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Membranoproliferative Glomerulonephritis Workup

  • Author: Pranay Kathuria, MD; Chief Editor: Vecihi Batuman, MD, FACP, FASN  more...
 
Updated: Jun 23, 2016
 

Approach Considerations

Patients with membranoproliferative glomerulonephritis (MPGN) may demonstrate abnormalities in their complete blood cell count (CBC) and other laboratory tests. Most often, patients have a normocytic normochromic anemia. Hyperlipidemia and low albumin levels may be seen with nephrotic syndrome.

Because hypocomplementemia is a characteristic finding in all types of MPGN, obtain complement profiles in patients with suspected MPGN.

To rule out secondary causes of MPGN, obtain antinuclear antibody studies (ANA), hepatitis screens, cryoglobulins, urine studies, and serum protein electrophoresis or serum free light-chain analysis.

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Urine Studies and Kidney Function Tests

Urinalysis in patients with membranoproliferative glomerulonephritis (MPGN) may reveal glomerular hematuria, which is characterized by dysmorphic red blood cells (RBCs) and RBC casts. Proteinuria is almost always present.

The urine protein-to-creatinine ratio is a good estimate of 24-hour urinary protein excretion. Nephrotic proteinuria is present in approximately 50% of patients.

Elevated serum creatinine and blood urine nitrogen (BUN) levels and a decreased estimated glomerular filtration rate (GFR) are evident in 20-50% of patients with MPGN at presentation. Patients with a nephritic presentation typically have a decreased GFR.

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Complement Profile

The complement profiles of types I-III membranoproliferative glomerulonephritis membranoproliferative glomerulonephritis (MPGN) are summarized below.

MPGN type I

C3 levels are low in about half of the patients with MPGN type I. There is evidence of activation of the classic pathway of complement (ie, low C4, C2, C1q, B, C3). Terminal complement components C3, C5, C8, and C9 may be low or within the reference range, and nephritic factor of the amplification loop (NFc or C4NeF) or nephritic factor of the terminal pathway (NFt) may be present.

MPGN type II

C3 levels are low in 70-80% of patients with MPGN type II. Early and terminal complement components are within the reference range. NFa (C3NeF) is present in more than 70% of patients, but factor H levels may be low.

MPGN type III

C3 levels are decreased in 50% of patients with MPGN type III. C1q and C4 levels are within the reference range. Terminal complement components are low, especially if C3 is markedly depressed. NFa is absent, and NFt is present in 60-80% of patients. Antistreptolysin-O (ASO) titers may be elevated in as many as 50% of patients at presentation.

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Kidney Biopsy and Histologic Features

Perform a kidney biopsy for definitive diagnosis of membranoproliferative glomerulonephritis (MPGN). Under light microscopy, the glomeruli are generally enlarged and hypercellular, with an increase in mesangial cellularity and matrix. Mesangial increase, when generalized throughout the glomeruli, causes an exaggeration of their lobular form (as demonstrated in the image below), giving rise to the alternative name of lobular nephritis. Infiltrating neutrophils and monocytes contribute to glomerular hypercellularity.

Membranoproliferative glomerulonephritis (MPGN) ty Membranoproliferative glomerulonephritis (MPGN) type I. Glomerulus with lobular accentuation from increased mesangial cellularity. A segmental increase occurs in the mesangial matrix, and the peripheral capillary walls are thickened (hematoxylin and eosin stained section; original magnification × 250). Courtesy of John A. Minielly, MD.

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The capillary basement membranes are thickened by interposition of mesangial cells and matrix into the capillary wall. This gives rise to the tram-track or double-contoured appearance of the capillary wall, which is best appreciated with the methenamine silver stain or the periodic acid-Schiff (PAS) reagent.

Crescents may be visible in 10% of patient biopsy specimens. Interstitial changes, including inflammation, interstitial fibrosis, and tubular atrophy, are observed in patients with progressive decline in glomerular filtration rate (GFR).

MPGN type I

On electron microscopy, electron dense deposits in subendothelial sites (as seen in the image below) are characteristic of MPGN type I. Mesangial and occasional subepithelial deposits also may be present. Irregular new basement membrane material is formed around the subendothelial deposits and mesangial projections, producing the tram-track appearance on light microscopy.

Membranoproliferative glomerulonephritis (MPGN) ty Membranoproliferative glomerulonephritis (MPGN) type I. Electron microscopy of prominent, glomerular, subendothelial, immune-type electron deposits (original magnification × 11,400). Courtesy of John A. Minielly, MD.

By immunofluorescence, prominent C3 deposition in a granular pattern is noted in the capillary walls, with variable mesangial C3 deposits. Early components of complement, immunoglobulin G (IgG),[23, 24] and, less commonly, IgM may be found in a distribution similar to C3. See the following image.

