acute kıdney

Clinical features and diagnosis of acute renal
allograft rejection
Authors:
Daniel C Brennan, MD, FACP
Tarek Alhamad, MD, MS, FACP, FASN
Andrew Malone, MB, BCh, MRCPI
Section Editor:
Christophe Legendre, MD
Deputy Editor:
Albert Q Lam, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2019. | This topic last updated: Nov 29, 2018.
INTRODUCTION
Acute renal allograft rejection is a major cause of
allograft dysfunction. Some kidneys do not regain function even with maximal
antirejection therapy.
Even among patients who recover, acute rejection episodes can have a negative
impact on long-term graft survival. Acute rejection is a major predictor of interstitial
fibrosis/tubular atrophy (IF/TA), formerly called chronic allograft nephropathy, which
is responsible for most death-censored graft loss after the first year posttransplant.
(See "Chronic renal allograft nephropathy", section on 'Importance of acute
rejection'.)
There has been a dramatic reduction in the incidence of acute rejection due to the
introduction of potent immunosuppressive drugs in the past three decades. However,
optimizing immunosuppression to both prevent allograft rejection and minimize drug
toxicity, new-onset diabetes, dyslipidemia, infection, and malignancy remains
challenging.
A discussion of the clinical features and diagnosis of acute renal allograft rejection is
presented in this topic review. The evaluation of renal allograft dysfunction and the
treatment of acute rejection are presented separately:
●(See
"Evaluation and diagnosis of the patient with renal allograft
dysfunction".)
●(See "Treatment of acute T cell-mediated (cellular) rejection of the renal
allograft".)
●(See "Prevention and treatment of antibody-mediated rejection of the renal
allograft".)
DEFINITIONS
Acute renal allograft rejection is defined as an acute
deterioration in allograft function associated with specific pathologic changes in the
graft. There are two principal histologic forms of acute rejection:
● Acute T cell-mediated (cellular) rejection (TCMR), which is
characterized by lymphocytic infiltration of the tubules, interstitium, and, in
some cases, the arterial intima.
● Active
(acute) antibody-mediated rejection (ABMR), the diagnosis of
which requires morphologic evidence of acute tissue injury, evidence of
circulating donor-specific alloantibodies, and immunologic evidence of an
antibody-mediated process (such as C4d deposition in the allograft).
ABMR and acute TCMR may coexist at the same time in the allograft.
Subclinical rejection is defined as the presence of histologic evidence of acute
rejection on biopsy without an elevation in the serum creatinine concentration [1-10].
Subclinical rejection is primarily detected by a protocol, or surveillance, biopsy, which
is obtained at a protocol-driven, prespecified time after transplantation rather than for
a clinical indication such as allograft dysfunction. Most of the reports of subclinical
rejection involve TCMR [1-8]. However, there are reports of allografts with histologic
manifestations of ABMR in the absence of functional deterioration of kidney function
[11]. (See 'Subclinical rejection' below.)
EPIDEMIOLOGY AND OUTCOMES
Acute rejection — The advent of calcineurin inhibitors and antiproliferative agents
dramatically lowered the incidence of acute rejection. Among adult patients who
received allografts between 2005 and 2009, the incidence of one episode of acute
rejection over five years following transplantation was approximately 17 percent for
living-donor kidneys and 20 percent for deceased-donor kidneys [12]. By comparison,
at least one acute rejection episode occurred in 50 to 60 percent of renal allograft
recipients in the 1980s [13].
The incidence of acute rejection among first-year posttransplant patients decreased
from 10 percent in 2009 to 2010 to 8 percent in 2013 to 2014, as reported by the
Organ Procurement and Transplantation Network (OPTN) [14]. Overall, the rate of
acute rejection in the first year posttransplant is 1 to 2 percent lower in living-donor
than deceased-donor kidney transplants. This difference is probably related to better
matching in living-donor transplants and less cold ischemia time.
Risk factors for the development of acute rejection include pre-sensitization (ie,
presence of donor-specific antibodies [DSAs] or a high panel reactive antibody
[PRA]), human leukocyte antigen (HLA) mismatches, pediatric recipient, AfricanAmerican ethnicity, blood group incompatibility, prolonged cold ischemia time, and
delayed graft function (DGF). In addition, patients with a previous episode of
rejection, those receiving a second or greater transplant, and those with medication
nonadherence are at increased risk for acute rejection. (See "Induction
immunosuppressive therapy in kidney transplantation in adults", section on
'Determining risk of acute rejection'.)
Acute rejection episodes are generally associated with a reduction in long-term
allograft survival, although not all rejection episodes have the same impact on longterm graft function. Factors such as timing of rejection, severity and number of acute
rejections, and degree of recovery of function after treatment all affect the long-term
outcome [15]. If renal function returns to baseline, acute rejection does not
necessarily cause irreparable damage or impact long-term graft survival [16,17].
(See "Risk factors for graft failure in kidney transplantation".)
Despite significant reductions in the incidence of acute rejection over the last decade,
there has not been a similar improvement in long-term allograft survival. The
underlying reasons for this are unclear. Possibilities include:
●Patients
that are at high risk for T cell-mediated rejection (TCMR) are also
at high risk for antibody-mediated rejection (ABMR). Although the use of
potent induction agents may prevent acute TCMR in predisposed
recipients, these patients may develop early interstitial fibrosis/tubular
atrophy (IF/TA) that is antibody mediated and not easy to diagnose or treat
[18].
●The beneficial effects of lower incidence of acute rejection are offset by
the negative effects of calcineurin inhibitor nephrotoxicity and
overimmunosuppression [19].
●More potent induction therapy might prevent acute rejections that would
have responded well to therapy. This leaves ABMR and mixed TCMR and
ABMR that frequently do not respond as well.
Subclinical rejection — As defined above, subclinical rejection is when histologic
changes of acute rejection are observed in the absence of an increased serum
creatinine concentration [1-8]. The incidence of subclinical rejection in the first six
months after a kidney transplantation is highly variable and depends on several
factors including degree of HLA matching, presence of DSAs, immunosuppressive
protocol, and the incidence of DGF [5].
As is acute rejection, subclinical rejection may be less common in the current era of
immunosuppressive regimens. As an example, in a multicenter, randomized trial of
240 kidney transplant recipients treated
with tacrolimus/mycophenolate/glucocorticoids, the overall prevalence of subclinical
rejection was only 4.6 percent [20], compared with a much higher prevalence cited in
previous studies [21]. Reduced rates of acute and subclinical rejection may also be
related to the increased sensitivity of pretransplant testing for preformed anti-HLA
antibodies, which improves the compatibility of transplanted organs.
One multicenter study examined the incidence of histologic manifestations of ABMR
in 551 protocol and 377 indication biopsies [11]. The major histologic finding under
study was C4d staining, which was generally associated with other morphologic
evidence of ABMR. Diffuse and focal C4d staining was observed in 2.0 and 2.4
percent of protocol biopsies, respectively, and in 12.2 and 8.5 percent of indication
biopsies, respectively [11]. The incidence of C4d-positive biopsies varied significantly
among centers, with a higher percentage of C4d-positive biopsies noted at a center
that transplanted a higher percentage of sensitized patients. In another study from
Europe, positive C4d staining was detected in 36 percent of patients with subclinical
ABMR [9].
