Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection

INTRODUCTION — Kidney allograft rejection is a major cause of allograft dysfunction. Some kidneys do not regain function even with maximal antirejection therapy.

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, posttransplant diabetes mellitus, dyslipidemia, infection, and malignancy remains challenging.

This topic will review the clinical features and diagnosis of acute kidney allograft rejection. The treatment of acute rejection and the general evaluation of kidney allograft dysfunction are presented separately.

●(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".)

●(See "Kidney transplantation in adults: Evaluation and diagnosis of acute kidney allograft dysfunction".)

DEFINITIONS — The following terminology will be used throughout this topic review:

●Acute rejection – Acute kidney allograft rejection is defined as an acute deterioration in allograft function associated with specific pathologic changes in the allograft. There are two principal forms of acute rejection:

•Acute T cell–mediated (cellular) rejection (TCMR) – This is characterized by lymphocytic infiltration of the tubules, interstitium, and, in some cases, the arterial intima. Acute TCMR is caused by T cells that react to foreign antigens, the most common of which are donor histocompatibility antigens, present within tubules, interstitium, vessels, and glomeruli of the allograft. However, natural killer cells, macrophages, and other cells may also contribute. (See 'Acute T cell-mediated (cellular) rejection' below.)

•Active antibody-mediated rejection (ABMR) – The diagnosis of ABMR is established by morphologic evidence of acute tissue injury, evidence of circulating donor-specific antibodies (DSAs), and evidence of antibody-endothelial cell interaction (such as C4d deposition in the allograft). However, the diagnosis of ABMR can be made without DSAs or C4d.

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 [1-4]. (See 'Active antibody-mediated rejection' below.)

Acute TCMR and ABMR may coexist at the same time in the allograft (ie, mixed acute rejection). Acute rejection may also coexist with chronic rejection. (See 'Mixed acute rejection' below.)

●Chronic rejection – Chronic rejection is characterized by a slow deterioration in allograft function associated with variable degrees of proteinuria and hypertension and is an important contributor to late graft loss. It usually occurs after the first year of transplantation and can occur with or without active inflammation. The three currently recognized types are chronic active ABMR, chronic inactive ABMR, and chronic active TCMR [5,6]. (See 'Chronic rejection' below.)

●Subclinical rejection – Subclinical rejection is defined as the presence of histologic evidence of acute rejection on biopsy without an elevation in the serum creatinine concentration [7-16]. Subclinical rejection is detected by a surveillance, or protocol, biopsy, which is obtained at a protocol-driven, prespecified time after transplantation or on detection of de novo DSAs [17] rather than for an indication such as allograft dysfunction. Most of the reports of subclinical rejection involve TCMR [7-14]. However, there are reports of allografts with histologic manifestations of ABMR in the absence of functional deterioration of kidney function [17,18]. (See 'Subclinical rejection' below.)

EPIDEMIOLOGY

Incidence — The incidence of acute rejection within the first posttransplant year has decreased dramatically over the past three decades with the advent of more potent immunosuppressive drugs. For kidney transplants performed in 2020, the rate of acute rejection in the first posttransplant year was 9.3 percent for recipients aged 18 to 34 years, 7.6 percent for recipients aged 35 to 49 years, 6.1 percent for recipients aged 50 to 64 years, and 5.3 percent for recipients aged ≥65 years (figure 1) [19]. By comparison, 50 to 60 percent of kidney transplant recipients in the 1980s experienced at least one acute rejection episode [20].

Overall, the rate of acute rejection in the first year posttransplant is 1 to 2 percent lower for living-donor compared with deceased-donor kidney transplant recipients. This difference is probably related to better matching in living-donor transplants and less cold ischemia time.

Data on the incidence of acute T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) come primarily from studies from centers that perform surveillance/protocol biopsies, and, as such, they may differ from the national estimates of acute rejection cited above.

●In one systematic review that included 12 studies of patients on tacrolimus and mycophenolate, the incidence of acute TCMR (greater than Banff borderline) was 16 percent during the first posttransplant year [21].

