Membranous Nephropathy

Question 1

Membranous Nephropathy

Epidemiology

Answer 1

Less than 5% in children and 15% to 50% in adults with nephrotic syndrome

Male-to-female ratio is 2:1

Question 2

Membranous Nephropathy

Epidemiology

Answer 2

US Renal Data System: 0.5% of end-stage kidney disease population

HLA-associated inherited risks reported

Familial forms reported but rare

Question 3

Membranous Nephropathy

Histopathology

Answer 3

LM:

Variably thick capillary walls; no hypercellularity or inflammatory changes.

Question 4

Membranous Nephropathy

Histopathology/LM

Answer 4

Methenamine (Jones) silver staining: projections of GBM between deposits giving a characteristic spike like pattern (stage 2). Resorption of subepithelial and intramembranous immune deposits leads GBM thickening with lucencies or double contours (stages 3 to 4)

Question 5

Membranous Nephropathy

Histopathology/LM

Answer 5

Glomerular leukocyte infiltration may occur in association with malignancy; polymorphonuclear leukocytes (PMN) infiltrates with renal vein thrombosis.

Question 6

Membranous Nephropathy

Histopathology/LM

Answer 6

Concurrent FSGS is present in up to 30% and may portend worse prognosis, example, rapid progression and poor response to therapy.

Question 7

Membranous Nephropathy

Histopathology/LM

Answer 7

Tubulointerstitial injury and fibrosis are common; may indicate advanced disease.

Question 8

Membranous Nephropathy

Histopathology/EM

Answer 8

EM:

Diffuse subepithelial granular electron dense deposits that parallel IgG staining

Question 9

Membranous Nephropathy

Histopathology/EM

Answer 9

In idiopathic MGN, deposits are not seen in mesangial or subendothelial sites, whereas in secondary MGN, there may be mesangial hypercellularity and deposits in mesangial ± endothelial sites.

Foot process effacement

Question 10

Membranous Nephropathy

Histopathology/IF

Answer 10

IF: IgG and complement components deposits

Generally, staining for IgG4 dominates in idiopathic MGN (iMGN), whereas IgG1, 2, and/or 3 dominate in secondary MGN.

Question 11

Membranous Nephropathy

Histopathology/IF

Answer 11

C3 is present in ~50% of patients and likely reflects active, ongoing immune deposit formation and complement activation. C1 and C4 are usually absent, indicating involvement of alternative pathway in association with podocyte injury. Minimal C3 staining suggests inactive or very early disease.

Question 12

Membranous Nephropathy

Histopathology/IF

Answer 12

Strong capillary staining for C1q, C3, IgG, IgM, and IgA, a.k.a. “full house,” is associated with membranous lupus.

Question 13

Membranous Nephropathy

Pathogenesis

Answer 13

Antibody–antigen (Ab–Ag) formation at podocytes leads to complement activation, formation of C5b-9.

Question 14

Membranous Nephropathy

Pathogenesis

Answer 14

Ab–Ag complexes are capped and shed to form subepithelial deposits. C5b-9 complexes (a.k.a. MACs) are incorporated into multivesicular bodies and transported by podocyte into urinary space.

Question 15

Membranous Nephropathy

Pathogenesis

Answer 15

Increased intracellular sublytic levels of C5b-9 activate podocytes, leading to release of oxidants and proteases that would lead to injury of underlying GBM.

Question 16

Membranous Nephropathy

Pathogenesis/Antigens associated with “idiopathic” MGN (iMGN):

Answer 16

What are the responsible antigens that lead to the development of MGN?

Phospholipase A2 receptor 1 antigen expressed on podocyte surface: antibodies made against PLA2R1 are anti-PLA2R1 antibody, IgG4 subtype (80% of iMGN).

Anti-PLA2R1 correlates with disease activity

Anti-PLA2R1 predicts outcome: lower titer is associated with better rate of spontaneous remissions and time to remission in those requiring therapy.

Question 17

Membranous Nephropathy

Pathogenesis/Antigens associated with “idiopathic” MGN (iMGN):

Answer 17

Thrombospondin type-1 domain-containing 7A antigen (THSD7A) (10% of iMGN)

Question 18

Membranous Nephropathy

Pathogenesis

Answer 18

iMGN is a diagnosis of exclusion. Secondary evaluation must still be performed even when biopsy findings suggest iMGN. iMGN is more common in adults, but secondary MGN is more common in children (e.g., in association with hepatitis B).