Many [1,2,4,22-27], though not all [3,6], studies have demonstrated an association
between subclinical rejection demonstrated by protocol biopsy and decreased
allograft survival and/or function. As examples:
●In
one study of 435 protocol biopsies, subclinical rejection with IF/TA was
an independent predictor of allograft loss (relative risk [RR] 1.86, 95% CI
1.11-3.12) [24].
●An analysis of 833 protocol and 306 clinically indicated biopsies found that
the presence of persistent inflammation on sequential biopsies was a
significant determinant of allograft function independent of an increased
serum creatinine; the prevalence of inflammatory infiltrates was the same
between protocol and clinically indicated biopsies [23].
Overall, patients with subclinical ABMR exhibit worse graft function compared with
those who have subclinical TCMR. In one study, graft survival at eight years in
patients with subclinical ABMR (defined as stable renal function with histologic
features of capillaritis and/or glomerulitis and evidence of DSA) detected on protocol
biopsy at one year posttransplant was 56 percent, compared with 88 percent in those
with subclinical TCMR. All patients with subclinical ABMR had a DSA at the time of
the biopsy, and 22 percent had a de novo DSA. Patients with subclinical TCMR had
similar graft survival as those without rejection (90 percent at eight years) [9].
The significance of subclinical C4d staining in relation to chronic ABMR, IF/TA, and
long-term graft function is not clear. The 2005 Banff diagnostic criteria changed the
ABMR category to reflect the finding of C4d in some cases of chronic allograft
dysfunction, suggesting that ABMR is a likely contributor to some forms of chronic
nephropathy [28].
It is unclear if the administration of therapy to patients with subclinical rejection
improves clinical outcomes. This is discussed elsewhere. (See "Treatment of acute T
cell-mediated (cellular) rejection of the renal allograft", section on 'Borderline and
subclinical rejection'.)
CLINICAL FEATURES
Clinical manifestations — Most episodes of acute rejection occur within the first six
months after transplantation, with many such episodes occurring early after surgery.
Rejection after 12 months is typically from noncompliance or overaggressive
reduction in immunosuppression.
Most patients who have acute rejection episodes are asymptomatic. However,
occasionally, patients present with fever, malaise, oliguria, and graft pain and/or
tenderness [29]. These manifestations are uncommon with modern
immunosuppressive drug regimens, particularly calcineurin inhibitors, unless
immunosuppression is completely discontinued. Since most patients are
asymptomatic, acute rejection is suggested only by an increase in the serum
creatinine or proteinuria.
●(See
"Overview of care of the adult kidney transplant recipient", section on
'Monitoring renal allograft function'.)
●(See "Evaluation and diagnosis of the patient with renal allograft
dysfunction".)
Laboratory manifestations — Patients with acute allograft rejection present with an
acute rise in the serum creatinine. A rising serum creatinine level, however, is a
relatively late development in the course of a rejection episode and usually indicates
the presence of significant histologic damage. Pyuria or new or worsening proteinuria
may also be present.
Plasma levels of donor-derived cell-free DNA (dd-cfDNA), which is released into the
bloodstream by dead cells in the injured allograft, may be elevated (>1 percent) in
patients with acute rejection [30-32]. In one study, plasma levels of dd-cfDNA were
measured in 102 kidney transplant recipients and correlated with allograft rejection
status as determined by renal allograft biopsy [30]. The dd-cfDNA level was able to
differentiate between biopsy specimens showing any form of rejection (T cellmediated rejection [TCMR] or antibody-mediated rejection [ABMR]) and those without
rejection. Using a cutoff of 1.0 percent, dd-cfDNA had a positive and negative
predictive value for active rejection of 61 and 84 percent, respectively. These findings
suggest that dd-cfDNA may serve as a noninvasive biomarker for the diagnosis of
allograft rejection.
Radiographic manifestations — Most findings obtained by renal imaging are
nonspecific, and such studies are generally performed to exclude other causes of
acute kidney injury (AKI). Ultrasonography may show increased graft size, with loss
of corticomedullary junction, prominent hypoechoic pyramids, and decreased
echogenicity of the renal sinus [29]. Renal Doppler studies obtained via ultrasound
may show elevated resistance indices (RIs), but this finding is not specific and may
also be observed with ureteral obstruction, acute tubular necrosis (ATN), renal vein
occlusion, pyelonephritis, and cyclosporine toxicity [33,34]. Nuclear medicine renal
scans may show delayed visualization of kidneys.
DIAGNOSIS
Acute renal allograft rejection should be suspected among all
transplant recipients who present with a creatinine that is increased above the
patient's usual baseline, and it is confirmed by renal allograft biopsy. However,
among transplant recipients, there are other potential causes of an increased serum
creatinine that do not require a biopsy to diagnose and should be excluded prior to
performing a biopsy. (See "Evaluation and diagnosis of the patient with renal allograft
dysfunction", section on 'Patients presenting with an elevated serum creatinine'.)
When to suspect acute rejection — Acute renal allograft rejection should be
suspected in patients with one or more of the following:
●New increase in serum creatinine of ≥25 percent from baseline or a serum
creatinine that is higher than expected (such as in recently transplanted
patients whose serum creatinine stops decreasing earlier than expected
after transplantation). However, in patients who are at increased risk for
antibody-mediated rejection (ABMR) (eg, highly sensitized patients,
recipients of ABO-incompatible renal allografts, patients with donor-specific
antibodies [DSAs], and patients with inadequate immunosuppression), any
incremental increase in serum creatinine should raise the suspicion for the
possibility of acute rejection.
●Worsening hypertension.
●Proteinuria >1 g/day.
●Plasma
donor-derived cell-free DNA (dd-cfDNA) >1 percent.
(See 'Laboratory manifestations' above.)
Confirming the diagnosis of rejection — The standard for the diagnosis of renal
allograft rejection is a renal allograft biopsy, which is used to accurately grade the
severity of rejection, differentiate between T cell-mediated rejection (TCMR) and
ABMR, and determine the degree of irreversible kidney damage (interstitial
fibrosis/tubular atrophy [IF/TA]). Biopsy of the renal allograft can also reveal other
causes of renal inflammation and injury, including cytomegalovirus (CMV) disease,
BK (polyomavirus) nephropathy, interstitial nephritis, pyelonephritis, de novo or
recurrent glomerular disease, and posttransplant lymphoproliferative disease (PTLD).
(See 'Differential diagnosis' below.)
There have been various attempts to standardize the histologic criteria for acute
rejection in order to allow comparisons of efficacy of different therapies and to help
guide treatment [35]. Classification systems that have been introduced include the
Banff classification system, published in 1993 [36], and the Cooperative Clinical
Trials in Transplantation (CCTT) [37]. The Banff and the CCTT systems were both
incorporated into the Banff 97 classification [38]. Increased histologic severity based
upon the 1997 Banff classification correlated with unresponsiveness to therapy and
decreased allograft survival [39].
The Banff 97 diagnostic categories have since been modestly revised [28,40-42].