●In another systematic review of 28 cohort studies, the incidence of active ABMR ranged from 1.1 to 21.5 percent although most studies reported an incidence of 3 to 12 percent within the first posttransplant year [22]. The incidence of chronic ABMR ranged from 7.5 to 20.1 percent at up to 10 years of follow-up.

Risk factors — Patients with one or more of the following risk factors are considered to be at high immunologic risk for acute rejection [23] (see "Kidney transplantation in adults: Induction immunosuppressive therapy", section on 'Assessment of immunologic risk'):

●One or more human leukocyte antigen (HLA) mismatches

●Younger recipient and older donor age

●Presence of a donor-specific antibody (DSA)

●Blood group incompatibility

●Delayed onset of graft function

●Cold ischemia time greater than 24 hours

●Previous episode of rejection

●Receipt of a second or greater transplant

●Medication nonadherence

Historically, an elevated pretransplant calculated panel reactive antibody (cPRA) was considered a risk factor for acute rejection and graft loss [23]. This was based on studies that used older and less sensitive and specific technology for PRA testing. With newer technology for PRA testing using single antigen bead assays and virtual cross-matching, elevated cPRA (a measure of probable anti-HLA antibody formation) in the absence of DSA is not associated with inferior graft survival or ABMR in the modern era [24-26]. (See "Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing", section on 'Determination of patient sensitization'.)

Clinical impact — 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 [27]. If kidney function returns to baseline, acute rejection does not necessarily cause irreparable damage or impact long-term graft survival [28,29]. (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 TCMR are also at high risk for 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 [30].

●The beneficial effects of lower incidence of acute rejection are offset by the negative effects of calcineurin inhibitor nephrotoxicity and overimmunosuppression [31].

●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.

●A substantial proportion (39 percent) of biopsy-proven TCMR persists even after treatment with anti-rejection therapy [21]. However, most of these rejections were treated with pulsed glucocorticoids only.

CLINICAL FEATURES

Clinical presentation — Most episodes of acute rejection occur within the first six months after transplantation, with many occurring early after surgery. Rejection after 12 months is typically from nonadherence to or overaggressive reduction in immunosuppression.

Most patients with acute allograft rejection are asymptomatic. However, patients rarely present with fever, malaise, and graft pain and/or tenderness [32]. These manifestations are uncommon with modern immunosuppressive drug regimens, particularly those including calcineurin inhibitors, unless immunosuppression is completely discontinued. Since most patients are asymptomatic, acute rejection is usually suggested by abnormal laboratory testing. (See 'Laboratory findings' below.)

Laboratory findings — Laboratory findings that can be observed in patients with kidney allograft rejection include the following:

●Elevated serum creatinine – An acute rise in the serum creatinine is the most common laboratory finding among patients with acute allograft rejection. A rising serum creatinine level, however, is not specific for acute rejection. It is a relatively late development in the course of a rejection episode and usually indicates the presence of significant histologic damage.

●New or worsening proteinuria – New or increasing proteinuria greater than 1 g/day can be seen in the setting of active antibody-mediated rejection (ABMR) or chronic ABMR. However, proteinuria after transplantation may also be caused by glomerulosclerosis or tubulointerstitial fibrosis from chronic rejection, recurrent glomerular disease, chronic allograft nephropathy, and de novo glomerulopathies.

●Pyuria – Pyuria may be present in patients with acute rejection but can also be seen in the setting of urinary tract infection. (See "Urinary tract infection in kidney transplant recipients".)

●Elevated plasma donor-derived cell-free DNA level – Donor-derived cell-free DNA (dd-cfDNA) is released into the bloodstream by dead cells in the injured allograft. Fractional plasma levels of dd-cfDNA >1 percent or serially increasing levels are associated with episodes of acute rejection [33-41]. In one study in which plasma levels of dd-cfDNA were measured in 102 kidney transplant recipients with acute elevations in serum creatinine, a plasma dd-cfDNA level of >1 percent had a positive predictive value (PPV) and negative predictive value (NPV) for acute rejection (T cell-mediated rejection [TCMR] or ABMR) of 61 and 84 percent, respectively [33].

