The official journal of the Japan Atherosclerosis Society and

the Asian Pacific Society of Atherosclerosis and Vascular Diseases

Review J Atheroscler Thromb, 2023; 30: 720-732. http://doi.org/10.5551/jat.RV22005

Progress in Pathological Diagnosis after Kidney Transplantation:

Current Trend and Future Perspective

Kosuke Masutani

Division of Nephrology and Rheumatology, Department of Internal Medicine, Faculty of Medicine, Fukuoka University, Fukuoka,
Japan

Advances in immunosuppressive therapy; posttransplant management of allograft rejection; and measures

against infectious diseases, cardiovascular diseases, and malignancy dramatically improved graft and patient
survival after kidney transplantation (KT). Among them, kidney allograft biopsy is an important tool and the
gold standard for the diagnosis of various kidney allograft injuries, including allograft rejection, virus-induced
nephropathy, calcineurin inhibitor toxicity, and posttransplant glomerular diseases. The Banff Conference on
Allograft Pathology has contributed to establishing the diagnostic criteria for kidney allograft rejection and
polyomavirus-associated nephropathy that are used as a common standard worldwide. In addition to the for-
cause biopsy, many transplant centers perform protocol biopsies in the early and late posttransplant periods to
detect and treat allograft injury earlier. Preimplantation biopsy in deceased-donor KT has also been performed,
especially in the marginal donor, and attempts have been made to predict the prognosis in combination with
clinical information and the renal resistance of hypothermic machine perfusion. Regarding the preimplantation
biopsy from a living kidney donor, it can provide useful information on aging and/or early changes in lifestyle
diseases, such as glomerulosclerosis, tubulointerstitial changes, and arterial and arteriolar sclerosis, and be used as
a reference for the subsequent management of living donors. In this review, morphologic features of important
kidney allograft pathology, such as allograft rejection and polyomavirus-associated nephropathy, according to the
latest Banff classification and additional information derived from protocol biopsy, and future perspectives with
recently developed technologies are discussed.

Key words: Allograft rejection, Banff classification, BK polyomavirus-associated nephropathy,

Molecular diagnostics, Protocol biopsy

malignancies has also improved graft and patient

Introduction
It is well-known that patients with chronic
kidney disease (CKD) and its terminal state, end-stage
kidney disease, are strongly associated with
arteriosclerotic disease 1, 2) and poor patient survival 3).
Patients who reach end-stage kidney disease usually
receive renal replacement therapies, including
hemodialysis, peritoneal dialysis, and kidney
transplantation (KT). Regarding modern KT,
advances in immunosuppressive treatment have
reduced the incidence and severity of early acute
rejection, and posttransplant management of rejection,
infectious diseases, cardiovascular diseases, and
survival. Currently, KT is considered the first choice
for renal replacement therapy worldwide.
Kidney allograft biopsy is an important tool for
posttransplant management and is the gold standard
for the diagnosis of various allograft injuries, including
acute or chronic active rejection, BK polyomavirus-
associated nephropathy (BKPyVAN), calcineurin
inhibitor toxicity, and recurrent or de novo glomerular
diseases 4-6). The Banff Conference on Allograft
Pathology has established the diagnostic criteria for
allograft rejection and other KT-related pathologies
that are used as a common standard. In addition to
the for-cause biopsy for allograft dysfunction and/or

Address for correspondence: Kosuke Masutani, Division of Nephrology and Rheumatology, Department of Internal Medicine, Faculty of Medicine, Fukuoka
University,Nanakuma 7-45-1, Jonan-ku, Fukuoka, 814-0180, Japan E-mail: kmasutani@fukuoka-u.ac.jp
Received: May 8, 2023 Accepted for publication: May 16, 2023
Copyright©2023 Japan Atherosclerosis Society
This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.