The 2011 Banff Conference on Allograft Pathology recognized the existence of C4dnegative ABMR in renal allografts but stopped short of adding a diagnostic category
of C4d-negative ABMR. Diagnostic criteria for C4d-negative ABMR were
incorporated into the 2013 Banff update [43]. The 2017 Banff Kidney Meeting Report
modified the diagnostic criteria for ABMR by stating that both C4d staining and
validated molecular assays could serve as potential alternatives to DSAs in the
diagnosis of ABMR [44]. (See 'Active (acute) antibody-mediated rejection' below.)
It may be difficult to distinguish between acute ABMR and severe acute TCMR, and
the two processes may also coexist. In addition, in up to 25 percent of cases of
allograft dysfunction attributed, at least in part, to ABMR, the histologic findings are
suggestive of only TCMR or acute tubular injury [45]. It is important to identify ABMR,
if possible, since it is often refractory to treatment modalities aimed at acute TCMR
and, unless adequately treated, often results in renal allograft loss.
Other methods used to help diagnosis acute renal allograft rejection have been the
focus of a large number of investigators and are discussed in detail separately.
(See "Investigational methods in the diagnosis of acute renal allograft rejection".)
Acute T cell-mediated (cellular) rejection — Acute TCMR is caused by T cells that
react to donor histocompatibility antigens present within tubules, interstitium, vessels,
and glomeruli of the allograft. The pathologic changes that occur with acute TCMR
include interstitial infiltration with mononuclear cells, and, occasionally eosinophils,
and disruption of the tubular basement membranes by the infiltrating cells (ie,
tubulitis) [36]. Tubulitis and interstitial mononuclear cell inflammation are the primary
lesions. Intimal arteritis may be seen in TCMR but can also be found in ABMR. The
presence of patchy mononuclear cell infiltrates without tubulitis is not uncommon in
normal functioning renal allografts and is not, by itself, sufficient to make the
diagnosis of acute TCMR. The presence of neutrophils is uncommon and suggests
the diagnosis of infection or ABMR.
The Banff classification of acute TCMR is divided into the following grades (picture
1):
– Mild interstitial inflammation (<25 percent of nonsclerotic
cortical parenchyma; i0 or i1) plus any tubulitis (t1, t2, or t3) or significant
interstitial inflammation (>25 percent of nonsclerotic cortical parenchyma; i2
or i3) plus foci of mild tubulitis (t1)
●Type IA – Significant interstitial inflammation (>25 percent of nonsclerotic
cortical parenchyma; i2 or i3) and foci of moderate tubulitis (t2)
●Type IB – Significant interstitial inflammation (>25 percent of nonsclerotic
cortical parenchyma; i2 or i3) and foci of severe tubulitis (t3)
●Type IIA – Mild-to-moderate intimal arteritis (v1) with or without interstitial
inflammation and tubulitis
●Type IIB – Severe intimal arteritis comprising >25 percent of the luminal
area (v2) with or without interstitial inflammation and tubulitis
●Type III – Transmural arteritis and/or arterial fibrinoid change and necrosis
of medial smooth muscle cells with accompanying lymphocytic
inflammation (v3)
●Borderline
The diagnosis of acute TCMR requires a histologic score of at least t2 and i2. Any
scores below this (eg, i1+t2 or i2+t1) are considered to be borderline rejection. The
significance of the presence of intimal arteritis alone (eg, v1) is controversial but still
allows for the diagnosis of TCMR.
Active (acute) antibody-mediated rejection — ABMR is caused by the binding of
circulating antibodies to donor alloantigens on graft endothelial cells, which results in
inflammation, cell damage, and, ultimately, graft dysfunction. Such antigens most
commonly include human leukocyte antigen (HLA) class I and class II antigens and,
in recipients of ABO-incompatible transplants, ABO blood group antigens; other nonmajor histocompatibility complex (MHC) alloantigens on the endothelium may also be
targeted [46-49].
The diagnosis of ABMR requires three components (table 1):
●Histologic
evidence of acute tissue injury (see 'Histologic findings' below)
●Evidence of antibody interaction with vascular endothelium (eg, C4d
staining in peritubular capillaries [PTCs]) (see 'C4d staining' below)
●Serologic evidence of circulating DSAs (see 'Detection of donor-specific
antibodies' below)
Patients with the first two criteria but no evidence of DSAs (eg, evidence of tissue
injury and positive C4d staining without a detectable DSA) were previously
considered to be "suspicious" for ABMR and typically treated as patients with ABMR.
In the Banff 2017 update [44], the presence of peritubular C4d staining and/or the
expression of validated gene panels strongly associated with ABMR can substitute
for DSAs in the diagnosis of ABMR. (See 'Detection of donor-specific
antibodies' below.)
Some patients have morphologic evidence of ABMR and a positive DSA with little or
no C4d staining. C4d-negative ABMR is often seen in patients with DSAs and
persistent microcirculation inflammation (ie, capillaritis and/or glomerulitis), resulting
in chronic microvascular remodeling [42]. The timing, type of transplant, and
technique used to detect C4d may impact the detection of and interpretation of C4d
or its absence. C4d-negative ABMR may also represent antibody-mediated injury that
does not activate the complement cascade (eg, antibody-dependent, cell-mediated
cytotoxicity). Patients with C4d-negative ABMR should be suspected of having ABMR
if all other features of ABMR exist.
●(See
'C4d-negative antibody-mediated rejection' below.)
'Detection of donor-specific antibodies' below.)
●(See "Prevention and treatment of antibody-mediated rejection of the renal
allograft".)
●(See
Histologic findings — Histologic features of ABMR include capillary endothelial
swelling, arteriolar fibrinoid necrosis, fibrin thrombi in glomerular capillaries (GC),
and, in severe cases, frank cortical necrosis. Severe vasculitis, glomerulitis with
neutrophils in the GC and PTCs, fibrin thrombi, fibrinoid necrosis, and interstitial
hemorrhage are more commonly seen with ABMR compared with TCMR (picture
2 and picture 3). In some cases, ABMR may present only with evidence of acute
tubular necrosis (ATN) [45]. The presence of linear staining for C4d, a degradation
product of the complement pathway that binds covalently to the endothelium, is
highly suggestive of ABMR. (See 'C4d staining' below.)
The initial description of histologic findings present in association with DSA and
allograft dysfunction, as well as a comparison of the findings in the setting of acute
rejection in the presence or absence of DSA, has helped to define the pathologic
associations [50-52]. Although GC and PTC neutrophil infiltration has classically been
associated with ABMR, monocyte infiltration of the GC and PTC (as detected by
CD68 staining) is likely a more sensitive histologic indicator of ABMR, based on an
association with C4d staining [53]. This has been further defined with the
demonstration that T cells are the predominant infiltrating cell in the glomerulus in
acute rejection associated with negative C4d staining, while the monocyte may be
the predominant type of infiltrating glomerular cell associated with C4d-positive acute
rejection [54]. It is the presence of intraglomerular rather than interstitial monocytes
that seems to correlate with C4d-positive ABMR [55]. Other histologic correlates may
include interstitial edema associated with a high percentage of plasma cells [56].
