Membranoproliferative GN

(MPGN)

• Membranoproliferative pattern of glomerular injury consists of two components:

• 1. mesangial expansion and hypercellularity, and

• 2. thickening of the peripheral capillary loops due to double contour formation ('tram-tracking', best appreciated on silver or PAS stains).

• This pattern of glomerular injury can be appreciated in three types of disorders:

• 1. IMMUNE COMPLEX-MEDIATED DISEASES• a. Idiopathic or primary forms (MPGN I, II, III)• b. Secondary forms (chronic infections, autoimmune diseases)

• 2. THROMBOTIC MICROANGIOPATHIES

• 3. PARAPROTEIN DEPOSITION DISEASES• a. monoclonal immunoglobulin deposition disease, such as light chain DD• b. fibrillary and immunotactoid glomerulopathy• c. cryoglobulin-associated GN• d. Waldenström macroglobulinemia• e. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, m-protein,

skin change)

Membranoproliferative glomerulonephritis (MPGN), idiopathic,

type I• Idiopathic membranoproliferative glomerulonephritis is an immune

complex-mediated disease of unknown etiology with a membranoproliferative pattern of glomerular injury (mesangial hypercellularity and expansion and double contour formations in peripheral capillary loops). The diagnosis of primary MPGN is one of exclusion, since similar morphologic findings can be seen in secondary forms with an MPGN pattern of injury (autoimmune diseases and chronic infections, see classification). There are three types (I, II, and III) of primary MPGN.

• Type I MPGN is the most common, “classic” type of primary MPGN, with subendothelial and mesangial deposits and with strong C3 and less intense IgG immunofluorescence reactivity.

• Etiology: • The disease is idiopathic (primary).

• Clinical: • Occurs more commonly in young patients (ages 7 – 30 years).• Usually presents with mixed nephrotic and nephritic syndrome,

with predominant nephrotic component; less commonly the presentation is purely nephritic

• C3 is reduced and C1q and C4 are commonly borderline or reduced

• C3 nephritic factor (autoantibody against C3bBb or alternate pathway C3 convertase) is associated with type II MPGN, but may be present in one-third of type I cases

• Histopathology: • Lobular appearance of glomeruli on low power magnification• Mesangial expansion due to increased mononuclear

inflammatory cells and matrix• Peripheral capillary loops are markedly thickened; on PAS and

silver stains, there are prominent double contour formations (“tram tracking”)

• Immunofluorescence: • There is fine granular deposition of IgG and C3 in the

mesangium and along the peripheral capillary loops; the reactivity for C3 is usually very strong, commonly stronger than reactivity for IgG

• Electron microscopy: • Visceral epithelial cells: Focal, sometimes marked effacement of

visceral epithelial cell foot processes• Glomerular basement membranes: Prominent subendothelial

widening due to cellular interposition and electron-dense deposits; secondary basement membrane forms under the displaced endothelium (double contour formation)

• Glomerular endothelial cells: Show loss of fenestrations and other non-specific changes; they do not contain tubuloreticular structures

• Mesangium: Mesangial expansion due to increased number of mononuclear inflammatory cells, an increase in the amount of matrix and a presence of electron-dense deposits

(MPGN), type II (Dense deposit disease)

• Type II membranoproliferative glomerulonephritis (MPGN) is a distinct and very rare form of MPGN characterized by dense intramembranous deposits (hence the synonym “dense deposit disease”) with C3 reactivity by IF; the disease is associated with serum C3 nephritic factor and is characterized by profound decrease in serum C3 levels.

• Etiology: • Formation of autoantibody (known as C3 nephritic

factor) against C3 convertase of the alternative pathway

• Clinical: • Occurs in children• Marked and persistent depression of C3;C4 is

normal• Can be associated with acquired partial

lipodystrophy

• Histopathology: • Mesangial prominence and hypercellularity• Capillary loops are thickened and may exhibit a ribbon-

like appearance due to intramembranous deposits; double contours are not a dominant feature

• Crescents and proliferative changes are rare but may be present

• Immunofluorescence: • Striking C3 positivity along the capillary loops and in the

mesangium, in the absence of immunoglobulins and other complement components (C4 and C1q)

• Electron microscopy: • Visceral epithelial cells: Focal, sometimes marked

effacement of visceral epithelial cell foot processes• Glomerular basement membranes: “Sausage-string”

appearance due to alternating normal with thickened segments containing very dense and homogeneous intramembranous deposits

• Glomerular endothelial cells: Show loss of fenestrations and other non-specific changes; they do not contain tubuloreticular structures

• Mesangium: Deposits of similar texture and quality to those seen in the GBM are also seen in the mesangium

(MPGN), type III (Burkholder, and Strife and Anders variants)

• Type III membranoproliferative glomerulonephritis (MPGN) consists of two variants; Burkholder variant (MPGN type I with subepithelial deposits) and Strife and Anders variant (complex intramembranous and subendothelial deposits, with marked basement membrane irregularities). Electron microscopy is essential in distinguishing these variants from classic type I MPGN.

