotherapy against the underlying pathologic clone (if detected) or based upon the isotype of the circulating monoclonal protein detected in the serum or urine if no pathologic clone is identified [52]. This approach is similar to that used in patients with PGNMID who have a detectable serum or urine monoclonal protein. (See 'Detectable monoclonal protein in the serum or urine' above.)

There is no high-quality evidence to guide the optimal therapy of patients with C3 glomerulopathy with monoclonal gammopathy. Support for a clone-directed approach to treatment comes mainly from observational studies [28,36,37,72,73]. As examples:

●A retrospective study compared outcomes among 50 patients with C3 glomerulopathy with monoclonal gammopathy who were treated with or without chemotherapy directed against the underlying plasma or B cell clone [28]. Among the 29 patients who received chemotherapy, 22 received a bortezomib-containing regimen, five received alkylator-based therapy with cyclophosphamide or melphalan, and two received rituximab. Patients who were not treated with chemotherapy received either immunosuppressive therapy (including glucocorticoids, rituximab, mycophenolate mofetil, azathioprine, or cyclophosphamide) or conservative therapy with renin-angiotensin system inhibition alone. Treatment with chemotherapy, compared with treatment without chemotherapy, was associated with a higher rate of renal response (as defined by a complete or partial reduction in proteinuria, improvement in serum albumin, and a <10 percent decrease in eGFR) and improved kidney survival at a median of 24 months. Importantly, kidney survival was higher among patients who achieved a hematologic complete or very good response compared with those who achieved a hematologic partial response or less. (See "Multiple myeloma: Evaluating response to treatment", section on 'Assessing tumor response'.)

●In a series of 36 patients with C3 glomerulopathy with monoclonal gammopathy (26 with MGRS, 5 with multiple myeloma, 2 with smoldering myeloma, 2 with chronic lymphocytic leukemia/lymphoma [CLL]), 16 received chemotherapy targeted against the monoclonal gammopathy, 17 received nontargeted therapy (mostly glucocorticoids alone or in combination with other immunosuppressive agents), and three were managed conservatively [72]. Targeted therapy against the monoclonal gammopathy resulted in a complete or partial renal response (defined as a complete or partial reduction in proteinuria and <10 percent decrease in eGFR) or stable kidney function in 44 percent of patients; 56 percent had no renal response. Among those who achieved a hematologic response (10 patients), 70 percent had a complete or partial renal response or stable kidney function, whereas none of the patients without a hematologic response had a renal response. Nontargeted therapy resulted in a complete or partial renal response in 41 percent of patients; 41 percent had no renal response, and 18 percent had unknown outcomes or were lost to follow-up.

While these data appear to suggest that outcomes are similar among patients treated with targeted versus nontargeted therapy, it should be noted that targeted therapy was preferentially given to those with more advanced hematologic disease (ie, multiple myeloma, smoldering myeloma, or CLL), whereas those with MGRS preferentially received nontargeted therapy (only 5 of 16 patients treated with targeted therapy had MGRS compared with all 17 patients treated with nontargeted therapy).

Additional studies are needed to evaluate the efficacy of targeted therapy in patients with C3 glomerulopathy associated with MGRS.

Among patients with C3 glomerulopathy with monoclonal gammopathy, the absence of monoclonal protein deposits within the kidney makes it difficult to establish a causal relationship between the circulating monoclonal protein and the kidney injury. Although C3 glomerulopathy and monoclonal gammopathy may coexist in a patient, the circulating monoclonal protein may not be responsible for the C3 deposition [36,37,54,57]. As an example, in a series of 41 patients with C3 glomerulopathy with monoclonal gammopathy, anti-complement autoantibodies were present in 20 patients (49 percent); however, in 77 percent of these patients, the light and heavy chain specificities of the autoantibody did not match those of the circulating monoclonal protein [36]. However, experimental evidence suggests the monoclonal immunoglobulin may enhance the ability of the polyclonal immunoglobulins to activate complement. Genetic testing can be helpful to clarify the association between the monoclonal protein and C3 glomerulopathy as patients with C3 glomerulopathy with monoclonal gammopathy rarely have complement gene mutations.

Treatment of other MGRS-associated kidney diseases

Light chain proximal tubulopathy — The optimal therapy for patients with light chain proximal tubulopathy is not known. In general, this disorder is considered to be an indolent condition with slow progression to ESKD [17]. In patients who have significant kidney function impairment and/or proteinuria, we treat with chemotherapy to eradicate the clone that is responsible for the production of the pathologic monoclonal protein [74]. Some experts treat these patients with additional autologous stem cell transplantation. (See "Treatment protocols for multiple myeloma" and "Treatment and prognosis of Waldenström macroglobulinemia" and "Treatment protocols for lymphoma".)