Other studies have suggested lower cutoff levels such as >0.75 or >0.5 percent, with one study showing that a 0.5 percent cutoff was better at detecting borderline rejection and early TCMR [38,41]. In general, dd-cfDNA is a continuous number. The higher the percentage, the higher the PPV for rejection, and the lower the percentage, the higher the NPV for the absence of rejection. Levels of dd-cfDNA cannot be used to distinguish between TCMR and ABMR.

●De novo donor-specific antibody (DSA) or rising DSA levels – The development of de novo serum antibodies directed against the donor's HLA antigens (ie, DSA) or rising DSA titers in a patient with a preexisting DSA can occur in patients with acute rejection and has been associated with ABMR [42-44]. In a systematic review and meta-analysis of seven retrospective cohort studies (1119 patients), the presence of DSA detected by solid-phase assay, despite a negative flow cytometry crossmatch result, was associated with nearly double the risk for ABMR (relative risk [RR] 1.98, 95% CI 1.36-2.89) and a higher risk of graft failure (RR 1.76, 95% CI 1.13-2.74) [44].

DSAs to non-HLA antigens have also been described in patients with ABMR. Such non-HLA antigens include the angiotensin II receptor [1], MHC class I polypeptide-related sequence A (MICA) [45,46], and endothelial cell antigens [45]. Other antigens have been identified in the research setting but are not currently tested in the routine clinical setting [3,47].

A negative DSA does not rule out the diagnosis of ABMR. In one study of 280 kidney biopsies from 272 kidney transplant recipients, for example, DSA was negative in 56 percent cases of ABMR diagnosed through molecular phenotyping and 51 percent of cases of ABMR diagnosed through histologic assessment of the biopsy [48]. (See 'Active antibody-mediated rejection' below.)

Not all DSAs are equally pathogenic. In one study, complement-binding antibodies (ie, C1q-binding DSAs) were associated with an increased rate of ABMR and worse graft survival compared with non-complement-binding DSAs [49]. However, testing DSAs for C1q-binding is not widely performed, and it is likely that there are non-complement-binding DSAs that are clinically relevant and not detected by this assay. These issues are discussed elsewhere. (See "Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing", section on 'C1q binding assay' and "Kidney transplantation in adults: Risk factors for graft failure", section on 'Sensitization'.)

A discussion of the assays used to detect DSAs is presented separately. (See "Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing", section on 'Crossmatch testing for donor-specific antibodies'.)

Imaging findings — Imaging studies are neither sensitive nor specific for acute rejection and are generally not used for the diagnosis of rejection. However, they may be obtained to rule out other causes of acute allograft dysfunction. Ultrasonography may show increased graft size, with loss of the corticomedullary junction, prominent hypoechoic pyramids, and decreased echogenicity of the renal sinus [32]. Duplex Doppler ultrasonography may show elevated resistive indices, but this finding may also be observed with ureteral obstruction, acute tubular necrosis, renal vein occlusion, pyelonephritis, and cyclosporine toxicity [50,51]. Nuclear medicine renal scans may show delayed visualization of kidneys.

MONITORING OF ASYMPTOMATIC PATIENTS — Since many kidney transplant recipients with acute rejection are asymptomatic, the primary means of monitoring for rejection is laboratory testing. The frequency of laboratory monitoring depends upon the time since transplantation and may vary among transplant centers. (See "Overview of care of the adult kidney transplant recipient", section on 'Routine follow-up and laboratory monitoring'.)

●Routine laboratory monitoring – The following lab tests are obtained at every lab visit to monitor allograft function (see 'Laboratory findings' above):

•Serum creatinine

•Urinalysis with, if available, a sediment examination

•Spot urine protein-to-creatinine ratio (some experts obtain a urine dipstick first and measure a spot urine protein-to-creatinine ratio if the dipstick reveals more than trace albuminuria)

●Donor specific antibody (DSA) – There is no consensus on when to test for DSA in the absence of allograft dysfunction. The frequency of DSA monitoring varies among transplant centers and depends upon the patient's immunologic risk. Some transplant centers perform routine DSA testing annually in stable transplant recipients.