Question 19

Membranous Nephropathy

Pathogenesis/Antigens associated with secondary MGN:

Answer 19

Autoimmune (dysregulated autoantibody formation against self-antigen): SLE, diabetes, rheumatoid arthritis, mixed connective tissue disease, dermatomyositis, ankylosing spondylitis, Crohn disease, graft versus host disease, temporal arteritis, Sjögren’s, bullous pemphigoid, autoimmune thyroid disease.

Question 20

Membranous Nephropathy

Pathogenesis/Antigens associated with secondary MGN:

Answer 20

Infectious antigens (think of chronic active infections): hepatitis B (presence of HBsAg, HBcAg and usually HBeAg)&raquo_space; C, syphilis, tuberculosis, HIV, enterococcal endocarditis, leprosy, filariasis, malaria, schistosomiasis, hydatid disease.

Question 21

Membranous Nephropathy

Pathogenesis/Antigens associated with secondary MGN:

Answer 21

Drugs/toxins: captopril, gold penicillamine, nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, hydrocarbons, mercury, formaldehyde, lithium, clopidogrel.

Question 22

Membranous Nephropathy

Pathogenesis/Antigens associated with secondary MGN:

Answer 22

Malignancies (tumor antigen): solid organs (lungs, GI, breast, kidney, etc.).

Question 23

Membranous Nephropathy

Pathogenesis/Antigens associated with secondary MGN:

Answer 23

Neutral endopeptidase (NEP—antigen expressed on podocytes)—Mothers without NEP may make antibodies (Abs) against fetal NEP and transfer the Abs to the fetus. These infants are born with nephrotic syndrome..

Question 24

Membranous Nephropathy

Clinical Manifestations

Answer 24

Gradual onset (as opposed to acute onset in MCD and often FSGS tip variant)

Question 25

Membranous Nephropathy Clinical Manifestations

Answer 25

Nephrotic syndrome common (60% to 80%), benign urinary sediment Microscopic hematuria (25% to 50%)

Question 26

Membranous Nephropathy Clinical Manifestations

Answer 26

Complements are typically normal, but can be low in ~50% of HBV-associated MGN

Question 27

Membranous Nephropathy Clinical Manifestations

Answer 27

Increased risk for thromboembolic disease (e.g., deep vein thrombosis, renal vein thrombosis, pulmonary embolism) (40%)

Question 28

Membranous Nephropathy Clinical Manifestations

Answer 28

Blood pressures normal to mildly elevated Dyslipidemia, increased cardiovascular risk

Question 29

Membranous Nephropathy Clinical Manifestations

Answer 29

Up to five times increased incidence of associated malignancy especially in those > 65 years old

Question 30

Membranous Nephropathy Clinical Manifestations

Answer 30

Resolution may occur within 1 week (NSAIDS) to years (gold, penicillamine), following withdrawal of responsible drugs.

Question 31

Membranous Nephropathy Clinical Manifestations

Answer 31

Natural history of iMGN: one-third rule: one-third achieves spontaneous remission, 1/3 remains the same, one-third slowly progresses to renal failure.

Question 32

Membranous Nephropathy Clinical Manifestations

Answer 32

Risks for worse renal outcome: older age, male gender, hypertension, severe hypoalbuminemia, reduced GFR, severe proteinuria (e.g., >8 g/d lasting >6 m), increased urinary IgG, β2-microglobulin, or C5b-9 excretion, biopsy with marked tubulointerstitial disease, glomerular focal sclerosis, or extensive GBM damage (overly thickened membrane, presence of lucencies due to resorbed immunoglobulin complexes).

Question 33

Membranous Nephropathy Clinical Manifestations Risk stratification for iMGN disease progression (see Management section for immunosuppressive options):

Answer 33

Low risk (<5% chance of progression): Normal kidney function and proteinuria < 4 g/d Conservative management: if disease deteriorates, initiate immunosuppressive therapy

Question 34

Membranous Nephropathy Clinical Manifestations Risk stratification for iMGN disease progression (see Management section for immunosuppressive options):

Answer 34

Medium risk: Normal kidney function and persistent proteinuria ≥ 4 and <8 g/d Conservative management for 6 m: if no improvement or deterioration of disease, initiate immunosuppressive therapy.