Graft dysfunction due to ABMR, as defined by DSA or C4d positivity, can be present,
despite the absence of histomorphologic features of rejection [57,58]. As an example,
up to 25 percent of cases of ABMR may be missed on a histologic basis alone [45].
Additionally, diagnostic criteria for C4d-negative ABMR have been incorporated into
the 2013 Banff update [43]. Acceptable evidence for antibody interaction with the
endothelium includes C4d positivity but alternatively includes moderate-to-severe
microvascular inflammation and/or molecular evidence of endothelial injury using a
validated assay [59], even if C4d negative. (See 'C4d staining' below and 'C4dnegative antibody-mediated rejection' below.)
The simultaneous occurrence of ABMR and TCMR, or "mixed rejection," may also be
a common event, and prominent histologic findings representative of TCMR may
mask those of ABMR [60]. Histologic findings representative of ABMR may also
occur in episodes of rejection that otherwise have no other evidence of humoral
rejection. (See 'Mixed acute rejection' below.)
Thus, it is recommended that, in addition to histology, C4d staining and the presence
of DSA be evaluated in suspected cases of rejection.
C4d staining — Detection of the complement split product C4d in renal allograft
biopsies is an important adjunctive tool to help understand the alloimmune response
and to diagnose ABMR. C4d is a degradation product of the classic complement
pathway. After an antigen-antibody complex fixes complement, a cascade of events
follows, with activation of several complement proteins. The complement protein C4
is split into C4a and C4b. C4b is then converted to C4d. A unique feature of C4d is
that it binds covalently to the endothelial and collagen basement membranes,
thereby serving as an immunologic footprint of complement activation and antibodymediated injury. (See "Complement pathways".)
In normal kidneys, C4d is detectable in the glomerular mesangium and at the
vascular pole. Deposition of C4d in the PTCs has only been described in renal
allografts and represents complement activity directed against donor antigen (picture
4) [61]. Staining for C4d is reported as diffusely positive when involving >50 percent
of PTCs and focally positive if <50 percent PTCs.
Multiple studies have demonstrated a correlation among positive C4d staining, DSAs,
and histopathologic findings in patients with ABMR [61-63]. In an early study of 16
indication allograft biopsies from 10 patients with circulating DSA and histopathologic
findings suggestive of ABMR, diffusely positive PTC C4d staining was observed in all
biopsies [64]. C4d deposition was seen in the media of arteries displaying fibrinoid
necrosis. In addition, C4d staining in PTC was negative in 14 biopsies with acute
TCMR (without DSA), in five of six cases of cyclosporine toxicity, and in four normal
biopsies. Forty percent of grafts with ABMR were lost, compared with none of those
with acute TCMR alone.
The sensitivity and specificity of C4d for DSA have also been investigated. In a study
of 81 patients with acute rejection, 30 percent had detectable C4d. C4d was found to
be 95 percent sensitive and 96 percent specific for the presence of DSA [45].
In patients with circulating DSA, inferior graft function and survival have been
observed in those with C4d-positive versus -negative staining, suggesting that C4d is
a marker of more significant humoral injury [65-67].
Collectively, the findings of these studies have led to general acceptance of the utility
of C4d in the identification of acute ABMR. In 2003, C4d staining was incorporated in
the Banff classification [41].
However, there are limitations to the use of C4d staining in the diagnosis of ABMR,
as illustrated by the following observations:
●Diffuse
PTC C4d staining can occur in the absence of other histologic
features of injury in recipients of ABO-incompatible kidney transplants, a
phenomenon known as graft accommodation [68]. This is discussed in
more detail elsewhere. (See "ABO incompatibility in kidney
transplantation".)
●Some patients who have a positive DSA and histologic evidence of ABMR
lack any detectable C4d staining in the PTCs [69]. This is known as C4dnegative ABMR and is discussed below. (See 'C4d-negative antibodymediated rejection' below.)
C4d-negative antibody-mediated rejection — Some patients have histologic
evidence of ABMR (microcirculatory inflammation) and a positive DSA but have little
or no C4d staining in the PTCs, an entity recognized as C4d-negative ABMR [69].
The concept of C4d-negative ABMR was introduced in a retrospective study of 1036
renal allograft biopsies from 1320 transplant recipients; only 36 percent of cases with
transplant glomerulopathy (a histologic lesion that is characteristic of chronic [late]
ABMR) had C4d-positive staining, despite the presence of DSAs in 73 percent [70].
Additional evidence for C4d-negative ABMR came from a molecular study in which
gene expression microarrays were performed in 173 indication biopsies to examine
endothelial activation and injury transcripts (ENDATs) [59,71]. High expression of
ENDATs correlated with histologic lesions of ABMR but not TCMR. Among renal
allografts with high ENDATs, positive DSA, and morphologic evidence of chronic
(late) ABMR, 60 percent were C4d negative.
In C4d-negative ABMR, DSA binding to endothelial cells may cause injury through
complement-independent mechanisms.
The clinical significance of C4d-negative ABMR has been shown in two separate
studies of transplant recipients who underwent allograft biopsies within the first three
months posttransplant. In one study of 54 presensitized (DSA-positive) kidney
transplant recipients who underwent protocol biopsies at three months
posttransplant, the presence of capillaritis, even in the absence of C4d, was a risk
factor for the later development of transplant glomerulopathy [10,72]. In a second
study of 98 renal allograft biopsies performed for clinical indications within the first
three months posttransplant, 16 had histologic evidence of ABMR and DSAs but
were C4d negative [73]. Patients with C4d-negative ABMR who were not treated for
ABMR had a higher rate of progression to transplant glomerulopathy compared with
those who were treated.
Detection of donor-specific antibodies — The ability to detect DSAs and diagnose
ABMR has improved markedly with the addition of flow cytometric analysis and solidphase assays such as Luminex (single HLA-coated microspheres) to standard
cytotoxicity assays [74]. The presence of DSAs in patients with renal allograft
dysfunction can provide significant diagnostic and prognostic information. In a study
of 103 kidney transplant recipients with increased serum creatinine values, testing for
HLA and non-HLA antibodies was performed using flow cytometry [75]. C4d-positive
acute rejection was eventually diagnosed in 75 percent of those positive for HLA
antibodies but in only 2 percent of those without such antibodies. Posttransplant
screening for the development of DSAs may also permit the early detection of acute
ABMR and allograft dysfunction, particularly in high-risk patients. In a single-center,
prospective study of 49 transplant recipients, the majority of patients with ABMR
developed DSAs before or concurrent with the ABMR event [76]. By comparison,
only 3 of 41 without ABMR developed DSAs.
DSAs detected by a sensitive solid-phase assay may provide additional prognostic
data. In a meta-analysis that included seven retrospective cohort studies (1119
patients), the presence of DSAs detected by solid-phase assay, but not by flow
cytometry, was associated with nearly twice the risk for ABMR (relative risk [RR]
1.98, 95% CI 1.36–2.89) and increased the risk for graft failure (RR 1.76, 95% CI
1.13–2.74) [77]. In a single-center study, 315 Canadian kidney transplant recipients
(72 percent Caucasian) were followed prospectively with serial DSAs by single-bead
assays and protocol biopsies over a mean six-year period [78]. In this low-risk
population, DSAs, defined as a mean fluorescent intensity >300, developed in 15
percent of patients over six years. The 10-year graft survival rate was lower among
those with de novo DSAs, compared with those without (56 versus 96 percent,
respectively). However, some patients who developed DSAs did well, suggesting
that, although development of de novo DSAs is associated with inferior graft survival,
not all DSAs may be pathogenic.