Posttransplant monitoring for the development of DSAs may permit the early detection of antibody-mediated rejection (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 [52]. By comparison, only 3 of 41 without ABMR developed DSAs.

The presence of circulating DSAs alone does not indicate active rejection; however, it does identify a patient at higher risk for ABMR. Other clinical and laboratory parameters need to be assessed in parallel with DSA testing. In the setting of an increasing or new DSA but no other indicators of acute rejection or a normal kidney allograft biopsy, most transplant centers would only augment maintenance immunosuppression. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)

●Donor-derived cell-free DNA (dd-cfDNA) – Some centers routinely monitor high-risk patients with dd-cfDNA levels at specified time points (eg, at 1, 3, 6, 9, and 12 months), with the rationale that monitoring would allow for early diagnosis of acute rejection. However, practice varies considerably, and some centers do not routinely monitor dd-cfDNA levels, while others may monitor dd-cfDNA levels only in patients at high risk for rejection, patients at higher risk of biopsy-related complications, or patients who have been treated for acute rejection. Routine monitoring of dd-cfDNA has been shown to detect an elevated dd-cfDNA three to four months before the onset of clinically evident rejection [53]. However, there are no data showing that routine monitoring results in improved kidney survival. At many transplant centers, monitoring of dd-cfDNA has replaced protocol biopsies.

Two studies have demonstrated the benefits of monitoring dd-cfDNA in kidney transplant recipients:

•In one multicenter study of 1092 adult kidney transplant recipients who were monitored with dd-cfDNA as part of their standard of care, elevations in dd-cfDNA (≥0.5 percent) were associated with significant eGFR decline at three years posttransplant, and persistently elevated dd-cfDNA (more than one result ≥0.5 percent) nearly doubled the risk of a 25 percent decline in eGFR [53]. An elevated dd-cfDNA was also associated with a nearly threefold elevation in the risk of future de novo DSA over two years of follow-up.

•In another multicenter study that included 280 kidney transplant biopsies, approximately half of all cases of ABMR were DSA negative; however, dd-cfDNA was elevated in patients with DSA-negative and DSA-positive ABMR [48]. A dd-cfDNA ≥1 percent predicted ABMR better than DSA positivity (area under the curve [AUC] 0.85 versus 0.66, respectively).

●Peripheral blood gene expression profiling – Blood gene expression testing is another biomarker that has been used at some centers for surveillance monitoring of kidney allograft health [54,55]. The test was developed as a microarray-based assay that analyzes gene expression profiles (GEP) in the peripheral blood. The results of the test are expressed as Transplant eXcellence (TX; stable serum creatinine, normal biopsy results) versus not-TX. TX refers to a high likelihood of immune quiescence and a low likelihood of histologic rejection; not-TX refers to a higher risk of immune activation and higher likelihood of rejection.

In an observational study of 208 transplant recipients with 428 surveillance biopsies, a non-TX result on GEP assay had a positive predictive value (PPV) of 47 percent and negative predictive value (NPV) of 82 percent for the diagnosis of subclinical rejection [56]. By comparison, a positive dd-cfDNA (defined as >0.7 percent) had a PPV of 56 percent and NPV of 84 percent. Combining a positive dd-cfDNA and a non-TX result on GEP assay increased the PPV to 81 percent.

●Surveillance/protocol biopsies – A small proportion (approximately 17 percent) of transplant centers perform surveillance (or protocol) kidney biopsies at specified time points after transplantation [57]. Surveillance/protocol biopsies are usually performed to identify subclinical rejection, which is characterized by histologic changes of acute rejection in the absence of an increased serum creatinine concentration. There are no data on the utility of surveillance/protocol biopsies in the modern era with the availability of less invasive biomarkers such as dd-cfDNA and gene expression panels. Biopsies are costly, inconvenient, associated with complications and sampling error, and rarely have agreement among interpretation, even among expert pathologists. However, protocol biopsies may have a limited role in carefully designed clinical trials. (See 'Subclinical rejection' below.)

