CMR/TCMR

The advent of robust im/m agents as part of induction/maintenance therapy for KTx has greatly limited the incidence of Ac rejection.

 

CMR/TCMR

 

 

 

Abbreviations (read twice please, put also UR comments):

 

 

o   AB: antibodies

o   ABMR/AMR: antibody-mediated (humoral) rejection

o   Ac Rj: acute rejection

o   Ag: antigen

o   ALm: Alemtuzumab

o   Am: antimicrobial

o   AMR: antibody-mediated (previously humoral) rejection

o   AMR: antibody-mediated rejection

o   ATG: Antithymocyte globulin

o   Aza: Azathioprine

o   BMD: bone mineral density

o   C: complement

o   CLL: chronic lymphocytic leukemia

o   CMV: cytomegalovirus

o   CyA: Cyclosporine

o   Dgx: diagnosis

o   Gctcds: glucocorticoids

o   IF/TA: interstitial fibrosis/tubular atrophy

o   Ig: Immunoglobulin

o   IgG: immunoglobulin G

o   im/m: immunosuppression/immunosuppressive

o   KTR: kidney transplant recipients

o   KTx: kidney transplantation

o   MMF: Mycophenolate mofetil

o   MR: Mortality rate

o   Mthyprd: methylprednisolone

o   NK: natural killer cells

o   PCP: Pneumocystis pneumonia

o   Pph: plasmapheresis

o   PPI: proton pump inhibitors

o   Pred: Prednisone

o   Prox: prophylactic

o   Prox: prophylaxis

o   PTLD: posttransplant lymphoproliferative disorder.

o   rATG-T: rabbit antithymocyte globulin (Thymoglobulin)

o   RCT: randomized controlled trial

o   Rj Dgx: rejection diagnosis

o   Rj: rejection

o   SCr: serum creatinine concentration

o   SE: side effects

o   Sms: symptoms

o   Sns: signs

o   SRL: Sirolimus

o   Tac: tacrolimus

o   TCMR/CMR: T cell-mediated (cellular) rejection

o   ttt: treatment

o   ttt: treatment

o   Tx: transplant/transplantation

o   UO: urine output

 

 

The advent of robust im/m agents as part of induction/maintenance therapy for KTx has greatly limited the incidence of Ac Rj that could be defined as an acute decline in allograft function combined with certain pathologic alterations in graft tissues. Utilizing the current im/m regimens, Ac Rj rates have dropped to 8 % at many Tx centers. Ac Rj can be generally classified into CMR & AMR. Kidney allograft biopsy is mandated to settle the Dgx and recognize the intensity of Rj to identify the most appropriate inlet to management. CMR & AMR may be coexisting simultaneously in the kidney allograft (i.e., mixed Ac Rj). The finding of tissue evidence of Ac Rj on biopsy with no associated rise in SCr is called subclinical Rj.

OUTCOMES/PROGNOSIS

Acute CMR is seen most commonly within the 1^st y after Tx and rarely reported after 5 y post-Tx. Generally, repeated attacks of Ac Rj would be complicated by decline in allograft longevity, despite not all Rj episodes have similar impact on allograft function. The effect of successful control of acute CMR on graft outcome has not been well assessed. Higher histological intensity of acute CMR (i.e., Banff grade > IA) has been complicated with lowered response to ttt. Greater histological scores (e.g., i: interstitial inflammation, t: tubulitis, v: intimal arteritis) with delayed onset of Rj (>3 mo post-Tx) have been complicated with worsened allograft outcome. Genetic studies have shown that several molecular bases driving acute CMR are also underlying the evolution of chronic histologic lesions of IF/TA that has been accompanied by graft failure. Dedicated algorithm has been designed (see alg.) & validated to anticipate the long-term risk of graft failure in KTR. It’s incorporating the functional, histological, and immunologic profile to identify a prognostic score (the iBox) for TR that can be applied at any time after Tx, even at the timing of Rj Dgx. Further studies are needed to recognize iBox utility regarding the clinical impact and management.

 

 

TREATMENT: ttt approach in TR with histological evidence of acute CMR is primarily guided by the histopathological intensity of Rj:

1)    TR with borderline CMR, there’s no consensus regarding optimal management. Some Tx centers do not provide specific ttt for Rj but only augment the maintenance im/m by targeting greater Tac levels (i.e., 5-7 ng/mL) in ptns with Tac trough values are in its lower levels (i.e., 3-5 ng/mL) and/or by optimizing MMF doses. Other Tx centers prefer to ttt borderline Rj like acute CMR. Subclinical Rj is usually identified on surveillance/protocol biopsy with lack of clinical Sms/Sns.