The presence of nonpathogenic DSAs is also supported by a study of 1016 patients
who received kidney transplants at two centers between 2005 and 2011 [79]. All
patients were tested for circulating HLA DSAs using stored serum samples, which
were obtained at the time of transplantation and at the time of allograft biopsy (which
was performed either at one year after transplantation or during an episode of acute
rejection during the first year after transplantation). Serum samples of patients who
were found to have HLA DSAs were further tested for the presence of C1q-binding
HLA DSAs using a single-antigen flow bead assay. ABMR was more common among
patients with C1q-binding antibodies, compared with those with non-C1q-binding
antibodies (48 versus 16 percent, respectively). Patients with C1q-binding HLA DSAs
also had inferior five-year graft survival compared with patients with non-C1q-binding
DSAs (54 versus 93 percent, respectively). It is important to note that patients with
non-C1q-binding HLA DSAs had lower graft survival and worse histologic features
(such as microvascular inflammation, C4d deposition, and transplant glomerulopathy)
than those without DSAs.
The C1q-binding assay is not widely used and has not been validated in other
institutions. There is concern that the C1q-binding assay may reflect a higher burden
of antibody, and the assay itself may not be an accurate reflection of inherent
complement-binding activity independent of antibody quantity. Furthermore, it is likely
that there are noncomplement-binding DSAs that are clinically relevant and will not
be detected by this assay. One study of 70 kidney transplant recipients who
developed de novo DSAs found a correlation between C1q positivity and DSA titer
and mean fluorescence intensity; however, C1q status was not independently
associated with allograft loss [80].
It is therefore possible that the increasing sensitivity of DSA testing methods that may
identify clinically irrelevant DSA will limit the utility of this screening test in clinically
stable patients [81]. There is no consensus on when to test for DSA, which is the
subject of ongoing prospective studies, particularly in the absence of allograft
dysfunction. In one study of 851 kidney transplant recipients, systematic monitoring
and characterization of DSA posttransplant, which included DSA subclass
identification and assessment of C1q-binding capacity, was found to modestly
improve prediction and risk stratification of allograft loss [82]. At our center, patients
with significant renal dysfunction undergo a kidney biopsy, thereby initiating
concurrent testing for DSA.
A perfect correlation between positive staining for C4d and DSA positivity does not
always occur for a variety of reasons [83]:
●Non-HLA
antibodies can also result in C4d deposition, as in ABOincompatible renal allografts [46,84-86]. Other non-HLA antibodies have
been described, for example, in one report describing refractory acute
vascular rejection and malignant hypertension in 16 patients, occurring in
association with angiotensin II receptor antibodies [46]. Five of the 16
cases demonstrated positive C4d staining despite the absence of
detectable HLA antibodies; by comparison, 13 of 13 patients with
detectable HLA DSA, but no angiotensin II receptor antibodies, had positive
C4d staining. Antiendothelial antibodies [85] and MHC class I polypeptiderelated sequence A (MICA) have also been implicated as potential causes
of ABMR associated with positive C4d staining [85]. Other non-HLA
antibodies include antibodies against vimentin [48], type IV collagen,
fibronectin [87], perlecan, endoglin, FLT3 ligand, ICAM4, and EDIL3; most
of these antibodies are studied in the research setting but are not currently
tested in the routine clinical setting [46].
●Cases in which C4d staining is positive but DSA cannot be detected may
also result from DSA being below the level of detection due to
immunoadsorption by the graft. Detection of HLA antibodies in eluates from
allograft biopsy samples may help overcome this challenge [88] but is not
part of current clinical practice. Further evaluation of DSA detection from
needle biopsy specimens in functioning allografts will be of significant
interest to help settle the issue of immunoadsorption in the setting of
apparent ABMR with negative DSA testing.
The production of complement-activating DSA would be expected to precede C4d
deposition, and a biopsy performed early in the course of ABMR may only detect
minimal or focal C4d deposition. In addition to in vivo and in vitro testing of
complement fixation (C4d), other characteristics, including antigen specificity and
binding strength, may assist in determining the clinical relevance of such DSA.
Mixed acute rejection — Both acute TCMR and ABMR can occur within the same
renal allograft. Estimates of the frequency of mixed acute rejection (both TCMR and
ABMR) have varied in different studies and over time. As an example, in one study,
the rates of acute TCMR, ABMR, and mixed acute rejection were 58, 19, and 23
percent, respectively [89]. However, in another study in which gene expression
microarray analysis, rather than histologic diagnosis, was used to establish the
diagnosis of acute rejection, the frequency of acute TCMR, ABMR, and mixed acute
rejection was 33, 54, and 12 percent, respectively [90].
Patients with mixed acute rejection may be misdiagnosed as having only TCMR or
ABMR, which can lead to these patients being undertreated or incorrectly treated. In
a retrospective analysis of 2079 kidney transplant recipients, 302 patients with
biopsy-proven acute TCMR or ABMR were reclassified into four different patterns of
rejection based upon clinical, histologic, and immunologic phenotypes: T cellmediated vascular rejection (9 percent), antibody-mediated vascular rejection (21
percent), TCMR without vasculitis (46 percent), and ABMR without vasculitis (24
percent) [91]. Of these four patterns, antibody-mediated vascular rejection was
previously unrecognized since vascular rejection (defined as the presence of arteritis
[ie, v1, v2, or v3 lesion]) was, prior to the Banff 2013 revision, considered as TCMR
and not ABMR. At six years posttransplant, patients with antibody-mediated vascular
rejection, 45 percent of whom had received a diagnosis of TCMR at the time of
biopsy, had the lowest rate of graft survival. In addition, those with antibody-mediated
vascular rejection who were treated for acute TCMR had a higher rate of graft loss
than those who received treatment for ABMR.
Chronic active antibody-mediated rejection — Chronic active ABMR was first
recognized in 2001 [92] and is now a distinct category in the Banff classification [28].
In contrast with active ABMR, chronic active ABMR lacks evidence of acute
inflammation and demonstrates findings consistent with matrix synthesis. Chronic
ABMR generally develops late (>6 months posttransplant) and can occur in patients
with or without a history of active ABMR [66].
The diagnosis of chronic active ABMR requires the following three components (table
1):
●Morphologic
evidence of chronic tissue injury (eg, transplant
glomerulopathy, multilayering of the PTC basement membrane, or chronic
arteriopathy with fibrous intimal thickening)
●Evidence of antibody interaction with vascular endothelium (eg, C4d
staining in PTCs indicative of endothelial injury) (see 'C4d staining' above)
●Serologic evidence of circulating DSAs (see 'Detection of donor-specific
antibodies' above)
Patients with the first two criteria but no evidence of DSAs can be diagnosed with
chronic active ABMR if there is C4d-positive staining of PTCs or expression of
validated gene panels associated with ABMR [44]. If neither is present, such patients
are considered to be "suspicious" for chronic active ABMR.