Question 35

Membranous Nephropathy Clinical Manifestations Risk stratification for iMGN disease progression (see Management section for immunosuppressive options):

Answer 35

High risk: Abnormal kidney function and/or persistent proteinuria > 8 g/d Conservative management ≤ 6 m, if no improvement, initiate immunosuppressive therapy

Question 36

Membranous Nephropathy Management Conservative management for all patients regardless of risks of progression:

Answer 36

ACEI or ARB as tolerated Statin (if LDL > 100 mg/dL) BP control < 130/80 mm Hg, consider ≤125/75 mm Hg if presenting proteinuria > 1 g/d

Question 37

Membranous Nephropathy Management Conservative management for all patients regardless of risks of progression:

Answer 37

Evaluate for secondary causes particularly malignancy for older patients > 60 years old (i.e., chest CT, kidney ultrasound, urine cytology, mammography, upper endoscopy, colonoscopy, prostate ultrasound and biopsy, colposcopy as clinically appropriate and indicated)

Question 38

Membranous Nephropathy Management Conservative management for all patients regardless of risks of progression:

Answer 38

Prophylactic anticoagulation therapy with oral warfarin (with heparin bridging) may be considered for iMGN patients with nephrotic syndrome, serum albumin < 2.0 to 2.5 g/dL and ≥1 of the following: proteinuria > 10 g/d, body mass index > 35 kg/m2, prior history of thromboembolism, family history of thromboembolism with documented genetic predisposition, NYHA class III or IV congestive heart failure, recent abdominal or orthopedic surgery, or prolonged immobilization. It is reasonable to maintain anticoagulation over duration of nephrotic syndrome when serum albumin < 3.0 g/dL.

Question 39

Membranous Nephropathy Management Immunosuppressive therapy for iMGN should be considered in patients with nephrotic syndrome and at least one of the following:

Answer 39

Urinary protein excretion persistently exceeds 4 g/d and remains >50% of baseline value during an observation period of at least 6 m.

Question 40

Membranous Nephropathy Management Immunosuppressive therapy for iMGN should be considered in patients with nephrotic syndrome and at least one of the following:

Answer 40

Presence of severe, disabling, or life-threatening symptoms related to nephrotic syndrome

Question 41

Membranous Nephropathy Management Immunosuppressive therapy for iMGN should be considered in patients with nephrotic syndrome and at least one of the following:

Answer 41

SCr increases by ≥30% within 6 to 12 m from time of diagnosis, but baseline eGFR still ≥30 mL/min/1.73 m2.

Question 42

Membranous Nephropathy Management Immunosuppressive therapy for iMGN should be considered in patients with nephrotic syndrome and at least one of the following:

Answer 42

Do not use immunosuppressive therapy if SCr is persistently >3.5 mg/dL or eGFR < 30 mL/min/1.73 m2 and reduction of kidney size on ultrasound or concomitant severe or potentially life-threatening infections.

Question 43

Membranous Nephropathy Management

Answer 43

Other considerations: A conservative management trial may be justified in patients with proteinuria < 4 g/d, improved proteinuria with conservative management, and preserved kidney function.

Question 44

Membranous Nephropathy Management

Answer 44

Initiation of immunosuppressive therapy is indicated for patients with declining kidney function, disabling symptoms, or “full-blown” nephrotic syndrome persisting for ≥6 m.

Question 45

Membranous Nephropathy Management

Answer 45

Risks versus benefits for those with advanced disease do not justify the use of immunosuppressive therapy (e.g., advanced interstitial fibrosis and tubular atrophy at biopsy, SCr > 3.5 mg/dL, or evidence of shrunken kidneys).

Question 46

Membranous Nephropathy Management Immunosuppressive Therapy Options for iMGN

Answer 46

Months 1, 3, 5: methylprednisolone 1 g/d × 3 days, followed by oral methylprednisolone 0.5 mg/kg/d × 27 days

Question 47

Membranous Nephropathy Management Immunosuppressive Therapy Options for iMGN

Answer 47

Months 2, 4, 6: oral chlorambucil (0.15 to 0.2 mg/kg/d) or PO CYC (2.0 mg/kg/d) × 30 days

Question 48

Membranous Nephropathy Management Immunosuppressive Therapy Options for iMGN

Answer 48

CYC is recommended over chlorambucil due to better safety profile.

