Thrombotic microangiopathy in HCV (+) renal allograft recipient

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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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