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 "Kidney transplantation in adults: Chronic allograft nephropathy", section on 'Alloantigen-dependent factors'.)
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 "Kidney transplantation in adults: Evaluation and diagnosis of acute kidney allograft dysfunction".)
●(See "Kidney transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection".)
●(See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection".)
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 evidence of antibody-endothelial cell interaction (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 detected by a protocol, or surveillance, biopsy, which is obtained at a protocol-driven, prespecified time after transplantation or on detection of de novo donor-specific antibodies (DSAs) [11] rather than for an 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 [11,12]. (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 [13]. By comparison, at least one acute rejection episode occurred in 50 to 60 percent of renal allograft recipients in the 1980s [14].
The incidence of acute rejection among first-year posttransplant patients decreased from 10 percent in 2009 to 2010 to 8 percent in 2016 to 2017, as reported by the Organ Procurement and Transplantation Network (OPTN) [15]. 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, 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. (See "Kidney transplantation in adults: Induction immunosuppressive therapy", section on 'Assessment of immunologic risk'.)
Acute rejection episodes are generally associated with a reduction in long-term allograft survival, although not all rejection episodes have the same impact on long-term 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 [16]. If kidney function returns to baseline, acute rejection does not necessarily cause irreparable damage or impact long-term graft survival [17,18]. (See "Kidney transplantation in adults: Risk factors for graft failure".)
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 [19].
●The beneficial effects of lower incidence of acute rejection are offset by the negative effects of calcineurin inhibitor nephrotoxicity and overimmunosuppression [20].
●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 [21], compared with a much higher prevalence cited in previous studies [22]. 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 [12]. 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 [12]. 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 [1,2,4,23-28], 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) [25].
●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 [24].
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 kidney 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 [29].
It is unclear if the administration of therapy to patients with subclinical rejection improves clinical outcomes. This is discussed elsewhere. (See "Kidney transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection", 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 [30]. 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 "Kidney transplantation in adults: Evaluation and diagnosis of acute kidney 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 [31-39]. 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 [31]. The dd-cfDNA level was able to differentiate between biopsy specimens showing any form of rejection (T cell-mediated 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 [30]. 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 [40,41]. 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 "Kidney transplantation in adults: Evaluation and diagnosis of acute kidney 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 [42]. Classification systems that have been introduced include the Banff classification system, published in 1993 [43], and the Cooperative Clinical Trials in Transplantation (CCTT) [44]. The Banff and the CCTT systems were both incorporated into the Banff 97 classification [45]. Increased histologic severity based upon the 1997 Banff classification correlated with unresponsiveness to therapy and decreased allograft survival [46].
The Banff 97 diagnostic categories have since been modestly revised [29,47-49]. The 2011 Banff Conference on Allograft Pathology recognized the existence of C4d-negative 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 [50]. 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 [51]. (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 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 [52]. 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 "Kidney transplantation in adults: Investigational methods in the diagnosis of acute kidney 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. However, natural killer (NK) cells, macrophages, and other cells may also contribute [53], and the degree of allograft dysfunction may correlate better with the degree of monocyte compared with T cell infiltration [54]. 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) [43]. 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):
●Borderline – 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)
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 thought to be 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 non-major histocompatibility complex (MHC) alloantigens on the endothelium may also be targeted [55-58].
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 [51], 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 [49]. 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.)
●(See 'Detection of donor-specific antibodies' below.)
●(See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection".)
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) [52]. 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 [59-61]. 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 [62]. 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 [63]. It is the presence of intraglomerular rather than interstitial monocytes that seems to correlate with C4d-positive ABMR [64]. Other histologic correlates may include interstitial edema associated with a high percentage of plasma cells [65].
Graft dysfunction due to ABMR, as defined by DSA or C4d positivity, can be present, despite the absence of histomorphologic features of rejection [66,67]. As an example, up to 25 percent of cases of ABMR may be missed on a histologic basis alone [52]. Additionally, diagnostic criteria for C4d-negative ABMR have been incorporated into the 2013 Banff update [50]. 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 [68], even if C4d negative. (See 'C4d staining' below and 'C4d-negative 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 [69]. 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 antibody-mediated 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) [70]. 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 [70-72]. 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 [73]. 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 [52].
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 [74-76].
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 [48].
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 [77]. This is discussed in more detail elsewhere. (See "Kidney transplantation in adults: ABO incompatibility".)
●Some patients who have a positive DSA and histologic evidence of ABMR lack any detectable C4d staining in the PTCs [78]. This is known as C4d-negative ABMR and is discussed below. (See 'C4d-negative antibody-mediated 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 [78]. 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 [79].
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) [68,80]. 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 [10,81]. 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 [82]. 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 solid-phase assays such as Luminex (single HLA-coated microspheres) to standard cytotoxicity assays [83]. 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 [84]. 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 [85]. 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) [86]. In a single-center study, 315 Canadian kidney transplant recipients were followed prospectively with serial DSAs by single-bead assays and protocol biopsies over a mean six-year period [87]. 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 [88]. 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 [89].
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 [90]. 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 [91]. At our center, patients with significant kidney 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 [92]:
●Non-HLA antibodies can also result in C4d deposition, as in ABO-incompatible renal allografts [55,93-95]. 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 [55]. 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 [94] and MHC class I polypeptide-related sequence A (MICA) have also been implicated as potential causes of ABMR associated with positive C4d staining [94]. Other non-HLA antibodies include antibodies against vimentin [57], type IV collagen, fibronectin [96], 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 [55].
●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 [97] 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 [98]. 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 [99].
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 cell-mediated vascular rejection (9 percent), antibody-mediated vascular rejection (21 percent), TCMR without vasculitis (46 percent), and ABMR without vasculitis (24 percent) [100]. 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 [101] and is now a distinct category in the Banff classification [29]. 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 [75].
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 [51]. 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 "Kidney transplantation in adults: Investigational methods in the diagnosis of acute kidney allograft rejection".)
DIFFERENTIAL DIAGNOSIS — As described above, most patients with acute rejection are asymptomatic and present only with an elevated creatinine [30]. 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 (UTO) 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 "Kidney transplantation in adults: Evaluation and diagnosis of acute kidney 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 kidney 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 [102]. 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 [103]. 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 "Kidney transplantation in adults: BK polyomavirus-associated nephropathy".)
●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 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'.)
●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 cell-mediated (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 pre-sensitization (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 long-term 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.
