Despite the greatly improving one-y kidney graft survival, the rate of chronic graft loss after the 1st y still crucial, however, it appears improving
ALLOGRAFT SURVIVAL
Abbreviations (Read twice please):
o AB: Antibodies
o Ac Rj: acute allograft
rejection
o ADH: antidiuretic
hormone (vasopressin).
o
Ag: antigen
o ALERT: Assessment of
Lescol in Renal Transplantation
o AMR: Antibody-mediated
rejection
o ATN: Acute tubular
necrosis
o BB: Beta blocker
o BDD: Brain-dead
donors
o BP: Blood pressure
o BTx: Blood
transfusion
o
C: Complement
o CAN: Chronic
allograft nephropathy
o CAD: Coronary
artery disease
o CAV1: Caveolin-1
o CCR5: Chemokine
receptor 5
o
CIT: Cold
ischemia time.
o CMS: Centres for
Medicare and Medicaid Services
o CMV: Cytomegalovirus
o CNI: Calcineurin
inhibitor
o DCDs: Deceased cardiac donors
o
DDK: Deceased-donor kidney.
o DGF: Delayed allograft function
o DI: Diabetes
insipidus
o DSAs: Donor-specific
antibodies
o DX: Dialysis
o ECDs: expanded-criteria donors.
o ELISA: enzyme-linked
immunosorbent assay.
o ESRD: end-stage
renal disease.
o FAVORIT: Vascular
Outcomes Reduction in Transplant Recipients
o GFR: Glomerular
filtration rate
o
Gm: Glomerular
o GN: Glomerulonephritis
o GSc: Glomerulosclerosis
o HIV: Human
immunodeficiency virus
o HLA: Human
leukocyte antigen
o HR: Hazard ratio
o HT: Hypertension
o im/m: Immunosuppressive/Immunosuppression
o KDPI: Kidney
Donor Profile Index
o KTx: kidney
transplants
o KwRw: weight of the
kidney to the weight of the recipient ratio
o LDK: living-donor kidney
o LRD: Living related donor
o MHC: Major
histocompatibility complex
o MR: mortality rate
o OPTN: Organ
Procurement and Transplantation Network.
o PP: pulse pressure
o PRA: Panel
reactive antibody
o Preetx: Pre-emptive Transplant
o RCT: randomized
control trial
o RADR: Renal
Allograft Disease Registry
o Rh: Rhesus blood
group
o
RI: Resistive index
o Rj: Rejection
o RR: Relative risk
o SCDs: Standard-criteria
donors
o SCr: Serum
creatinine
o Snz: Sensitization
o SRTR: Scientific
Registry of Transplant Recipients.
o TPA: Tissue
plasminogen activator.
o
TR: Transplant recipients
o Tx: Transplants/transplantation.
o U/S: Ultrasonographic
o UNOS: United
Network of Organ Sharing
o USRDS: United States
Renal Data System.
o VC: Vasoconstriction
o
Wt: Weight
o WIT: Warm ischemia
time.
Despite the greatly improving one-y kidney graft survival,
the rate of chronic graft loss after the 1st y still
crucial, however, it appears improving by time. A 2004 study: analysed 1st KTx proceeded between 1995 & 2000 reported that despite the reduced Ac Rj episodes, the long-term graft longevity was not improving
over the last 10 ys. However,
the rate of drop in renal graft function seems to be slowing that suggests that
improving the long-term allograft longevity is greatly amenable.
The annual data (2016) reported of the OPTN/SRTR highlights current,
despite incremental, improved allograft & ptn survival for both DDK & LDK Tx. The kidney graft longevity rates are also variable with different
ethnic cohorts that can be partially explained by the finding of a
disproportionate increasing number of risk agents among specific cohorts with variable
accesses of health support.
I will promote various variables of short- & long-term graft longevity. However, this distinction is to some extent arbitrary as many factors can impact both survivals. Any short-term agent may predispose to episodic Ac Rj will then induce greater possibility of chronic graft loss. Moreover, many of these agents affect each other, e.g., mismatched HLA that may trigger the risk of Ac Rj with subsequently expected premature allograft loss.
SHORT-TERM SURVIVAL
The risk of allograft loss has commonly
been classified into an early, high-risk period
and a late period of constantly lower
risk. The great improvement in the kidney allograft longevity in
the past 20
ys has been attributed to the relatively eliminated early risk period. A variety of factors have
been incriminated in the progress in the short-term allograft
survival. These may include DGF, HLA AB, type of donor
graft, donor illnesses, centre policy, and others.
