Membranous Nephropathy Flashcards
Membranous Nephropathy
Epidemiology
Less than 5% in children and 15% to 50% in adults with nephrotic syndrome
Male-to-female ratio is 2:1
Membranous Nephropathy
Epidemiology
US Renal Data System: 0.5% of end-stage kidney disease population
HLA-associated inherited risks reported
Familial forms reported but rare
Membranous Nephropathy
Histopathology
LM:
Variably thick capillary walls; no hypercellularity or inflammatory changes.
Membranous Nephropathy
Histopathology/LM
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)
Membranous Nephropathy
Histopathology/LM
Glomerular leukocyte infiltration may occur in association with malignancy; polymorphonuclear leukocytes (PMN) infiltrates with renal vein thrombosis.
Membranous Nephropathy
Histopathology/LM
Concurrent FSGS is present in up to 30% and may portend worse prognosis, example, rapid progression and poor response to therapy.
Membranous Nephropathy
Histopathology/LM
Tubulointerstitial injury and fibrosis are common; may indicate advanced disease.
Membranous Nephropathy
Histopathology/EM
EM:
Diffuse subepithelial granular electron dense deposits that parallel IgG staining
Membranous Nephropathy
Histopathology/EM
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
Membranous Nephropathy
Histopathology/IF
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.
Membranous Nephropathy
Histopathology/IF
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.
Membranous Nephropathy
Histopathology/IF
Strong capillary staining for C1q, C3, IgG, IgM, and IgA, a.k.a. “full house,” is associated with membranous lupus.
Membranous Nephropathy
Pathogenesis
Antibody–antigen (Ab–Ag) formation at podocytes leads to complement activation, formation of C5b-9.
Membranous Nephropathy
Pathogenesis
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.
Membranous Nephropathy
Pathogenesis
Increased intracellular sublytic levels of C5b-9 activate podocytes, leading to release of oxidants and proteases that would lead to injury of underlying GBM.
Membranous Nephropathy
Pathogenesis/Antigens associated with “idiopathic” MGN (iMGN):
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.
Membranous Nephropathy
Pathogenesis/Antigens associated with “idiopathic” MGN (iMGN):
Thrombospondin type-1 domain-containing 7A antigen (THSD7A) (10% of iMGN)
Membranous Nephropathy
Pathogenesis
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).
Membranous Nephropathy
Pathogenesis/Antigens associated with secondary MGN:
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.
Membranous Nephropathy
Pathogenesis/Antigens associated with secondary MGN:
Infectious antigens (think of chronic active infections): hepatitis B (presence of HBsAg, HBcAg and usually HBeAg)»_space; C, syphilis, tuberculosis, HIV, enterococcal endocarditis, leprosy, filariasis, malaria, schistosomiasis, hydatid disease.
Membranous Nephropathy
Pathogenesis/Antigens associated with secondary MGN:
Drugs/toxins: captopril, gold penicillamine, nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, hydrocarbons, mercury, formaldehyde, lithium, clopidogrel.
Membranous Nephropathy
Pathogenesis/Antigens associated with secondary MGN:
Malignancies (tumor antigen): solid organs (lungs, GI, breast, kidney, etc.).
Membranous Nephropathy
Pathogenesis/Antigens associated with secondary MGN:
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..
Membranous Nephropathy
Clinical Manifestations
Gradual onset (as opposed to acute onset in MCD and often FSGS tip variant)
Membranous Nephropathy
Clinical Manifestations
Nephrotic syndrome common (60% to 80%), benign urinary sediment
Microscopic hematuria (25% to 50%)
Membranous Nephropathy
Clinical Manifestations
Complements are typically normal, but can be low in ~50% of HBV-associated MGN
Membranous Nephropathy
Clinical Manifestations
Increased risk for thromboembolic disease (e.g., deep vein thrombosis, renal vein thrombosis, pulmonary embolism) (40%)
Membranous Nephropathy
Clinical Manifestations
Blood pressures normal to mildly elevated
Dyslipidemia, increased cardiovascular risk
Membranous Nephropathy
Clinical Manifestations
Up to five times increased incidence of associated malignancy especially in those > 65 years old
Membranous Nephropathy
Clinical Manifestations
Resolution may occur within 1 week (NSAIDS) to years (gold, penicillamine), following withdrawal of responsible drugs.
Membranous Nephropathy
Clinical Manifestations
Natural history of iMGN: one-third rule: one-third achieves spontaneous remission, 1/3 remains the same, one-third slowly progresses to renal failure.
Membranous Nephropathy
Clinical Manifestations
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).
Membranous Nephropathy
Clinical Manifestations
Risk stratification for iMGN disease progression (see Management section for immunosuppressive options):
Low risk (<5% chance of progression):
Normal kidney function and proteinuria < 4 g/d
Conservative management: if disease deteriorates, initiate immunosuppressive therapy
Membranous Nephropathy
Clinical Manifestations
Risk stratification for iMGN disease progression (see Management section for immunosuppressive options):
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.
