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AMR

  A M R   Abbreviations ( read twice please ):   o     AB : antibody o     Ag: antigen o     a HUS: atypical hemolytic ...

 

AMR

 

Abbreviations (read twice please):

 

o    AB: antibody

o    Ag: antigen

o    aHUS: atypical hemolytic uremic syndrome.  

o    AKI: acute kidney injury

o    ALm: Alemtuzumab

o   AMR: Antibody-mediated rejection

o    ARB: angiotensin II receptor blocker

o    Belat: belatacept

o    BM: bone marrow

o    Bortz: bortezomib  

o    BW: body weight

o   C: complement

o   C1 INHs: C1 inhibitors

o    CDC: C-dependent cytotoxicity

o   Ch. AMR: Chronic AMR

o   CMV: cytomegalovirus

o    CMX: crossmatch

o    CyA: cyclosporine

o   DD KTR: deceased-donor kidney transplant recipients

o    Dgx: diagnosis

o   DSA: donor-specific antibodies

o   Dsnz: Desensitization.

o    DX: dialysis

o    Ecz: Eculizumab

o   eGFR: estimated glomerular filtration rate

o    ENDATs: endothelial cell-associated transcripts

o    EOD: every other day.

o    Evrol: everolimus

o    FDA: Food and Drug Administration

o    FFP: fresh frozen plasma

o    Gcrtcd: glucocorticoids

o   HLA: human leukocyte Ag.

o   IA: immunoadsorption

o    iABO: incompatible ABO

o   IF/TA: interstitial fibrosis/tubular atrophy

o    Ig: immunoglobulin

o   IL-6: interleukin-6

o    im/m: immunosuppression

o    IVIG: intravenous immunoglobulin

o   KPD: kidney paired donation

o   KTR: kidney transplant recipients

o   KTx: kidney transplantation

o    MAC: membrane attack complex.

o   MCS: median channel shift

o   MFI: mean fluorescence intensity

o   MM: multiple myeloma

o   MMF: Mycophenolate mofetil.

o   Mthyprd: Methylprednisolone

o   NFkB: nuclear factor kappa-B

o   NK: natural killer.

o    PCP: Pneumocystis pneumonia

o   PE: plasma exchange

o   PMN: polymorphonuclear neutrophils

o    PNH: paroxysmal nocturnal hemoglobinuria

o   Pph: plasmapheresis

o    Pred: Prednisone

o    Prox: prophylaxis

o    PT: prothrombin time

o    Ptc: peritubular capillary score

o    PTT:  partial thromboplastin time  

o    rATG-T: rabbit antithymocyte globulin-Thymoglobulin

o    RCT: randomized, controlled trials

o    RITUX ERAH: Impact of ttt With Rtx on the Progression of Humoral Acute Rj After Renal Transplantation.

o    Rj: rejection

o    Rtx: Rituximab

o    SCr: serum creatinine

o    SE: side effects

o   Snz: sensitized/sensitization

o   SRL: sirolimus

o    Tac: Tacrolimus

o   TCMR: T cell-mediated (cellular) rejection

o   TG: transplant glomerulopathy

o   TMA: thrombotic microangiopathy

o   TR: Transplant recipients

o   ttt: treatment/treated

o   tttp: therapy

o   Tx: transplant/transplantation

o    UNOS: United Network for Organ Sharing

o   UO: Urine output

 

 

 

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AMR is the most common cause of allograft loss after KTx. The revised Banff 2017 has classified AMR into active (= acute) and ch. active AMR as states of histologic evidence of acute/ch. injury + evidence of current/recent AB interaction with vascular endothelium + serologic evidence of DSA to HLA or non-HLA Ags.

The cellular & molecular pathways regulating AMR still to be recognized. However, evidence showed that B cell & plasma cell activation > DSAs production that bind to HLA or non-HLA molecules found on the endothelial lining within kidney allograft. In active AMR, AB bind the graft endothelium with C-dependent & -independent activating mechanisms and recruiting NK cells, PMN, platelet cells, & macrophages contributing to the peritubular capillaritis, glomerulitis, cellular necrosis, TMA, with rapid loss in graft function.