2)    TR with Banff grade I Rj are mostly provided with pulse high-dose IV steroids, followed by tapered oral Gctcds. Moreover, maintenance im/m would be augmented. TR with Banff IB Rj with few/no chronic histological changes presenting < one y post-Tx, we give rATG-T added to the pulse steroids.  

3)    TR with Banff II/III Rj, we provide pulse high-dose IV steroids, followed by an oral tapered steroid. Moreover, we provide rATG-T + augmented maintenance im/m. If rATG-T not tolerated, we give ALm.  

4)    TR with evidence of combined acute CMR & AMR; i.e., mixed Ac Rj, on allograft biopsy should be ttt for both CMR & AMR.

Banff I Rj: Suggested approach for ptns with Banff I Rj:

a)    Biopsy-proven Banff IA/IB CMR (no evidence of AMR), ptns admission is typically advocated. We give pulse IV Mthyprd at 3-5 mg/kg/d for 3-5 doses, maximum 500 mg/d. After pulse steroids, oral steroids are tapered rapidly to the maintenance oral Pred kept before to the attack. If there’re no concern about non-adherence, we provide augmented maintenance Pred dose, e.g., if the Rj seen while TR was on 5 mg/d, we may raise Pred to 10 mg/d. Moreover, other members of maintenance im/m adjusted as required. Some Tx centers prefer to ttt Banff IA CMR with an equivalent dose of high-dose oral steroids as an OPD, provided that ptns can return for frequent lab monitoring.  

b)    In Banff IB CMR + few/no chronic histological lesions presenting < one y post-Tx, we provide rATG-T with pulse steroids at 1.5-3 mg/kg/dose/ 1-3 ds for total dosing of 3-6 mg/kg in the 1^st y. In these ptns, Mthyprd is provided as 3-5 mg/kg (maximum 500 mg) before each dose of rATG-T. Shorter/higher-dosing of ttt (i.e., single dose of rATG-T 3 mg/kg) is preferred to limit cost & length of hospitalization. The rationale for rATG-T addition is based on evidence that severe (t3) tubulitis that distinguishing Banff IB from IA CMR, is complicated by worse allograft outcome as compared to milder (t1 or t2) tubulitis and warranting more robust ttt.

Pulse Mthyprd is the 1^st-line therapy for acute CMR in most Tx centers. Added to the intensified maintenance im/m, such pulse steroids are commonly the only added ttt if Rj is Banff IA or IB. The percentage reversing rate for the 1^st episode of acute CMR is 60-70 % with this protocol. Successful response: UO increased & SCr starts declining within 5 days after the start of therapy.

TR are mostly responding to steroids; few high-quality reports comparing the efficacy of various steroid regimens for ttt of CMR. One trial: 95 episodes of kidney allograft Rj seen in 45 KTR, ttt with IV pulse Mthyprd (1 g boluses) or high-dose oral Pred induced the same rate of reversal of Rj (about 60 %). Fluid retention was commonly seen among ptns ttt with high-dose oral Pred. This study was proceeded before CMR & AMR dealt as separate entities.

 

Banff G II/III Rj, suggested approach for Banff II/III Rj:

●TR with biopsy-proven Banff IIA, IIB, or III CMR, in-ptns admission is preferred. We can provide pulse IV Mthyprd 3-5 mg/kg/d./ 3-5 doses (maximum 500 mg/d.), followed by rapidly-tapered oral Pred dosing. Typical steroid taper would be starting with Pred 40 mg/d and to decrease the daily dosing by 10 mg every 5 ds until 10 mg d., after which the daily dosing is decreased to 5 mg daily after another 5 ds. Moreover, we give daily rATG-T at 1.5-3 mg/kg/dose for total dosing of 5-10 mg/kg. Total No. of doses is limited by Banff severity, e.g., with Banff IIA CMR, we may give rATG-T 2.5 mg/kg/d./2 d, and in Banff III, we give 2 mg/kg/d/4-5 ds according to the response in SCr levels. Other members of maintenance im/m adjusted as required. Ptns not tolerating rATG-T, we give ALm: 30 mg single IV dose. Such ptns may include TR with allergic history to rATG-T (e.g., with induction or during previous ttt of Rj) or ptns with WBCs < 2000/microL or platelet count < 75,000/microL. We may also give ALm, rather than rATG-T, to ptns having previous history of severe rabbit exposure (i.e., having raised or ingested rabbits) and, so, may be at risk of serum sickness after rATG-T.

●ALL ptns ttt with rATG-T (or ALm) & high-dose steroids, we resume Am & antiviral Prox/3 mo with a regimen similar to that provided in immediate post-Tx timing including Prox against PCP, CMV infection/disease, & herpes simplex infection (in ptns at low-CMV risk). Moreover, we also provide antifungal Prox.

