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Thrombotic microangiopathy in HCV

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					    Thrombotic microangiopathy
       in HCV (+) renal allograft
                            recipient

Agnieszka Perkowska-Ptasinska
Transplantation Institute, Warsaw Medical University, Poland
       HCV (+) male renal allograft recipient

• native kidneys’ function loss due to
  nephroangiosclerosis at the age of 50,
• KTX at the age of 55,
• donor: cadaveric, female, age 45,
        cause of death: multiple injuries due to a car
        accident,
• post-TX     basic immunosuppression:
                  Pred + MMF + tac
• immediate graft function after KTX
               4 weeks after KTX

• serum creatinine concentration elevation,
• platelet count, LDL, and haptoglobin levels:
  within normal limits


           → kidney transplant biopsy:
     - an acute vascular rejection (Banff IIA)
     - mild thrombotic microangiopathy
     - no C4d deposition.
 First graft biopsy
(4 weeks after Tx)
The 1st graft biopsy
 (4 weeks after Tx)
                  Further course

• good response to antirejection treatment
  (steroid pulse therapy) with the decrease in
  the serum creatinine concentration to the
  pre-rejection value of 1,0 mg/dl,
• due to the biopsy findings: a change in the
  IS regimen: ↓tac
                MMF exposure
             A year after Tx

• proteinuria of 2,0 g/day,

• a rise in serum creatinine
 concentration to 1,3 mg/dl.
                    A year after Tx
• Clinically: signs of intravascular coagulation (mildly
  decreased platelet count, slightly elevated LDL and
  decreased haptoglobin levels),
• no anti-HLA antibodies against class I and class II
  antigens in the serum,
• further serological testing: anticardiolipin antibodies
  in IgG class,
• HCV-PCR: high number of viral copies in patient’s
  blood, but the liver function tests normal.
                                 →      2nd graft biopsy
                      The 2nd biopsy
                     (a year after Tx)
• LM:
  - acute lesions: thrombi in some of the glomerular capillaries
  and arterioles,
  - chronic lesions: double contouring of some of glomerular
  capillaries, IFTA I, moderate arteriolar hyalinisation, arterial
  intimal sclerotisation with mild reduction in vascular lumen,
  - no C4d deposition in PTCs,
• the immunofluorescence: negative for Ig and complement
  components.
• EM: electron-lucent expansion of the subendothelial zone
  with the deposition of basement membrane/lamina densa-like
  material.
The 2nd graft biopsy
  (a year after Tx)
The 2nd graft biopsy
(a year after Tx)
          FINAL
        DIAGNOSIS

Chronic active thrombotic

microangiopathy, most probably due to

HCV-related presence of anticardiolipin

antibodies
                Further course
• treatment: intravenous immunoglobulins and
  plasmapheresis,
• response:
  - decrease in the anticardiolipin antibodies level
  - stabilization of renal function, and the level of
  proteinuria,
• liver biopsy: mild chronic hepatitis with portal to
  portal (Ishak’s stage 3 ) fibrosis


The patient is currently receiving antiviral therapy.
               Thrombotic microangiopathy
               after kidney transplantation

• relatively common lesion (affects about 20% of
  kidney grafts recipients), may occur any time
  after TX, although the risk seems to be higher
  in the first 6 months after Tx,

• may be clinically silent or overt, limited to the
  graft or widespread
              Thrombotic microangiopathy
              after kidney transplantation

Prognosis:
• depends on the etiopathogenesis of this process,
• is better in TMA localized to the graft,
• is better in cases limited to glomeruli
• depends on the intensity of lesions (both acute
  and chronic): TMA may affect single arterioles
  and/or glomeruli, it may be also widespread and
  complicated by the focal infarcts of kidney
  tissue,
              Thrombotic microangiopathy
              after kidney transplantation
Morphology of acute TMA:
• edematous widening of the subendothelium in
  capillaries and arterioles,
• mucoid thickening of the arterial intima,
• the presence of fibrin and/or platelet
  thrombi within the wall or in the vascular
  lumen,
• red cell fragmentation and entrapment within
  edematous vascular walls,
• focal fibrinoid necrosis of the vascular wall
  (capillaries, arterioles, arteries),
• in glomeruli: thrombi, mesangiolysis, collapse
  and wrinkling of GBM (acute ischemia)
                Thrombotic microangiopathy
                after kidney transplantation
Morphology of chronic TMA:
• glomeruli
  – double contours of capillary walls,
  - chronic ischemia of the tuft,
  - secondary FSGS without immunological complexes in IF,
  - in EM: thickening and reduplication of the glomerular
  capillary basement membrane with cellular interposition,
• arteries
  – sclerotisation of the intima, in the early phase without
  the multiplication of the elastica,
• arterioles
  – sclerotisation of the subendothelial region,
  - hyalinisation.
                Thrombotic microangiopathy
                after kidney transplantation

Pathogenesis:
             Two broad categories:
• the recurrence of TMA after Tx,
• TMA that evolves de novo after Tx.

The differentiation between the recurrent vs de novo TMA
  is not possible on morphological grounds.
                 Thrombotic microangiopathy
                 after kidney transplantation


Recurrent TMA
• usually within the first year (sometimes first
  days) after Tx,
• in majority of cases the recurrence of TMA leads
  to the graft loss (70%)
  (3-years graft survival ± 50%)
                    TMA recurrence after Tx –
                          risk factors
Types of common recurrences:
• the deficiency of factors I, B, H,
  ADAMTS13 (vWF cleaving protease),

• the presence of Ab against complement components,
• antiphospholipid syndrome,
• idiopathic HUS,
• TMA in scleroderma,
Very rare recurrences:
• familial TMA caused by the deficiency of MCP and
  thrombomodulin (both are transmembrane proteins),
• HUS associated with E.coli or S.dysenteriae infection
                    TMA recurrence after Tx –
                          risk factors

The risk of TMA recurrence:
• rises with older age of the disease presentation in native
  kidneys,
• is higher in cases characterized by more dynamic evolution
  of TMA-dependant ESKD in native kidneys,
• is higher in living-related donation,
• is higher in patients treated with CNI
                  TMA evolving de novo after KTX
                           – risk factors
• ischemia-reperfusion injury:
  - stimulates endothelial apoptosis, and the release of prothrombotic
  substances,
• CNI toxicity, mTOR inhibitors toxicity:
  - direct injury to the endothelium,
  - suppression of antithrombotic factor C activity,
  - increased tissue thromboplastin and vWF multimers production,
• OKT3 toxicity (currently very rare complication):
  - production of procoagulants by stimulated by OKT3 inflammatory
  cells,
• acute graft rejection, especially ABMR:
  - T-cell, DSA toxicity to the endothelium,
• viral infections:
  - direct injurious effect of the influenza virus A, CMV, HCV, HHV6,
  parvovirus),
  - indirect effect of CMV, HIV, HBV and HCV through the stimulation
  of anticardiolipin Ab production
                         Conclusions

• TMA is a relatively common complication after KTX,
• it may have diverse clinical manifestation, it may be
  clinically silent,
• it may be a recurrent phenomenon, or it may evolve
  de novo after Tx,
• it’s pathogenesis is complex, and rarely definable
  solely upon the morphology of kidney graft biopsy,
• the differentiation of TMA etiology requires
  additional diagnostic tools including serological
  (DSA, antiphospholipid antibodies, complement
  components) and virological testing

				
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