DIAGNOSIS

When to suspect rejection — Acute 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 kidney 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.

●New or increasing proteinuria >1 g/day.

●Worsening hypertension. (See "Hypertension after kidney transplantation", section on 'Allograft dysfunction'.)

●Plasma donor-derived cell-free DNA (dd-cfDNA) >1 percent or a rising trend in serial dd-cfDNA measurements. (See 'Laboratory findings' above and 'Monitoring of asymptomatic patients' above.)

●A non-TX result on a peripheral blood gene expression profile (GEP) assay combined with a dd-cfDNA >1 percent. (See 'Monitoring of asymptomatic patients' above.)

All kidney transplant recipients who are suspected of acute rejection should undergo an evaluation to exclude other potential causes of acute allograft dysfunction. The evaluation of acute kidney allograft dysfunction is discussed in more detail elsewhere. (See "Kidney transplantation in adults: Evaluation and diagnosis of acute kidney allograft dysfunction", section on 'Evaluation of acute allograft dysfunction'.)

Establishing the diagnosis — The diagnosis of acute rejection is presently defined histologically by kidney allograft biopsy. There are no specific laboratory findings that can accurately diagnose acute rejection. A kidney allograft biopsy is required to differentiate between T cell-mediated rejection (TCMR) and ABMR, to accurately grade the severity of rejection, and to determine the degree of irreversible kidney damage (interstitial fibrosis/tubular atrophy [IF/TA]). Biopsy of the kidney allograft can also reveal other causes of kidney inflammation and injury, including cytomegalovirus (CMV) disease, BK polyomavirus-associated nephropathy (BKPyVAN), interstitial nephritis, pyelonephritis, de novo or recurrent glomerular disease, and posttransplant lymphoproliferative disease (PTLD). (See 'Differential diagnosis' below.)

A classification system for TCMR and ABMR has been developed and revised by an expert panel of pathologists, immunologists, physicians, surgeons, and immunogeneticists to standardize the histologic criteria for diagnosing and grading the severity of rejection (ie, Banff classification) [5,58-65].

It may be difficult to distinguish between active ABMR and severe acute TCMR, and the two processes may also coexist. In reality, the diagnoses of ABMR and TCMR are part of a continuum representing different presentations of the alloimmune response. 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 [66]. It is important to identify ABMR, if possible, since ABMR is more refractory to treatment and, unless adequately treated, often results in kidney allograft loss [67].

Other methods used to help diagnosis acute kidney 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 kidney allograft rejection".)

Acute T cell-mediated (cellular) rejection — The diagnosis of acute TCMR is established histologically by the presence of certain pathologic features in the kidney allograft biopsy, which include (picture 1) [58]:

●Interstitial infiltration with mononuclear cells, most of which are lymphocytes. Monocytes, plasma cells, and occasionally eosinophils may also be present. Neutrophils are uncommon and suggest the diagnosis of infection or ABMR.

●Tubular inflammation (ie, tubulitis), whereby infiltrating lymphocytes and monocytes cross the tubular basement membranes and extend into the walls and lumina of the tubules. Tubulitis must be documented in normal-appearing, nonatrophic tubules. The presence of patchy mononuclear cell infiltrates without tubulitis is not uncommon in normal functioning kidney allografts and is not, by itself, sufficient to make the diagnosis of acute TCMR.

●Vascular inflammation, whereby lymphocytes, monocytes, and foam cells infiltrate the arterial endothelium but rarely extend into the muscularis (ie, intimal arteritis). Intimal arteritis can also be seen in ABMR.

The severity of acute TCMR is graded using the Banff classification, which assesses these three specific features (interstitial inflammation [i], tubulitis [t], and intimal arteritis [v]) and scores them on a scale from one to three [65]:

●Borderline – Foci of tubulitis (t1, t2, or t3) with mild interstitial inflammation (i1), or mild (t1) tubulitis with moderate to severe interstitial inflammation (i2 or i3).

