Focal segmental glomerulosclerosis – a histologic lesion which is due to injury to visceral epithelial cell or podocyte which is attached to the GBM via foot processes. Can also involve injury to parietal epithelial cells.

How is FSGS formed in the kidney?

  1. Podocyte injury

podocyteinjury

2. Sclerosis

pathogenesisofsclerosis

Presentation:

  1. Insidious onset of nephrotic syndrome
  2. Microscopic haematuria with varying ranges of proteinuria
  3. Hypertension
  4. Renal insufficiency

Primary/Idiopathic FSGS

  • most often presents with nephrotic syndrome
    • Causes postulated:
      • High level of suPAR (soluble urokinase plasminogen activating receptor)
        • induces FSGS in mice
      • Expression of microRNA in podocytes leading to down regulation of Wilms Tumour protein (important for a variety of genes involved in podocyte function) may be an intracellular mechanism responsible
        • found in glomeruli of patients with acquired (non genetic) FSGS

Secondary FSGS

  • normally non-nephrotic range proteinuria with some CKD
  • result from scarring due to a previous injury
    • Focal proliferative GN, e.g. active IgA, lupus nephritis, vasculitis
    • Hereditary nephritis, e.g. Alport’s
    • Membranous
    • TMA
  • refers to FSGS due to adaptive response/compensation to hyper filtration or glomerular hypertrophy
    • Disorders with reduced renal mass and/or renal vasodilation, e.g. unilateral renal agenesis, CAN
    • Renal vasodilatation e.g. in diabetes, sickle cell anaemia, Type 1 glycogen storage disorders, familial autonomic insufficiency
    • Intraglomerular hypertrophy/hyperfiltration e.g. due to severe pre eclampsia, anabolic steroid use, interferon use and obesity
    • Prior nephron loss e.g. reflux nephropathy
    • Ischaemia e.g. in benign hypertensive nephrosclerosis
  • Infections/Virus Associated
    • HIV (HIVAN)
    • Parvovirus B19
  • Toxins/drugs
    • CyA, pamidronate/alendronate, heroin, interferon-a, Lithium
  • Genetic abnormalities/Familial
    • Autosomal dominant with variable penetrance.
    • Normally steroid resistant
    •  NPHS1 – nephrin (can be tested), NPHS2 – podocin (can be tested), alpha-actinin-4, the TRPC6 ion channel, CD2AP
    • 2ndy FSGS familial forms copy
    • Microsoft Word - cqn_61_Figures
      Parts of the podocyte where genetics can cause podocytopathy
  • renal atherothromboembolic disease
  • Malignancy
    • Lymphoma

Differentiation between primary and secondary FSGS

  • Primary normally presents with acute or subacute onset of nephrotic syndrome; secondary will have non nephrotic range proteinuria, presenting with increasing proteinuria and rising Cr over a period of time
  • Histologically, primary FSGS has diffuse foot process fusion; in secondary FSGS, this tends to be focal and limited to the sclerotic areas
  • Treatment wise, 50-60% of primary FSGS respond to steroids while aim of treating secondary FSGS is to reduce intraglomerular pressure, i.e. with the use of ACEi.

Diff FSGS copy

And as if that isn’t enough, someone decided that FSGS can also be subdivided to their histologic variants.

histologicvariantsfsgs-copy

  • fsgs_4-types

Collapsing variant associated with

  • HIVAN
  • Parvovirus
  • APOL1 gene
  • Bisphosphonate therapy

APOL1 – Apolipoprotein L1 gene

  • An important gene to talk about.
  • Polymorphism in the region of MYH9 on chromosome 22
  • Common in African Americans vs European (60% vs 4%)
  • Increase risk of FSGS and HIVAN
  • Defense against a subspecies of Trypanosomes, conferring an advantage against the sleeping sickness

 

KDIGO Definition of FSGS in Adults

Classification Definition
Complete remission <0.3g/d proteinuria

Normal Cr

Albumin >35

Partial remission 0.3-3.5g/d

Cr change <25% OR

0.3-3.5g/d

Decrease > 50% Cr and change in Cr <25%

Relapse >3.5g/d after complete remission
Frequent relapse Not defined
Steroid dependent 2 relapses during therapy OR

within 2 weeks of completing steroid therapy

Steroid resistant Persistence of proteinuria despite pred 1mg/kg/d or 2mg/kg/d alt day for >4months

Initial treatment

Only FSGS with nephrotic syndrome – steroids/IS therapy

1st line therapy : Steroids to be given at 1mg/kg/d (max 80mg) or 2mg/kg/d alt days (max 120mg)

Treatment continuation for steroids

  • Min 4 weeks to max 16 weeks, as tolerated
    • Until remission has been achieved or 16 weeks, whichever is earlier
  • Tapered over 6 months when remission achieved
  • If steroids CI e.g. diabetes/osteoporosis/psychiatric condition
    • 1st line therapy : CNIs

Relapse

  • 1st line : oral cyclophosphamide 2-2.5mg/kg/d for 8 weeks
  • 2nd line: relapse despite cyclo/wish to protect fertiliity : CNI; Fk 0.05-0.1mg/kg/d or CyA 3-5mg/kg/d in divided doses
  • 3rd line : if not tolerant of steroids/cyclo/CNIs : MMF 500-1g BD for 1-2 years

Steroid resistant FSGS

  • CyA 3-5mg/kg/d in divided doses for 4-6 months
    • if partial/complete remission, continue with slow taper for at least 12 months
  • If CyA NOT tolerated
    • MMF and high dose dexamethasone
Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

w

Connecting to %s