MPGN

Question 1

MPGN

Epidemiology

Answer 1

MPGN is a glomerular injury pattern common to a heterogeneous group of diseases.

Accounts for 7% to 10% of all cases of biopsy-confirmed GN.Third or fourth leading cause of ESRD among primary GN

Question 2

MPGN

Histopathology

LM:

Answer 2

Mesangial hypercellularity, endocapillary proliferation, and capillary wall remodeling (with formation of double contours), all leading to lobular accentuation of glomerular tufts (chunky segments/pieces)

Glomerular changes are due to deposition of complement factors with or without immunoglobulins in the glomerular mesangium and along capillary walls.

Question 3

MPGN

Histopathology

EM:

Answer 3

Subendothelial deposits with mesangial migration and interposition with duplication of basement membrane forming capillary double contours, variable mesangial deposits, subepithelial and intramembranous deposits in type III MPGN.

Question 4

MPGN

Histopathology

Traditional classification of MPGN was based on EM findings:

Answer 4

MPGN I: subendothelial deposits

Idiopathic

Secondary causes: subacute/chronic infections, hepatitis C > B, cryoglobulinemia, lymphoproliferative malignancies, carcinomas, C2 or C3 deficiency, autoimmune disease, C3 glomerulopathy

Question 5

MPGN

Histopathology

Traditional classification of MPGN was based on EM findings:

Answer 5

MPGN III: MPGN type I features with additional subepithelial and/or intramembranous deposits.

Question 6

MPGN

Histopathology

Traditional classification of MPGN was based on EM findings:

Answer 6

MPGN II: dense deposits in GBM, a.k.a. “dense-deposit disease,” “DDD”

Idiopathic

Secondary causes: complement dysregulation due to deficiency or mutations of complement regulatory proteins, autoantibody formation against regulatory proteins, C3 nephritic factor autoantibodies (C3NeF), familial and acquired partial lipodystrophy

Question 7

MPGN

Histopathology

Traditional classification of MPGN was based on EM findings:

Answer 7

IF: Findings from IF studies may define the underlying pathogenesis of the MPGN.

Question 8

MPGN

Histopathology

Immune Complex–Mediated MPGN:

Proposed sequence of events:

Answer 8

Involves classical pathway c3 e c4

IF typically shows both Ig and complement deposits.
Chronic increase in immunoglobulin production due to infections, autoimmune disease, or monoclonal gammopathies leads to:
Binding of the immunoglobulins to GBM and activation of the complement cascade and induction of inflammatory changes (cellular or proliferative), followed by a:
Reparative phase where new mesangial matrix is formed (mesangial expansion) along with new GBM formation (duplication of GBM “tram tracks or double contours”).
New GBM formation may entrap capillary wall deposits ± inflammatory cells, mesangial, and endothelial cells, leading to thickened appearance of capillary walls and formation of double contours along capillary walls.

Question 9

MPGN

Histopathology

Immune Complex–Mediated MPGN:

Conditions leading to increased Ig production:

Answer 9

Infections: chronic viral infections (e.g., hepatitis C&raquo_space; B ± cryoglobulins); bacterial infections (endocarditis, shunt/indwelling catheter nephritis, abscesses; common organisms: Staphylococcus, Mycobacterium tuberculosis, streptococci, Propioibacterium acnes, Mycoplasma pneumoniae, Brucella, Coxiella burnetii, Nocardia, Meningococcus; fungal infections, parasitic infections.

Question 10

MPGN

Histopathology

Immune Complex–Mediated MPGN:

Conditions leading to increased Ig production:

Answer 10

Autoimmune diseases: systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis, mixed connective tissue diseases

Paraproteinemias: monoclonal gammopathies ± cryoglobulins

Question 11

MPGN

Histopathology

Complement-Mediated MPGN:

Answer 11

Involves complement dysregulation in the alternative pathway
Dysregulated complement activation leads to abnormal C3 convertase activity and resultant inflammatory changes, endothelial/GBM/podocyte injury, and subsequent reparative phase similar to that seen with immune complex–mediated injury. With the exception of DDD, EM cannot distinguish between immune complex–mediated and complement-mediated MPGN.

Question 12

MPGN

Histopathology

Complement-Mediated MPGN:

Dysregulation of complement activation may occur via different mechanisms:

Answer 12

Antibody formation against:

C3 convertase (antibodies against C3 convertase are also known as C3 nephritic factor (C3NF)—C3NF binds to and stabilizes C3 convertase, thereby prolonging its half-life and allowing continuing activation of the alternative pathway.

Complement regulators (Factor H, I, or B)

Question 13

MPGN

Histopathology

Complement-Mediated MPGN:

Dysregulation of complement activation may occur via different mechanisms:

Answer 13

Mutations of complement regulators: factor H, factor I, membrane cofactor protein MCP/CD46, complement factor H-related protein CFHR5, CFHR 3-1

Allele variants: C3, MCP

Question 14

MPGN

Histopathology

Complement-Mediated MPGN:

Dysregulation of complement activation may occur via different mechanisms:

Answer 14

Dysregulation of alternative pathway may be subdivided into DDD and C3 glomerulonephritis (C3GN) based on EM findings. Both disease entities, however, are thought to be part of a continuum of the same condition.

Differences in histopathology are likely due to the degree or site, or both, of the dysregulation of the alternative pathway. Certain allele variations of complement regulating proteins may be associated with DDD, while others (e.g., CFHR5) with C3GN.

Question 15

MPGN

Histopathology

Complement-Mediated MPGN:

Dysregulation of complement activation may occur via different mechanisms:

Answer 15

DDD: Characterized by osmiophilic, sausage-shaped, wavy, dense deposits that replace GBM and also occur in mesangium (old classification: MPGN II). MPGN II is associated with partial lipodystrophy and ocular drusen.