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 Progress in Kidney Allograft Pathology
urinary abnormalities, many institutes perform
protocol biopsies at 3, 6, and 12 months or later
mainly to detect subclinical rejection 7, 8). A baseline
biopsy is performed preimplant (0-hour biopsy) or
1-hour postreperfusion (1-hour biopsy), which can
also provide useful information about the donor. In
addition, a baseline biopsy from a living kidney donor
is a valuable opportunity to observe the effects of
aging and/or lifestyle diseases without CKD on early
renal pathological changes and can be used as a
reference for the subsequent management of living
kidney donors.
In this review, morphologic features of important
kidney allograft pathology, such as acute or chronic
active rejections and BKPyVAN, according to the
latest Banff classification and additional information
derived from protocol biopsy, and future perspectives
are discussed.
Diagnosis of Kidney Allograft Rejection: Contribution
of the Banff Conference on Allograft Pathology
Histopathological changes associated with kidney
allograft rejection have been reported since the
1960s 9, 10). However, no standardized diagnostic
criteria were present at that time. The Banff
Conference on Allograft Pathology was founded in
1991 by a group of renal pathologists, nephrologists,
and transplant surgeons 11), and the conference has
been held biannually thereafter. In the Banff
Conference, they have discussed mainly allograft
rejection by the following methods: creating working
groups, proposing diagnostic criteria, verifying their
validity, revising the criteria, and publishing the
meeting reports.
From 1991 through 1997, the conference
focused on the evaluation of individual pathological
lesions and the establishment of the lesion scoring
system (score 0–3), which can be used across countries
and specialties: tubulitis (t), intimal arteritis (v),
mononuclear cell interstitial inflammation (i),
glomerulitis (g), interstitial fibrosis (ci), tubular
atrophy (ct), allograft glomerulopathy (cg), mesangial
matrix increase (mm), arterial fibrous intimal
thickening (cv), arteriolar hyaline thickening (ah) 12).
They also outlined allograft pathology in six
categories: category 1, normal; category 2, antibody-
mediated rejection (ABMR; hyperacute and accelerate
acute); category 3, borderline changes “suspicious” for
acute rejection; category 4, acute/active rejection;
category 5, chronic/sclerosing allograft nephropathy;
and category 6, others. The Banff 97 Working
Classification forms the basis of the subsequent
revisions 12).
Acute/active rejection in the Banff 97 classification
mainly indicated acute T-cell-mediated rejection
(TCMR) (Fig. 1A–C), and an ABMR component
should be suspected if polymorphonuclear leukocytes are
confirmed in peritubular and glomerular capillaries or a
type III vascular lesion (v3, fibrinoid change/transmural
arteritis) is found. Diagnostic criteria for pure acute/
active antibody-mediated rejection had been discussed in
the 2001 Banff Conference, in which peritubular
capillary staining with split C4 complement component
(C4d) was accepted as a useful marker of ABMR, and
classification of ABMR was established as follows: Type I:
C4d+, acute tubular necrosis-like change with minimal
inflammation; Type II: C4d+, capillary margination and/
or thrombosis; and Type III: C4d+, transmural arteritis
(v3) (Fig. 2A–C) 13). Until the Banff 2015 Conference,
evaluation of C4d staining (immunohistochemical
staining and immunofluorescence), diagnostic criteria
for ABMR without C4d deposition in peritubular
capillaries, and inclusion of increased expression of
gene transcripts in the biopsy tissue indicative of
endothelial injury were discussed and validated 14).
Diagnostic criteria of chronic active ABMR were also
discussed and are characterized by persistent capillary
endothelial cell injury resulting in a double contour of
the glomerular basement membrane (by light or
electron microscopic observation) and peritubular
capillary basement membrane multilayering on
electron microscopy (Fig. 3A and 3B).
Since short- to medium-term kidney allograft
survival has improved, the diagnosis and treatment of
chronic active rejection have become more important
for long-term graft survival. The Banff 2015 and 2017
Conferences mainly concentrated on the clinical
outcomes of inflammation in the areas of interstitial
fibrosis and tubular atrophy (i-IFTA) and its
association with TCMR (Fig. 3C). Inflammation
involving ＞ 25% of areas of cortex with IFTA,
corresponding to Banff 2015 i-IFTA scores 2 and 3,
was associated with a high risk of graft loss 15, 16). Thus,
the Banff 2017 Conference revised the classification
and added moderate i-IFTA plus moderate or severe
tubulitis as diagnostic of chronic active TCMR 17).
Chronic allograft arteriopathy (arterial intimal fibrosis
with mononuclear cell inflammation in the fibrosis
and formation of neointima) might be found in a
more severe form of chronic active TCMR (Fig. 3D).
This arterial lesion may also be a manifestation of
chronic active ABMR or mixed ABMR/TCMR. The
impact of chronic active TCMR at 1-year protocol
biopsy was investigated using the large retrospective
cohort of two Japanese centers, and it was
demonstrated that 8% of biopsies were diagnosed as
chronic active TCMR. Determinants of the diagnosis
were cyclosporin use, previous acute rejection, and
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Fig. 1. Pathological findings of acute TCMR

A. Severe interstitial mononuclear cell infiltration was found in more than half of the cortical area (i3 score) (PAS stain).
B. Severe tubulitis with ＞ 10 mononuclear cells in the tubulus (t3 score) (PAS stain).
C. Severe intimal arteritis with at least 25% narrowing of the luminal area by subendothelial edema and infiltrating mononuclear cells (arrow)
(v2 score) (PAS stain).

