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Kidney transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection

Kidney transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection
Authors:
Daniel C Brennan, MD, FACP
Andrew Malone, MB, BCh, MRCPI
Section Editors:
Christophe Legendre, MD
John Vella, MD, FACP, FRCP, FASN, FAST
Deputy Editor:
Albert Q Lam, MD
Literature review current through: Dec 2022. | This topic last updated: May 03, 2022.

INTRODUCTION — The use of potent immunosuppressive agents as part of induction and maintenance therapy for kidney transplantation has significantly reduced the incidence of acute rejection, which is defined as an acute deterioration in kidney allograft function associated with specific pathologic changes in the graft. With existing immunosuppressive protocols, acute rejection rates have fallen to approximately 7 percent at one year posttransplant in the United States [1].

Acute rejection can be broadly categorized into T cell-mediated (cellular) rejection (TCMR) and antibody-mediated (previously known as humoral) rejection (ABMR). A kidney allograft biopsy is required to establish the diagnosis and determine the severity of rejection in order to determine the most appropriate approach to therapy. TCMR and ABMR may also coexist at the same time in the kidney allograft (ie, mixed acute rejection). The presence of histologic evidence of acute rejection on biopsy without an elevation in the serum creatinine concentration is known as subclinical rejection.

The treatment of acute TCMR of the kidney allograft will be reviewed here. The clinical features and diagnosis of acute rejection and the treatment of acute ABMR are discussed separately:

(See "Kidney transplantation in adults: Clinical features and diagnosis of acute renal allograft rejection".)

(See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection".)

GENERAL PRINCIPLES

Goals of therapy — The goals of therapy for treatment of acute TCMR are to reverse the rejection and return kidney allograft function to as close to baseline (prior to the acute TCMR) as possible.

Banff grading system — The severity of acute TCMR is graded using the Banff classification (picture 1) [2,3]:

Borderline – ≤25 percent interstitial inflammation (i1) with any tubulitis (t1, t2, or t3) or >25 percent interstitial inflammation (i2 or i3) with mild tubulitis (t1)

Type IA – >25 percent interstitial inflammation (i2 or i3) with moderate tubulitis (t2)

Type IB – >25 percent interstitial inflammation (i2 or i3) with severe tubulitis (t3)

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

Type IIB – Severe intimal arteritis (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)

APPROACH BASED ON HISTOLOGIC SEVERITY — The approach to initial therapy in patients with histologic evidence of acute TCMR is guided predominantly by the histopathologic severity of rejection. (See 'Banff grading system' above.)

Banff grade I rejection — Our approach in patients with Banff grade I rejection (see 'Banff grading system' above) is as follows:

Banff grade IA – For patients with biopsy-proven Banff grade IA TCMR (with no evidence of antibody-mediated rejection [ABMR]), we suggest treatment with glucocorticoids rather than glucocorticoids plus other immunosuppressive therapies. We typically advocate inpatient admission for management. We administer pulse IV methylprednisolone at 3 to 5 mg/kg daily for three to five doses, with a maximum daily dose of 500 mg. After the glucocorticoid pulse, we resume the maintenance dose of oral prednisone the patient had been taking prior to the episode. However, some experts prefer a more gradual taper of oral glucocorticoids after pulse glucocorticoids. In addition, we adjust the other components of the patient's maintenance immunosuppression as needed. This is discussed in more detail elsewhere. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Patients with acute rejection'.)

Alternatively, some transplant centers choose to treat patients with Banff grade IA TCMR with an equivalent dose of high-dose oral glucocorticoids on an outpatient basis, provided that these patients are able to return for frequent laboratory testing. (See 'Monitoring and modifying therapy' below.)