Membranoproliferative glomerulonephritis (MPGN) ty Membranoproliferative glomerulonephritis (MPGN) type I. Immunofluorescent stained section. Intense, peripheral, glomerular, capillary loop deposition of immunoglobulin G (IgG) in an interrupted linear pattern corresponding to extensive subendothelial immune deposits (original magnification × 400). Courtesy of John A. Minielly, MD.

MPGN type II (dense deposit disease)

The basement membranes of the glomerulus, Bowman capsule, tubules, and peritubular capillaries are thickened in type 2 disease. The basement membrane appears irregular and ribbonlike on special stains (eg, PAS, thioflavine-T, toluidine blue).

On electron microscopy, the basement membrane is thickened by discontinuous, amorphous, electron dense deposits, as shown in the image below, that reside in the lamina densa layer (hence, the alternative name of dense deposit disease). Mesangial and subepithelial dense deposits may be noted.

Membranoproliferative glomerulonephritis (MPGN) ty Membranoproliferative glomerulonephritis (MPGN) type II. Electron microscopy of glomerular basement membrane, intramembranous, somewhat linear, electron dense deposit (ie, dense deposit disease; original magnification × 11,400). Courtesy of John A. Minielly, MD.

Immunofluorescence reveals complement component C3 deposited in an irregular granular pattern in the basement membranes on either side but not within the dense deposits or in nodular ring forms in the mesangium. Little or no deposition of immunoglobulins occurs in the glomeruli.

MPGN type III

The type III variant of MPGN, also called the Burkholder variant, displays combined features of MPGN type I and membranous nephropathy.

Subepithelial, subendothelial, and mesangial deposits are present on electron microscopy. Successive generations of subendothelial and subepithelial deposits disrupt the basement membrane, and concurrent formation of new lamina densa material is present, giving the basement membrane a complex laminated appearance.

Immunohistology shows granular deposition of C3, C5, properdin, IgG,[23, 24] and IgM, predominantly in the capillary walls.

C3 glomerulonephritis

Immunofluorescence microscopy in C3 glomerulonephritis reveals extensive C3 deposition along the capillary wall and mesangium with no immunoglobulin deposition. On the other hand, electron microscopy does not reveal intramembranous and mesangial deposits in C3 glomerulonephritis as it does in dense deposit disease.

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Contributor Information and Disclosures
Author

Pranay Kathuria, MD FACP, FASN, FNKF, Professor of Medicine, Director, Division of Nephrology and Hypertension, University of Oklahoma School of Community Medicine

Pranay Kathuria, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American Heart Association, American Society of Hypertension, American Society of Nephrology, National Kidney Foundation

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ajay K Singh, MB, MRCP, MBA Associate Professor of Medicine, Harvard Medical School; Director of Dialysis, Renal Division, Brigham and Women's Hospital; Director, Brigham/Falkner Dialysis Unit, Faulkner Hospital

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FACP, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System

Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, International Society of Nephrology

Disclosure: Nothing to disclose.

Additional Contributors

F John Gennari, MD Associate Chair for Academic Affairs, Robert F and Genevieve B Patrick Professor, Department of Medicine, University of Vermont College of Medicine

F John Gennari, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Federation for Medical Research, American Heart Association, American Physiological Society, American Society for Clinical Investigation, American Society of Nephrology, International Society of Nephrology

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Martin Senitko, MD, and Sandeep Singh, MD, to the development and writing of the source article.

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Membranoproliferative glomerulonephritis (MPGN) type I. Glomerulus with lobular accentuation from increased mesangial cellularity. A segmental increase occurs in the mesangial matrix, and the peripheral capillary walls are thickened (hematoxylin and eosin stained section; original magnification × 250). Courtesy of John A. Minielly, MD.
Membranoproliferative glomerulonephritis (MPGN) type I. Electron microscopy of prominent, glomerular, subendothelial, immune-type electron deposits (original magnification × 11,400). Courtesy of John A. Minielly, MD.
Membranoproliferative glomerulonephritis (MPGN) type I. Glomerulus with mesangial interposition producing a double contouring of basement membranes, which, in areas, appear to surround subendothelial deposits (Jones silver methenamine–stained section; original magnification × 400). Courtesy of John A. Minielly, MD.
Membranoproliferative glomerulonephritis (MPGN) type II. Electron microscopy of glomerular basement membrane, intramembranous, somewhat linear, electron dense deposit (ie, dense deposit disease; original magnification × 11,400). Courtesy of John A. Minielly, MD.
Membranoproliferative glomerulonephritis (MPGN) type I. Immunofluorescent stained section. Intense, peripheral, glomerular, capillary loop deposition of immunoglobulin G (IgG) in an interrupted linear pattern corresponding to extensive subendothelial immune deposits (original magnification × 400). Courtesy of John A. Minielly, MD.
 
 
 
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