Delayed graft function: Development
of DGF has a major adverse impact upon
both short- & long-term graft survival. Single-centre report: 518 ptns, multivariate analysis showed: DGF was the fundamental agent underlying
kidney graft longevity at one y; in contrary, Ac Rj, HLA matching,
degree of Snz, & re-Tx did
NOT seriously impact short-term survival.
HLA AB: Certain data suggest that the finding of HLA AB
is complicated by a higher risk of early allograft failure. Considering
data from about 5000 TR, the prevalence
of HLA AB was 21 % among kidney TR.
Almost > 2000 ptns have been followed
prospectively, with 91 allograft failure and
34 deaths. The risk of allograft loss
at one y. was increasingly elevated among those with HLA AB (6.6 vs 3.3 %),
as well as among TR developing such AB de novo (8.6 vs 3 %). Moreover,
such AB place ptns on W/L with a remarkable
disadvantage waiting for a kidney graft that is markedly extended with an increasing
risk of both DGF & Rj in the peri-operative period of Tx.
The finding of HLA AB
also has an adverse impact
on the long-term allograft longevity.
Type
of the graft: It is well-known that not all grafts offered
for Tx are
currently equal. These allografts have long been characterizing by the donor
source, either living or cadaveric. LDK Tx have a higher short-term longevity as
compared with DDK. The Graft survival
rates for LDK
Tx and cadaveric, non-ECDs;
now referred to as KDPI
(>85 %) are 98 vs 96 % at 3
mo and 96 vs
92 % at one
y, resp. An allograft survival benefits with LDK has
been also observed with the 2nd allografts, a difference reflecting
the optimized circumstance in the setting of living,
related donation as compared to the
potentially injuring events of DDK donation.
Before 2014, DKD were classified
into SCDs
& ECDs.
ECD kidneys
are from BDD
that’re further recognised by a rise of 1.7 in the RR of premature
graft failure within the 1st y post-Tx. Such kidneys collected from donors >60 ys of age, as well as those with HT or
stroke as a direct cause of death. ECD grafts are commonly associated with lowered
short-term graft survival, especially among TR planning
for re-Tx. However, application of
this primitive classification shows the limitation of the presence of currently
overlapped outcomes and allograft quality as the ECD class is large and non-uniformly including allografts
with variable outcomes. The ECD category may include-for example- both an entirely
healthy 60
y old donor with a normal kidney profile
and a 55-y old one with DM, HT, & a SCr of
1.6 mg/dL.
A recognizing centrally featured and revised renal
allocated system that was accomplished in the US in
2014, is the KPI that is a continuing,
rather than a dichotomous, index of the qualities of the donor grafts, from the
highest quality (carrying the longest
functional post-Tx lifetime), to the
lowest one (carrying the shortest functional post-Tx
lifetime). The more granulated KDPI, entirely based upon
donor criteria, comprising a variety
of donor risk factors for allograft failure into a solitary
number. One study: using the KDPI (or KDRI)
to categorise DDK, the highest
quintile (equal to the highest risk for allograft failure or
lowest project longevity) had a calculated 5-y
survival of 63 % as compared to the lowermost 2 risk quintiles that showed projected 5-y survivals of 82 & 79 %, resp. The KDPI system
may overlap with the ECD/SCD system in that the % of ECD grafts rose with an elevated risk
quintile. However, 32 % of ECD kidney grafts studied showed KDRI < the 85th
percent.
Centre effect: In the US, Europe, & Canada, a crucial centre impact regarding short-term graft longevity has been reported that can’t be explained by various clinical criteria of enrolled TR. It seems to be a persistent finding that has been seen along the last decades, an era of highly effective im/m therapy. Possible background explanations may include centre effect and variabilities in long-term TR therapeutic policies.
Donor age: an older
donor age is complicated with lowered longevity of grafts offered from a
cadaveric donor. Analysing 6490 DDK Tx identified from the UK
Tx registry, compared with donor age <40
ys, donor age >60 ys was complicated
with a higher risk of allograft failure (HR 95%).