• Etiology: • Unknown

• Clinical: • Most commonly occurs in children and young

adults• Presents with mixed nephrotic and nephritic

syndromes and hypocomplementemia• C3 nephritic factor (autoantibody against C3bBb or

alternate pathway C3 convertase) is absent in type III MPGN.

• Histopathology: • Lobular appearance of glomeruli on low power magnification• Mesangial expansion due to increased mononuclear

inflammatory cells and matrix• Peripheral capillary loops are markedly thickened; on PAS and

silver stains, there are prominent double contour formations (“tram tracking”)

• Immunofluorescence: • There is fine granular deposition of IgG and C3 in the

mesangium and along the peripheral capillary loops; the reactivity for complement component is usually very strong, commonly stronger than reactivity for IgG

• Electron microscopy: • Visceral epithelial cells: Focal, sometimes marked effacement of

visceral epithelial cell foot processes• Glomerular basement membranes: In the Burkholder variant, in

addition to subendothelial deposits similar to MPGN type I, there are subepithelial, sometimes “hump”-like electron-dense deposits. In the Strife and Anders variant, there are complex intramembranous and subendothelial deposits, with marked basement membrane irregularities; there is breakage, lamellation, and disrupted appearance of the basement membranes

• Glomerular endothelial cells: Show loss of fenestrations and other non-specific changes; they do not contain tubuloreticular structures

• Mesangium: Mesangial expansion due to increased number of mononuclear inflammatory cells, an increase in the amount of matrix, and a presence of electron-dense deposits

Cryoglobulin-associated glomerulonephritis

• Cryoglobulin-associated glomerulonephritis is a form of glomerulonephritis with membranoproliferative pattern of glomerular injury secondary to cryoglobulin deposition. Cryoglobulins are a group of circulating proteins with the physical property of precipitating in cold and dissolving when heated.

• Etiology: • Production of cryoglobulins can result from neoplastic or non-neoplastic

monoclonal or polyclonal B-cell proliferation, associated with dysproteinemia, chronic infections, or autoimmune diseases. (1)Type 1 cryoglobulinemia (with singe monoclonal Ig) is associated with B-cell lymphoproliferative disorders (multiple myeloma, lymphomas, Waldenstrom macroglobulinemia) (2)Type 2 (mixed monoclonal and polyclonal Ig) is associated with hepatitis C, other infections (EBV, bacterial endocarditis, hepatitis B), autoimmune diseases (SLE, SS, RA), or paraproteinemias (3)Type 3 (mixed polyclonal Ig) is associated with chronic infections and autoimmune disorders

• Clinical: • Hematuria, proteinuria, renal failure• Systemic vasculitis (purpura, arthralgias, arthritis, Raynaud’s phenomenon,

peripheral neuropathy, abdominal pain)• Underlying systemic diseases; chronic infection (hepatitis C), autoimmune

diseases, dysproteinemia• Low complements

• Histopathology: • Lobular appearance of glomeruli on low power magnification.• Commonly, mesangial expansion with increased mononuclear

inflammatory cells and matrix and peripheral capillary loop thickening (MPGN-like pattern of injury); rarely, there is diffuse or focal proliferative pattern of glomerulonephritis

• Subendothelial or intraluminal “microthrombi” that are composed of cryoglobulins

• Vasculitis may be present in some cases

• Immunofluorescence: • In type 1 cryoglobulinemia, there will be a monoclonal immunoglobulin

(often IgG/kappa). Monoclonal IgM is seen in cryoglobulinemia associated with Waldenstrom macroglobulinemia. In type 2, associated with hepatitis C, there is staining for IgG and IgM, C3, C1q, kappa and lambda light chains, but the reactivity is stronger for IgM/kappa.

• Electron microscopy: • Visceral epithelial cells: Focal effacement of visceral

epithelial cell foot processes• Glomerular basement membranes: May show mild

irregularities. Subendothelial space is expanded by sometimes large deposits, with or without substructural organization; the deposits can exhibit curvilinear or microtubular organization

• Glomerular endothelial cells: Loss of fenestrations and other non-specific changes; they do not contain tubuloreticular structures

• Mesangium: Usually expanded by matrix and deposits; an increase in cells may be also noted

Lupus Nephritis Class IV• Histopathology: • Light microscopic examination reveals segmental or global

endocapillary proliferative changes. The mesangium is variably expanded and hypercellular

• The peripheral capillary loops are irregular in thickness, sometimes showing 'wire loops' and intraluminal 'microthrombi' (hyaline thrombi)

• Leukocyte infiltration, focal necrosis, hematoxilin bodies, and cellular crescents can all be seen

• In some cases, membranoproliferative pattern of injury may be dominant in glomeruli (class IV)

• The tubulointerstitium may show active interstitial nephritis

• Immunofluorescence: • There is 'full house' reactivity (reactivity for IgG, IgM, and IgA), with

granular deposits in the mesangium.

