What has been identified as idiopathic membranoproliferative glomerulonephritis (MPGN) appears to be doing a disappearing act, as a possible underlying etiology is likely to be found in most cases of the condition.
MPGN, also known as mesangiocapillary glomerulonephritis, refers to a specific histologic pattern of glomerular injury characterized by mesangial expansion.
With this expansion, the glomerular tufts take on an accentuated lobular appearance, meaning the individual segments become discernible; mesangial and subendothelial deposits develop; and there are varying degrees of cellular interposition into the capillary wall, with the synthesis of new basement membrane giving rise to duplicated or split basement membranes.
Systemic conditions associated with membranoproliferative glomerulonephritis include autoimmune diseases like systemic lupus erythematosus and chronic infections like hepatitis C.
Less well known, however, is the association of MPGN with monoclonal gammopathy, which is defined as an excessive secretion of immunoglobulin.
Most kidney diseases associated with monoclonal gammopathy are secondary to the deposition of either of the two types of light-chain immunoglobulin segments—kappa or lambda—and not heavy-chain segments or intact immunoglobulins.1
Association Between MPGN & MGUS
We recently analyzed renal biopsies of patients diagnosed with membranoproliferative glomerulonephritis at the Mayo Clinic between 2001 and 2006 (Sethi S, unpublished data, 2009).
The important finding of the study is the association it revealed between MPGN and monoclonal gammopathy of unknown significance (MGUS). MGUS is the most commonly recognized plasma cell disorder and is a potential precursor for multiple myeloma.2,3
Among the 65 patients with hepatitis-negative MPGN, 28 patients (43.1%) were identified as positive for monoclonal or biclonal immunoglobulins. Renal biopsies showed a pattern of injury characteristic of MPGN.
Immunofluorescence microscopy was done, and it showed granular immune deposits in the mesangium and/or along the capillary walls.
These deposits were of IgM kappa in 11 patients; IgG kappa in four; IgG only in two; and IgG lambda, IgM lambda, or IgG/IgM lambda in one case each, with the results correlating with those from immunofixation electrophoresis. In most biopsies, the deposits were more prominent along the capillary walls than in the mesangium.
Three biopsies did not contain glomeruli or contained only globally sclerotic glomeruli. In five biopsies, significant immune deposits were not noted, but three of them did show C3 deposits along the capillary walls.
All patients had thickening of the capillary walls and subendothelial deposits in electron microscopy examinations. There was also cellular interposition, new basement membrane formation with double contours, and granular deposits, while substructures typically were absent.
In four biopsies, there were scattered subepithelial deposits, and, in 21, the mesangium contained electron-dense deposits. Podocytes showed segmental effacement, or flattening, of the foot processes, and many of the capillary loops had leukocyte infiltration, while tubuloreticular structures were not seen in the endothelial cells.
Underlying Lymphoplasmacytic Disorder
Sixteen of the 28 patients had a normal bone marrow biopsy and were classified as having a monoclonal gammopathy of unknown significance.
This study also shows that MPGN with monoclonal gammopathy can be seen in the setting of other lymphoplasmacytic diseases, including low-grade B-cell lymphoma, chronic lymphocytic leukemia, and multiple myeloma.
In one interesting case, serum electrophoresis studies were negative for a monoclonal gammopathy, even though the renal biopsy suggested such a condition. A few months after the biopsy, however, serum immunofixation results returned positive for a monoclonal gammopathy.
Thus, membranoproliferative glomerulonephritis may often be the first sign of an underlying lymphoplasmacytic disorder. Although a direct relationship between the presence of a monoclonal protein and the development of MPGN has not been proved, the current observations point in that direction.
Recognition of a monoclonal gammopathy associated with MPGN is also important in the transplant setting.
In a recent review of renal allograft protocol biopsies in patients who developed end-stage renal disease (ESRD) secondary to MPGN, patients with monoclonal gammopathy had a particularly high incidence of MPGN recurrence (66.7%) compared with patients without monoclonal proteins (30%).4
Consistent with this observation, we recently showed that, in patients with fibrillary glomerulonephritis, the presence of serum monoclonal proteins is associated with a high incidence of disease recurrence posttransplant.5
Recently, Nasr et al described proliferative glomerulonephritis associated with IgG deposition.6,7 Retrospectively identified were 37 patients, most of whom were white (81%), female (62%), or older than 50 years (65%).7
Of the 37 patients, 49% had nephrotic syndrome, 68% had renal insufficiency, and 77% had hematuria at presentation. A monoclonal serum protein with the same heavy- and light-chain isotypes as the glomerular deposits (mostly IgG1 or IgG2) was identified in 30% of the patients, but only one patient had myeloma.
In most patients, histologic patterns were membranoproliferative (57%) or endocapillary proliferative (35%) with membranous features.
Among the 32 patients with available data during the average 30.3 months of follow-up, 38% had complete or partial recovery of renal function, 38% had persistent renal dysfunction, and 22% progressed to ESRD.
The deposits were composed exclusively of monoclonal IgG, however, and thus may belong to a subgroup of the monoclonal gammopathies that were noted in our unpublished study at the Mayo Clinic. Bone marrow biopsy was performed in 22 of 37 cases, with only one patient showing multiple myeloma.
Since a monoclonal gammopathy was identified in only 30% of cases, the authors did not ascribe the lesions to MGUS, lymphoproliferative disease, or multiple myeloma.
Need for Studies in Larger Cohorts
Still lacking is information about the best therapy for membranoproliferative glomerulonephritis associated with monoclonal gammopathies.
In the report by Nasr et al., the investigators were unable to show a statistical benefit of treatment, probably in part because of the small sample size and the tendency for selectively treating patients with the worst renal failure and/or crescents on biopsy.7
Prospective, controlled studies in larger cohorts of patients who have membranoproliferative glomerulonephritis associated with monoclonal gammopathies are needed to determine the optimal therapeutic regimen.
Until such a study is performed, treatment recommendations must be made purely on the basis of clinical experience in small numbers of patients.
In patients with progressive renal disease or biopsy features suggestive of progression, like crescents, a trial of immunosuppressive therapy targeted to B cells/plasma cells, like cyclophosphamide, seems reasonable.
Treatment with rituximab, a monoclonal antibody against the CD20 antigen expressed on the surface of B cells, is a logical but still unproven approach.
Treatment with rituximab could potentially spare the adverse effects of prednisone and other traditional immunosuppressive agents. It is, however, unlikely to work if the disease pathogenesis resides in the plasma cells.
Renal biopsies in membranoproliferative glomerulonephritis should be analyzed with anti-light chain antibodies to detect a possible underlying monoclonal gammopathy, and all patients should undergo a full work-up for gammopathies, which should include serum and urine immunofixation studies. If positive, a bone marrow biopsy should also be performed.