Donor illness: DDK graft survival may also affected by the aetiology
of donor mortality and/or history of the associated co-morbid diseases. For
example, KTx due to stroke event showed a
lowered one-y graft survival rate than observed with DDK Tx (79
vs 84 %).
DX & Preetx: Early graft longevity may vary with maintained
DX and
possibly the module of DX before Tx.
LONG-TERM SURVIVAL: The recognition of clinical risk agents determining the long-term allograft loss has been evaluated via several reports proceeded in the current im/m era, e.g., in the ALERT study, along 5-6 y, 2000 ptns were randomly exposed to Fluvastatin or to placebo. The placebo g. showed graft loss in 137 ptns that was primarily induced by CAN. Multivariate analysis showed that the independent risk factors for increased risk of graft loss may include:
1)
Higher SCr (RR: 3.12/every 100 micromol/L rise),
2)
Proteinuria (RR of 1.6 /1 g/d), &
3)
PP (RR of 1.12/every rise of
10 mmHg).
4)
Declined graft function at one y.
One study showed progressive drop in
the graft ½-life for each incremental rise in the SCr
level at 6 mo & at one y. The
underlying pathogenetic mechanism responsible of CAN and result in long-term graft loss still
uncertain. Both allo-Ag-dependent &
independent factors have been incriminated. Long-term allograft survival
is usually assessed in terms of the ½ -life that’s defined as:
Time elapsed after the 1st post-Tx y., where 50 % of the function of allograft has been lost.
Allo-Ag related factors: Chronic Rj + allograft loss is more
likely to evolve with:
1)
History of Ac Rj,
2)
Infectious episodes,
3)
Inadequate im/m agents.
4)
Higher degrees of HLA mismatch.
These factors are consistent with the crucial impact
of the immunological or allo-Ag-dependent
injury in the consequent evolution of chronic graft malfunction.
Ac Rj Episodes: Ptns with frequent
history of Ac Rj episodes are more prone to experience a late
allograft loss. Study: 63,045 primary
renal TR with
episodic Ac Rj from 1996-1997 was complicated
with a 5.2-fold increasing risk for CAN as
compared to TR with no Rj in a control g. from 1988-1989.
HLA matching: An
increasing degree of HLA Ag mismatching is usually
accompanied with a higher risk of chronic allograft loss, possibly
due to persistent particular immunologic stress. If graft allocation is primarily
based on HLA
typing, one crucial concern is the impact of CIT, cold ischemic time on long-term longevity.
The beneficial impact of HLA matching
seems to be outweighing the harmful impact of prolonging the cold ischemic time
in Tx
kidney. The currently available registries inform that the 5-y allograft survival of 6-Ag-matched cadaveric kidney is similar regardless the kidney grafts underwent 3 or 36
hs of cold ischemic time.
However, the hazardous impact of prolonged CIT appears more evident in TR of mismatched grafts. A stepwise 1-2 % decline in survival has been reported associated with
incremental 12-h rises in CIT. The adverse impacts of CIT can
also be seen if graft survival is compared between the TR of a 1st
cadaveric
donor Tx and the recipient of the 2nd
donor kidney Tx (mean of 19.9 vs 25.6
h.s CIT). The 5- & 10-y
survival was 72 & 55 % for the 1st KTx, resp, as compared to 65 & 40 % for the 2nd
KTx.
Considering the relative contributors to graft
survival of HLA matching & CIT
is also provided if we consider the allograft longevity rates of living, unrelated kidney. The allograft survival rate
of a kidney offered by a spouse are remarkably similar to the kidney
donated by a family member with a one-haplotype mismatch (½ -life of 12 ys). If HLA mismatching were the sole factor
affecting allograft longevity, the living,
unrelated allografts should show poorer
long-term longevity, possibly in the range of randomly matched cadaveric graft
(that is mostly have 3 HLA mismatches
& an average ½ -life of 8.4 ys).
So, both CIT & HLA matching exert crucial impacts on the long-term
allograft survival. However, 6-Ag matching entirely overcomes the impact of ischemia, and lesser magnitude of matching (even with the
presence of ischemia) yield superior
results than zero-Ag-matched
grafts. The graft immunogenicity alterations induced by tissue injury before death
in deceased
Tx may be also contributing to the lowered long-term longevity
with DKD in
contrary to LDK.
Sensitization (Snz): AB against HLA class I (A, B, C) or class II (DR, DQ)
have been observed in subjects with prior immunization to these glycoproteins via:
1)
BTx, or
2)
Pregnancy,
3)
previous HLA-mismatched
grafting.