• Electron microscopy: • Visceral epithelial cells: Show different degrees of injury and

degenerative changes, with focal, but sometimes extensive, effacement of foot processes. Subepithelial deposits can be seen in many cases

• Glomerular basement membranes: May be irregular in thickness, with the presence of intramembranous, subepithelial, and/or subendothelial deposits. Subendothelial deposits can be rather large and may demonstrate substructural organization ('fingerprint'-like pattern)

• Glomerular endothelial cells: May contain tubuloreticular structures

• Mesangium: Expanded by increase in cellular elements and extracellular matrix, with sometimes large and confluent fine granular, electron-dense deposits

Lupus Nephritis Class IV

Thrombotic microangiopathy, chronic (CTMA)

• Thrombotic microangiopathies are a diverse group of disorders that affect small vasculature and/or glomerular capillary walls. In chronic TMAs, there are no active thrombotic lesions, but there is a membranoproliferative type of glomerular injury, with widespread glomerular capillary loop double contour formations, in the absence of immune complex or paraprotein deposition. Chronic TMAs present with chronic renal insufficiency.

• Etiology: • Etiology varies between different entities in this group of

disorders (see classification). Common pathogenic denominators are endothelial cell injury and platelet activation and consumption in acute TMAs; alternating injury and repair lead to complex remodeling of vascular and glomerular capillary wall elements, as seen in chronic TMAs

• Clinical: • Progressive chronic renal failure• Clinical history reveals thrombophilia (acquired or inherited),

autoimmune disease, previous episode of HUS/TTP, chemotherapy/ immunosuppressive regimens, malignancy, or other factors that may have resulted in vascular injury

• Histopathology: • Lobular appearance of glomeruli on low-power

magnification• Mesangial expansion by matrix and increase in cell

elements• Peripheral capillary loops are markedly thickened; on

PAS and silver stains, there are prominent double contour formations (“tram tracking”)

• Immunofluorescence: • Reactivity for fibrin can be demonstrated in thrombi

within glomeruli and small vessels

• Electron microscopy: • Visceral epithelial cells: Usually focal, sometimes marked

effacement of visceral epithelial cell foot processes• Glomerular basement membranes: Prominent subendothelial

widening by basement membrane material and interposed cellular elements, in the absence of electron-dense or organized deposits. A new, usually irregular and thin layer of basement membrane is seen under the regenerated endothelium (double contours); cellular interposition between the two layers of basement membrane is common

• Glomerular endothelial cells: Loss of fenestrations, detachment from the original basement membranes, and focal swelling; they do not contain tubuloreticular structures

• Mesangium: Cellular debris may be deposited, but electron-dense deposits are not seen

Thrombotic microangiopathy, acute (ATMA)

• Thrombotic microangiopathies are a diverse group of disorders that affect small vasculature and/or glomeruli. Acute TMAs area a histopathologic term that defines glomerular, arterial and arteriolar lesions, characterized by patchy distribution, bloodless glomeruli, mesangiolysis, intimal cell proliferation, thickening and necrosis of the vascular walls, thrombi, and narrowed lumens. Clinically, acute TMAs present with microangiopathic hemolytic anemia, microvascular thrombosis, and thrombocytopenia.

• Etiology: • Etiology varies between different entities in this group of disorders (see

table); common pathogenic denominators are endothelial cell injury and platelet activation and consumption

• Shiga-toxin (verotoxin) of E. coli O157:H7 in typical (diarrheal) HUS• Abnormalities in complement regulators (factors H and I, membrane cofactor

protein - MCP) in atypical (non-diarrheal) HUS {1} {2}

• Clinical: • Microangiopathic hemolytic anemia (anemia, schistocytosis,

thrombocytopenia) with purpura and fever• Acute renal failure, with or without anuria• Neurologic deficits (more common in TTP)• Diarrhea (in E. coli associated HUS)• Indirect hyperbilirubinemia, reticulocytosis, and low heptoglobin may be

present.

• Histopathology: • Thrombosis and fibrinoid necrosis of small vessels and/or glomerular tufts. Renal cortical

necrosis in severe cases• Bloodless glomeruli: lumens of the capillary loops are obliterated due to endothelial swelling

(endotheliosis)

• Immunofluorescence: • Reactivity for fibrin can be demonstrated in thrombi within glomeruli and small vessels.