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Fig. 2. Pathological findings of active ABMR

A. Transplant glomerulitis with mononuclear infiltrate and enlargement of endothelial cells (PAS stain).
B. Severe peritubular capillaritis with ＞ 10 mononuclear cell infiltration (ptc3 score) (PAS stain).
C. Diffuse C4d staining in peritubular capillaries, as demonstrated by immunofluorescence microscopy (c4d3 score).

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Fig. 3. Pathological findings of chronic active ABMR (A, B) and chronic active TCMR (C, D)
A. Double contours affecting more than 50% of peripheral capillary loops in the non-sclerotic glomerulus (cg3 score) (PAM stain).
B. Peritubular capillary basement membrane multilayering on electron microscopy (arrow) (ptcml1 score).
C. Active interstitial inflammation in the scarred area in the cortical area (i-IFTA 3 score) (PAS stain).
D. Fibrous arterial intimal thickening with mononuclear infiltrate (arrow) (cv3 score) (Masson Trichrome stain).

Table 1. Summary of Banff lesion scores used for grading acute and chronic active T-cell mediated rejection (TCMR) and
antibody-mediated rejection (Reference 4)
Acute Banff scores (score 0, 1, 2, 3) Chronic Banff scores (score 0, 1, 2, 3) Acute and Chronic Banff scores (score 0, 1, 2, 3)
i ci ti
t ct i-IFTA
v cv t-IFTA
g cg
ptc ptcml
c4d
i: Interstitial inflammation, t: Tubulitis, v: Intimal arteritis, g: Glomerulitis, ptc: Peritubular capillaritis, c4d: c4d deposition in peritubular capillary,
ci: Interstitial fibrosis in cortex, ct: Tubular atrophy in cortex, cv: Arterial intimal fibrosis, ptcml: Peritubular capillary basement membrane
multilayering, ti: Total cortical inflammation, i-IFTA: Inflammation in scarred cortex, t-IFTA Tubulitis in tubules within scarred cortex.

previous BKPyVAN. Longitudinal observation
revealed that chronic active TCMR had a higher risk
of graft dysfunction than normal tissue, and the
incidence of graft dysfunction was comparable with
ABMR, BKPyVAN, and glomerulonephritis 8). A
summary of the Banff lesion score and the latest Banff
classification is summarized in Tables 1 and 2 4).
Importantly, molecular diagnostics using
microarray technology have significantly contributed
to the validation of the diagnosis of ABMR, TCMR,
viral infection, acute kidney injury, and the
corresponding pathological lesions. The utility of gene
expression analysis has been discussed since the 2001
Banff Conference and has been an important part of
the scientific program at every meeting thereafter. The
ultimate purpose of molecular diagnostics is to
improve diagnostic precision, and the 2013 Banff
classification officially included molecular diagnostics
in the criteria of ABMR as an equivalent to C4d
deposition in peritubular capillaries, based on the
results that the overexpression of endothelial cell-
associated transcript in the presence of donor-specific
antibodies was associated with graft loss even in the
absence of C4d deposition in peritubular capillaries 18).