Highly Snz
ptns have a lowered statistical chance of being Tx owing to the higher likelihood of a +ve pre-Tx crossmatch. Enhanced Snz to
lymphocyte Ags
(measured via PRA), incrementally triggers
the risk of allograft failure. 5-y DDK,
non-ECD graft survival rates in
the 2007 SRTR annual report were:
o 71 % for ptns with PRA of 0-9 %
o 61 % with a PRA of 10-79 %
o 69 % with a PRA of >80 %
UNOS retrospective
analysis: the 10-y graft survival = 44 % for highly Snz ptns (PRA ≥98 %), as compared to 52 % for non-Snz ptns
(PRA =
0). It is greatly
considered that the finding of pre-formed HLA DSAs has an adverse impact on allograft longevity.
With the advent of overly sensitive HLA-specified
assays, allograft outcome at 8
ys was assessed among 43 ptns with & 194 ptns without pre-formed DSAs.
Allograft longevity = 68 vs 77 % for those with & without DSAs, resp. Moreover, the incidence of AMR rates was 9-folds higher in TR with pre-formed
DSAs.
C-binding HLA DSAs are particularly associated
with declined allograft survival. This was shown in a study of 1016 TR who received a KTx at 2 centres between 2005
& 2011. All ptns were examined
for circulating HLA DSAs via stored serum samples collected at
the time of Tx and at the time of graft
biopsy (taken either at one y after Tx
or within episodic Ac Rj in the 1st y after Tx). Serum samples of TR having HLA DSAs were further examined for the presence of C1q-binding HLA DSAs via single- Ag flow bead assay. Generally, ptns
with HLA DSAs
had worse 5-y allograft
survival as compared to those with lack of such AB
(83 vs 94 %, resp). TR with C1q-binding DSA HLA AB (n
= 77) had worsened allograft survival as compared to ptns with non-C1q-binding DSA HLA AB (n = 239) and
compared to ptns with no DSA HLA AB (n = 770; 54
vs 93 &
94 %, resp). With adjusted various
clinical, functional, histological, and other immunologic agents, the finding of C1q-binding DSA HLA was complicated by > 4-fold higher risk of allograft
loss ([HR 4.78, 95%). C1q-binding AB were also complicated by a higher rate of AMR with increasing deposited C4d in the graft.
However, the C1q -binding assessment
is not widely applied and has not been approved yet in many centres. Moreover, there’re
some non-C-binding DSAs that are clinically incriminated in allograft
failure that cannot be identified by this assay.
Limited data suggesting that Snz may, sometimes, representing non-HLA immunity,
with higher levels associated with lowered longevity. Retrospective study:
> 4000 TR
of HLA-identical sibling Tx assessing
the long-term longevity associating PRA
levels. Considering that the Tx were between HLA-identical
siblings, the finding of PRA was thought representing anti-HLA Ags
AB not present in the Tx kidney. However, the 10-y survival was the highest
among TR devoid of PRA (72 %) vs those with either 1-50
% PRA (63 %) or >50 %
PRA (56 %) that suggesting: non-HLA Tx immunity,
as identified by PRA, may play a role
in long-term graft survival.
The significant role of non-HLA immunity
was further supported by 2-y
prospective study: 2231 ptns. At 2 ys, graft
longevity was more significant among
1781 ptns with No HLA AB (93 vs 85 %). Outcomes could be better correlated
with the finding of cytotoxicity examination vs ELISA
or HLA beads suggesting: the finding
of non-HLA
AB can be correlated to a lowered longevity.
Although mismatching at the Rh blood g. Ag is NOT
dealt as risk factor for graft Rj, a multivariate
analysis of UNOS data found that Rh incompatibility may grant a worsened long-term survival. In
this study, Rh identification between the TR & donor was significantly correlated with a better graft longevity (RR 0.43). {Role
of Rh in allograft survival has to be
re-evaluated}.
Allo-Ag-independent factors: Variable clues
from clinical Tx database support the impact
of the following in the evolution of chronic graft dysfunction with
poor long-term renal outcome:
1)
Post-Tx HT,
2)
Post-Tx hyperlipidemia,
3)
More marginal grafts,
4)
Inadequate graft mass,
5)
Previous/current tissue injury,
6)
Recurrent/de novo Gm disorder
7)
And, on the long run:
o CNI toxicity &
o Death of the TR.