ATG: a polyclonal Ig that’s prepared via injecting human thymocytes into rabbits (rATG-T) or horses (Atgam). ATG can induce T lymphocyte depletion in the peripheral blood mainly via C-dependent cell lysis; it also shows some B cell-AB, inhibiting B cell proliferation leading to B cell apoptosis. ATG has been used both for Prox against and for initial ttt of Ac Rj. Reversal rate for Ac Rj is between 75 & 100 % in several series, with SCr reversal to baseline several days-week.

Comparing rATG-T to Atgam was conducted in a multicenter, double-blind, RCT of 163 KTR with Ac Rj. Compared with Atgam, rATG-T induced higher rate of Rj reversal (88 vs 76 %) with lowered rate of recurrent Rj within 90 d. after AB therapy (17 vs 36 %). Ptns & graft survival and the rates of SE and infectious episodes were similar. Given the greater efficacy of rATG-T in ttt of Ac Rj, Atgam is no longer provided routinely in most Tx centers, although it’s sometimes used in ptns having known allergy to rabbits or rATG-T if ALm is not available.

Optimal dose & duration of rATG-T for ttt of Ac Rj is not certain. Pivotal trial: that approved rATG-T as ttt for Rj (US), the medium total dose was 10 mg/kg given along 6 doses. It’s now established that more intense & durable lymphocytic depletion that’s believed to be one of the major mechanisms of rATG-T action can be achieved via larger but fewer doses along short time. ALm is a humanized anti-CD52 monoclonal AB that’s approved for CLL. CD52 Ag is present on T & B lymphocytes, NK cells, and, to a less extent, on monocytes & macrophages. ALm can lyse lymphocytes via C activation & AB-dependent cytotoxicity. A few reported studies, ALm has been conducted for the ttt of Ac Rj.

ALm advantages: may include peripheral, rather than central, venous route with short ttt course. Large study: ALm reversed Ac Rj in 63 % of KTR on Tac monotherapy with either steroid-resistant Rj or at least Banff IB Rj. Other measures included reversing Tac weaning, steroids, and/or adding SRL. Infectious episodes were observed in 35 % of ptns, 2 ptns died, one due to infection and the other developed PTLD. ALm has been also efficacious for CMR in pediatrics.

Borderline/subclinical Rj: There’s no available consensus in ttt borderline Rj and, specifically, whether anti-Rj ttt should be provided. Some Tx centers do not provide specific ttt for Rj but rather augment maintenance im/m via targeting greater Tac levels (i.e., 5-7 ng/mL) in TR with Tac trough levels with lowered range (i.e., 3-5 ng/mL) and/or via optimizing MMF doses. Other Tx centers prefer to ttt borderline Rj as acute CMR, considering observational data showing pathologic Dgx of borderline Rj is complicated by adverse clinical & histological outcomes, e.g., progressive fibrosis & greater risk of subsequent Rj, graft failure, and ptn MR. However, other reports question the benefit of Rj ttt in this type of Rj.

Subclinical Rj can be defined as: = [the finding of histological evidence of Ac Rj on biopsy without rise in SCr]. It can be found on a surveillance/protocol biopsy with no associated clinical Sms/Sns. Application of protocol biopsy is generally confined to ptns conducted in experimental im/m regimens considering the lowered incidence of subclinical Rj in ptns on Tac, MMF, & steroids. It’s not clear if the advent of therapy with subclinical Rj may improve clinical outcome. A few reports have managed this question:

1)     Report: 72 ptns ttt with CyA, Aza, & steroids were assigned to biopsy at 1, 2, 3, 6, & 12 mo post-Tx (biopsy g.) or to biopsy at 6 & 12 mo (control g.). Subclinical Rj found at mo: 1, 2, & 3 in biopsy g. was ttt with high-dose steroids. Compared with no ttt, steroids therapy was associated with less attacks of Ac Rj & lowered SCr at 2 ys (1.5 vs 2 mg/dL, 133 vs 183 micromol/L).

2)    Multicenter report: 240 KTR ttt with Tac, MMF, & steroids assigned to protocol biopsies or control arm, with subclinical Rj ttt with steroids. At 6 mo, there was no difference in allograft function between g.s. Authors reported that protocol biopsy was NOT beneficial with robust im/m (i.e., Tac/MMF/ steroids).

Further workup with prolonged follow-up is needed to conclude whether protocol biopsy, combined with robust im/m given for ttt of subclinical Rj, improving long-term outcomes.

Monitoring ttt response: All ptns being ttt for acute CMR, it’s preferable to advocate in-ptns admission during management. SCr monitoring on daily basis while the ptn is hospitalized to evaluate response to ttt. After discharge, SCr can be monitored on a weekly basis until corrected to the baseline (before Rj) or a plateau on new baseline has been established.  

