Focal Segmental Glomerulo-Sclerosis

Dr. Amit Agrawal

Learning objectives

• Filtration barrier• Pathophysiology of FSGS• Genetics of FSGS• Management of FSGS• Recurrence of FSGS in Graft• Management of Recurrence

Glomerular Filtration Barrier

Progressive changes

(1) Foot process effacement; (2) Podocyte apoptosis/loss and exposed

glomerular basement membrane; (3) Filtration of non-specific plasma proteins;(4) Capillary expansion;(5) Misdirected filtration at points of synechiae;(6) Formation of synechiae; (7) Mesangial matrix proliferation

Causes of Focal Segmental Glomerulosclerosis

Primary (idiopathic) form:• Specific cause unknown• Mediated by circulating permeability factorsSecondary forms:Familial or genetic:Mutations in specific podocyte genes

Virus-associated:• Human immunodeficiency virus type 1• Parvovirus B19 • Simian virus 40• Cytomegalovirus• Epstein–Barr virus

Drug-induced :• Heroin• Interferon's Alfa, beta, and gamma • Lithium• Pamidronate • Sirolimus• Calcineurin-inhibitor nephrotoxicity • Anabolic steroids

Adaptive

Conditions with reduced renal mass:• Oligomeganephronia• Very low birth weight• Unilateral renal agenesis • Renal dysplasia• Reflux nephropathy• Sequela to cortical necrosis• Surgical renal ablation • Renal allograft • Aging kidney• Any advanced renal disease with reduced functioning nephrons

Conditions with initially normal renal mass

• Systemic hypertension,• Acute or chronic vaso-occlusive processes (atheroembolization, thrombotic

microangiopathy, renal-artery stenosis)• Elevated body-mass index (obesity)• Increased lean body mass [bodybuilding]• Cyanotic congenital heart disease • Sickle cell anaemia

Treatment

Recurrence of FSGS after renal transplantation

• Primary type FSGS recurs in about 30% of grafts after transplantation. The time of diagnosis averages about two wk

after surgery in children and 7.5 months in adults

Risk factors for recurrence of FSGS

• Childhood onset (onset under the age of 6yr is associated with a recurrence rate of 50–80%)

• Age <15 yr, rapid progression (within three yr) from diagnosis to ESRD

• Diffuse mesangial hypercellularity in the native kidney

• Recurrence of FSGS in a previous allograft• Collapsing FSGS

• Two clinical presentations of FSGS after transplantationEarly recurrenceLate recurrence

Pathogenesis

• Podocyte injury could be caused by circulating factor secreted by an abnormal clone of T cells

• The permeability factor may induce redistribution and loss of nephrin as well as reduced expression of podocin

Histo-Pathology• Podocyte foot process effacement is considered the

pathognomonic feature of the early stage of recurrence of FSGS

• Podocyte detachment from the GBM and loss of podocytes

• Podocytes hyperplasia- pathological factor in disease progression• Transdifferentiation, • Dysregulation,• Epithelial mesenchymal transformation develop in

hyperplastic epithelial cells in FSGS

Treatment

• Plasma exchanges only• High-dose oral or intravenous cyclosporine A• Plasma exchange plus cyclophosphamide• Plasma exchange plus CyA• Plasma exchange plus CyA plus cyclophosphamide

Plasma exchange

• Replacement of 1.5 plasma volumes (50–60 ml/kg) by 5% albumin.

• Least three plasma exchanges per week and a progressive tapering down plus

• 10–14 days of IV CyA (trough level 200–400 ng/ml) followed by

• oral CyA with C2 levels of 1200–1400 ng/ml

• Very intensified plasma exchange (daily for 10 days followed by 3 per week over 2 weeks)

• Together with oral CyA (C2 1600– 2000 ng/ml)

Plasma exchange and cyclophosphamide

• Plasma exchanges, which was performed 6 –10 times over 15–24 days, plus oral cyclophosphamide

• Plasmapheresis performed 10 times over 2 weeks followed by one session per week for 2 months, combined with cyclophosphamide

Rituximab• Weekly infusions of 375 mg/ m2of rituximab

for 2 – 4 weeks.Adalimumabdirected against tumor necrosis factor α (TNF- α)RosiglitazonePeroxisome proliferator-activated receptor-γ

agonist

• Galactose: Block the binding site or change the

configuration of the free soluble factor, preventing it from binding to the podocytes

• Podocyte stem cells therapy