On the other hand, ch. AMR is a separate pathophysiological subset resulting from repeated thrombotic events with inflammatory alterations leading to endothelial injury with graft matrix remodeling. It is presented histologically as TG with slow/progressive loss of allograft function. Growing evidence suggesting that prevention & ttt of AB-mediated injury mandates combined regimen to inhibit B cell evolution, maturation, and activity. Despite the wide No. of observational reports, it’s still unclear which combined tttp is the safest & most efficacious.

OUTCOME PREDICTORS:

Active & ch. AMR are both associated with poor longevity after KTx. Ptns with active AMR are at higher risk for subsequent Rj, ch. AMR, & allograft loss. Similarly, ptns with ch. AMR have an increased risk for allograft loss and mortality. However, not all TR with AMR express poor outcome, and many ptns maintain stabilized graft function for ys after ttt of the early episode of Rj.

Histologic features: Some histopathological criteria on allograft biopsy at the time of Rj are predicting worse survival, e.g., associated acute TCMR is an independent risk factor for allograft loss in ptns with AMR. There’s also obvious & independent link between microvascular injury & C4d staining (including focal C4d st. in post-reperfusion biopsy) with poor survival in active or ch. AMR. Similarly, TG & the degree of ch. injury (with semi-quantitative assessment via ch. interstitial, tubular, vascular & glomerular Banff scores) are linked to worse allograft survival.

DSACertain criteria of DSAs have been associated with poor outcome in AMR:

1]    DSA strength: Study: 402 DD KTR, the risk for both AMR & allograft loss directly correlating with peak pre-existing anti-HLA DSA strength via MFI. Ptns with a peaked anti-HLA DSA MFI of > 6000 had > 100-fold higher risk for AMR compared with MFI of <465. Allograft survival with a peak anti-HLA DSA MFI of >3000 was less than that with MFI of ≤ 3000. However, lack of tissue-proven Rj & acute inflammation, HLA DSA may not be complicated with higher risk of graft failure.

2]    DSA subclass: The Ig subclass of DSA can predict outcome. Study: 125 ptns with DSAs recognized in the 1st y. post-tx, the IgG4 immunodominant DSA was associated with:

1)    IF/TA.

2)    Late graft injury,

3)    Higher graft glomerulopathy, &

In contrary, IgG3 immunodominant DSA was associated with:

1)    Short time to Rj,

2)    Greater microvascular damage,

3)    C4d capillary deposition, & graft failure.

3]    C-binding capacity: The ability of anti-HLA DSAs to bind C, (via C1q assay), may recognize TR at higher risk for allograft loss. However, one study: C1q-binding capacity of DSAs is largely reflecting the difference in AB strength, denoting the biologic importance of C1q assay.

4]     DSA type: either (pre-existing or de novo) may be a predictor of worse outcomes. De novo DSA, mostly related to non-adherence or under im/m, has been linked to poorer outcome compared to preexisting DSA (i.e., pre-Snz ptns).

5]    DSA response to ttt: A growing evidence that lowered DSA strength after ttt showed better graft longevity, despite little data about the +ve DSA response.

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Graft function
: The magnitude of graft dysfunction during biopsy is directly correlated with poor outcome in TR with AMR. Retrosp. Analysis: 205 ptns with biopsy- approved AMR, eGFR of <30 mL/min per 1.73 m2 at Dgx & urine protein-to-Cr ratio of ≥ 0.30 g/g at the timing of biopsy were determined as independent factors of allograft loss. Another study: 123 ptns with ch. AMR, SCr of >3 mg/dL and urine protein-to-Cr ratio of >1 g/g at the timing of Dgx were independently correlated to allograft failure.

Other risk factors: The finding of ENDATs & DSA-selective transcripts has been observed to be a biomarker of active AB-mediated injury predicting worse allograft outcome. These molecular assays that’re not yet included in clinical practice, reflecting the alterations in micro-endothelium not normally identified by routine histopathology and DSA testing to upgrade risk stratification and prognosis.