Tissue injury: Allograft injury exerts a crucial role in both
short- & long-term allograft function, as well as in the development of kidney
graft Rj. Such injury may be induced via
variable agents, including:
1)
CIT,
2)
Brain death,
3)
infectious episodes
4)
ischemia and/or reperfusion injury.
●Brain death:
Traumatic
brain death or devastating intracranial
hemorrhage is complicated by variable
adverse events on the donated organs before Tx.
Under this environment, graft tissue became "primed" and TR T-cell
activation by donor allo-Ag is more prone
to develop. In BDD the
following cascades have been expected:
1)
Brain oedema > increased intracranial pressure > compressed cerebral tissue & venous congestion > increased brain
turgor & rigidity.
Massive catecholamines efflux then ensues inducing profound VC with endothelial injury.
2)
Injury-induced inflammation > upregulated
adhesion molecules & class-II MHC on graft
endothelium.
3)
Pro-coagulation state due to endothelial activation, cytokine release, C activation, & depleted TPA.
4)
Anterior pituitary hormonal release leading to reduced levels of thyroid
hormones, cortisol, insulin, and ADH.
5)
DI rapidly developed; cardiac arrhythmia & rapidly fluctuated BP are common.
- Such events may clearly adversely impact the
function as well as allograft integrity.
●Ischemia and/or reperfusion
injury is thought to be a crucial risk factor for both early DGF & late graft dysfunction. One
report: 3829 adult TR of a 1st
DDK, there was a proportionate rise
in the risk for graft loss & death over 12 ys for each hour
of CIT. The dominant aetiology of DGF is post-ischemic
ATN. ATN incidence
increased if the CIT > 18 h.s, especially with older donated grafts. CIT alone is also a crucial factor impacting
long-term allograft longevity.
Preserved grafts with pulsatile preservation may improve long-term longevity as compared
to that seen with simple cold storage.
Injury alone
may NOT impact graft longevity in absence of Rj, as reported in some reports, e.g., > 9000 grafts retrieved & analysed from the UK national
Tx databases,
reported injury at graft retrieval or placement was NOT significantly correlated with allograft
survival at 3 ys.
The environmental
factors related to organ removing, storage, & engraftment may trigger allograft immunogenicity. These factors may include:
o Upregulation of MHC Ags &
o Cytokine-adhesion molecule cascade enhancement.
Such factors may ultimately enhance the evolution
of chronic allograft dysfunction, e.g., blocking co-stimulatory pathways can alleviate organ dysfunction in rat models of
ischemia/reperfusion. There’re limited data concerned with the relative magnitude of injury
with grafts harvested from DDK with or without a heart
beating. Grafts from donors with no heart beating or DCDs can be complicated with certain degree of
irreversible damage that leads to relative degree of poor
long-term graft longevity. However, some reports suggest outcome may be satisfactory.
●CMV: The finding of CMV seropositivity enhances both acute & chronic allograft
loss development. Seronegative TR
of seronegative grafts appear to have a 10 % higher allograft
survival than TR of seropositive allografts that is can be explained by an
activated CMV-induced cytokine promoting allograft
injury. Allograft longevity rates are also affected by previous CMV serostatus and by prior CMV prophylaxis.
Inadequate kidney mass: Tx of inadequate
renal mass may be complicated by
an increasing risk of allograft failure. Data in favour of this
hypothesis in humans depends on the observation of lowered allograft
survival rates with older & very young donor kidney, TR in whom donor graft has disproportionately fewer nephrons, and ratio
of donor kidney Wt to TR Wt:
o Old & very young donor kidneys: Old & very young kidneys have relatively lowered numbers of actively
functioning nephrons with less survival rate after Tx. Inherited factors of the older kidney may also
impact the overall graft longevity.
o Disproportionate fewer nephrons: Large-sized TR require a wide
physiologic demand on the Tx graft. The
increasing demand with "inadequate" Tx nephrons may induce lowered long-term graft survival rate
seen in ptns of >100
kg BW.
o Several trials have assessed
the relation between graft function/longevity and the ratio of donor kidney Wt to TR Wt. Largest study:1189 renal TR, the ratio of KwRw was assessed regarding
risk of proteinuria, GSc, & graft failure. A lowered KwRw ratio (<2.3 g/kg) was complicated by a higher risk of GSc (17 vs 4.7 %), proteinuria, & long-term graft failure (1.55-fold higher risk starting 2 ys after surgery). The level of risk for cadaveric
graft survival with
lowered KwRw ratio is nearly
simulating the risk related to an Ac Rj episodes or DGF.