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Table 2. 2019 Banff classification for ABMR, borderline changes, TCMR, and polyomavirus nephropathy (Reference 4)
Category 1: Normal biopsy or nonspecific changes
Category 2: Antibody-mediated changes
Active ABMR; all 3 criteria must be met for diagnosis
1. Histologic evidence of acute tissue injury, including 1 or more of the following:
- Microvascular inflammation (g ＞ 0 and/or ptc ＞ 0), in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline
infiltrate, or infection, ptc ＞ 1 alone is not sufficient and g must be ＞ 1
- Intimal or transmural arteritis (v ＞ 0) - Acute thrombotic microangiopathy, in the absence of any other cause
- Acute tubular injury, in the absence of any other apparent cause
2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
- Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections, or C4d ＞ 0 by IHC on paraffin sections)
- At least moderate microvascular inflammation ([g＋ptc] ＞ 2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR,
borderline infiltrate, or infection, ptc ＞ 2 alone is not sufficient and g must be ＞ 1
- Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
3. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above
in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised
whenever criteria 1 and 2 are met
Chronic active ABMR; all 3 criteria must be met for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
- Transplant glomerulopathy (cg ＞ 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron
microscopy (EM) alone (cg1a)
- Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
- Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favour chronic ABMR if there is no prior history of TCMR, but
are not required
2. Identical to criterion 2 for active ABMR, above
3. Identical to criterion 3 for active ABMR, above, including strong recommendation for DSA testing whenever criteria 1 and 2 are met. Biopsies meeting criterion 1 but
not criterion 2 with current or prior evidence of DSA (post-transplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for
diagnosis of chronic active or active ABMR
Chronic (inactive) ABMR
1. cg ＞ 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
C4d staining without evidence of rejection; all 4 features must be present for diagnosis
1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d ＞ 0 by IHC on paraffin sections)
2. Criterion 1 for active or chronic active ABMR not met
3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR
4. No acute or chronic active TCMR, or borderline changes
Category 3: Borderline (Suspicious) for acute TCMR
Foci of tubulitis (t1, t2, or t3) with mild interstitial inflammation (i1), or mild (t1) tubulitis with moderate-severe interstitial inflammation (i2 or i3) No intimal or
transmural arteritis (v = 0)
Category 4: TCMR
Acute TCMR
Grade IA: Interstitial inflammation involving ＞ 25% of non-sclerotic cortical parenchyma (i2 or i3) with moderate tubulitis (t2) involving 1 or more tubules, not
including tubules that are severely atrophic
Grade IB: Interstitial inflammation involving ＞ 25% of non-sclerotic cortical parenchyma (i2 or i3) with severe tubulitis (t3) involving 1 or more tubules, not including
tubules that are severely atrophic
Grade IIA: Mild to moderate intimal arteritis (v1), with or without interstitial inflammation and/or tubulitis
Grade IIB: Severe intimal arteritis (v2), with or without interstitial inflammation and/or tubulitis
Grade III: Transmural arteritis and/or arterial fibrinoid necrosis involving medial smooth muscle with accompanying mononuclear cell intimal arteritis (v3), with or
without interstitial inflammation and/or tubulitis
Chronic active TCMR
Grade IA: Interstitial inflammation involving ＞ 25% of sclerotic cortical parenchyma (i-IFTA2 or i-IFTA3) AND ＞ 25% of total cortical parenchyma (ti2 or ti3) with
moderate tubulitis (t2 or t-IFTA2) involving 1 or more tubules, not including severely atrophic tubules; other known causes of i-IFTA should be ruled out
Grade IB: Interstitial inflammation involving ＞ 25% of sclerotic cortical parenchyma (i-IFTA2 or i-IFTA3) AND ＞ 25% of total cortical parenchyma (ti2 or ti3) with
severe tubulitis (t3 or t-IFTA3) involving 1 or more tubules, not including severely atrophic tubules; other known causes of i-IFTA should be ruled out
Grade II: Chronic allograft arteriopathy (arterial intimal fibrosis with mononuclear cell inflammation in fibrosis and formation of neointima). This may also be a
manifestation of chronic active or chronic ABMR or mixed ABMR/TCMR
Category 5: polyomavirus nephropathy
PVN Class 1: pvl 1 and ci 0-1
PVN Class 2: pvl 1 and ci 2-3 OR pvl 2 and ci 0-3 OR pvl 3 and ci 0-1
PVN Class 3: pvl 3 and ci 2-3
ABMR: Antibody mediated rejection, TCMR: T-cell mediated rejection, TMA: Thrombotic microangiopathy, DSA: Donor-specific antibody,
HLA: Human leukocyte antigen, PVN: Polyomavirus nephropathy