Prediction model: Novel prediction models have been introduced to anticipate long-term renal graft failure, including post-Rj tttp. Cohort study: 7557 KTR from 10 Tx centers from Europe/US, 32 prognostic factors for renal graft survival were evaluated: 8 functional, histological, & immunologic factors were independently correlated with graft failure and combined into a risk prediction score (iBox) showing distinct calibration/discrimination. The iBox score presents accuracy if used at several times of evaluation post-Tx and was approved in several clinical scenarios that include response to Rj tttp suggesting that iBox risk prediction score can help monitoring TR with further improvement of designing & developing valid & early new endpoint in clinical trials.

PREVENTION: A suggested approach to prevent AMR development depends on detecting DSA before (pre-existing DSA) or after (de novo DSA) Tx.

Pre-existing DSA before Tx: Ptns with pre-existing DSA before Tx have a higher risk for AMR with allograft loss as compared to non-Snz ptns. This risk is correlated to the strength of DSA as ptns with +ve CDC CMX (1st) have increasing risk of AMR and allograft loss than TR with +ve flow CMX (2nd), who’s in turn show increasing risk than ptns with +ve virtual CMX (3rd). Despite avoiding Tx highly Snz ptns is usually considered to prevent AMR, this option makes ch. DX the only option, with its sequalae on health and quality of life. Long-term outcome in KTR has been improved with Dsnz programs evolution that can be offered to limit DSAs levels before Tx. Moreover, ptns enrollment in specific plans to optimize matching may be enrolled in a timely Tx with better outcome. A suggested approach to prevent AMR with preexisting DSA before Tx include:

TR with potential living donor, according to the findings of the most recent CMX:

(1) TR with +ve CDC CMX or strongly +ve flow CMX > use KPD program, rather than Dsnz, given the higher risk of AMR & graft loss in these ptns. KPD program (National Kidney Registry, the Alliance for Paired Donation, & UNOS KPD Pilot Program) enables Snz ptns with immunologically incompatible living donors to be Tx with high-quality graft from other living donor with similar setting and agreed to exchange organ. Despite cost could be a matter for kidney exchange registry in the US, KPD could help assisting Tx centers avoiding a costly Dsnz protocol with better long-term outcome. Mathematic modeling has anticipated that an optimum matching algorithm with national KPD program could improve allograft outcome and limit health care costs for highly Snz TR. Some Tx centers may combine Dsnz & KPD.

(2) In TR with +ve virtual CMX or a mild/moderate flow CMX (i.e., MCS <250), we employ HLA Dsnz program including ttt with Pph, rATG-T, & Rtx.

o   TR without a potential living donor, we admit HLA Dsnz plans.  

o   All ptns with a preexisting DSA before Tx undergoing KTx > use induction & maintenance im/m tttp suitable for high-risk TR developing acute Rj.

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Post-Tx monitoring
: Monitoring of graft function in TR with preexisting DSA prior to Tx is similar to non-Snz ptns. Moreover, routine monitoring of DSA level at mo 1, 3, 6, & 12 post-Tx, then yearly. In TR with significantly higher DSA or developing de novo DSA within the 1st 3 mo > allograft biopsy that’s largely consistent with the recommendations of the Consensus Guidelines on the Testing & Clinical Management Issues Associated with HLA and Non-HLA AB in Tx. Ptns with pre-Tx DSA should perform protocol biopsy at mo 3 & 12 post-Tx. Some experts perform a post-reperfusion kidney graft biopsy at the timing of Tx to determine TR at risk for AMR. In ptns having evidence of +ve C4d staining, Pph (2-3 sessions) + single dosing of Rtx 375 mg/m2 (after the last Pph session) could be included in the induction im/m.

Ptns with de novo DSA after Tx: KTR developing de novo DSA after Tx may present as late-onset AMR. AMR with de novo DSA has been complicated by poorer outcome as compared to AMR with pre-existing DSA. The 2 most common causes of AMR due to de novo DSA are:

1]    Under im/m, &

2]    Non-adherence to tttp.