Most of the evidence regarding treatment of light chain proximal tubulopathy comes from small case series. The following studies illustrate the range of findings:

●One retrospective study evaluated the response to antimyeloma therapy among 49 patients with light chain proximal tubulopathy (38 with MGRS) [70]. At baseline, median eGFR and proteinuria were 33 mL/min per 1.73 m² and 1.5 g/day, respectively. All patients had at least one manifestation of proximal tubular dysfunction, and 17 had complete Fanconi syndrome. Among the 42 patients who were treated with chemotherapy, 38 received antimyeloma agents. A hematologic response was achieved in all 38 patients and was associated with stabilization of kidney function in all cases. Thirteen patients had an improvement in proximal tubular dysfunction. Of the seven patients who did not receive specific treatment, four progressed to ESKD after a median of 15 years.

●In another series of 46 patients with light chain proximal tubulopathy (21 with MGRS), 27 were treated with chemotherapy (11 with additional stem cell transplantation), and nine received no treatment [18]. Treatment was associated with a higher rate of improved kidney function compared with no treatment (32 versus 14 percent). ESKD occurred in 29 percent of untreated patients but none of those who were treated.

Light chain crystalline podocytopathy — The optimal therapy for patients with light chain crystalline podocytopathy is unknown. In patients who have significant kidney function impairment and/or proteinuria, we treat with chemotherapy to eradicate the clone that is responsible for the production of the pathologic monoclonal protein [47]. Some experts treat these patients with additional autologous stem cell transplantation, especially if multiple myeloma is present. (See "Treatment protocols for multiple myeloma" and "Treatment and prognosis of Waldenström macroglobulinemia" and "Treatment protocols for lymphoma".)

Evidence regarding the treatment and prognosis of light chain crystalline podocytopathy comes primarily from small case series and reports. In the largest case series of 25 patients who were followed for a median of 36 months, 21 received antiplasma cell-directed chemotherapy (18 with a bortezomib-containing regimen as first-line therapy), and six (29 percent) also underwent autologous stem cell transplantation [47]. Kidney response was dependent upon hematologic response: among patients with a hematologic complete or very good partial remission, 80 percent had a kidney response, compared with only 13 percent of those with a hematologic partial or no response. Overall, six patients (26 percent) progressed to ESKD over a median of 13 months, all of whom had focal segmental glomerulosclerosis (four with the collapsing variant) on kidney biopsy.

Less common disorders — The optimal treatment of MGRS-associated crystal-storing histiocytosis and cryocrystalglobulinemia is not known. These are rare forms of MGRS with isolated case reports [49-51,75-78]. The decision to treat patients with these kidney lesions should be made on a case-by-case basis, depending upon the severity of the kidney disease and risk of progression. In patients who present with significant kidney function impairment and/or proteinuria, treatment should focus upon eradication of the plasma cell or B cell clone that is responsible for producing the pathologic monoclonal protein. The role of plasmapheresis in these disorders is not known.

●(See "Treatment protocols for multiple myeloma".)

●(See "Treatment and prognosis of Waldenström macroglobulinemia".)

Monitoring the response to therapy — In all patients with MGRS who are being actively treated, we obtain the following studies on a monthly basis to monitor both the hematologic and renal response to therapy:

●Serum protein electrophoresis and immunofixation

●24-hour urine collection for total protein, protein electrophoresis, and immunofixation

●Serum free light chain assay

●Serum creatinine

In patients who have completed active treatment, we perform these studies every two to three months.

However, a significant proportion of patients with MGRS, particularly those with PGNMID, do not have detectable circulating monoclonal proteins at baseline. In such patients, it is not possible to assess a hematologic response, and serum creatinine and quantification of proteinuria may be the only parameters that can be used to monitor the response to therapy. Nevertheless, we continue to monitor monoclonal protein studies as described above, because some monoclonal proteins that are initially undetectable may be detectable later in the course of the disease.

Among patients with immunoglobulin light chain (AL) amyloidosis and MIDD, a hematologic response of VGPR (defined as a difference of involved to uninvolved free light chains of <40 mg/L) or better has been associated with improved kidney outcomes [11,32,79]. Similarly, in a study of patients with light chain proximal tubulopathy, achieving VGPR or better was associated with stabilization of kidney function [70]. However, it is unclear if these parameters are associated with clinical outcomes in patients with other forms of MGRS.