Non-compliance: is one of the more crucial risks for allograft failure on the long term. Assessing the frequency of non-compliance and its impact to kidney graft loss is somehow difficult to assess owing to the wider variability in study designs & results.
Post-Tx HT: Post-Tx
HT may exert a negative impact on the
long-term graft/ptn survival. Multivariate analysis: adjusting baseline kidney
function, the RR of graft
failure = 1.3 for each 10 mmHg rise in the mean arterial pressure at
one y post-Tx.
Hyperlipidemia: is well-known risk
factor for arteriosclerosis & CAD in all ptns, including cardiac & kidney TR; it may also induce higher rates of allograft
loss.
Recurrent or de novo GN: Recurrent or de
novo GN can result in significant lowered long-term allograft
survival:
o Retrospective study: assessed the outcome of 5000 KTx (in the RADR), 167 of which had clinical & biopsy-proven recurrent or de novo Gm disease. The RR for allograft
loss was 1.9
for TR with Gm disease. At 5 ys, ptns with Gm disease had a
much higher rate of graft loss (60 vs 32 % in those with no Gm disease).
o For 1505 renal TR with ESRD due to GN, graft loss due to biopsy-proven recurrent GN was reported in 52 ptns (3.5 %). The 10-y incidence of graft loss due to recurrent
disease was estimated
to be 8.4 %; recurrent GN
was the 3rd most common cause of allograft failure
among this group.
The improving long-term
survival seen in well-matched HLA allografts
may also be less apparent in TR with
a primary Gm disease. One report:
60 ptns with identical-, HLA, LRD Tx, graft
survival was correlated with the original kidney disease. Among the 33 ptns
with an underlying GN, the 5-, 10-, & 20-y allograft survival was 88, 70,
& 63 %, resp; in contrary, no
one case of allograft failure was reported among other ptns with
non-Gm kidney disease. Recurrent disease seems to be the principal aetiology of allograft
loss.
Type of donated kidney: LDK Tx have
a higher long-term graft longevity as compared with DDK
(primarily BDD). The 2009 SRTR report: the 5-y graft survival for LDK,
non-ECD, and ECD kidneys
were 81, 72,
& 57 %, resp. An allograft
survival benefit with living Tx is also reported with the 2nd allografts. The observed
difference is reflecting the optimal environment around the living,
related donated grafts as compared
to the current injurious events around the deceased donation. Moreover, allograft
survival decline can be correlated with the lowered
quality of the deceased kidney. There
is also an increasing body of evidence from Japan that long-term longevity with
DCD kidneys
seems to be adequate. One Japanese study: overall allograft survival at 5 &
10 ys: 72
& 53 %, resp.
It is not certain if DCD kidneys from older donors may experience worsened outcome as compared
with grafts from BDD of a comparable age. One study: grafts from DCD donors
>65 ys of age showed lowered GFR at one y with tendency to a lowered 5-y allograft survival as compared to younger DCD
donors. However, no significant difference in allograft survival
if kidneys with intense vascular lesions
have been excluded. Moreover, the report of UK registry
showed no difference in allograft failure for DCD donors
>60 ys of age as compared to BDD with similar
ages. Along the last several ys, in the US, there
is observed steady improving in outcomes of the DCD
kidneys. Considering the UNOS database, outcomes of DCD
KTx at 5
ys post-Tx, both in terms of ptn (81 %) & graft (67 %) longevity, is
not significantly different from that of kidneys from BDD.