Question 16

MPGN

Histopathology

Complement-Mediated MPGN:

Dysregulation of complement activation may occur via different mechanisms:

Answer 16

C3GN is characterized by mesangial, subendothelial, and sometimes subepithelial and intramembranous deposits

Question 17

MPGN

Histopathology

MPGN without IC or complement:

Answer 17

May be seen with thrombotic microangiopathies (TMA)

Pathologic characteristics: absence of immunoglobulins or complements on IF; absence of electron-dense deposits in mesangium or capillary walls on EM

Question 18

MPGN

Histopathology

MPGN without IC or complement:

Answer 18

Associated conditions: thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome, atypical hemolytic-uremic syndrome, antiphospholipid antibody syndrome, drug-induced TMA, malignant hypertension, radiation nephritis, bone marrow transplant-associated nephropathy, connective tissue disorders

Question 19

MPGN

Clinical Manifestations

Answer 19

Asymptomatic hematuria and proteinuria

Acute nephritic syndrome

Nephrotic syndrome

CKD

Rapidly progressive glomerulonephopathy

Question 20

MPGN

Diagnosis

Complement levels:

Answer 20

IC-mediated MPGN: typically low C3 and low C4

Complement-mediated MPGN: typically low (but may be normal) C3 and normal C4

Question 21

MPGN

Diagnosis

Serologies per kidney biopsy:

Immunofluorescence with both immunoglobulin and complement deposits:

Answer 21

Blood cultures, polymerase chain reaction and serologic tests for viral (e.g., hepatitis B, C, cytomegalovirus (CMV), bacterial, occult infections, malaria, and fungal infections (per local prevalence and/or symptoms)

Question 22

MPGN

Diagnosis

Serologies per kidney biopsy:

Immunofluorescence with both immunoglobulin and complement deposits:

Answer 22

Cryoglobulins, (consider rheumatoid factor: 70% cross-reactivity with cryoglobulins)

Serum protein electrophoresis and immunofixation, serum free light chains

Screening for autoimmune disorders, particularly SLE

Question 23

MPGN

Diagnosis

Serologies per kidney biopsy:

Immunofluorescence with complement deposits alone (with or without dense deposits on EM):

Answer 23

Evaluation of alternative pathway: serum complement levels, serum membrane-attack complex levels, alternative pathway functional assay, hemolytic complement assay

Retinal scan to evaluate for ocular drusen

Question 24

MPGN

Diagnosis

Serologies per kidney biopsy:

Immunofluorescence with complement deposits alone (with or without dense deposits on EM):

Answer 24

Consider genetic analysis for mutations and allele variants of complement factors and assays for presence of autoantibodies to complement-regulating proteins, including C3 nephritic factor.

Evaluation of monoclonal gammopathy (particularly in older individuals)

Question 25

MPGN

Diagnosis

Serologies per kidney biopsy:

Immunofluorescence with complement deposits alone (with or without dense deposits on EM):

Answer 25

Immunofluorescence without immunoglobulin or complement deposits: C3, complement factor H, ADAMST13, blood smear for schistocytes, LDH, indirect bilirubin, platelet count and volume

Question 26

MPGN

Diagnosis

Serologies per kidney biopsy:

Management
Routine:

Answer 26

Use ACEI or ARB for proteinuria as safely tolerated.

Question 27

MPGN

Diagnosis

Specific therapy:

Answer 27

Idiopathic MPGN: all MPGN patients must be evaluated for secondary causes.

Question 28

MPGN

Diagnosis

Specific therapy:

Answer 28

KDIQO suggests that patients with presumed idiopathic MPGN accompanied by nephrotic syndrome and decline in kidney function may be treated with either PO CYC or MMF and alternating or daily steroids, with initial therapy limited to 6 months.

Question 29

MPGN

Diagnosis

Specific therapy:

Secondary MPGN: Treat underlying disease (i.e., infections, monoclonal gammopathy, autoimmune disease) if applicable.

Answer 29

Rituximab may be beneficial if monoclonal gammopathy but without overt hematologic malignancy.

Consider plasmapheresis if association with symptomatic cryoglobulinemia.

Question 30

MPGN

Diagnosis

Specific therapy:

Answer 30

Glucocorticoids as monotherapy in adults: currently undefined

Rapidly progressive disease or crescentic glomerulonephritis: Limited data but may consider CNI, high-dose pulse steroids as monotherapy or in combination with AZA, CYC, or MMF.

Question 31

MPGN

Diagnosis

Specific therapy:

MPGN due to complement dysregulation due to factor H abnormality or C3 nephritic factor autoantibody formation:

Answer 31

Glucocorticoids + cytotoxic agents

Consider plasmapheresis in severe cases.

Question 32

MPGN

Diagnosis

Specific therapy:

MPGN due to congenital mutations leading to complement dysregulation:

Answer 32

Consider therapy that inhibits membrane attack complex (MAC) formation (e.g., eculizumab), particularly if high serum levels of MAC.

Question 33

MPGN

Diagnosis

Specific therapy:

MPGN due to congenital mutations leading to complement dysregulation:

Answer 33

Eculizumab is an anti-C5 monoclonal antibody that inhibits C5 activation.

Eculizumab has been shown effective in the treatment of atypical HUS due to complement dysregulation in the alternative pathway.

Eculizumab may be effective in some patients with DDD.

Question 34

MPGN

Kidney Transplantation

Answer 34

High recurrence rates: MPGN I (15% to 50%), DDD (80% to 100%)

DDD: universal recurrence (80% to 100%)