A PowerPoint presentation for the pediatric residents and pediatric nephrology fellows

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Membranous Nephropathy
Ibrahim Sandokji

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Introduction
• MN is an immune complex glomerulonephritis characterized by:
– Thickened glomerular basement membrane (GBM)
– Presence of subepithelial immune deposits (IgG & sometimes C3)
– Lack of cellular proliferation or infiltration within glomeruli
• Usually present with proteinuria/nephrotic syndrome
• Leading cause of nephrotic syndrome in Caucasian adults
• Uncommon in children (mostly secondary MN)
– 1-10% of nephrotic syndrome in children
– 22% of nephrotic syndrome in children 13 to 19 years
• 0.6% of pediatric ESRD patients in the United States due to MN
Membranous Nephropathy
Primary Secondary

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MN occurs in
20% of the children
with SLE nephropathy
MBV & Malaria are common causes in endemic areas
Universal HBV vaccination & Rx of Malaria decreased rate of MN
William. CJASN (2017)
Secondary MN

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Primary MN
Podocyte
antigens
Anti-neutral endopeptidase
antibodies (NEP)
• First podocyte antigen discovered
• Neonatal MN due to placental
transfer of anti NEP IgG
M-type phospholipase A2-receptor (PLA2R) autoantibodies
• 70% of adult patients with MN
• Absent in secondary MN
• Correlates with disease activity
Circulating
antigens
Antibodies to Bovine Serum
Albumin (BSA)
• Children < 5 y
• Trypsin digestion of cow’s milk or
beef protein in the gut
Herrmann. Curr Opin Nephrol Hypertens (2012)

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Pathogenesis
Beck. J Clin Invest (2014)

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Pathology
Normal glomerulus
There are only 1 or 2 cells per capillary tuft, the capillary
lumens are open, the thickness of the glomerular capillary
wall (long arrow) is similar to that of the tubular
basement membranes (short arrow), and the mesangial
cells and mesangial matrix are located in the central or
stalk regions of the tuft (arrows).
MN
Diffuse thickening of the glomerular capillary basement
membrane by subepithelial immune complex deposition
Qiao's Pathology (2009)

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Pathology
Silver-methenamine stain showing
pathognomonic “spikes” of basement
membrane projecting from the outer
surface of the glomerular basement
membrane (arrows)
Couser CJASN (2017)
IgG
PLA2R antigen
Membrane attack complex C5b-9

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Electron Microscopy
Stage 1: Initial subepithelial electron dense-deposits Stage 2: Basement membrane enveloping electron-
dense deposits (arrow head). Characteristic spikes
Stage 3: Electron-dense deposits incorporated into the
basement membrane
Stage 4: Repair of the basement membrane and
resolution of the dense deposits, scalloped electron-
lucent appearance (arrow)
Kher et al (2016). Clinical Pediatric Nephrology, 3rd Edition

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Pathology
Kher et al (2016). Clinical Pediatric Nephrology, 3rd Edition

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Clinical Features in Children
• MN should be suspected in SRNS, especially > 10 y
• Proteinuria (nephrotic or subnephrotic range)
• Low serum albumin
• Microscopic hematuria is common
• Gross hematuria in 40%
• Hypertension is uncommon
• Renal function usually normal at onset
• Serum complement C3 and C4 are normal in the primary MN

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Pediatric vs Adult MN
Kher et al (2016). Clinical Pediatric Nephrology, 3rd Edition

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Treatment
– No clear consensus, limited data, largely based on trials in adults
– Spontaneous improvement is common (approximately 30%)
• Secondary MN -> Rx the cause
• Treatment strategies for idiopathic MN
– Corticosteroids
– Corticosteroids and alkylating agents in cyclical therapy
– Calcineurin inhibitor
– MMF
– Rituximab
– Adrenocorticotrophin hormone (ACTH)
• Supportive therapy:
– BP control , proteinuria (ACEi /ARBs), growth and development,
nutrition, & chronic kidney disease management

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KDIGO Guidelines
KDIGO Clinical Practice Guideline for Glomerulonephritis (2012)

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Summary
• MN is a relatively unusual cause of nephrotic syndrome in
children
• The majority of adult idiopathic MN is due to autoantibodies to M-
type phospholipase A2-receptor (PLA2R).
• Children may develop MN as a result of autoantibodies to Bovine
Serum Albumin (BSA) or alloantibodies to neutral endopeptidase
antibodies (NEP)
• The diagnosis of MN is suspected in children with SRNS or >10
years, and relies on the characteristic renal histologic findings
• Immunosuppressive regimens are the primary form of therapy
in MN
• Corticosteroid therapy as a monotherapy is not recommended

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Extra Slides

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Corticosteroids
• Three RCT have shown that corticosteroid monotherapy is not
superior to symptomatic therapy alone
• The Kidney Disease Improving Global Outcomes (KDOQI)
guidelines do not recommend corticosteroids as a monotherapy
Corticosteroids and alkylating agents in cyclical therapy
KDIGO Clinical Practice Guideline for Glomerulonephritis (2012)

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• RCT
• 81 adult patients with MN
– Supportive therapy alone
– Six-month course of corticosteroids alternated with
chlorambucil every other month
• Remission
– Treatment group 28/42, and 22/30 at 5 yr follow up
– Control group 9/39, and 10/25 at 5 yr follow up
Ponticelli NEJM (1989)