The former cause can be frequently linked to the advent of the minimizing strategies. Moreover, acute TCMR, malignancy, & opportunistic infections (e.g., BK polyomavirus & CMV) requiring reducing im/m may also impact the development of late-onset AMR. Preventing AMR must focus on non-adherence & under-im/m while balancing the safety & efficacy of long-term im/m. TR mostly maintained on triple im/m tttp (Tac, MMF & Pred) with whole blood Tac monthly monitoring in the 1st 3 ys post-Tx and every 3 mo thereafter. TR not tolerating Tac > switch to Belat, rather than SRL or Evrol. All ptns with de novo DSA should be vulnerable for annual:

1)    DSA estimation&

2)    Kidney allograft biopsy.

Analysis of 2 RCT: converting CyA to Evrol at 3-4.5 mo after Tx was complicated with significant increasing rates of de novo DSA (10 vs 23 %) & AMR (3 vs 13 %). In contrary, Belat, a selective co-stimulation blocker targeting CD80,86,28 interaction preventing T cell activation, has a lowered rate of de novo DSA over 7 ys of ttt in phase III trials suggesting that co-stimulation blockade may be safer & effective in blocking de novo DSA & late AMR. Gcrtcd withdrawal/avoidance also may not augment the risk of de novo DSA if appropriate im/m is maintained. In a 5-y, longitudinal study: 37 KTR randomly assigned to ch. Gcrtcd tttp or early Gcrtcd withdrawal at d. 7 post-Tx; all TR receiving rATG-T for induction & Tac & MMF as maintenance im/m. Only one ptn in the ch. Gcrtcd arm & none in the Gcrtcd withdrawal arm have developed de novo DSA.

ACTIVE AMR tttp

The primary target of AMR ttt is to eliminate the existing DSAs + B cells/plasma cells eradication that’s responsible for their production. Generally, ALL ptns with evidence of active AMR on allograft biopsy should be treated. Despite some centers may not routinely apply protocol biopsy, they would ttt ptns having subclinical AMR via surveillance biopsy. Moreover, they may ttt ptns with C4d -ve AMR with the same approach applied in ptns with C4d +ve AMR. Optimal tttp of active AMR is not certain, as there’re no RCT to compare the safety & efficacy of different regimens. The recommended ttt of AMR is mainly based on the available, low-quality evidence that’re consistent with 2009 KDIGO clinical practice guidelines & 2019 Tx Society Working Group Expert Consensus.

Initial tttpTR with active AMR may be ttt as out ptns, but we prefer ptns hospitalization due to protocol complexity. Suggested approach to initial ttt of active AMR depending on the timing of AMR Dgx alg.:

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Active AMR within the 1st y post-Tx > combined Gcrtcd, Pph + IVIG, and, in some ptns, Rtx as follows:

IV Mthyprd 300-500 mg daily for 3-5 ds, followed by rapid oral Pred tapered to the last maintenance Pred dosing. If there’re no fear of non-adherence, we may augment the maintenance Pred dosing, e.g., if Rj seen while ptn on 5 mg/d, we may increase the maintenance Pred dosing to 7.5-10 mg/d.

Pph is offered daily or EOD maximum 6 sessions or until SCr is within 20-30 % of its baseline. Initial ttt is typically a one-and-one-half-volume exchange with albumin, followed by a one-volume exchange with albumin. We prefer an EOD Pph as albumin alone can be provided for replacement with interval recovery of the PT, PTT, & fibrinogen to an accepted levels with no need to give FFP. This avoids the risk of Ag Snz development; however, 1-2 units of FFP may be supplied for replacement at the end of Pph if indicated via pre-procedural lab values or in the clinical setting, e.g., same-d. graft biopsy.  

