4. Until the early 1990s, rejection of the renal allograft was classified into the four
types: 1) hyperacute, 2) acute, 3) accelerated acute, and 4) chronic
Hyperacute rejection - immediate (minutes to hours) rejection of the graft due
to the presence of preformed antibodies
Acute rejection-rejection occurring after 5–7 days due to activated T cells
Accelerated acute-rejection occurring within five days, due to formation of
antibodies in a presensitized patient
Chronic rejection -slow progressive graft dysfunction after three months
There was considerable heterogeneity among pathologists
Hence, it was felt that standardization of renal allograft biopsy was necessary
5.
6.
7. Banff introduced the category ‘chronic allograft nephropathy’ (CAN) as a
histopathological correlate of chronic allograft dysfunction
CAN was thought to include at least four entities at that period of time viz. chronic
rejection, chronic cyclosporine toxicity, hypertensive changes, and chronic
infection
The features suggestive of CAN were:
a) Glomerulopathy: Glomerular basement membrane duplication and mesangial
cell proliferation, and
b) Vasculopathy: Fibrous intimal thickening often with fragmentation of internal
elastic lamina
c) IFTA
8. The revised Banff 2005 classification system, which was reported in
2007, renamed CAN as ‘interstitial fibrosis and tubular atrophy
(IF/TA)’ without evidence of any specific etiology“
This was done because the term "chronic allograft nephropathy" was
thought to diminish attempts to determine the underlying cause of the
histologic lesions
Even after removal, the term is being used commonly
9.
10. CAN is defined as:
Chronic allograft dysfunction (rise in s.creat and/or new or worsening
proteinuria)
Occurring atleast 3 months
In absence of active rejection, drug toxicity (mainly CNI) or other
diseases
Has diagnostic features on biopsy
Manifested by slow rise in plasma creatinine, increase proteinuria and
worsening hypertension
Uptodate
11. No standardised definition
KDIGO 2009 used the term ‘Chronic Allograft Injury’ (CAI) rather
than CAN
CAI is :
a diagnosis by exclusion
characterized by progressive reduction in graft function
not due to recurrence of disease or other recognized cause
histologically defined by IFTA
may include features like subclinical rejection, TG or transplant
vasculopathy
12.
13.
14.
15.
16. Exact incidence unclear as there are no universally
accepted diagnostic criteria or definition
17.
18.
19.
20.
21. Data from experimental and human models indicate role of all
elements of the immune system:
i. Cell mediated immune response(delay type hypersensitivity
response by macrophages and CD4+ T cells)
ii. Humoral alloantibody response against donor antigen
iii. Inflammatory cytokines like IFNγ
iv. Effectiveness of anti-inflammatory cytokines like hepatocyte
growth factor
v. Growth factors like PDGF, Tβ
vi. Vasoactive and mitogenic peptide endothelin
22. From observation study:
half-lives of better matched allograft are longer than
less well matched deceased donor graft
IST withdrawal leads to accelerated CAN and graft loss
Carpenter CB et al. Kidney Int Suppl. 1995;50:S40
Terasaki PI, Cecka JM, Cho Y. Overview. In: Clinical
Transplants, Terasaki PI (Ed), UCLA Tissue Typing Laboratory, Los Angeles 1989. p.585.
Retrospective study: in 4000 KTRs of HLA-identical
sibling Tx- (Opelz G. Lancet. 2005;365(9470):1570)
PRA 10 yr graft survival
0 72%
1-50 63%
>50 49%
23. Incidence of CAN
Rejection Living related donor Cadeveric kidneys
No acute rejection 0.8% 0%
Acute rejection within ≤ 60 days 20% 36%
Acute rejection after > 60 days 43% 60%
Basadonna GP et al. Transplantation. 1993;55(5):993.
24. Incidence of CAN
only 1 AR vs >1 AR : 8.9 vs 34.8%(p=0.001)
Humar A et al. Transplantation. 2000;69(11):2357.
Half–life of graft survival
no AR vs AR : 12.5 vs 6.6 years
Creatinine Cl at 1-5 yr post transplant
no AR vs AR: 45-47 ml/min vs 54-60 ml/min
Lindholm A et al. Transplantation. 1993;56(2):307.
25. 1)ABMR
Chronic ABMR is the leading cause of graft loss/failure(2nd only to
death with functioning graft)
In recent study, 64% of graft losses are due to ABMR (Sellares J et al.
Am J Transplant 2011)
Ab contributing to chronic ABMR are:
DSA
MIC-A(MHC class I related chain A antibody)
Angiotensin II type 1 receptor-activating Ab
Antiendothelial cell Ab
26.