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 Progress in Kidney Allograft Pathology
Although the use of molecular diagnostics for the
analysis of kidney allograft biopsies remains limited to
a small number of centers, mainly in North America
and Western Europe, standardization of molecular
diagnostics across laboratories and multicenter
validation studies, including the definition of
diagnostic and clinically relevant thresholds for
molecular analyses, is progressing. Most of the
published studies of molecular diagnostics in the
biopsy samples used microarray techniques performed
on an extra biopsy core in addition to routine
pathological diagnosis. More recently, the results
derived from formalin-fixed paraffin-embedded
section analysis have emerged, which revealed the
expression of the gene sets overlapping with previously
reported microarray analyses, demonstrating that
significant associations between molecular and
pathologic phenotypes are reported 19, 20). The
advantage of this technique for formalin-fixed
paraffin-embedded sections is that the analysis can be
performed on the same sample that is used for routine
light microscopic observation. In addition, it can be
used in large-scale retrospective and prospective
studies with multicenter collaboration so that the
associations between gene expression and clinical
endpoints such as allograft loss can be investigated.
BKPyVAN: Pathology and Risk Prediction of Graft
Dysfunction
Modern immunosuppressive regimens are more
potent and T-cell-specific and have reduced the
incidence of early graft loss caused by acute rejection.
Conversely, infectious complications are still an
important issue. Adenovirus and BKPyV are major
pathogens that could directly involve kidney allograft
injury. Of those, adenovirus can cause hemorrhagic
cystitis and tubulointerstitial nephritis of the kidney
allograft. While patients show apparent clinical
symptoms such as fever, dysuria, gross hematuria, and
frequency and urgency of urination, and most patients
show acute allograft dysfunction, these symptoms and
graft dysfunction are generally reversible 21). As
compared with adenovirus infection, BKPyV infection
in kidney transplant patients rarely shows clinical
symptoms, but the incidence of viruria, viremia, and
tissue invasive nephropathy (BKPyVAN) is higher
than that observed in adenovirus infection 22). Kidney
Disease: Improving Global Outcomes and the
American Society of Transplantation (AST) Infectious
Disease Community of Practice published guidelines
that recommend screening for viral replication by
quantitative PCR and preemptive reduction of
immunosuppression in patients with viremia 23, 24).
Although the detection of viremia by the PCR
method is helpful, the gold standard for diagnosing
BKPyVAN is a kidney allograft biopsy. On light
microscopic observation, various degrees of interstitial
inflammation with mononuclear cells and occasionally
with plasma cells are evident. This interstitial
inflammation is difficult to distinguish from acute
TCMR by light microscopic observation alone. More
specific findings of BKPyVAN are cytopathic changes
in tubular epithelial cells caused by viral replication.
These changes are associated with intranuclear
inclusion bodies, tubular cell necrosis resulting in the
cell shedding into the tubular lumen and denudation
of the tubular basement membrane (Fig. 4A and 4B).
Typical cytopathic changes in tubular cells are focally
observed and may cause misdiagnosis through
sampling error, especially in the early stages of the
disease. In addition to the light microscopic
observation, most centers add immunohistochemical
staining for Simian Virus 40 large T-antigen (Fig. 4C),
which is a more sensitive staining than the one using
anticapsid protein VP1 antibody 25).
Currently, no safe and effective antiviral therapy
has been established, and modification of
immunosuppressive regimens remains the mainstay of
treatment for BKPyVAN. As BKPyVAN is a
pathological diagnosis, there has been an interest in
exploring the effects of pathological findings on
response to treatment and graft outcome. A composite
system to stage BKPyVAN based on viral cytopathic
effect, severity of inflammation, and fibrosis was first
proposed by Drachenberg et al. 26), and subsequently,
the AST Infectious Disease Community of Practice
published modifications of this scheme 24). The Banff
Working Group on Polyomavirus Nephropathy also
proposed their first staging system in 2009 (Banff
Working Proposal 2009), emphasizing the degree of
virus-induced tubular epithelial injury, measured by
necrosis, cell lysis, shedding into the tubular lumen,
and denudation of tubular basement membranes 27).
Both staging systems categorize severe IFTA as stage C,
which is associated with poor graft function reversal.
However, regarding stages A and B, the discriminating
power for serum creatinine reversal was low in both
systems 28), and it was necessary to reconsider the
staging system.
Further statistical analysis by the Banff Working
Group using a retrospective cohort of 192 patients
identified two independent histological factors
associated with clinical presentation: intrarenal viral
load (Banff pvl score) and the extent of interstitial
fibrosis (ci score). They proposed a new classification
using those parameters in 2013 (Banff Working
Proposal 2013, Fig. 5) 18) and published the final
results of a multicenter study in 2018 29). They
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Fig. 4. Pathological findings of BKPyVAN

A. Intranuclear inclusion bodies in the tubular epithelial cells (arrow) (H&E stain).
B. Tubular cell shedding into the lumen and denudation of tubular basement membrane (arrow) (H&E stain).
C. Positive immunohistochemical staining for SV40 large T-antigen in the infected tubular epithelial cells.
D. Electron microscopy to demonstrate intranuclear viral particles measuring 45–55 nm in diameter.

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demonstrated that changes in serum creatinine levels
from baseline after 12 and 24 months were
significantly higher in class 3 than in classes 1 and 2.
Importantly, those values were also significantly
different between classes 1 and 2. Graft failure rates
within 24 months were 16% in class 1, 31% in class
2, and 50% in class 3, suggesting that the Banff
Working Proposal 2013 has a strong discriminating
power for graft outcome in BKPyVAN 30). Eventually,
the proposal was incorporated into the latest Banff
classification as a new category 5 (Table 2) 3).