Patients with end-stage kidney disease — In patients with ESKD caused by MGRS, the goal of therapy is no longer to preserve kidney function. In general, we do not treat such patients unless they have extrarenal complications (eg, cardiac involvement in patients with AL amyloidosis) or they are candidates for kidney transplantation. MGRS recurs frequently and rapidly after kidney transplantation, and, therefore, achieving complete hematologic remission (CR; defined by a normal serum free light chain ratio and the absence of monoclonal protein on immunofixation) is essential prior to transplantation [22,27,32,80]. The role of treating patients without detectable monoclonal gammopathy to prevent or prolong recurrent disease after kidney transplant is not known.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute kidney injury in adults" and "Society guideline links: Glomerular disease in adults" and "Society guideline links: Multiple myeloma" and "Society guideline links: Immunoglobulin light chain (AL) amyloidosis" and "Society guideline links: Monoclonal gammopathy of undetermined significance" and "Society guideline links: Waldenström macroglobulinemia".)

SUMMARY AND RECOMMENDATIONS

●General principles – Monoclonal gammopathy of renal significance (MGRS) represents a group of disorders in which a monoclonal immunoglobulin secreted by a nonmalignant or premalignant B cell or plasma cell clone causes kidney damage. By definition, these disorders do not meet diagnostic criteria for overt, symptomatic multiple myeloma or a lymphoproliferative disorder. Although MGRS is considered a nonmalignant or premalignant hematologic condition, its effects on the kidney are not benign, and patients with MGRS frequently develop progressive kidney disease and end-stage kidney disease (ESKD). (See 'Epidemiology and prognosis' above and 'Pathogenesis' above.)

●Classification – MGRS-associated kidney diseases encompass a wide spectrum of kidney pathology and can be categorized according to the ultrastructural characteristics of the deposits in the kidney. Deposits can be divided into those that are organized (ie, with substructure) and those that are nonorganized (ie, granular, without substructure). In some cases of MGRS, there are no visible deposits within the kidney. (See 'Classification according to pathology' above.)

●Clinical manifestations – MGRS can present with acute or subacute kidney injury, chronic kidney disease, proteinuria and/or nephrotic syndrome, or electrolyte abnormalities. The most common presenting symptoms are kidney function impairment and proteinuria, with or without hematuria. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of MGRS should be suspected in the following patients (see 'When to suspect MGRS' above):

•All patients with a nonmalignant or premalignant monoclonal gammopathy (eg, monoclonal gammopathy of undetermined significance [MGUS], smoldering multiple myeloma, smoldering Waldenström macroglobulinemia, or monoclonal B cell lymphocytosis [MBL]) who present with unexplained kidney function impairment and/or proteinuria.

•All patients who present with unexplained kidney function impairment and/or proteinuria and are found to have a monoclonal gammopathy during their evaluation of kidney disease.

In most patients suspected of having MGRS, we perform a kidney biopsy, unless contraindicated. The presence of monoclonal immunoglobulin deposits in the kidney establishes the diagnosis of MGRS. In all patients with a confirmed diagnosis of MGRS, we perform monoclonal protein testing and a bone marrow aspirate and biopsy to characterize the clone responsible for the production of the monoclonal protein. (See 'Establishing the diagnosis' above and 'Subsequent evaluation of patients with confirmed MGRS' above.)

●Treatment – The treatment of MGRS is determined primarily by the pathologic type of kidney injury, the nature of the clone (either plasma cell, B cell, or lymphoplasmacytic) that is producing the nephrotoxic monoclonal immunoglobulin, and the likelihood of reversal of the kidney damage. Once the specific lesion has been identified by kidney biopsy, we prefer a treatment approach that employs chemotherapy directed against the pathologic clone, with the primary goal of preserving kidney function. (See 'Overview of our approach' above.)

•PGNMID – For most patients with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), we suggest clone-directed chemotherapy rather than non-clone-directed immunosuppressive therapy or conservative therapy (Grade 2C). However, in patients who have no detectable clone or monoclonal protein in the serum or urine, normal kidney function, and proteinuria <1 g/day, we prefer conservative therapy with antiproteinuric agents and blood pressure control; if there is no reduction in proteinuria or improvement in kidney function after three months, a trial of chemotherapy is reasonable. (See 'Patients with PGNMID' above.)

•C3 glomerulopathy with monoclonal gammopathy – For patients with C3 glomerulopathy with monoclonal gammopathy, we suggest clone-directed chemotherapy rather than non-clone-directed immunosuppressive therapy or conservative therapy (Grade 2C). This approach is similar to that used in patients with PGNMID who have a detectable serum or urine monoclonal protein. (See 'Patients with C3 glomerulopathy with monoclonal gammopathy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jonathan Hogan, MD, who contributed to earlier versions of this topic review.