2. Thrombotic microangiopathy
• lesion of arteriolar and capillary vessel wall thickening with intraluminal
platelet thrombosis and partial or complete obstruction of the vessel lumina
4. Classification of post-transplant TMA.
. Recurrent TMA after transplantation
• Atypical hemolytic uremic syndrome
• Thrombotic thrombocytopenic purpura
• Autoimmune disorders and glomerulonephritis
with previously documented
• TMA in native kidneys
-. scleroderma
-systemic lupus erythematosus, (+/-APLA)
De novo TMA after transplantation• .
• Immunosuppressive medication –CNI or mTOR
or combination of the two
• AMR associated
• Genetic- complement regulatory gene
abnormalities
• Medication related e.g. anti-vascular endothelial
growth factor inhibitors
• Viral infections, e.g. hep C, CMV, BKV
• C3 glomerulopathies as cause of ESRD, where
phenotypical shift to aHUS after transplantation
can occur
• Recurrent TMA, where a native kidney biopsy is
not pursued and TMA as cause of ESRD is not
established
5. EPIDEMIOLOGY
• Reynolds et al- De novo TMA after renal transplantation -3% to 6% (follow-up time
unspecified).
• Zarifian et al- 14% over 2 years, but 24 of 26 cases of TMA were confined to the
renal allograft.
• Scwhimmer et al- only 2.8% of renal transplant recipients had de novo TMA over a
15-year period.
• Reported rates of recurrent HUS in renal transplant recipients have varied
considerably, ranging from 9% to 29%, and are not reported per person-years at risk
to allow comparison between studies.
7. a HUS post transplant
• TMA recurs in the allograft in 60% of the patients with aHUS.
• Reported rates of recurrent HUS in renal transplant recipients have varied
considerably, ranging from 9% to 29%, and are not reported per person-
years at risk to allow comparison between studies.
• If untreated, recurrent aHUS leads to graft loss in 90% of affected patients,
80% of these occur within the first year after transplantation
8. • risk of recurrence after transplantation determined by underlying abnormality
• Factors H and I
manufactured predominantly in the liver.
• most common diagnosis associated with recurrence
production of abnormal factors H and I persists after kidney transplantation
resulting in a 70 to 90 percent recurrence rate
• Membrane cofactor protein (MCP)
trans-membrane complement regulatory protein
synthesized locally in the renal endothelial cells.
After transplantation donor endothelial cells in the transplanted organ able to
produce normal MCP
TMA recurrence depends on whether any additional complement regulatory defects
are present
9. Thrombotic thrombocytopenic purpura
• second major diagnosis
• genetic or acquired deficiency of a disintegrin and metalloproteinase with a
thrombospondin type 1 motif, member 13 (ADAMTS13), a von-Willebrand
factor-cleaving protease
11. De novo TMA
• Allograft outcomes in affected patients are generally considered to be poor,
with graft loss rates as high as 40% at 2 years
12. CNI- associated
• Well documented with cyclosporine and tacrolimus
• USRDS-based- incidence of TMA is in fact significantly higher in patients
who did not receive initial maintenance CNI treatment (11.9/1000 patient-
years) as compared to patients who were placed on initial maintenance CNI
therapy (5.0/1000 patient-years)
• They are not alone in this
•
13. MECHANISM
Loss of normal equilibrium between vasoactive peptides (increased
biosynthesis of vasoconstrictor substances such as thromboxane A2 and
endothelin, and reduced expression of vasodilatory molecules such as
prostaglandin (PG) E2 and prostacyclin (PGI2)) leads to arteriolar
vasoconstriction renal ischemia endothelial injury
of CNIs especially when the endothelium is already injured Platelet
activating, pro-coagulant and anti-fibrinolytic effects as a result of other
mechanisms such as ischemia-reperfusion injury, antibody mediated rejection
cyclosporine causes the endothelial cells to release microparticles that
activate the alternate complement pathway
14. mTOR inhibitor-associated TMA
• Langer et al-1.5% of de novo TMA in a retrospective series with a mean
follow-up time of 25 months in patients treated with sirolimus,
• Risk may even be higher than with CNIs (Reynolds et al )---?confounding
15. MECHANISM
• Leads to decreased renal expression of vascular endothelia VEGF and death of
endothelial progenitor cells
• Keir et al. -VEGF inhibition leads to decreased Factor H synthesis in the kidney,
and that podocytes carrying CFH genetic variants are less efficient at inhibiting the
alternate complement pathway and therefore potentially more susceptible to
reduction in Factor H levels in the presence of VEGF antagonism
• CFH mutations described in kidney transplant recipients with de novo TMA; these
patient vulnerable
• Increased procoagulant and reduced fibrinolytic state
16. • Risk of developing TMA is higher with a combined CNI and mTOR
inhibitor immunosuppressive regimen as compared to either medication
alone alone.