●IA – Significant interstitial inflammation (>25 percent of nonsclerotic cortical parenchyma; i2 or i3) and foci of moderate tubulitis (t2).

●IB – Significant interstitial inflammation (>25 percent of nonsclerotic cortical parenchyma; i2 or i3) and foci of severe tubulitis (t3).

●IIA – Mild to moderate intimal arteritis (v1) with or without interstitial inflammation and tubulitis.

●IIB – Severe intimal arteritis comprising >25 percent of the luminal area (v2) with or without interstitial inflammation and tubulitis.

●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; a v lesion is not required for the diagnosis of TCMR. Any scores below this (eg, i1+t2 or i2+t1) are considered to be borderline. The significance of the presence of intimal arteritis alone (eg, v1) is controversial but still allows for the diagnosis of TCMR.

The treatment of acute TCMR is discussed elsewhere. (See "Kidney transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection".)

Active antibody-mediated rejection — The diagnosis of active ABMR is established by the presence of the following three criteria (table 1) [65]:

●Histologic evidence of acute tissue injury – The kidney allograft biopsy should demonstrate histologic evidence of acute tissue injury. The findings in ABMR can vary widely from acute tubular injury, microvascular inflammation (ie, infiltration of glomerular and peritubular capillarities by lymphocytes and other immune cells that may include neutrophils; also known as capillaritis) to intimal or transmural arteritis, or acute thrombotic microangiopathy (picture 2 and picture 3). Other less common lesions can include endothelialitis, fibrinoid necrosis, or transmural inflammation.

●Evidence of current/recent antibody interaction with vascular endothelium – This is defined by the presence of at least one of the following:

•Linear immunofluorescence or immunohistochemical staining for C4d (a degradation product of the classic complement pathway) in the peritubular capillaries (PTCs). C4d binds covalently to the endothelial and collagen basement membranes, thereby serving as an immunologic footprint of complement activation and antibody-mediated injury. 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 kidney allografts and represents complement activity directed against donor antigen (picture 4) [68]. In one study, C4d staining in the PTCs was 95 percent sensitive and 96 percent specific for the diagnosis of ABMR [66].

•Increased expression of gene transcripts/classifiers in the biopsy tissue that are strongly associated with ABMR. (See "Investigational methods in the diagnosis of acute kidney allograft rejection", section on 'The molecular microscope'.)

•At least moderate microvascular inflammation in the kidney allograft biopsy.

●Serologic evidence of circulating DSAs – The presence of serum antibodies directed against the donor's human leukocyte antigen (HLA) class I and II antigens (ie, DSAs) supports a diagnosis of ABMR (see 'Laboratory findings' above). If DSA testing is negative, the presence of C4d staining in the PTCs and/or the expression of validated gene panels strongly associated with ABMR can substitute for DSAs in the diagnosis of ABMR [5].

If all three of these criteria are met, the patient is diagnosed with ABMR. However, certain clinical scenarios exist in which patients have ABMR but do not meet all three criteria:

●Patients with C4d-negative ABMR – 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 [69,70]. In C4d-negative ABMR, DSA binding to endothelial cells may cause injury through complement-independent mechanisms. In one study of 2006 adults who underwent kidney transplantation between 2004 and 2014, 10.3 percent developed ABMR; approximately one-quarter of these cases were C4d-negative [71].

Patients with C4d-negative ABMR are treated using the same approach as that for patients with C4d-positive ABMR. (See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection", section on 'Patients with C4d-negative ABMR'.)

●Patients without a detectable DSA – As discussed above, DSA testing may be negative among patients with ABMR (see 'Laboratory findings' above). Patients who have ABMR without a detectable circulating DSA may not benefit from antibody-lowering therapies used to treat ABMR (such as plasmapheresis).