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Protocol Biopsies after KT to Detect and Treat
Subclinical Rejection
In modern KT, immunosuppressive protocols
commonly consist of antibody induction (rabbit-
derived antithymocyte globulin or IL-2 receptor
antagonist) followed by a triple drug regimen
consisting of calcineurin inhibitors, antimetabolites,
and corticosteroids. As a result, the onset of acute
rejection is delayed, and the severity is reduced. The
rate of subclinical rejection without elevated serum
creatinine levels is also increased. Mehta et al. 30) and
Nankivell and Chapman 31) described literature review
for subclinical rejection, which revealed that the
incidence of subclinical rejection reported by different
centers and eras was widely distributed from 2.6% to
60.8%, but the incidence was relatively lower in
individuals receiving tacrolimus and mycophenolate
mofetil-based regimens with or without
corticosteroids 30, 31). The incidence of subclinical
rejection appeared to be multifactorial and was
influenced by several clinical characteristics, such as
recipient demographics, HLA mismatch counts, ABO
incompatibility, timing of protocol biopsies, use or
non-use of T-cell depleting antibodies, maintenance
immunosuppression, and steroid therapy.
The author and coinvestigators reviewed the
results of protocol biopsies performed 3 and 12
months after KT, separately for ABO blood-type
compatible (N = 226) and incompatible transplants
(N = 101) without preformed donor-specific
antibodies 7). At our institute, approximately 85% of
KT patients underwent protocol biopsy, and more
than 93% of the patients underwent induction
immunosuppression with basiliximab, followed by
tacrolimus, mycophenolate mofetil, and
methylprednisolone for maintenance, and
desensitization with a single dose (200 mg/body) and
plasmapheresis for ABO-incompatible KT. The Banff
2009 classification was used for pathological
interpretation. Under those uniform policies,
subclinical rejection defined by Banff grades IA or
higher in acute TCMR was found in 6.9% and 9.9%
of patients in the ABO-compatible and ABO-
incompatible KT groups at 3 months (P = 0.4) and in
12.4% and 10.1% at 12 months, respectively (P = 0.5).
ABMR mixed with TCMR was found in only one
patient who underwent ABO-incompatible KT. Those
results suggested comparable allograft pathology and
medium-term graft survival between ABO-compatible
and ABO-incompatible KTs under desensitization
with low-dose rituximab and plasmapheresis.
However, subsequent Banff classifications have
changed the diagnostic criteria for chronic active
ABMR and chronic active TCMR and have also
changed the diagnostic threshold for borderline
changes, so the pathology of protocol biopsies needs
to be revisited.
There have been a few studies to demonstrate the
beneficial effect of subclinical TCMR on kidney
allograft function. An early randomized controlled
study reported by Rush et al. investigated the 72
patients who underwent either repeated protocol
biopsy at 1, 2, 3, 6, and 12 months (biopsy arm) or at
6 and 12 months (control arm) and treated subclinical
rejection based on the biopsy findings. A 2-year
follow-up revealed better allograft function in the
biopsy arm 32). Another randomized study conducted
by Kurtkoti et al. investigated 102 living-donor kidney
transplant patients randomly assigned to receive
protocol biopsies or for-cause biopsies only. Although
the incidence of clinically evident rejection episodes
was similar between the two groups, the biopsy group
showed a lower serum creatinine level at 6 months
and 1 year 33). Szederkényi et al. also reported the
results of their single-center randomized trial,
consisting of 113 patients in the protocol biopsy
group and 51 in the control group. The protocol
biopsy group revealed significantly better graft
function at 3 years and better graft survival at 5 years
than the control group 34).
Those findings suggest that intensive protocol
biopsy and treatment of subclinical TCMR might be
beneficial. However, those randomized trials have
several limitations, such as a small sample size, a lack
of long-term follow-up, and differences in
immunosuppressive therapy depending on the era.
Mehta et al. simulated various potential scenarios
(incidence of clinical TCMR, incidence of subclinical
TCMR, and reduction rate of event with an
intervention) and sample size calculations and
estimated that at least 294 and possibly as many as
3,213 cases will be required based on 80% power and
5% type I error 30). The incidence of subclinical
ABMR is relatively rare compared to that of
subclinical TCMR and is found in patients with
ABO- and HLA-incompatible KTs. Although the
study of the treatment of subclinical ABMR is limited,
Parajuli et al. conducted a single-center retrospective
study and demonstrated that patients with subclinical
ABMR who are treated with bolus steroids,
plasmaphereses, and intravenous immunoglobulins
show good graft survival that is similar to that of
