Chronic Allograft Nephropathy

1. CHRONIC ALLOGRAFT NEPHROPATHY
CHRONIC ALLOGRAFT INJURY
PRESENTED BY
Dr.C.MALSAWMKIMA
DM NEPHROLOGY STUDENT
DEPTT OF NEPHROLOGY
AIIMS JODHPUR
Date :19-03-2020

2.  Introduction
 Definition/Epidemiology/Risk factors/Pathogenesis
 Clinical presentation
 Diagnosis
 Prevention
 Treatment

3.  Incompletely understood clinic-pathological entity
 Variously called as-chronic rejection, transplant
nephropathy, chronic renal allograft dysfunction,
transplant glomerulopathy, chronic allograft injury or
chronic allograft nephropathy

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

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

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

16.  Exact incidence unclear as there are no universally
accepted diagnostic criteria or definition

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

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

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

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

40.  Female Donor
 reduced nephron mass(Nephron Underdosing)
 difference in immunogenicity?

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.

45.  BKVN
 mimics interstitial
cellular rejection
 differentiate by SV40
antigen staining

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

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

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

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

63.  Minimization – the only beneficial CNI strategy
 Conversion
 Withdrawal
 Avoidance

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

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.

78.  Nephroprotection
 ACEi/ARBs provide special benefits???
 remains to be determined
 conflicting retrospective data

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

82. Overlap between treatment and prevention

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

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

89. 