27. Pre-existing DSA- should be undetectable at time of Tx
de novo DSA incidence in post Tx:
1st yr - 2%
5th yr-10%
10th yr-20%
Not all DSA are equal and some DSA do not cause graft
dysfunction/CAI
Complement binding DSA are more likely to have AMR on biopsy
DSA IgG subclass: IgG3 and IgG4 DSA subclass have PPV 100% to
identify Ab mediated injury
28. MICA is a product of HLA related polymorphic gene
Expressed on monocytes, keratinocytes, fibroblasts and
endothelial cells
Exact function:
unclear
recognized by subpopulation of intestinal gamma delta T
cells →may play role in activation of subpopulation of NK
cells
Ab against MICA may affect allograft function and survival
29.
30.
31. Some author recommend universal testing of KTR for
DSA + MICA and careful monitoring of creatinine if
tests+
Some recommend MICA test in patient with ABMR
without DSA
Overall, not widely performed
32. AT1R is a G-protein coupled receptor
Component of renin-angiotensin system (RAS)
Expressed on endothelial and vascular smooth
muscles, podocytes and other kidney tissue
Function: via action of AT-II, AT1R regulates blood
flow, salt and H2O retention, aldosterone secretion,
inflammation and vascular remodelling
33. Anti-AT1R antibodies in KTRs has been associated
with poor renal outcomes like AR and graft loss
Due to increased expression of inflammatory and
coagulation proteins
By contrast, few studies do not find association
between anti-AT1R antibodies and renal outcomes
34. 2)T-cell mediated rejection
-Contribute to CAI
-Adequately treated Early acute TCMR has no impact on
longterm graft survival
-Late chronic-active TCMR in which serum creat remains
elevated translates into IFTA and/or vascular damage and graft
injury
-Multiple and severe Late acute TCMR contributes to CAI
-Subclinical TCMR may contribute to CAI
35. 3)Insufficient therapy and Non-adherence
-In recent study, about half of rejection related graft loss
were due to nonadherence
Sellares J et al. Am J Transplant 2011
36.
37. Donor factors
DGF
Donor Age(old) and sex(F)
Deceased donor (DBD, DCD)
Donor vascular disease, long ischemic time,
ischemic/reperfusion injury
38. Recipient factors
BKVN
CNI toxicity
De novo or recurrent GN
Diabetes (pre or postTx)
High BMI/obesity
HTN
Hyperlipidemia
Hyperfiltration and Hypertophy of glomerulus
Smoking
UTI
Ureteral obstruction
39. Older donor
effect more pronounced in deceased donor than living
donor
differential response of older organ to injury
impaired capacity to withstand stress
limited ability to repair structural damage
amplification of external injury by pre-existing
structural anomalies
41. Glomerular Hyperfiltration and Hypertrophy
Tx kidney has only one-half of nephrons of two native
kidneys
compensatory glom. Hypertrophy and hyperfiltration+
possibility due to donor-recipient size mismatch (child to
adult, female to male, Tx in >100kg wt) described
Brenner BM et al.J Am Soc Nephrol 1992 Oct;3(4):1038.
subsequent two studies failed to show effect on size
mismatch on allogaft outcome
Miles AM et al.Transplantation. 1996;61(6):894.
Gaston RS et al. Transplantation. 1996;61(3):383.)
42. DGF
higher risk of CAI
ATN(m.c) leading to fewer functioning nephrons and
increasd glom. Hyperfiltration and progressive graft failure
risk factor for IFTA, acute rejection and late graft failure
one Japanese study showed DGF at 9 days had 5 yr graft
survival of only 50% and CAN was responsible in 2/3rd of
the lost kidneys
Okoyama I et al . Clin Transplant. 1994;8(2 Pt 1):101.
43. Ischemic/ reperfusion injury
longer ischemia/cold ischemia time is risk factor for IFTA at
6m post tx
ischemia-reperfusion/oxidative injury triggers adaptive
immune response/upregulation of MHC antigens, APCs
and TLRs and release of proinflammatory cytokines
lead to acute rejection and IFTA
#can reduce by-therapeutic hypothermia of DOD, reduce cold
storage of kidneys by pulsatile machine perfusion
44. Hyperlipidemia
hypertriglyceridemia but not hypercholesterolemia
independent risk factor for graft loss
??unclear cause-effect relationship
De Vries AP et al.Am J Transplant. 2004;4(10):1675.
46. CNI toxicity
Contributes only small portion of graft failure
DeKAF(deterioration of kidney allograft function) study
showed 70% of patient with histological evidence of CNI
toxicity had C4d and DSA indicating the role of
alloimmunity rather than CNI nephrotoxicity
Affects all histological compartments but not specific
47. CNI lesion includes-medial arteriolar hyalinosis(nodular
hyaline deposits in media of afferent arterioles ), striped
interstitial fibrosis, global glomeruloscerosis and tubular
microcalcification
arteriolar hyalinosis is is most reliable diagnostic marker –need
exclusion of other causes
striped fibrosis-dense stripe of cortical fibrosis and atrophic
tubules adjacent to normal cortex is traditionally regarded as
pathognomic, but can be seen in other causes of fibrosis/
microvascular injury
48. arteriolopathy and luminal narrowing leads to Watershed
infarct within area of ischemia→local hypoxia leads to
free radicals formation→TGFβ upregulation→fibrosis and
atrophy
49.