donor-specific antibody-positive and no rejection
patients 35). Conversely, the prevalence of borderline
changes is higher, and the significance of antirejection
treatment for subclinical borderline changes is also to
be clarified. Currently, the Treatment of Early
Borderline Lesions in Low Immunological Risk
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 Kosuke Masutani
Kidney Transplant Patients (TRAINING) trial
(clinicaltrials.gov: NCT04936282) is undergoing 36).
Significance of Preimplantation Biopsy in
Deceased- and Living-Donor KTs
Shortage of kidney donors is a serious problem
worldwide, and expanded criteria donors (ECDs,
including those aged ＞ 60 years or 50–59 years and
meeting at least two of the following criteria:
cerebrovascular death, history of hypertension, or last
serum creatinine of ＞ 1.5 mg/dL) and kidney donor
profile index (KDPI, evaluating 10 donor-related
factors including age, height, weight, history of
diabetes and hypertension, serum creatinine, hepatitis
C status, ethnicity, cause of death, and donation after
cardiac death) are mainly used as criteria for predicting
the prognosis after KT and evaluating whether the
deceased-donor is suitable for transplantation or
not 37). Preimplantation biopsy is performed in many
kidney transplant centers as an important predictive
tool, as well as renal resistance to hypothermic
machine perfusion 38) . In deceased-donor KT,
preimplantation biopsy is recommended when the
deceased-donor meets the criteria of ECD or a high
KDPI. There are many studies investigating the
correlation between preimplantation biopsy findings,
clinical features of the donor, and outcomes after KT.
Those studies mainly focused on global
glomerulosclerosis, IFTA, arteriolar hyalinosis, and
arterial fibrous intimal thickening, and some of them
created composite scoring systems and demonstrated
their predictive value on graft survival 39-41) .
Preimplantation biopsy was also discussed at the Banff
Conference. It created a preimplantation biopsy
working group and published their discussion of
various issues and limitations, such as tissue sampling,
interobserver reproducibility of individual lesions,
histopathological factors associated with graft
function, comprehensive clinical evaluation using
KDPI, urinary biomarkers, training of general
pathologists to read donor biopsies, and adoption of
rapid formalin-fixation and paraffin-embedding
protocols 42).
In the living-donor KT, kidneys are donated by
non-CKD, healthy individuals who undergo detailed
preoperative evaluation 43). Thus, a preimplantation
biopsy is not conducted to determine whether to
proceed with transplantation. Instead, living kidney
donors will survive for a long time after donation, so
we consider the donors as patients with newly
developed CKD due to kidney donation, assess
possible complications based on the implantation
biopsy, and continue a careful follow-up. A baseline
biopsy may be performed as a preimplantation (0-hour
728
biopsy) or postreperfusion (1-hour biopsy), depending
on the institute. In the latter, ischemia–reperfusion
injury and, rarely, early changes in ABMR can be
observed. Tissue sampling is performed by either
wedge biopsy or needle core biopsy. Different from
the deceased-donor KT, there is no urgent need for
evaluation, so formalin-fixed paraffin-embedded
sections are evaluated, and the quality of the specimen
is good. Histopathological evaluation also includes
global glomerulosclerosis, interstitial inflammation,
IFTA, arterial fibrous intimal thickening, arteriolar
wall thickening, and hyaline changes possibly
associated with aging, hypertension, and other lifestyle
diseases of the living-donor. Although rare, subclinical
glomerular diseases might be diagnosed on baseline
biopsy 44), and latent glomerular IgA and C3
deposition are often observed 45). As in the deceased-
donor KT, there have been several observational
studies that examined the relationship between
pathological lesions in the donor kidney and allograft
function 46) and recipients’ posttransplant anemia 47).
Preimplantation biopsy in living-donor KT is a
valuable opportunity to estimate predonation clinical
settings and early histopathological changes. The
author and coinvestigators retrospectively analyzed the
specific histopathological findings of preimplantation
biopsies from living kidney donors. We identified
renal arteriolar hyaline changes in 158 (40.2%) and
arteriolar wall thickening in 148 (37.6%) among 393
biopsy samples from living kidney donors and
demonstrated that serum uric acid concentration was
the independent risk factor of arteriolar hyaline
changes after the multivariable adjustment (odds ratio
of quartile 4 versus quartile 2 [reference], 2.22; 95%
confidence interval, 1.17–4.21). Importantly, the
serum uric acid level of quartile 4 corresponds to ＞ 6.5
mg/dL in males and ＞ 5.1 mg/dL in females,
suggesting that the development of arteriolar injury
could be influenced by a high normal range of serum