Gene polymorphisms: Variations in
the ability to mount an effective immune response against the graft, as well as
difference in underlying agents involving graft fibrosis,
represent allo-Ag-independent factors
that may impact allograft survival:
o CAV1: has a crucial
role in the evolution of organ fibrosis. Retrospective study:
CAV1 polymorphism is complicated
with a higher risk of graft failure that is highly related
to allograft fibrosis.
o CCR5: Study: assessed graft
survival in 1227 renal TR screened for the 32-base-pair
deletion for CCR5. Ptns with homozygous deletion (leading to non-functional receptor & seen in 1
% of Europe/North America Caucasians) had significantly better
graft survival than non-homozygous ptns (90 vs 25 % survival at 20 ys).
o
C3 allotypes: The impact of C3 allotypes on
clinical outcome still uncertain. 2 C3 allotypes, F for fast & S for slow that seems to have an impact on the inflammatory
disorders. One study: graft
survival was significantly increasing with C3F/F & C3F/S donor kidney, with a benefit unique to TR with no C3F allele. However, larger
study: no relation between improved survival & various types of C3.
U/S resistive
index (RI): Higher
RI (by Doppler U/S) has been complicated by marked decline in
allograft longevity in some but not all reports:
o Single-centre German study: assessed 601 stable ptns at
least 3 mo after
success-ful KTx; all ptns
were followed for 3 ys. RI of >80
% that is non-specific reflection of higher vascular
resistance, was reported in 20 % of ptns.
Compared with ptns with a lower RI, ptns with a RI >80 % were more prone to get the composite endpoint of a 50 % decline in allograft function, need
for DX, or recipient
death. TR with RI of >80
% had a multivariate RR of allograft
loss of 9.1.
o Recent study: correlated RI with ptn survival, allograft longevity, and graft histology. This prospective study of 321 kidney TR confirmed the
previous study’s findings that a RI >0.8 was complicated with a higher
risk for a composite endpoint of a 50 % decline in allograft function, need for DX, or TR death.
The more recent report showed: RI ≥0.8 at 3,
12, & 24 mo was complicated with a higher MR as compared
to TR with
index <0.8
but not with allograft failure or with renal histopathology (protocol
biopsy), and via the latter time points, a higher RI
correlated mostly with TR older age;
other factors included higher PP,
lower mean BP, BB use, and
diuretics. These data suggesting a RI
obtained at certain times after Tx reflects
TR but not allograft criteria. Among
biopsies obtained for allograft dysfunction, higher RI correlated
with AMR &
ATN
but could not differentiate between them. Variabilities in study design,
especially timing of obtaining RI,
the short follow-up period, altered im/m,
and antiviral prophylaxis in addition to variabilities in the technical facilities
may explain the discordancy in results.
Hyperhomocysteinemia: Increased
homocysteine levels are accompanied with declined graft survival.
Prospective study: 733 renal TR comparing baseline fasting plasma total homocysteine
levels with kidney allograft longevity within 6.1 ys follow-up. Higher
levels of homocysteine (≥12
micromol/L) were complicated
with a higher risk of allograft failure (HR 95%) & MR (HR 95%). A RCT (Folic
acid for FAVORIT) did not detect any
benefit of adding high-dose B
complex vit. supplementation, however.
Proteinuria: The finding
of proteinuria (including levels of <1 gm/d) is a predictor of
long-term allograft failure. This correlation likely reflecting
the finding of ischemia-reperfusion lesion (s), ongoing immunological/non-immunological
graft injury.
Geography: may be a predictor of
long-term allograft longevity. For example, one analysis indicated: long-term longevity
of TR in the US is
significantly declined as compared to that of TR
in Australia/New Zealand, Europe, & Canada. The reason for
this finding is not certain, despite variable immunotherapy
plans may be implicated.
OPTIMIZING OUTCOMES: Pre-, peri-, &
post-Tx factors
affecting allograft survival.
o Pre-Tx: The aim of Tx team is engrafting
as many TR as possible meanwhile
limiting sequelae affecting graft/ptn survival. However, such targets may vary.
The wide use of KDPI >85 % kidneys can augment the number of Tx whilst negatively impact allograft longevity. So, a key target of the
organ selecting programs is to optimize such variables via secondary benefits supplies
e.g., waiting time decline for candidate TR. Tx plans should consider
ptn selection criteria as vital predictors of survival. Tx a higher % of "high-risk" TR will adversely
affect survival rates.
o Peri-Tx: Minimizing CIT & WIT is a crucial target to limit the risk of DGF & lowered allograft survival. In fact, allocated &
transported organ delay are logistic reality with little influence of the
concerned programs.
o Post-Tx: Optimized titration of im/m is crucial after successful Tx. Control of Rj rates should
be in balance with the risk of infection. Considering co-morbidities e.g., HT & dyslipidaemia can help improving the long-term outcome.
COMMENTS