Thrombotic microangiopathy in HCV (+) renal allograft recipient

1. Thrombotic microangiopathy in HCV (+) renal allograft recipient Agnieszka Perkowska-Ptasinska Transplantation Institute, Warsaw Medical University, Poland

2. 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

3. 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.

4. First graft biopsy (4 weeks after Tx)

5. The 1st graft biopsy (4 weeks after Tx)

6. 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

7. A year after Tx • proteinuria of 2,0 g/day, • a rise in serum creatinine concentration to 1,3 mg/dl.

8. 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

9. 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.

10. The 2nd graft biopsy (a year after Tx)

11. The 2nd graft biopsy (a year after Tx)

12. FINAL DIAGNOSIS Chronic active thrombotic microangiopathy, most probably due to HCV-related presence of anticardiolipin antibodies

13. 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.

14. 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

15. 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,

16. 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)

17. 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.

18. 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.

19. 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%)

20. TMA recurrence after Tx – risk factors Types of commonrecurrences: • 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

21. 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

22. 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

23. 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