uric acid levels even in non-CKD individuals, beyond
conventional atherosclerotic risk factors 48). Another
study focused on the global glomerulosclerosis and
predonation left ventricular hypertrophy of the living
kidney donor. We categorized 238 preimplantation
biopsies into tertiles according to the percentage of
global glomerulosclerosis. The left ventricular mass
index was measured by echocardiography. Donors
with high tertiles (global glomerulosclerosis ≥ 11.77%)
had a sevenfold greater risk of having left ventricular
hypertrophy than those with low tertiles (0%–3.45%),
even after adjusting for age, gender, systolic blood
pressure, history of diabetes, total serum cholesterol,
and measured glomerular filtration rate by
radioisotopic technique 49). Those findings suggest that
 Progress in Kidney Allograft Pathology
renal impairment associated with lifestyle diseases and
cardiac hypertrophy associated with cardio-renal
syndrome could develop early even in individuals
without meeting the criteria for CKD. If a baseline
kidney biopsy reveals any of those findings, careful
and long-standing management of the living kidney
donor is necessary.
Future Perspectives
Current diagnostics for kidney allograft biopsy
have developed over the more than 30-year history of
the Banff Conference on Allograft Pathology. In
addition to conventional diagnostics using light
microscopy, immunofluorescence studies, and electron
microscopy, they have discovered molecular
diagnostics. In the 2013 classification, increased
expression of endothelial gene transcript was
incorporated into the criteria of ABMR for the first
time, and molecular diagnostics of TCMR, calcineurin
inhibitor toxicity, and viral infections (BKPyV,
cytomegalovirus, Epstein–Barr virus) have also been
investigated. Recently, the Banff NanoString
consortium established a consensus-based and
commercially available standardized Banff Human
Organ Transplant (B-HOT) discovery gene panel that
can be reproducibly applied to formalin-fixed and
paraffin-embedded samples across organs and in
multicenter studies. They also suggested that data
integrated platform (DIP) design consists of three
elements: 1) data production (histology, molecular,
and clinical), 2) DIP (web interface, cloud computing)
to centralize, check, and validate data, and 3) results
production by participating physicians or scientists
using built-in analytical tools 50).
In addition to tissue-based diagnostics, the
discovery of non-invasive molecular markers for
effective diagnosis of kidney allograft rejection is of
interest and an active field of research. Several body
fluid assays, such as kSORT (kidney solid organ
response test, comprising peripheral blood
transcriptome assessment), chemokines CXCL9 and
CXCL10, and donor-derived cell-free DNA, for
diagnosing kidney allograft rejection from peripheral
blood or urine sediment, have been launched
commercially 51). Thus far, the sensitivity and
specificity of those assays are insufficient to allow
using them as a replacement for allograft biopsy, as
none of the suggested markers appear to be sufficiently
specific for the phenotypic heterogeneity of transplant
pathology.
Digital pathology has become increasingly
common in pathology practice, not only in the
diagnosis of biopsy samples but also for research
purposes. At the 2019 Banff Conference, a digital
pathology working group was formed. Digital
pathology refers to a broad collection of computerized
techniques applied to pathology, including whole slide
imaging, algorithms of morphometric analysis,
algorithms employing artificial intelligence or machine
learning, and natural language processing. According
to the survey in the international transplant pathology
community conducted by the Banff digital pathology
working group, routine scanning of whole slide images
was performed in 71% of the centers, a digital
pathology image analysis algorithm to examine certain
features was available in 24%, and artificial
intelligence or machine learning in the analysis of
digital pathology images was available in 12% 52). They
also described their future plans: practice
standardization, integrative approaches for study
classification, scoring of histologic parameters (e.g.,
IFTA and inflammation), algorithm classification, and
precision diagnosis (e.g., molecular pathways and
therapeutics) 52). Several studies investigating the utility
of immunohistochemical staining, whole-scan images,
and an automated image analysis algorithm for
individual pathological lesions have already been
published 53, 54), and further development in this field
is expected.
Acknowledgement
The author thanks Drs. Akihiro Tsuchimoto,
Kaneyasu Nakagawa, Yuta Matsukuma, Kenji Ueki
and Eri Ataka from Kyushu University for providing
pathological images of kidney allograft biopsy in this
article.
Conflict of Interest
The author declares to have no relevant financial
interests.
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