•We give IVIG 100 mg/kg after each Pph session> usually 500 mg/kg/d for 1-2 ds after the last session of Pph > total cumulative target dose of 1000 mg/kg of IVIG. Certain centers determine the IVIG dose according ideal BW. Sucrose-free IVIG that’re no > 5 % are usually preferred to limit the risk of AKI.  

o   The finding of Microvascular inflammation on biopsy (i.e., Banff glomerulitis score (g) + (ptc) >0) > Rtx single dosing 200-375 mg/m2 after Pph & IVIG.

o   Augment other members of maintenance im/m as required.

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Active AMR after the 1st y post-Tx
: Gcrtcd tttp with similar approach as above in AMR within the 1st y post-Tx. However, we do not provide Pph in such ptns due to lack of evidence supporting Pph safety & efficacy in late-onset AMR. We give IVIG at 200 mg/kg/2 wks/3 doses. In obese ptns, some clinicians provide the IVIG dose according to ptn’s ideal BW. Sucrose-free IVIG fluids not > 5 % are preferred to limit the risk of AKI. With microvascular inflammation on biopsy, we provide Rtx 375 mg/m2 single dose after IVIG and augment maintenance im/m. ALL TR ttt for active AMR, we resume antimicrobial & antiviral Prox in a regimen similar to that given in the immediate post-Tx period including Prox against PCP, CMV, & herpes simplex (with low CMV risk) for 3 mo. Moreover, we may provide antifungal Prox & Prox H2 blocker to prevent peptic ulceration. We do not routinely provide IA, Bortz, Toci, Ecz, or splenectomy in initial tttp AMR, rather we may provide them to TR not responding to initial ttt. There’s lack of high-quality RCT to guide the optimal tttp of PCP, CMV with active AMR. The best available data come from:

1) Systematic review: 5 RCT & 7 non-RCT assessed the effects of different ttt on graft outcome among KTR with active AMR. All about PCP, CMV were small, & mostly proceeded via outdated criteria for AMR. 4 RCT assessed the benefit of Pph; one study: benefit, one reported potential harm, and 2 reported no effect. However, the Pph protocol differed in dose, frequency, & ttt interval, & IVIG was not provided. One RCT: a benefit of using protein IA. The non-RCT: potential benefit from tttp with Rtx, Pph, & Bortz; however, as some trials used combined tttp, the impact of individual agents couldn’t be specified.

2) Phase III, multicenter, RCT: RITUX ERAH examined the impact of Rtx among 38 KTR with tissue-approved, active AMR. Ptns randomly assigned to Rtx (375 mg/m2) or placebo at d 5 of ttt; all ptns provided Pph, IVIG, & Gcrtcd > no difference between 2 g.s in frequency of the initial endpoint = composite measure of graft loss or lack of improved graft function at d 12. Both gs showed: improved histologic features of AMR & Banff score at one & 6 mo, with a trend favoring Rtx g. Despite both g.s showed declined DSA intensity as early as d. 12, no difference between g.s at 12 mo.

3) The benefit of combined tttp of Pph, IVIG, & Rtx was given by an observational study (France) compared the efficacy of Pph/IVIG/Rtx vs high-dose IVIG alone in the ttt of AMR. Graft survival at 36 mo was 92 % among ptns ttt with Pph/IVIG/Rtx vs 50 % with IVIG alone. At 3 mo post-ttt, DSAs were significantly lowered in Pph/IVIG/ Rtx g. Another study: confirmed that active clinical/subclinical AMR in the 1st y. post-Tx have better outcome if ttt with combined regimen including Pph.