50. Recurrent or de novo GN
effect on graft loss increases as graft survival lengthens
has implication on treatment and retransplant
reccurent GN should be looked for carefully in patient
with prior Dx of GN
51.
52. Gradual deterioration of graft function manifested by
slow rise in plasma creatinine , increase in proteinuria
(both late sign)
And worsening HTN
The reliance on clinical features result in late Dx of CAI,
often culminating in allograft loss
Proteinuria>1g/d seen in- denovo or recurrent GN ,
severe chronic ABMR like TG
53. The etiology can be multifactorial
Biopsy and clinical history combination can identify
specific etiology
History-
Alloimmunity -pre-existing donor disease, prior rejection,
high titres of anti-HLA(DSA)
Non-immune causes like CNI toxicity, de novo or
recurrent renal disease
54. USG and Renal Doppler with RI- to exclude ureteral
and vascular problem
DSA-for early Dx of ABMR
many centers perform DSA screening at different time
points even in stable graft function for early Dx
2013 Transplant Society Concensus
non-sensitized: once in 3-12 m post-Tx
sensitized : more frequently
55. BK DNA PCR
during deteriorating graft function
in all KTRs @ every 3m x 2yrs post-Tx
Allograft biopsy-to r/o specific pathology
specific staining such as C4d for ABMR, SV40 if
suspect BKV
IF-Ig, complement
EM-may be useful to r/o recurrent or denovo
56. IFTA :
represents the final pathway of
nephron injury
not specific for any graft disease
Found in most late graft biopsies
result of early graft damage
(e.g.,ischemic reperfusion injury,
subclinical rejection or pre-existing
disease of donor) or later graft damage
(CNI toxicity, HTN, dyslipidemia,
recurrent GN , immune mediated
injury) or unknown IFTA
57. Chronic ABMR is characterized by :
GBM remodelling/duplication/double contouring(so called TG)
mesangial expansion in absence of immune deposits
ptc basement membrane multilayering (EM)
arterial intimal fibrosis of new onset
± C4d in ptc and glomerular capillaries (C4d absent in >50% of
chronic ABMR, so no longer prerequisite for Dx)
EM-can detect early changes like expansion of subendothelial
spaces with flocullent/fibrillary material deposits, mesangial
expansion
58.
59.
60.
61. Important preventable cause of graft failure
Measures to prevent:
Minimize no. of daily doses/stop non essential drug/ use OD medication
if possible
Educate patient
Educate and update physician/medical staff-drug protocol and drug
interaction
Help for patient-family, friends, public health aides, mobile phone
applications for reminder
Financial issue-assign someone to help, use cheaper drug
Identify high risk of nonadherence-e.g., adolescents fear cosmetic effect.
Risk factor intervention
62.
63. Minimization – the only beneficial CNI strategy
Conversion
Withdrawal
Avoidance
64.
65. Minimization of CNI when combined with MMF
better renal function and lower biopsy proven acute
rejection (RR 0.84, 95% CI 0.75-0.95)
lower graft loss (RR 0.76, 95% CI 0.61-0.94)
Minimization when combined with mTOR
no effect on acute rejection and graft loss
66. Conversion
no effect on any end point studied
Withdrawal
increased risk of acute rejection
RR 3.17 in MMF based, 1.71 in mTOR based regimen
Avoidance
nine trials; no benefits
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77. Aggressive control of BP and hyperlipidemia
Low dose Aspirin
Vitamin D
Control human trials failed to show benefits of
antiplatelets, thromboxane antagonists, fish oil and low
protein diet.
81. Results:
significant increase in baseline Scr (p < 0.001) prior to starting
calcitriol
deceleration in the rate of loss of graft function (p = 0.031 at day
300 of therapy)
graft survival was also prolonged in calcitriol-treated patients
compared to a control population with evidence of chronic
allograft nephropathy but no calcitriol therapy (p < 0.03)
Am J Nephrol. 2002 Sep-Dec;22(5-6):515-20
84. If evidence of CNI toxicity+
dose reduction or withdrawal may help
but CNI withdrawal increases more acute rejection and DSA
formation
Limited evidence on CSA to TAC conversion
(TAC induces lesser TGF-beta and fibrosis, improve GFR)
But, large multicentric trial showed no difference in GFR,
longterm graft and patient survival
85. If MMF is not being used
change from AZA to MMF may ameliorate progressive
renal dysfunction
86. Early diagnosis and treatment of acute rejection-both
acute cell mediated and acute ABMR
Early diagnosis and treatment of chronic ABMR
87.
88. Other than death with functioning graft, chronic ABMR is
the most common cause of CAI
Clinical signs and symptoms manifest late and often result
in delay in Dx
Pre and post Tx DSA status can help in early Dx
Nonadherence is common and preventable cause of
allograft loss
Early Dx and treatment of acute rejection is essential
CNI minimization when combined with MMF is helpful
‘CAN’ is misnomer and should not be used