The only difference between the diagnostic criteria for chronic active and active
ABMR is the requirement for histologic evidence of chronic, rather than acute, tissue
injury in chronic ABMR; otherwise, the remaining two criteria are the same.
One of the morphologic features consistent with chronic tissue injury is "transplant
glomerulopathy," a term used to describe the thickening or duplication of GC
basement membranes with an occasional double-contour appearance, resembling
that seen in membranoproliferative glomerulonephritis (MPGN) but without dense
deposits. The glomeruli may also be enlarged and show a lobular pattern; segmental
or, in severe cases, global sclerosis also may be seen. Electron microscopy may
show mesangial cell interposition and subendothelial accumulation of electron-lucent
material (picture 5 and picture 6). Immune complex deposition is generally not a
prominent part of transplant glomerulopathy. Other associated histologic features of
chronic active ABMR include multilamination, or multilayering, of the PTC basement
membranes, chronic arteriopathy with fibrous intimal thickening, and absence of
elastic lamellae.
Investigational methods — Histologic evaluation of a renal allograft biopsy remains
the gold standard for the diagnosis of acute allograft rejection among transplant
recipients. However, a number of alternative methods of diagnosis are under
investigation. These have the potential to improve the accuracy of diagnosis but still
require validation in clinical trials before they can be applied to mainstream clinical
practice. A discussion of these investigational methods is presented elsewhere.
(See "Investigational methods in the diagnosis of acute renal allograft rejection".)
DIFFERENTIAL DIAGNOSIS
As described above, most patients with
acute rejection are asymptomatic and present only with an elevated creatinine [29]. In
patients who present with fever, malaise, oliguria, and/or graft pain or tenderness, the
diagnosis of infection, urinary leak, and obstruction should also be considered.
(See "Clinical manifestations and diagnosis of urinary tract obstruction and
hydronephrosis".)
Among kidney transplant recipients, the causes of an elevated serum creatinine
concentration vary with the time after transplantation and are generally classified as
immediate-, early-, and late-period renal allograft dysfunction. The evaluation and
differential diagnosis of renal allograft dysfunction are discussed in detail separately.
(See "Evaluation and diagnosis of the patient with renal allograft dysfunction".)
Other diseases, such as posttransplant lymphoproliferative disease (PTLD),
cytomegalovirus (CMV) disease, BK (polyomavirus) nephropathy, interstitial nephritis,
and pyelonephritis, may have similar histologic findings to allograft rejection:
(CMV) infection – CMV may manifest as an increased
serum creatinine, with a renal biopsy histologic appearance similar to
rejection. In one study, treatment of the CMV rather than antirejection
treatment was associated with "reversal" of rejection and improvement in
graft function in 17 of 21 patients [93]. In general, whole blood or plasma
CMV viral load testing will identify patients with active CMV disease.
●BK nephropathy – The histologic appearance of BK nephropathy may
mimic the tubulitis and/or arteritis classically associated with rejection [94].
Among such patients, it is extremely important to attempt to differentiate BK
nephropathy from rejection as the two treatments are diametrically
opposed, and increased immunosuppression in the setting of BK
nephropathy will lead to further viral proliferation and potential allograft
loss. However, distinguishing BK nephropathy from acute rejection on the
basis of histology is not always possible, and, in some patients, the two
diagnoses may simultaneously overlap.
Among all patients, special stains for BK should be performed on the
biopsy sample if there is concern for BK nephropathy, even in the absence
of typical viral inclusions on the biopsy. It is essential that medullary tissue
be available for analysis since BK is tropic for medullary tubules more than
cortical tubules. (See "BK polyomavirus-associated nephropathy in kidney
transplantation".)
●Drug- or infection-related interstitial nephritis – Drug- or infection-related
interstitial nephritis may also mimic rejection. Peripheral eosinophilia may
suggest drug-induced acute interstitial nephritis, although its absence does
not exclude its presence.
●Transplant pyelonephritis – Transplant pyelonephritis can cause an
elevation in serum creatinine as well as interstitial and tubular infiltrates.
However, the infiltrate mostly consists of polymorphonuclear cells rather
than lymphocytes. Urine culture will usually be positive for gram-negative
●Cytomegalovirus
organisms, although gram-positive bacteria can cause urinary tract
infections (UTIs) in rare cases. (See "Urinary tract infection in kidney
transplant recipients", section on 'Microbiology'.)
●Posttransplant lymphoproliferative disease (PTLD) – PTLD is suggested
by a diffuse lymphocytic infiltrate of such severity that it is difficult to
visualize tubular architecture, which can occasionally be observed in
patients with severe T cell-mediated rejection (TCMR) (frequently
secondary to noncompliance with immunosuppression).
Since the treatment options for rejection and PTLD are markedly different,
additional studies must be performed to differentiate the two possibilities.
Studies include special stains for T and B cell populations, Epstein-Barr
virus (EBV) antigens, and monoclonal light chains, as well as quantitative
EBV polymerase chain reaction (PCR) and serum and urine protein
electrophoresis. Imaging of the graft should also include the abdomen,
pelvis, and any other clinically relevant areas (see "Treatment and
prevention of post-transplant lymphoproliferative disorders"). Detection of
specific cell markers for T cells, B cells, plasma cells, and monocytes may
also be useful to guide rejection therapy in the setting of a significant
cellular infiltrate with graft dysfunction.
SOCIETY GUIDELINE LINKS
Links to society and government-
sponsored guidelines from selected countries and regions around the world are
provided separately. (See "Society guideline links: Kidney transplantation".)
SUMMARY AND RECOMMENDATIONS
●Acute
renal allograft rejection is a major cause of allograft dysfunction.
Some kidneys do not regain function even with maximal antirejection
therapy. Even among patients who recover, acute rejection episodes can
have a negative impact on long-term graft survival.
(See 'Introduction' above.)
●Acute renal allograft rejection is defined as an acute deterioration in
allograft function associated with specific pathologic changes in the graft.
There are two principal histologic forms of acute rejection, acute T cellmediated (cellular) rejection (TCMR) and active antibody-mediated
rejection (ABMR). ABMR and acute TCMR may coexist at the same time in
the allograft. Subclinical rejection is defined as the presence of histologic
evidence of acute rejection on biopsy without an elevation in the serum
creatinine concentration. (See 'Definitions' above.)
●Risk factors for the development of acute rejection include presensitization (ie, presence of donor-specific antibodies [DSAs] or a high
panel reactive antibody [PRA]), human leukocyte antigen (HLA)
mismatches, pediatric recipient, African-American ethnicity, blood group
incompatibility, prolonged cold ischemia time, and delayed graft function
(DGF). In addition, patients with a previous episode of rejection, those
receiving a second or greater transplant, and those with medication
nonadherence are at increased risk for acute rejection. Acute rejection
episodes are generally associated with a reduction in long-term allograft
survival, although not all rejection episodes have the same impact on longterm graft function. Despite significant reductions in the incidence of acute
rejection over the last decade, there has not been a similar improvement in
long-term allograft survival. (See 'Epidemiology and outcomes' above.)