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Response to tttp
: A suggested approach for ptns monitoring during tttp of active AMR primarily depends on whether the ptn is admitted for ttt or as an out-ptns. Ptns can be ttt as an out ptn basis, but it’s typically preferred in-ptn admission considering the complexity of the tttp protocol. For out-ptn setting, we can monitor SCr, electrolytes, & CBC before each Pph session or wkly/4 wks if Pph is not provided. Ptns receiving Pph revised and assessed during Pph tttp and then in the OPD at 4 wks from the start of tttp; TR not receiving Pph perform wkly labs for one mo and monthly thereafter. All ptns are revised for follow-up in the clinic at 3 mo from the start of ttt, we assess DSA level and repeat graft biopsy if not performed before. Data concerned with reversal of AMR are scarce. Generally, one-y graft survival after ttt of clinical & subclinical AMR is almost 80 & 95 %, resp. TR are considered having successful reversal of AMR if they meet ALL of the following criteria within 3 mo of tttp:

1)    Decline in SCr of 20-30 % of the basal line

2)    Decline in proteinuria to its baseline value

3)    Decline in immunodominant DSA by > 50 %

4)    Corrected AMR-associated alterations on repeated biopsy  

Most ptns with AMR with a successful response to anti-Rj tttp will be reflected on SCr decline within 7 ds of ttt. Next steps are based on TR response to initial tttp:

v  Ptns with SCr decline in response to ttt > augment maintenance Tac to get a trough level 20-25 % above the level at timing of Rj, then resuming the routine monitoring. Ptns taking immediate-release formula of Tac and not tolerating higher doses, the extended-release formula of Tac with its fewer SE allowing higher/therapeutic trough, can be provided. Maintenance im/m can be also augmented via increasing the daily dosing of oral Pred.

v  Ptns with no decline in SCr after 7 d of Rj ttt are considered failed initial ttt. In these TR, ongoing Rj and/or another etiology of graft dysfunction should be expected, repeated biopsy should be considered. Next approach depends according to the histopathological/clinical findings. If biopsy findings reveal lack of acute, reversible finding or show extensive fibrosis (= dead renal tissue), > hold ttt of acute Rj. If biopsy shows evidence of persistently active AMR, 2nd-line agents for tttp of AMR can be instituted as rescue tttp. However, the magnitude of added tttp with Pph and other medications e.g., Bortz & anti-C tttp should be balanced with associated comorbidities and the risk of infections and malignant sequalae.

 

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2nd-line agents with failed initial tttp
:  TR with active AMR will be mostly responding to combined Gcrtcd, Pph, IVIG, & Rtx. However, ptns not responding to initial ttt with this formula, the following agents may be tried as rescue tttp.

BortezomibBortz is a potent, reversible proteasome inhibitor approved by FDA as 1st line tttp for MM since 2008. Bortz decreases intracellular protein degradation via inhibiting proteasomal activity leading to apoptosis, primarily via inhibiting NFkB-induced survival signals. It’s specifically efficacious against differentiated plasma cells owing to their high rate of protein synthesis. Multiple case reports/series have shown the efficacy of Bortz in AMR tttp, reversing acute Rj, and/or DSAs decline. One study: 2 ptns ttt with Bortz for active AMR showed a transient decline in BM plasma cells in vivo with constant changes in allo-AB specifications. Total IgG levels were not changed, suggesting proteasome activity is crucial for plasma cell survival and its suppression may control AB production in vivo. Another study: 2 ptns have Bortz-based tttp for active AMR seen within 1st 2 wks post-Tx. Both ptns showed proper reversal of AMR and removal of detectable DSA within 14 ds. On the other hand, a follow-up study: 28 ptns with active AMR reported that Bortz tttp was associated with better DSA and histological response with early (< 6 mo of Tx) Rj but not late AMR.

Bortz in late AMR was evaluated in a RCT of 44 KTR with ≥6 mo post-Tx, had a +ve DSA, and histological evidence of active or ch. AMR. Ptns were assigned to 2 cycles of Bortz (1.3 mg/m2 IV on d: 1, 4, 8, & 11) or placebo; baseline im/m was designed according to a pre-existing protocol. At 24 mo post-ttt, no clear difference between the g.s in eGFR/ y. (-4.7 vs -5.2 mL/min/1.73m2 /y. in Bortz- & placebo-ttt groups, resp). Ptns/graft outcome were comparable, and there were no differences in average GFR, proteinuria, DSA values, or morphologic or molecular Rj phenotypes in 24-mo graft biopsies. On the other hand, Bortz-ttt ptns showed frequent GI & hematologic toxicities.