• Fortin et al.- risk was the highest in the groups where a CNI and an m-TOR
inhibitorwere used together: incidence of 20.7% and relative risk of 16.1 in
the cyclosporine+ sirolimus group and incidence of 6.1% and relative risk of
6.1 in the tacrolimus + sirolimus group
• Nava et al-( 396 kidney transplant recipients) CNI and the m-TOR inhibitor
levels higher in the TMA group compared to those who did not develop this
complication, the sum of concentrations of these two drugs was also higher
in the former group
• Endothelial damage by CNI, in setting of mTOR inhibitor related
impediment to repair of endothelial injury is postulated as the reason for this
additive risk
17. LESSON LEARNED
• caution with use of combination of these two classes of medications in the
early post-transplant period when higher therapeutic levels are desirable, or
in the presence of other risk factors for endothelial injury, for example
presence of mutations in complement regulatory genes
18. AMR-associated TMA
• Meehan et al, saltskar et al
• difference in the prevalence of TMA in C4d positive biopsies
• (33/245; 13.6%) vs TMA in C4d negative biopsies (26/715; 3.6%) suggests
• that humoral rejection itself plays a role in pathogenesis of posttransplant
• TMA
19. Other causes
• viral infections such as chronic hepatitis C infection (with or without
associated anti-cardiolipin seropositivity), cytomegalovirus , parvovirus, BK
virus
• antiviral therapy with ribavirin/interferon ,leflunomide
• disseminated histoplasmosis
• Acquired ADAMTS13 deficiency
• Ischemia-reperfusion injury
20.
21. Complement regulatory gene abnormalities
• Chua et al. documented that complement activation in the kidney is the
common denominator in this heterogeneous condition.
• Le Quintrec et al.
22. Clinical presentation
• most frequently diagnosed in the initial 3 to 6 months after transplantation
• classic triad of the laboratory findings of systemic TMA:
micro-angiopathic hemolytic anemia (evidenced by drop in hemoglobin, elevated
serum lactate dehydrogenase (LDH) enzyme level, low serum haptoglobin level and
presence of schistocytes on peripheral smear),
absolute or relative thrombocytopenia,
acute kidney injury.
• localized TMA -with slowly progressive renal insufficiency and/or worsening
hypertensionbeing the only clinical manifestations
24. acute or active process
Dominance of endothelial cell
injury, platelet aggregation
and formation of thrombi,
and to a minor extent active
inflammation
25. chronic thrombotic angiopathies
• Persistent endothelial injury
• signs of remodeling of the glomerular capillary
walls and the arterial and arteriolar intima and
media
• formation of duplicated basement membranes
(double contours in the glomerular capillaries
and multi-layering of the basement membrane
of the peritubular capillaries)
• increase in the layers of matrix and cells in the
arterial and arteriolar walls that result in sclerosis
with characteristic onion skin lesions
Misdiagnosed as
“hypertensive nephrosclerosis”
27. Plasmapharesis
• Karthikeyan et al. plasma exchange in addition to CNI withdrawal resulted in a graft
salvage rate of 80%
• Removal of platelet aggregating factor such as thromboxane A2 and simultaneous
replenishment of deficient factors such as PGI2-stimulating factor.
• acute TMA and underlying complement dysregulation, PLEX may lead to improved
outcomes by providing normal functioning complement proteins and/or removing
defective mutant proteins and/or auto-antibodies to complement factors
• In AMR-associated TMA, improved outcomes have been documented with PLEX
and IVIG therapy, presumably as a result of removal of and/or down-regulation of
production of anti Donor HLA antibodies
28. Belatecept
• Belatacept is a cytotoxic T-lymphocyte-associated antigen immunoglobulin
(CTLA4-Ig) that blocks co-stimulatory interaction between CD80 and CD86
surface ligands on antigen presenting cells and CD28 on T cells.
• DOES NOT TREAT but serve immunosuppressive substitute for CNIs or
mTOR inhibitors
29. Eculizumab
• Eculizumab, a recombinant, fully humanized hybrid IgG2/IgG4 monoclonal
antibody targeted against human complement protein C5 blocks generation of the
lytic C5b-9 membrane attack complex
• Chua et al.-widespread renal deposition of C4d was observed in all histologically
confirmed cases of post-transplant TMA; furthermore, C4d deposits co-localized
with terminal complement complex C5b-9 deposits in most
• Given these conflicting results and the expense of the drug, we recommend use of
eculizumab in AMR-associated TMAwhere hemolysis persists despite maximal
management including PLEX and in those with PLEX dependency.
30. Prognosis
• Forty to 50% of patients lose their grafts within two years of diagnosis
• USRDS-based study by Reynolds et al.( 2003)- mortality at 50% at three
years after diagnosis.
• Other studies- 30–40% graft loss rate at 2 to 3 years after transplant .
• Systemic TMA leads to early graft loss more frequently than localized TMA.
• study by Schwimmer et al., 54% of patients with systemic TMA developed
dialysis requiring acute kidney injury and 38% had TMA related graft loss.
31. TO SUMMARIZE……..
• The diagnosis of post-transplant TMA portends poor patient and allograft
survival
• Clinical presentation is highly variable,
• Availability of alternative immunosuppressive medications such as belatacept
and anti-complement therapies such as eculizumab provide encouraging
options for use in these patients.
• Further long-term data are needed to document efficacy of these treatments
in patients with the diagnosis of de novo post-transplant TMA.
