Cryoglubulins & The Kidney

In short – CG

CGs are immunoglobulins and complement components that precipitate upon refrigeration of plasma.

Brouet’s Classification of CG

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Pathogenesis

Everyone in general has a low level of CG; this reflects ongoing background clearance of endogenous immune complexes with RF activity. Abnormally raised levels of  CG would mean:

  1. Chronic immune stimulation or lymphoproliferative disease leading to higher concentrations of mono, oligo or polyclonal CGs.
  2. Immune complex formation between the CGs and their target antigens
  3. Insufficient or defective clearing of CGs

Mixed CGs

  • Deposition of Ab-Ag complexes in capillaries and small arterioles along the vessel wall with cryoproteins within the vessel lumen
  • Skin biopsy shows a leukocytoclastic vasculitis
  • C4 is normally low (but not always) reflecting complement consumption via the classical pathway of the complement cascade

CGs and the Kidney

  • >80% show MPGN with thickening of the GBM and cellular proliferation and +++macrophages
  • Light microscopy : capillary microthrombi
  • Immunofluoroscence : Diffuse IgM deposition in the capillary loops
  • EM : Subendothelial deposits in the mesangium with characteristics ‘finger print’ appearance. CGs are too big to pass through the GBM hence uncommon to appear in the sub epithelial space
  • Presentation can be:
    • Haematuria +/- renal insufficiency
    • Nephrotic syndrome
    • Acute nephritis
    • AKI

 

Treatment

Source : The Lancet, 2012

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FSGS

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
    • e.g. active IgA, lupus nephritis, vasculitis
  • 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
    • Renal vasodilatation e.g. in diabetes, sickle cell anaemia, Type 1 glycogen storage disorders, familial autonomic insufficiency
    • Intraglomerular hypertension 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
    • HIV
  • Toxins
    • CyA, pamidronate, heroin, interferon
  • Genetic abnormalities
    • Autosomal dominant with variable penetrance.
    • Normally steroid resistant
    •  NPHS1 (can be tested), NPHS2 (can be tested), alpha-actinin-4, the TRPC6 ion channel, CD2AP
  • renal atherothromboembolic disease

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.

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

histologicvariantsfsgs-copy

  • fsgs_4-types

 

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