●Most episodes of acute rejection occur within the first six months after
transplantation, with many such episodes occurring early after surgery.
Rejection after 12 months is typically from noncompliance or
overaggressive reduction in immunosuppression. Most patients who have
acute rejection episodes are asymptomatic. However, occasionally,
patients present with fever, malaise, oliguria, and graft pain and/or
tenderness. Hypertension is also a common finding. (See 'Clinical
manifestations' above.)
●Patients with acute allograft rejection present with an acute rise in the
serum creatinine. A rising serum creatinine level, however, is a relatively
late development in the course of a rejection episode and usually indicates
the presence of significant histologic damage. Pyuria or new or worsening
proteinuria may also be present. Most findings obtained by renal imaging
are nonspecific, and such studies are generally performed to exclude other
causes of acute kidney injury (AKI). (See 'Laboratory manifestations' above
and 'Radiographic manifestations' above.)
●Acute renal allograft rejection should be suspected in patients with one or
more of the following:
•New increase in serum creatinine of ≥25 percent from baseline or a
serum creatinine that is higher than expected (such as in recently
transplanted patients whose serum creatinine stops decreasing earlier
than expected after transplantation). However, in patients who are at
increased risk for ABMR (eg, highly sensitized patients, recipients of
ABO-incompatible renal allografts, patients with DSAs, and patients
with inadequate immunosuppression), any incremental increase in
serum creatinine should raise the suspicion for the possibility of acute
rejection.
•Worsening hypertension.
•Proteinuria >1 g/day. (See 'When to suspect acute rejection' above.)
•Plasma donor-derived cell-free DNA (dd-cfDNA) >1 percent.
●The standard for the diagnosis of renal allograft rejection is a renal
allograft biopsy, which is used to accurately grade the severity of rejection,
differentiate between TCMR and ABMR, and determine the degree of
irreversible kidney damage (interstitial fibrosis/tubular atrophy [IF/TA]).
Biopsy of the renal allograft can also reveal other causes of renal
inflammation and injury, including cytomegalovirus (CMV) disease, BK
nephropathy, interstitial nephritis, pyelonephritis, de novo or recurrent
glomerular disease, and posttransplant lymphoproliferative disease (PTLD).
(See 'Confirming the diagnosis of rejection' above.)
●Chronic active ABMR was first recognized in 2001 and is now a distinct
category in the Banff classification. In contrast with active ABMR, chronic
active ABMR lacks evidence of acute inflammation and demonstrates
findings consistent with matrix synthesis. Chronic ABMR generally
develops late (>6 months posttransplant) and can occur in patients with or
without a history of active ABMR. (See 'Chronic active antibody-mediated
rejection' above.)
ACKNOWLEDGMENT
The editorial staff at UpToDate would like to
acknowledge W James Chon, MD, FACP, who contributed to an earlier version of
this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
Topic 7352 Version 31.0
GRAPHICS
Histology of acute T cell-mediated rejection
(A) This periodic acid-Schiff (PAS)-stained, high-power microscopic image depicts an example of
mild tubulitis identified in a patient with borderline acute T cell-mediated rejection. The arrow is
pointing to a rare lymphocyte within the tubular epithelium (400x).
(B) Example of moderate tubulitis in a case of Banff IA acute T cell-mediated rejection. Thick
arrows point to lymphocytes within the tubular epithelium (H&E, 400x).
(C) As the degree of cellular rejection increases, increased numbers of lymphocytes are seen within
the tubular epithelium (short arrows). Severe tubulitis is seen in this example of Banff IB acute T
cell-mediated rejection (PAS, 400x).
(D) Vascular rejection is defined by the presence of endothelialitis (attachment of lymphocytes to
the vascular wall; arrowhead). In this case of Banff IIA rejection, the endothelialitis is mild (H&E,
400x).
(E) In this example of Banff IIB acute T cell-mediated rejection, the endothelialitis is severe
(dashed arrow, H&E, 400x).
Courtesy of Joseph P Gaut, MD, PhD.
Graphic 116699 Version 1.0
Revised Banff 2017 classification of antibodymediated rejection in renal allografts
met for diagnosis*¶
y, including one or more of the following:
0Δ 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 i
>0)◊
y other cause
ce of any other apparent cause
raction with vascular endothelium, including at least one of the following:
or C4d3 by IF on frozen sections, or C4d >0 by IHC on paraffin sections)
inflammation ([g + ptc] ≥2)§
scripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated¥
her antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, inclu
ised whenever criteria 1 and 2 are met.
must be met for diagnosis*‡
injury, including 1 or more of the following:
ronic TMA or chronic/de novo glomerulonephritis
multilayering (requires EM)**
nset, excluding other causes¶¶
raction with vascular endothelium, including at least one of the following:
or C4d3 by IF on frozen sections, or C4d >0 by IHC on paraffin sections)
inflammation ([g + ptc] ≥2)§
scripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated¥
her antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, inclu
ised whenever criteria 1 and 2 are met.
ction; all 4 features must be present for diagnosisΔΔ
3 by IF on frozen sections, or C4d >0 by IHC on paraffin sections)
ABMR not met
criterion 2 for active and chronic, active ABMR
rderline changes
ABMR: antibody-mediated rejection; g: Banff glomerulitis score; ptc: peritubular capillary; TCMR: T cellmediated rejection; v: Banff arteritis score; TMA: thrombotic microangiopathy; IF: immunofluorescence;
IHC: immunohistochemistry; DSA: donor-specific antibody; HLA: human leukocyte antigen; TG:
transplant glomerulopathy; cg: Banff chronic glomerulopathy score; EM: electron microscopy; ENDAT:
endothelial activation and injury transcript; GBM: glomerular basement membrane.
* For all ABMR diagnoses, it should be specified in the report whether the lesion is C4d positive (C4d2 or
C4d3 by IF on frozen sections; C4d >0 by IHC on paraffin sections) or without evident C4d deposition
(C4d0 or C4d1 by IF on frozen sections; C4d0 by IHC on paraffin sections).
¶ These lesions may be clinically acute, smoldering, or subclinical. Biopsies showing two of the three
features, except those with DSA and C4d without histologic abnormalities potentially related to ABMR or
TCMR (C4d staining without evidence of rejectionΔΔ), may be designated as "suspicious" for acute/active
ABMR.
Δ Recurrent/de novo glomerulonephritis should be excluded.
◊
It should be noted that these arterial lesions may be indicative of ABMR, TCMR, or mixed ABMR/TCMR.
"v" lesions are only scored in arteries having a continuous media with two or more smooth muscle layers.
§ In the presence of acute TCMR, borderline infiltrates or evidence of infection, ptc ≥2 alone is not
sufficient to define moderate microvascular inflammation, and g must be ≥1.
¥ The only validated molecular marker meeting this criterion is ENDAT expression[1], and this has only
been validated in a single center (University of Alberta). The use of ENDAT expression at other centers or
other test(s) of gene expression within the biopsy as evidence of ABMR must first undergo independent
validation as was done for ENDAT expression[1].