Question 49

Membranous Nephropathy Management Immunosuppressive Therapy Options for iMGN

Answer 49

Monitor SCr, urinary protein excretion, serum albumin, and white blood cell (WBC) count every 2 weeks × 2 months, then every month × 6 months.

Question 50

Membranous Nephropathy Management Immunosuppressive Therapy Options for iMGN

Answer 50

Hold chlorambucil or CYC if WBC count < 3,500/mm3 until recovery to >4,000/mm3. Opinion: Restart at ~25% reduced dose.

Question 51

Membranous Nephropathy Management ``` Definitions of Complete and Partial Remission of iMGN Complete remission (CR): ```

Answer 51

Urinary protein excretion < 0.3 g/d (or urine protein to creatinine ratio (uPCR) < 0.3 g/g creatinine), confirmed by two values at least 1 week apart, accompanied by a normal serum albumin concentration and normal SCr.

Question 52

Membranous Nephropathy Management ``` Definitions of Complete and Partial Remission of iMGN Complete remission (CR): ```

Answer 52

Partial remission (PR): Urinary protein excretion < 3.5 g/d (or uPCR < 3.5 g/g creatinine), and a ≥50% reduction from peak values; confirmed by two values at least 1 week apart, accompanied by an improvement of normalization of serum albumin concentration and stable SCr.

Question 53

Membranous Nephropathy Management REVIEW Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.

Answer 53

If you give steroids alone it is not effective and it is not recommended. If you give steroids plus and alkylating agents such as cyclophosphamide or chlorambucil, there is increased probability of complete or partial remission. It improves long-term kidney survival.

Question 54

Membranous Nephropathy Management REVIEW Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.

Answer 54

Remember that cyclophosphamide is preferred over chlorambucil due to better safety profile. Efficacy is confirmed by randomized controlled trials. Caution for leukopenia, oncogenic risk with more than 36 g cumulative doses, and gonadotoxicity.

Question 55

Membranous Nephropathy Management REVIEW Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.

Answer 55

For iMGN resistant to initial steroids plus alkylating agent therapy, switching to calcineurin inhibitor therapy, and vice versa, is recommended.

Question 56

Membranous Nephropathy Management REVIEW Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.

Answer 56

Next is calcineurin inhibitors such as the cyclosporine or tacrolimus. There is increased probability of complete or partial remission with these agents.

Question 57

Membranous Nephropathy Management REVIEW Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.

Answer 57

Monitor calcineurin levels regularly and without unexplained rise in serum creatinine. Discontinue if no partial or complete remission after six months of therapy.

Question 58

Membranous Nephropathy Management REVIEW Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.

Answer 58

Calcineurin inhibitors are contraindicated for serum creatinine greater than 2 mg/dL. Relapse is frequent after drug withdrawal. Caution for nephrotoxicity and hypertension risks.

Question 59

Membranous Nephropathy Management REVIEW Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.

Answer 59

Cyclosporine 3.5 – 5 mg per kilogram per day orally in two equally divided doses 12 hours apart plus prednisone 0.15 mg per kilogram per day time six months. Start a lower range and increase as safely tolerated.

Question 60

Membranous Nephropathy Management REVIEW Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.

Answer 60

Tacrolimus is 0.05 mg - 0.075 milligrams per kilogram per day orally in two divided doses 12 hours apart, without prednisone for 6 to 12 months start at a lower range and increase slowly as safely tolerated.

Question 61

Membranous Nephropathy Management REVIEW Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.

Answer 61

Then there is mycophenolate mofetil or MMF which may be effective if given with steroids but not when given alone. There is limited data.

Question 62

Membranous Nephropathy Management REVIEW Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.

Answer 62

In terms of MMF versus cyclosporine for membranous nephropathy there a similar complication rates. MMF may not be as effective as cyclosporine in terms of remission and relapse.

Question 63

Membranous Nephropathy Management REVIEW Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.

Answer 63

Then there is ACTH or adrenocorticotropic hormone which may be effective but again there is limited data. Still awaiting her advice control trials. And it's high-cost.

Question 64

Membranous Nephropathy Management REVIEW Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.

Answer 64

Finally there is Rituximab which may be effective as well and the optimal dose and treatment duration is unclear. No head-to-head comparison with other treatments have been done. And it's is also high cost.