Banff grade IB – For patients with Banff grade IB TCMR, we suggest treatment with rabbit antithymocyte globulin (rATG)-Thymoglobulin in addition to pulse glucocorticoids, rather than glucocorticoids alone. Our rationale for adding rATG-Thymoglobulin in these patients is based upon evidence that severe (t3) tubulitis, which distinguishes Banff grade IB from IA TCMR, is associated with worse graft outcomes compared with milder (t1 or t2) grades of tubulitis and, therefore, may warrant more aggressive treatment [4]. However, practice varies among different transplant centers, and some experts prefer to treat all patients with Banff grade IB TCMR with glucocorticoids alone and reserve the use of rATG-Thymoglobulin for those who do not respond to glucocorticoids. Other experts treat with glucocorticoids alone if the patient presents early (≤1 year) after transplant and with rATG-Thymoglobulin plus glucocorticoids if the patient presents later (>1 year) after transplant. There is no high-quality evidence to support one of these treatment approaches over another.

We administer rATG-Thymoglobulin at 1.5 to 3 mg/kg per dose over one to three days for a total dose of 3 to 6 mg/kg in the first year. We prefer to give a shorter, higher-dose course of treatment (ie, a single dose of rATG-Thymoglobulin 3 mg/kg) to reduce cost and length of hospital stay. Methylprednisolone is administered as 3 to 5 mg/kg (maximum dose of 500 mg) prior to each dose of rATG-Thymoglobulin. After the glucocorticoid pulse, we resume the maintenance dose of oral prednisone the patient had been taking prior to the episode although some experts prefer a more gradual taper of oral glucocorticoids after pulse glucocorticoids. In addition, we adjust the other components of the patient's maintenance immunosuppression as needed.

Pulse methylprednisolone is the first-line therapy for acute TCMR in most centers [5,6]. In addition to the intensification of maintenance immunosuppression therapy, such pulse glucocorticoids are usually the only additional treatment added if the rejection is Banff class IA or IB although some experts (including the authors of this topic) prefer to add rATG-Thymoglobulin in patients with IB TCMR. The expected reversal rate for the first episode of acute TCMR is 60 to 70 percent with pulse glucocorticoids. With a successful response, the urine output increases and the serum creatinine starts decreasing within five days after initiating therapy.

Although the majority of patients respond to glucocorticoids, few high-quality studies have compared the efficacy of various glucocorticoid regimens for the treatment of TCMR. In one trial involving 95 episodes of kidney allograft rejection occurring in 45 kidney transplant recipients, treatment with IV pulse methylprednisolone (given as 1 g boluses) or high-dose oral prednisolone resulted in a similar rate of reversal of rejection (approximately 60 percent) [5]. Fluid retention was more common among patients treated with high-dose oral prednisolone. The study was performed prior to the understanding that TCMR and ABMR are separate diagnoses and, therefore, did not differentiate between these types of rejection.

There are no studies specifically examining the use of rATG-Thymoglobulin in patients with Banff grade IB TCMR. Evidence supporting the use of rATG-Thymoglobulin for acute rejection is presented below. (See 'Banff grade II or III rejection' below.)

Banff grade II or III rejection — Our approach in patients with Banff grade II or III rejection (see 'Banff grading system' above) is as follows:

For patients with biopsy-proven Banff grade IIA, IIB, or III TCMR, we suggest treatment with rATG-Thymoglobulin plus glucocorticoids, rather than glucocorticoids alone. We typically advocate inpatient admission for management.

We administer pulse IV methylprednisolone 3 to 5 mg/kg daily for three to five doses (with a maximum daily dose of 500 mg). Following glucocorticoid pulse, we resume the maintenance dose of oral prednisone the patient had been taking prior to the episode. However, some experts prefer a more gradual taper of oral glucocorticoids after pulse glucocorticoids.

In addition, we administer daily rATG-Thymoglobulin at 1.5 to 3 mg/kg per dose for a total dose of 5 to 10 mg/kg. The total number of doses is determined by severity of Banff grading. As an example, in patients with Banff class IIA TCMR, we would give rATG-Thymoglobulin 2.5 mg/kg daily for two days, and in patients with Banff class III TCMR, we would give 2 mg/kg daily for four to five days depending upon the response in serum creatinine.

We also adjust the other components of the patient's maintenance immunosuppression as needed. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Patients with acute rejection'.)