• Electron microscopy: • Visceral epithelial cells: Usually focal, sometimes marked effacement of visceral epithelial cell

foot processes• Glomerular basement membranes: Prominent subendothelial widening by electron-lucent

fluffy material that may contain fibrin elements, fragments of platelets and red blood cells. Electron-dense or organized deposits are not present.

• Glomerular endothelial cells: Swelling, loss of fenestrations, and detachment from the original basement membranes. They may be missing in some places

• Mesangium: Areas of mesangiolysis are characterized by electron-lucent spaces that may contain fibrin and fragments of platelets and red blood cells. Cellular debris may be deposited, but electron-dense deposits are not seen

Fibrillary GN• Histopathology: • Commonly, there is mesangial expansion with increased mononuclear inflammatory cells and matrix and

peripheral capillary loop thickening (MPGN-like pattern of injury); sometimes, the predominant pattern is mesangioproliferative (if the deposition is not involving capillary loops) or even less commonly, membranous, diffuse proliferative, or sclerosing patterns may be seen {2}

• Proliferative changes, such as increased endocapillary proliferation or crescent formation, are uncommon but occur

• Congo red stain is negative• Silver stain may reveal “moth eaten” appearance (non-reactive deposits admixed with reactive matrix)

• Immunofluorescence: • There is polyclonal deposition of IgG (most often IgG1 or IgG4) and C3 in the mesangium and along the

peripheral capillary loops; in less than 10% of cases, the reactivity will be of monoclonal IgG; in very rare cases there will be no immunoglobulin reactivity.

• Electron microscopy: • Visceral epithelial cells: Focal, sometimes marked effacement of visceral epithelial cell foot processes• Glomerular basement membranes: Usually marked thickening of the membranes with extensive fibrillary

deposits; the deposition extends to subepithelial, subendothelial, and paramesangial spaces. The fibrils are non-branching, randomly oriented, 12-30 nm in diameter

• Glomerular endothelial cells: Show loss of fenestrations and other non-specific changes; they do not contain tubuloreticular structures

• Mesangium: Usually expanded by matrix and organized fibrillary deposits

Immunotactoid glomerulopathy• Histopathology: • Commonly, there is mesangial expansion with increased mononuclear

inflammatory cells and matrix and peripheral capillary loop thickening (MPGN-like pattern of injury); rarely, the predominant pattern can be mesangioproliferative (if the deposition is not involving capillary loops) or, even less commonly, predominantly membranous

• Proliferative changes, such as increased endocapillary proliferation or crescent formation, can be seen on rare occasions

• Congo red stain is negative• Silver stain may reveal “moth eaten” appearance (non-reactive

deposits admixed with reactive matrix)

• Immunofluorescence: • Monoclonal (kappa or lambda) reactivity of immunoglobulins (usually

IgG)

• Electron microscopy: • Visceral epithelial cells: Focal, sometimes marked effacement of

visceral epithelial cell foot processes• Glomerular basement membranes: Microtubular deposits,

frequently in parallel arrangements, can be seen in subepithelial and intramembranous locations, extending to the paramesangial and mesangial compartment; the basement membrane can be affected with deposits in various degrees. The fibrils or microtubules are non-branching, usually greater than 30 nm (10-90 nm) in diameter

• Glomerular endothelial cells: Show loss of fenestrations and other non-specific changes; they do not contain tubuloreticular structures

• Mesangium: Usually expanded by matrix and organized microtubular deposits

Monoclonal immunoglobulin deposition disease (MIDD)

• Histopathology: • Marked mesangial expansion, with formation of distinct nodules

(nodular glomerulosclerosis)• Nodules may show hypercellularity, some may be hypocellular and

laminated• No fibrin caps, capsular drops, or prominent hyalinosis• The tubular basement membranes show marked thickening, with

refractile appearance• The vessel walls may be thickened• Congo red stain is negative

• Immunofluorescence: • There is immunofluorescence reactivity restricted to abnormal

truncated protein (one of the light chains - kappa or lambda, or a single heavy chain - gamma, mu, alpha)

• Electron microscopy: • Visceral epithelial cells: Focal, sometimes marked effacement of

visceral epithelial cell foot processes• Glomerular basement membranes: Markedly thickened, with

band-like, sometimes laminated deposition of powdery, very dense fine granular material. The deposits show no substructural organization. Usual place of deposition is within lamina rara interna and inner portion of lamina densa; similarly, in tubular basement membranes, the deposits are found on the interstitial side of the membrane

• Glomerular endothelial cells: Loss of fenestrations and other non-specific changes

• Mesangium: Deposition of powdery, very dense fine granular material; the deposits show no substructural organization