Some patients with negative testing for anti-HLA antibodies may have antibodies against non-HLA antigens. If anti-HLA antibody testing is negative but the patient has evidence of acute tissue injury and antibody interaction with the vascular endothelium, testing for non-HLA antibodies can be considered. However, there are no universally established or validated clinical assays to detect these antibodies. Thus, testing for non-HLA antibodies is of limited utility. (See 'Laboratory findings' above.)

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 [72] but is not part of current clinical practice.

The prevention and treatment of ABMR are discussed elsewhere. (See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection".)

Mixed acute rejection — The diagnosis of mixed acute rejection is established when both acute TCMR and ABMR coexist within the same kidney allograft. Criteria for the diagnosis of TCMR and ABMR are discussed above. (See 'Acute T cell-mediated (cellular) rejection' above and 'Active antibody-mediated rejection' above.)

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.

The treatment of mixed acute rejection is discussed elsewhere. (See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection", section on 'Patients with mixed acute rejection'.)

DIFFERENTIAL DIAGNOSIS — As described above, most patients with acute rejection are asymptomatic and present only with an elevated creatinine [32]. 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 kidney allograft dysfunction. The evaluation and differential diagnosis of kidney 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-associated nephropathy (BKPyVAN), 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 that of rejection. CMV infection can be distinguished by the presence of cytoplasmic or nuclear viral inclusions and CMV-specific immunohistochemical staining on kidney biopsy. 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 [73]. In general, whole blood or plasma CMV viral load testing will identify patients with active CMV disease.

●BKPyVAN – The histologic appearance of BKPyVAN may mimic the tubulitis and/or arteritis classically associated with rejection [74]. Among such patients, it is extremely important to attempt to differentiate BKPyVAN from rejection, as the two treatments are diametrically opposed and increased immunosuppression in the setting of BKPyVAN will lead to further viral proliferation and potential allograft loss. However, distinguishing BKPyVAN 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 BKPyV should be performed on the biopsy sample if there is concern for BKPyVAN, even in the absence of typical viral inclusions on the biopsy. It is essential that medullary tissue be available for analysis since BKPyV 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 the diagnosis.

●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 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 nonadherence 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 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.

SUBCLINICAL REJECTION — Subclinical rejection is when histologic changes of acute rejection are observed in the absence of an increased serum creatinine concentration [7-14]. Subclinical rejection is usually detected by surveillance (or protocol) biopsies. (See 'Monitoring of asymptomatic patients' above.)

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 human leukocyte antigen (HLA) matching, presence of donor-specific antibodies (DSAs), immunosuppressive protocol, and the incidence of delayed graft function [11].

Many [7,8,10,75-80], though not all [9,12], studies have demonstrated an association between subclinical rejection demonstrated by protocol biopsy and decreased allograft survival and/or function. Patients with subclinical antibody-mediated rejection (ABMR) appear to exhibit worse graft function compared with those who have subclinical T cell-mediated rejection (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 [15]. Patients with treated subclinical TCMR had similar graft survival as those without rejection (90 percent at eight years).

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'.)

CHRONIC REJECTION — Chronic rejection refers to rejection that usually occurs after the first posttransplant year, in the absence of calcineurin inhibitor nephrotoxicity and other causes of allograft dysfunction. It can occur without histologic evidence of inflammation. Chronic kidney allograft rejection is classified as chronic active T cell-mediated rejection (TCMR), chronic active antibody-mediated rejection (ABMR), and chronic inactive ABMR.

●Chronic active TCMR – Chronic active TCMR is characterized by the presence of the inflammatory infiltrates in areas of interstitial fibrosis and tubular atrophy (IF/TA) in the kidney allograft [5,65]. Like acute TCMR, the severity of chronic TCMR is also graded using the Banff classification [65].

●Chronic ABMR – Chronic ABMR refers to chronic microvascular injury that leads to remodeling of the glomerular or peritubular capillaries. Chronic ABMR is further classified into chronic active and chronic inactive subtypes:

•Chronic active ABMR – Chronic active ABMR generally develops late (>6 months posttransplant) and can occur in patients with or without a history of active ABMR [81]. The only difference between the diagnostic criteria for chronic active and active ABMR is the requirement for histologic evidence of chronic tissue injury, which is defined by certain histologic lesions such as transplant glomerulopathy (double contouring of glomerular capillary walls (picture 5 and picture 6)), severe multilayering of the peritubular capillary basement membrane, and/or arterial intimal fibrosis; otherwise, the remaining two criteria are the same [65]. (See 'Active antibody-mediated rejection' above.)