For patients who cannot receive rATG-Thymoglobulin, we give alemtuzumab as a single IV dose of 30 mg. Such patients include those with a known history of allergic reaction to rATG-Thymoglobulin (such as during induction therapy or during previous treatment of rejection) or those with a white blood cell count less than 2000/microL or a platelet count less than 75,000/microL. We also give alemtuzumab, rather than rATG-Thymoglobulin, to patients who have a previous history of significant rabbit exposure (ie, history of having raised or ingested rabbits) and, therefore, may be at risk for developing serum sickness after treatment with rATG-Thymoglobulin [7]. (See 'Treatment-related toxicity' below.)

Antithymocyte globulin (ATG) is a polyclonal immune globulin that is prepared by injecting human thymocytes into rabbits (rATG-Thymoglobulin) or horses (Atgam). ATG induces T lymphocyte depletion in the peripheral blood primarily by complement-dependent cell lysis; it also contains some B cell-specific antibodies, inhibiting B cell proliferation and inducing B cell apoptosis [8]. ATG has been used both for prophylaxis against and for the primary treatment of acute rejection (see "Kidney transplantation in adults: Induction immunosuppressive therapy"). The reversal rate for acute rejection has been between 75 and 100 percent in different series [9-13], with the plasma creatinine concentration returning to baseline several days to a week after initiating therapy.

There are no data directly comparing the use of rATG-Thymoglobulin with glucocorticoids specifically in patients with Banff grade II or III rejection. Most of the trials comparing these regimens for acute rejection did not differentiate between TCMR and ABMR and were conducted before the development of the Banff grading system [9-14]. In a meta-analysis that included five trials comparing rATG with glucocorticoids for treatment of acute rejection, patients receiving rATG had a lower risk of failure to reverse acute rejection (risk ratio 0.40, 95% CI 0.22-0.74) and a lower risk of death-censored graft loss within 18 months (risk ratio 0.63, 95% CI 0.44-0.89) [13]. There were no significant differences in the risks of death or recurrent rejection up to 12 months posttherapy. It is important to note that maintenance immunosuppression used in most of these trials was different from contemporary regimens.

A direct comparison between rATG-Thymoglobulin and Atgam was performed in a multicenter, double-blind, randomized trial of 163 kidney transplant recipients with acute rejection [15]. Compared with Atgam, rATG-Thymoglobulin resulted in a higher rate of reversal of rejection (88 versus 76 percent) and a lower rate of recurrent rejection at 90 days after antibody therapy (17 versus 36 percent). Patient and graft survival and the rates of adverse events and infections were similar between the two groups. Given the superior efficacy of rATG-Thymoglobulin in the treatment of acute rejection, Atgam is no longer used routinely in most transplant centers, although it is occasionally used in patients who have a known allergy to rabbits or rATG-Thymoglobulin, when alemtuzumab is not available.

The optimal dose and duration of rATG-Thymoglobulin therapy for the treatment of acute rejection is not well defined. In the pivotal trial that led to the approval of rATG-Thymoglobulin as treatment for rejection in the United States, the average total dose achieved was 10 mg/kg administered over six doses [15]. It is now recognized that more profound and durable lymphocyte depletion, which is believed to be one of the main mechanisms of action of rATG-Thymoglobulin, is achieved by administering larger but fewer doses over a shorter duration without interruption [16-18].

Alemtuzumab is a humanized anti-CD52 monoclonal antibody that is approved for the treatment of chronic lymphocytic leukemia. CD52 antigen is present on T and B lymphocytes, natural killer cells, and, to a lesser extent, on monocytes and macrophages. Alemtuzumab lyses lymphocytes via complement activation and via antibody-dependent cellular cytotoxicity. As reported in a few limited studies, alemtuzumab has been used for the treatment of acute rejection [19-21].

Practical advantages with this agent include peripheral, rather than central, venous access administration and a shorter treatment course. In the largest study, alemtuzumab reversed acute rejection in 25 of 40 (63 percent) kidney transplant recipients on tacrolimus monotherapy with either glucocorticoid-resistant rejection or at least Banff type IB rejection [20]. Other adjunctive measures included reversal of tacrolimus weaning, glucocorticoid administration, and/or the introduction of sirolimus. Infectious complications, however, were observed in 14 patients (35 percent). There were two patient deaths reported, one related to infection and the other to posttransplant lymphoproliferative disorder (PTLD).