‡ Lesions of chronic, active ABMR can range from primarily active lesions with early TG evident only by
EM (cg1a) to those with advanced TG and other chronic changes in addition to active microvascular
inflammation. In the absence of evidence of current/recent antibody interaction with the endothelium
(those features in the Second Section), the term active should be omitted; in such cases, DSA may be
present at the time of biopsy or at any previous time posttransplantation.
† Includes GBM duplication by EM only (cg1a) or GBM double contours by light microscopy.
** Seven or more layers in one cortical ptc and ≥5 in two additional capillaries[2], avoiding portions cut
tangentially.
¶¶ While leukocytes within the fibrotic intima favor chronic rejection, these are seen with chronic TCMR
as well as chronic ABMR and are therefore helpful only if there is no history of TCMR. An elastic stain
may be helpful as absence of elastic lamellae is more typical of chronic rejection, and multiple elastic
lamellae are most typical of arteriosclerosis, although these findings are not definitive.
ΔΔ The clinical significance of these findings may be quite different in grafts exposed to anti-blood-group
antibodies (ABO-incompatible allografts), where they do not appear to be injurious to the graft[3,4] and
may represent accommodation. However, with anti-HLA antibodies, such lesions may progress to chronic
ABMR[5], and more outcome data are needed.
References:
1.
Sis B, Jhangri G, Bunnag S, et al. Endothelial gene expression in kidney transplants with alloantibody
indicates antibody-mediated damage despite lack of C4d staining. Am J Transplant 2009; 9:2312.
2.
Liapis G, Singh HK, Derebail VK, et al. Diagnostic significance of peritubular capillary basement
membrane multilaminations in kidney allografts: Old concepts revisited. Transplantation 2012;
94:620.
3.
Haas M, Rahman MH, Racusen LC, et al. C4d and C3d staining in biopsies of ABO- and HLAincompatible renal allografts: Correlation with histologic findings. Am J Transplant 2006; 6:1829.
4.
Setoguchi K, Ishida H, Shimmura H, et al. Analysis of renal transplant protocol biopsies in ABOincompatible kidney transplantation. Am J Transplant 2008; 8:86.
5.
Bravou V, Galliford J, McLean A, et al. A case of chronic antibody-mediated rejection in the making.
Clin Nephrol 2013; 80:306.
From: Haas M. An updated Banff schema for diagnosis of antibody-mediated rejection in renal allografts.
Am J Transplant 2014; 14:272. http://onlinelibrary.wiley.com/doi/10.1111/ajt.12590/abstract. Copyright
© The American Society of Transplantation and the American Society of Transplant Surgeons.
Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned by
Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or
emailed. Please contact Wiley's permissions department either via email: [email protected] or use
the RightsLink service by clicking on the 'Request Permission' link accompanying this article on Wiley
Online Library (http://onlinelibrary.wiley.com).
Updated with information from:
1.
Haas M, Loupy A, Lefaucheur C, et al. The Banff 2017 Kidney Meeting Report: Revised diagnostic
criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for
integrative endpoints for next-generation clinical trials. Am J Transplant 2018; 18:293.
Graphic 103469 Version 3.0
Light microscopy showing antibody-mediated rejection in renal
transplant biopsy, ATN, and polymorphonuclear leukocytes
Numerous interstitial polymorphonuclear leukocytes (PMNs) and extensive acute tubular necrosis
are evident in this renal transplant biopsy. Histologic findings in antibody-mediated rejection may
include PMN infiltration. This specimen also demonstrated positive C4d staining on
immunofluorescence.
ATN: acute tubular necrosis.
Courtesy of Dr. Helen Liapis, Washington University School of Medicine.
Graphic 81994 Version 4.0
Light microscopy showing antibody-mediated rejection in renal
transplant biopsy, polymorphonuclear leukocytes, and endotheliitis
A section of a renal biopsy specimen demonstrating numerous intersitial polymorphonuclear cells
(PMNs) and an adjacent artery with endotheliitis, another histologic marker suggestive of antibodymediated rejection.
Courtesy of Dr. Helen Liapis, Washington University School of Medicine.
Graphic 70194 Version 4.0
Immunofluorescence C4d staining in a renal transplant biopsy
Immunofluorescence with C4d monoclonal antibody demonstrating diffuse and strong peritubular
capillary deposition in a renal transplant biopsy. The yellow staining indicates C4d deposition. This
is consistent with antibody-mediated rejection.
Courtesy of Dr. Helen Liapis, Washington University School of Medicine.
Graphic 68422 Version 6.0
Transplant glomerulopathy
Light micrograph of transplant glomerulopathy shows a membranoproliferative pattern with
capillary wall thickening and a double-contour appearance due to mesangial interposition (arrow).
Courtesy of Helmut Rennke, MD.
Graphic 58239 Version 2.0
Normal glomerulus
Light micrograph of a normal glomerulus. There are only 1 or 2 cells per capillary tuft, the capillary
lumens are open, the thickness of the glomerular capillary wall (long arrow) is similar to that of the
tubular basement membranes (short arrow), and the mesangial cells and mesangial matrix are
located in the central or stalk regions of the tuft (arrows).
Courtesy of Helmut G Rennke, MD.
Graphic 75094 Version 4.0
Transplant glomerulopathy
Electron micrograph of transplant glomerulopathy reveals marked narrowing of the vascular lumen
due to widening of the subendothelial space both by mesangial cell processes (arrow) and by
amorphous, electron-lucent material.
Courtesy of Helmut Rennke, MD.
Graphic 79914 Version 2.0
Electron micrograph of a normal glomerulus
Electron micrograph of a normal glomerular capillary loop showing the fenestrated endothelial cell
(Endo), the glomerular basement membrane (GBM), and the epithelial cells with its interdigitating
foot processes (arrow). The GBM is thin, and no electron-dense deposits are present. Two normal
platelets are seen in the capillary lumen.
Courtesy of Helmut G Rennke, MD.
Graphic 50018 Version 7.0
Contributor Disclosures
Daniel C Brennan, MD, FACPGrant/Research/Clinical Trial Support: CareDx [Antibody
mediated rejection (Allosure)]. Consultant/Advisory Boards: Alexion; Sanofi; Veloxis [Atypical
hemolytic uremic syndrome, antibody mediated rejection, long-term outcomes,
immunosuppression, induction (Eculizumab, tacrolimus, antithymocyte globulin)].Tarek
Alhamad, MD, MS, FACP, FASNGrant/Research/Clinical Trial Support: Mallinckrodt
[Nephrotic syndrome (ACTH gel)]; Angion [Delayed graft function (BB3 analogue)]. Speaker's
Bureau: Veloxis [Immunosuppression medications (Tacrolimus XR)]; Sanofi [Induction
medication (Thyroglobulin)]; CareDx [Donor-derived cell-free DNA (AlloSure)].
Consultant/Advisory Board: Veloxis [Immunosuppression medications (Tacrolimus
XR)].Andrew Malone, MB, BCh, MRCPINothing to discloseChristophe Legendre,
MDSpeaker's Bureau: Alexion [aHUS (eculizumab)]. Consultant/Advisory Boards: Alexion
[aHUS (eculizumab)].Albert Q Lam, MDNothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When
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content is required of all authors and must conform to UpToDate standards of evidence.
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