Assessment of peripheral blood donor-derived cell-free DNA (dd-cfDNA) can be applied to support Ac Rj Dgx to monitor ttt response. Ptns with raised plasma dd-cfDNA (i.e., >1 %) at the timing of Dgx, we may repeat dd-cfDNA at 1-2 mo after start of ttt. Ptns responding to ttt, dd-cfDNA fraction should decline back to normal (<1 %) within 2 mo. The current dd-cf DNA tests in clinical practice have not been validated to define low-grade (Banff 1A or less) or borderline Rj, nor have they been accepted to assess the response of low-grade CMR to ttt.

As mentioned before, some Tx centers ttt ptns with less severe Ac Rj (i.e., Banff IA) with higher-dose oral steroids on an out-ptns basis. In such ptns, SCr should be assessed EOD, if possible, until returned to its baseline or became plateaus at a new baseline, then routine follow up can be resumed. TR with CMR ttt with steroids & rATG-T and not having intense chronic histological changes (e.g., IF/TA, vascular intimal sclerosis, arteriolar hyaline thickening) or frank necrosis, a favorable result to ttt is anticipated, typically within 3-5 d. of ttt start. Decline in SCr to within 10 % of baseline is considered to be a successful reversal of Rj. Ptns with evidence of chronic injury & fibrosis are less likely to have reversal of allograft dysfunction.

Next steps to ttt according to the response to initial therapy:

o   SCr decline: keep augmented im/m + low-dose oral Pred indefinitely.  

o   No decline in SCr after 5 d of Rj ttt are considered initial ttt failure. So, ongoing Rj and/or alternate Dgx of allograft dysfunction should be suspected. Next steps depend on the initial ttt for Rj:

o   Ptns ttt with steroids only, we can provide rATG-T. Ptns cannot tolerate rATG-T, we can provide a single dose of ALm.  

o   Ptns ttt with rATG-T (or ALm if ptn not tolerating rATG-T), we may repeat a graft biopsy to exclude an alternate Dgx or a more intense histological lesion (e.g., higher Banff or AMR). If higher Banff is identified, we ttt with appropriate therapy for the higher Banff, as above. If biopsy shows evidence of AMR, we start ttt for AMR. If biopsy shows absence of reversible changes or extensive fibrosis (= dead renal tissue), hold ttt of Ac Rj.  

When to hold therapy: It is difficult decision but crucial & determined by overall clinical situation of the TR. Therapy withdrawal is recommended with:

1)    Current infectious episodes with undue risks with further im/m augmentation.

2)    Lack of response after intense course of pulse steroids and/or rATG-T, and absent evidence of AMR on repeat biopsy (dictating alternate ttt plan) or any other alternative etiology for persistent graft dysfunction.

3)    Dead renal tissue on biopsy. It’s beneficial to get trichrome stain to assess fibrotic status. The magnitude of chronic alterations on initial biopsy can help guiding the power/duration of im/m. With low evidence for reversible changes, risk of infection/malignancy due to high-dose im/m may outweigh any benefit.

Current toxicities: The major sequalae of pulse steroids is the higher susceptibility to infection, particularly oral candidiasis. Other sequalae may include hyperglycemia, HT, peptic ulceration, and psychiatric upsets e.g., euphoria & depression. Prox histamine-2 (H2) blockers or PPI & antifungals are usually advised. Bone disease is commonly seen in KTR, with the most crucial risk factor being the loss of BMD due to the cumulative effect of steroids. The highest steroids-induced bone loss is in the 1^st 3-12 mo after Tx. As most CMR observed within the 1^st y. post-Tx, further steroids may intensify its cumulative dose.

Fever & chills may be developed during initial rATG-T administration. Anaphylactoid reactions, e.g., respiratory distress & hypotension, are currently rare. Concurrently given pulse steroids before rATG-T may prevent or significantly limit infusion-induced reactions. Considering the risk of phlebitis, rATG-T should be provided via central venous route; however, rATG-T can be given via peripheral line if mixed with heparin and antihistaminic premedication.

Pruritic skin rash can be seen in 20 % of rATG-T-ttt ptns. Contaminated rATG-T with platelets & RBCs can induce AB production & SE of thrombocytopenia. Thymoglobulin preparation also have anti-leukocyte IgG that can induce transient leukopenia. Both CMV & herpes infection can be seen after rATG-T ttt but rarely life threatening with current Prox antivirals. PTLD can also be reported. ATG-induced serum sickness responding to Pph has been also reported including one case with rapidly progressive paralysis linked to serum sickness. Rapid cure can be seen with therapeutic Pph. Previous exposure to rabbits may augment the risk of developing serum sickness with the 1^st dose of rATG-T.