Alemtuzumab has also been shown to be effective in reversing resistant acute TCMR in children [22].

Borderline and subclinical rejection — There is no consensus in the management of borderline rejection (see 'Banff grading system' above) and, in particular, whether antirejection treatment should be utilized. Some transplant centers do not administer specific treatment for rejection but augment maintenance immunosuppression by targeting higher tacrolimus levels (ie, 5 to 7 ng/mL) in patients whose tacrolimus trough levels are in the lower range (ie, 3 to 5 ng/mL) and/or by optimizing mycophenolate dosing. Other transplant centers choose to treat borderline rejection as acute TCMR, given observational data showing that a pathological diagnosis of borderline rejection is associated with adverse clinical and histologic outcomes, such as progressive fibrosis and an increased risk of subsequent rejection, allograft failure, and patient mortality [23]. However, other studies question the utility of rejection treatment in these patients [24,25].

Subclinical rejection is defined as the presence of histologic evidence of acute rejection on biopsy without an elevation in the serum creatinine concentration [26-33]. Subclinical rejection is detected on a surveillance or protocol biopsy in the absence of clinical symptoms or signs. The use of protocol biopsies is generally restricted to patients undergoing experimental immunosuppressive protocols because the incidence of subclinical rejection in patients treated with tacrolimus, mycophenolate, and glucocorticoids is very low. At our institutions, we do not perform surveillance or screening biopsies unless the patient is part of a protocol that requires them and, therefore, do not detect subclinical rejection. Some studies have found an association with subclinical rejection and adverse outcomes [34-37].

It is unclear if the administration of therapy to patients with subclinical rejection improves clinical outcomes. A few studies have examined this question [23,38-40]:

In one report, 72 patients who were being treated with cyclosporine, azathioprine, and glucocorticoids were randomly assigned to biopsy at 1, 2, 3, 6, and 12 months posttransplantation (biopsy group) or to biopsy at 6 and 12 months (control group) [39]. Subclinical rejection discovered at months 1, 2, and 3 in the biopsy group was treated with high-dose glucocorticoids. Compared with no treatment, glucocorticoid therapy was associated with fewer episodes of acute rejection and with a lower serum creatinine concentration at two years (1.5 versus 2 mg/dL [133 versus 183 micromol/L]).

However, in another multicenter study, 240 kidney transplant recipients were treated with tacrolimus, mycophenolate, and glucocorticoids and randomly assigned to protocol biopsy arm or control arm, with subclinical rejection treated with glucocorticoids [38]. At six months, there was no difference in kidney function between groups. The authors concluded that protocol biopsy was not useful in the setting of stronger immunosuppression (ie, tacrolimus/mycophenolate/glucocorticoids) and the resulting low prevalence of subclinical rejection.

Further study with longer follow-up is required to determine whether surveillance biopsies, combined with enhanced immunosuppression administered for the treatment of subclinical rejection, improve long-term outcome.

Mixed acute rejection — Patients who have evidence of both acute TCMR and acute antibody-mediated rejection (ABMR; ie, mixed acute rejection) on kidney biopsy should be treated for both TCMR and ABMR. 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'.)

MONITORING AND MODIFYING THERAPY

Monitoring the response to therapy — We typically advocate inpatient admission for most patients receiving treatment for acute TCMR. However, as discussed above, some transplant centers treat patients with less severe acute rejection (ie, those with Banff grade IA TCMR) on an outpatient basis. (See 'Banff grade I rejection' above.)

Kidney function – In patients who are admitted for management, we monitor serum creatinine levels daily to assess the response to treatment. After the patient has been discharged, we monitor serum creatinine on a weekly basis until it has returned to the baseline level (prior to the episode of rejection) or until it plateaus at a new baseline level, after which routine monitoring of kidney function can be resumed. (See "Kidney transplantation in adults: Overview of care of the adult kidney transplant recipient", section on 'Monitoring kidney allograft function'.)