Membranous Nephropathy
Clinical Manifestations
Risk stratification for iMGN disease progression (see Management section for immunosuppressive options):
High risk:
Abnormal kidney function and/or persistent proteinuria > 8 g/d
Conservative management ≤ 6 m, if no improvement, initiate immunosuppressive therapy
Membranous Nephropathy
Management
Conservative management for all patients regardless of risks of progression:
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
Membranous Nephropathy
Management
Conservative management for all patients regardless of risks of progression:
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)
Membranous Nephropathy
Management
Conservative management for all patients regardless of risks of progression:
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.
Membranous Nephropathy
Management
Immunosuppressive therapy for iMGN should be considered in patients with nephrotic syndrome and at least one of the following:
Urinary protein excretion persistently exceeds 4 g/d and remains >50% of baseline value during an observation period of at least 6 m.
Membranous Nephropathy
Management
Immunosuppressive therapy for iMGN should be considered in patients with nephrotic syndrome and at least one of the following:
Presence of severe, disabling, or life-threatening symptoms related to nephrotic syndrome
Membranous Nephropathy
Management
Immunosuppressive therapy for iMGN should be considered in patients with nephrotic syndrome and at least one of the following:
SCr increases by ≥30% within 6 to 12 m from time of diagnosis, but baseline eGFR still ≥30 mL/min/1.73 m2.
Membranous Nephropathy
Management
Immunosuppressive therapy for iMGN should be considered in patients with nephrotic syndrome and at least one of the following:
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.
Membranous Nephropathy
Management
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.
Membranous Nephropathy
Management
Initiation of immunosuppressive therapy is indicated for patients with declining kidney function, disabling symptoms, or “full-blown” nephrotic syndrome persisting for ≥6 m.
Membranous Nephropathy
Management
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).
Membranous Nephropathy
Management
Immunosuppressive Therapy Options for iMGN
Months 1, 3, 5: methylprednisolone 1 g/d × 3 days, followed by oral methylprednisolone 0.5 mg/kg/d × 27 days
Membranous Nephropathy
Management
Immunosuppressive Therapy Options for iMGN
Months 2, 4, 6: oral chlorambucil (0.15 to 0.2 mg/kg/d) or PO CYC (2.0 mg/kg/d) × 30 days
Membranous Nephropathy
Management
Immunosuppressive Therapy Options for iMGN
CYC is recommended over chlorambucil due to better safety profile.
Membranous Nephropathy
Management
Immunosuppressive Therapy Options for iMGN
Monitor SCr, urinary protein excretion, serum albumin, and white blood cell (WBC) count every 2 weeks × 2 months, then every month × 6 months.
Membranous Nephropathy
Management
Immunosuppressive Therapy Options for iMGN
Hold chlorambucil or CYC if WBC count < 3,500/mm3 until recovery to >4,000/mm3. Opinion: Restart at ~25% reduced dose.
Membranous Nephropathy
Management
Definitions of Complete and Partial Remission of iMGN Complete remission (CR):
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.
Membranous Nephropathy
Management
Definitions of Complete and Partial Remission of iMGN Complete remission (CR):
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.
Membranous Nephropathy
Management REVIEW
Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.
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.
Membranous Nephropathy
Management REVIEW
Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.
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.
Membranous Nephropathy
Management REVIEW
Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.
For iMGN resistant to initial steroids plus alkylating agent therapy, switching to calcineurin inhibitor therapy, and vice versa, is recommended.
Membranous Nephropathy
Management REVIEW
Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.
Next is calcineurin inhibitors such as the cyclosporine or tacrolimus. There is increased probability of complete or partial remission with these agents.
Membranous Nephropathy
Management REVIEW
Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.
Monitor calcineurin levels regularly and without unexplained rise in serum creatinine. Discontinue if no partial or complete remission after six months of therapy.
Membranous Nephropathy
Management REVIEW
Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.
Calcineurin inhibitors are contraindicated for serum creatinine greater than 2 mg/dL. Relapse is frequent after drug withdrawal. Caution for nephrotoxicity and hypertension risks.
Membranous Nephropathy
Management REVIEW
Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.
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.
Membranous Nephropathy
Management REVIEW
Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.
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.
Membranous Nephropathy
Management REVIEW
Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.
Then there is mycophenolate mofetil or MMF which may be effective if given with steroids but not when given alone. There is limited data.
Membranous Nephropathy
Management REVIEW
Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.
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.
Membranous Nephropathy
Management REVIEW
Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.
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.
Membranous Nephropathy
Management REVIEW
Here we will talk about the therapeutic options for idiopathic membranous glomerulonephropathy.
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.