•Chronic inactive ABMR – Chronic inactive ABMR is characterized by histologic evidence of chronic tissue injury (ie, transplant glomerulopathy and/or peritubular capillary basement membrane multilayering), without microvascular inflammation and without evidence of current/recent antibody interaction with the endothelium (eg, no C4d deposition in peritubular capillaries) [65]. Patients with chronic inactive ABMR have a prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of donor-specific antibody (DSA).

The treatment of chronic ABMR is discussed elsewhere. (See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection", section on 'Treatment of chronic antibody-mediated rejection'.)

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

●Definitions – Acute kidney allograft rejection is defined as an acute deterioration in allograft function associated with specific pathologic changes in the allograft. There are two principal forms, 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. (See 'Definitions' above.)

●Clinical features

•Clinical presentation – Most episodes of acute rejection occur within the first six months after transplantation, with many occurring early after surgery. Patients are mostly asymptomatic but occasionally present with fever, malaise, oliguria, and graft pain and/or tenderness. (See 'Clinical presentation' above.)

•Laboratory findings – An acute rise in the serum creatinine is the most common laboratory finding in acute rejection. New or worsening proteinuria or pyuria may also be present. Fractional plasma levels of donor-derived cell-free DNA (dd-cfDNA) >1 percent or serially increasing levels are associated with acute rejection. The development of de novo serum antibodies against donor HLA antigens (ie, donor-specific antibody [DSA]) or rising DSA titers in a patient with a preexisting DSA can also occur in patients with acute rejection. (See 'Laboratory findings' above.)

•Imaging findings – Most findings obtained by kidney imaging are nonspecific, and such studies are generally performed to exclude other causes of acute kidney injury. (See 'Imaging findings' above.)

●Monitoring of asymptomatic patients – Since many kidney transplant recipients with acute rejection are asymptomatic, the primary means of monitoring for rejection is laboratory testing. The frequency of laboratory monitoring depends upon the time since transplantation and may vary among transplant centers. (See 'Monitoring of asymptomatic patients' above.)

●Diagnosis

•When to suspect rejection – Acute rejection should be suspected in patients with one or more of the following (see 'When to suspect rejection' above):

-New increase in serum creatinine of ≥25 percent from baseline or a serum creatinine that is higher than expected. However, in patients who are at increased risk for ABMR, any incremental increase in serum creatinine should raise the suspicion for the possibility of acute rejection.

-New or increasing proteinuria >1 g/day.

-Worsening hypertension.

-Plasma dd-cfDNA >1 percent or a rising trend in serial dd-cfDNA measurements.

•Establishing the diagnosis – The diagnosis of acute rejection is presently established by kidney allograft biopsy. A kidney allograft biopsy is required to differentiate between TCMR and ABMR, accurately grade the severity of rejection, and determine the degree of irreversible kidney damage (interstitial fibrosis/tubular atrophy [IF/TA]). Biopsy of the kidney allograft can also reveal other causes of kidney inflammation and injury, including cytomegalovirus (CMV) disease, BK polyomavirus-associated nephropathy (BKPyVAN), interstitial nephritis, pyelonephritis, de novo or recurrent glomerular disease, and posttransplant lymphoproliferative disease. (See 'Establishing the diagnosis' above and 'Differential diagnosis' above.)

●Chronic rejection – Chronic rejection is characterized by a slow deterioration in allograft function and is an important contributor to late graft loss. It usually occurs after the first year of transplantation and can occur with or without active inflammation. The three classic types are chronic active ABMR, chronic inactive ABMR, and chronic active TCMR. (See 'Chronic rejection' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge W James Chon, MD, FACP, who contributed to earlier versions of this topic review.