In patients with less severe acute rejection who are being managed as an outpatient, serum creatinine should be measured on an every-other-day basis, if possible, until it has returned to the baseline level or until it plateaus at a new baseline level, after which routine monitoring can be resumed. (See 'Banff grade I rejection' above.)

Donor-derived cell-free DNA – Measurement of peripheral blood donor-derived cell-free DNA (dd-cfDNA), which can be used as an aid to the diagnosis of acute rejection, can also be used to monitor the response to therapy. At our centers, in patients with an elevated plasma dd-cfDNA level (ie, >1 percent) at the time of diagnosis, we obtain a repeat dd-cfDNA level at one to two months after the initiation of treatment. In patients who respond to treatment, the dd-cfDNA fraction should decrease back to the normal range (<1 percent) within two months of therapy [41]. Existing dd-cfDNA tests in clinical practice have not been validated to discriminate low-grade (Banff 1A or less) or borderline rejection, nor have they been validated to monitor the response of low-grade TCMR to treatment. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute renal allograft rejection", section on 'Laboratory manifestations'.)

In most patients with TCMR who are treated with glucocorticoids and rabbit antithymocyte globulin (rATG)-Thymoglobulin and who do not have significant chronic histologic findings (eg, interstitial fibrosis/tubular atrophy [IF/TA], vascular intimal sclerosis, arteriolar hyaline thickening) or frank necrosis, a favorable response to treatment is expected, typically within three to five days of treatment initiation [42-44]. A decrease in serum creatinine to within 10 percent of the baseline level is considered to be successful reversal of rejection [45]. However, a substantial proportion of patients have persistent biopsy-proven rejection even after treatment, suggesting that histology is also important in determining remission [46]. Patients with evidence of chronic injury and fibrosis are less likely to have reversal of allograft dysfunction with treatment.

Our subsequent approach to treatment is based upon the response to initial therapy:

In patients with a decrease in serum creatinine in response to therapy, we maintain augmented immunosuppression and continue low-dose oral prednisone indefinitely. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Patients with acute rejection'.)

Patients without any decrease in serum creatinine after five days of rejection treatment are considered to have failed initial treatment. In such patients, ongoing rejection and/or another cause of kidney allograft dysfunction should be suspected. Our subsequent approach depends upon the initial treatment for rejection:

In patients who have been treated with glucocorticoids only, we administer rATG-Thymoglobulin (see 'Banff grade I rejection' above). In those patients who cannot receive rATG-Thymoglobulin, we give a single dose of alemtuzumab. (See 'Banff grade II or III rejection' above.)

In patients who have been treated with rATG-Thymoglobulin (or alemtuzumab if the patient was unable to receive rATG-Thymoglobulin), we repeat a kidney allograft biopsy to exclude an alternative diagnosis or a more severe histologic lesion (eg, higher Banff grade TCMR or antibody-mediated rejection [ABMR]). If higher Banff grade TCMR is detected, we treat with appropriate therapy for the higher Banff grade, as described above. If the biopsy demonstrates evidence of ABMR, we initiate treatment for ABMR. If the biopsy reveals no evidence of an acute reversible process or reveals extensive fibrosis (indicating nonviable kidney tissue), we discontinue treatment of acute rejection. (See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection" and 'When to stop therapy' below.)

When to stop therapy — The decision of when to stop treating patients with rejection is difficult but important and is determined by the overall clinical status of the patient. We generally stop therapy if:

A concurrent infectious process represents undue risk with further intensification of immunosuppression.

There is no evidence of response following an intense course of treatment with pulse glucocorticoids and/or rATG-Thymoglobulin, and there is no evidence of ABMR on repeat biopsy (which would dictate an alternate treatment regimen) or any other apparent additional etiology for continued kidney allograft dysfunction.

Repeat kidney biopsy shows nonviable kidney tissue. We have found it useful to obtain a trichrome stain to assess fibrosis to help in this decision. The extent of chronic changes on the initial biopsy can also help guide the intensity and duration of immunosuppression. If there is little evidence for a reversible process, the risk of infection and malignancy resulting from high-dose immunosuppression probably outweighs any benefit.

OTHER TREATMENT CONSIDERATIONS

Treatment-related toxicity — Treatment of acute TCMR with high-dose glucocorticoids and/or rabbit antithymocyte globulin (rATG)-Thymoglobulin is associated with certain adverse effects, as discussed below:

Glucocorticoids – The major complication of pulse glucocorticoids is increased susceptibility to infection, especially oral candidiasis. Other potential problems include acute hyperglycemia, hypertension, peptic ulcer disease, and psychiatric disturbances including euphoria and depression. Prophylactic histamine-2 blockers or proton pump inhibitors as well as antifungal prophylaxis are generally recommended. (See "Major side effects of systemic glucocorticoids".)

Bone disease is also common in kidney transplant recipients, with the most important risk factor being the loss of bone density due to the cumulative dose of glucocorticoids [47]. The highest glucocorticoid-associated rates of bone loss are in the first 3 to 12 months after transplant. As most TCMR occurs within the first year posttransplant, further glucocorticoid treatment adds to the cumulative dose. (See "Kidney transplantation in adults: Bone disease after kidney transplantation".)

rATG-Thymoglobulin – Fever and chills may develop in some patients during the initial rATG-Thymoglobulin infusion. Anaphylactic reactions, including respiratory distress and hypotension, are exceedingly rare. Administration of the concurrently given pulse glucocorticoids prior to rATG-Thymoglobulin will prevent or significantly reduce infusion-related reactions. Due to the risk of phlebitis, rATG-Thymoglobulin should generally be administered via central venous access; however, rATG-Thymoglobulin can be administered via peripheral line when the drug is mixed with heparin and patients are premedicated with an antihistamine [48].

A pruritic skin rash can occur in approximately 20 percent of patients treated with rATG-Thymoglobulin. Contamination of rATG-Thymoglobulin preparations with platelets and red blood cells can lead to antibody generation and the side effects of thrombocytopenia and, rarely, anemia. Thymoglobulin preparations also have antileukocyte immunoglobulin G, which can induce transient leukopenia [49]. Both cytomegalovirus (CMV) and herpes infections can occur after rATG-Thymoglobulin treatment but are rarely life threatening with current prophylactic antiviral therapy. Posttransplant lymphoproliferative disorder (PTLD) may also be observed. (See "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients" and "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders" and "Treatment and prevention of post-transplant lymphoproliferative disorders".)

Antithymocyte globulin (ATG)-induced serum sickness that responds to plasmapheresis has been reported in a number of patients [50,51]. This includes one case with a rapidly progressive descending paralysis due to serum sickness [52]. Rapid improvement occurred with therapeutic plasmapheresis. Prior exposure to rabbits may increase the risk of development of serum sickness with the first course of rATG-Thymoglobulin [7].

Prevention of opportunistic infections — In all patients who are treated with rATG-Thymoglobulin (or alemtuzumab) and high-dose glucocorticoids, we recommence antimicrobial and antiviral prophylaxis for at least three months with a regimen that is identical to that administered in the immediate posttransplant period. This includes prophylaxis against Pneumocystis jirovecii pneumonia (PCP), CMV infection and disease, and herpes simplex infection (in patients who are at low-CMV risk). In addition, we also administer antifungal prophylaxis although this practice may vary by transplant center. A detailed discussion of the different prophylactic regimens is presented separately.

PCP prophylaxis – (See "Prophylaxis of infections in solid organ transplantation", section on 'Pneumocystis pneumonia'.)

CMV prophylaxis – (See "Prevention of cytomegalovirus disease in kidney transplant recipients", section on 'Universal prophylaxis (high risk)'.)

Antifungal prophylaxis – (See "Prophylaxis of infections in solid organ transplantation", section on 'Antifungal prophylaxis'.)

PROGNOSIS — Acute TCMR occurs most commonly within the first year after transplantation and rarely occurs after five years posttransplant [53,54]. In general, episodes of acute rejection have been associated with a reduction in long-term allograft survival although not all rejection episodes have the same impact on long-term graft function. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute renal allograft rejection", section on 'Epidemiology and outcomes' and "Kidney transplantation in adults: Risk factors for graft failure", section on 'Episodes of acute rejection'.)

The impact of successfully treating acute TCMR on graft outcomes has not been well studied. Greater histologic severity of acute TCMR (ie, Banff grade greater than IA) has been associated with lower response rates to therapy [42]. Higher histologic scores (eg, i: interstitial inflammation, t: tubulitis, v: intimal arteritis), a later onset of rejection (>3 months posttransplant), and poor response to treatment have been associated with worse graft outcomes [55-58]. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute renal allograft rejection", section on 'Acute T cell-mediated (cellular) rejection'.)

Gene expression profiling studies have shown that many of the molecular mechanisms driving acute TCMR are also responsible for the development of the chronic histologic lesion of interstitial fibrosis/tubular atrophy (IF/TA) [59], which has been associated with graft failure [60,61]. (See "Kidney transplantation in adults: Chronic allograft nephropathy".)

An algorithm has been developed and validated to predict the long-term risk of allograft failure among kidney transplant recipients [62]. This algorithm, which incorporates functional, histologic, and immunological parameters to calculate a prognostic score (named the iBox) for an individual patient, can be used at any time after transplantation, including at the time of rejection diagnosis. Additional studies are required to determine its utility with regards to clinical decision making and management.

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

Goals of therapy – The goals of therapy for treatment of acute T cell-mediated (cellular) rejection (TCMR) are to reverse the rejection and return kidney allograft function to as close to baseline (prior to the acute TCMR) as possible.

Approach to treatment – Our approach to the treatment of acute TCMR is guided predominantly by the Banff histologic grade of TCMR.

Banff grade I – For kidney transplant recipients with Banff grade IA rejection, we suggest glucocorticoids alone, rather than glucocorticoids plus other immunosuppressive therapies (Grade 2C). For patients with Banff grade IB rejection, we suggest treatment with rabbit antithymocyte globulin (rATG)-Thymoglobulin in addition to pulse glucocorticoids, rather than glucocorticoids alone (Grade 2C). (See 'Banff grade I rejection' above.)

Banff grade II or III – For patients with Banff grade II or III rejection, we suggest treatment with rATG-Thymoglobulin plus glucocorticoids, rather than glucocorticoids alone (Grade 2C). In patients who are unable to receive rATG-Thymoglobulin, we treat with alemtuzumab. (See 'Banff grade II or III rejection' above.)

Borderline rejection – In patients with borderline TCMR, there is no consensus regarding optimal management. Some transplant centers do not administer specific treatment for rejection but augment maintenance immunosuppression by targeting higher tacrolimus levels (ie, 5 to 7 ng/mL) in patients whose tacrolimus trough levels are in the lower range (ie, 3 to 5 ng/mL) and/or by optimizing mycophenolate dosing. Other transplant centers choose to treat borderline rejection as acute TCMR. (See 'Borderline and subclinical rejection' above.)

Mixed acute rejection – In patients who have evidence of both acute antibody-mediated rejection (ABMR) and acute TCMR (ie, mixed acute rejection) on kidney biopsy, we treat for both TCMR and ABMR. 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'.)

Monitoring – In most patients being treated for acute TCMR, we advocate inpatient admission for management. We monitor serum creatinine levels daily while the patient is admitted to assess the response to treatment. After the patient has been discharged, we monitor serum creatinine on a weekly basis until it has returned to the baseline level (prior to the episode of rejection) or until it plateaus at a new baseline level, after which routine monitoring of kidney function can be resumed. Some transplant centers treat patients with less severe acute rejection (ie, those with Banff grade IA TCMR) with high-dose oral glucocorticoids on an outpatient basis. In such patients, serum creatinine should be measured on an every-other-day basis, if possible. (See 'Monitoring the response to therapy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges W James Chon, MD, FACP, who contributed to an earlier version of this topic review.

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Topic 7358 Version 30.0

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