EculizumabEcz is a fully humanized, monoclonal AB directed against the C5 fragment of the C cascade & inhibiting the generation of MAC. It’s approved by FDA for PNH & aHUS tttp. In KTx, Ecz has been utilized to prevent AMR in highly Snz TR who already undergone Dsnz. There’re also reports of beneficial use as a salvage tttp in refractory active AMR. Dosing has been similar to those given for aHUS tttp, and duration of dosing was variable. Lack of RCT showing its efficacy & safety has prohibited its use in KTR. Moreover, AMR has been observed in KTR receiving Ecz for other indications e.g., receipt of +ve CMX kidney or HUS. Ecz also has not been shown to be effective for ttt of C4d -ve active & ch. AMR, suggesting its efficacy may be confined to acute, C-mediated processes.

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Special cohorts

Mixed acute Rj: Ptns with mixed acute Rj (i.e., histological evidence of both AMR + acute TCMR [Banff 2A or more]) should be ttt for both AMR & TCMR. We ttt with combined Gcrtcd, Pph, & IVIG, as above, with + rATG-T added to the ttt plan. Here, we provide Pph & IVIG on an alternate-d. (e.g., Mon, Wed, Fri., & Sun.) for minimum 4 ttt. We provide rATG-T (1.5-3 mg/kg) on an alternate-d. on the intervening days (e.g., Tues, Thur., and Sat.), total 3 doses.

Subclinical Rj: = finding of histologic evidence of acute Rj on biopsy without rise in SCr. This Dgx is typically settled by a protocol/ surveillance biopsy in a protocol-designed after Tx rather than clinically indicated. With subclinical AMR, we admit the same regimen used in clinical AMR. Retrosp. Studies: ttt of subclinical AMR can be associated with better graft outcome. One study: compared graft outcome of 219 KTR with AMR (77 subclinical, 142 clinical) with matched controls with no AMR. One- & 5-y graft survival among ptns with subclinical AMR were 95.9 & 75.7 %, resp, compared with 96.8 & 88.4 % in controls. Risk of allograft loss with subclinical AMR was 2.15-fold > that in matched controls. However, there was no significant difference in allograft loss between ttt subclinical AMR & controls.

C4d -ve AMR: Some TR with histologic evidence of AMR & +ve DSA but have little or no C4d st. in the peritubular capillaries (C4d -ve AMR). Such ptns ttt in similar approach as that for C4d +ve.

TR with non-HLA DSA: AMR can also occur in ptns with non-HLA DSAs, e.g., anti-angiotensin II type 1 (AT1) receptor AB & anti-endothelial AB. The im/m ttt of AMR in such ptns is generally the same as that with AMR and an anti-HLA DSA. Ptns found to have an anti-AT1 receptor AB should receive, added to im/m tttp, an ARB that may inhibit AT1-receptor AB-mediated impacts.

Less frequent therapies

Immunoadsorption: with protein A (IA) has been utilized to correct AMR. The only controlled, open-label trial: 10 ptns with severe AMR were assigned to IA or no IA (with rescue IA after 3 wks). ALL IA-ttt ptns responded to tttp, while 4 controls remained DX dependent. Rescue IA was not efficacious. Whilst not available in the US, selective IA is an attractive alternate to the non-selective combined Pph & IVIG. Given the improved outcome in ttt AMR with Pph & IVIG, as compared with controls, and with IA, compared to controls in this small trial, further analysis would compare the 2 ttt plans in a larger cohort. Although both types of ttt are expensive, selective modality of IA with no need for IVIG would be preferable if similar outcome is evident. The relative role of IVIG or Pph in ttt AMR still uncertain.

Splenectomynot offered routinely in AMR, considering the lack of proper evidence as a safer/ efficacious procedure than current tttp. Some centers may consider splenectomy for refractory AMR.

o   4 (2 iABO, one CMX +ve, one with clear risk factors) with AMR + failed standard tttp (mean 11 d.) with steroid, Pph, IVIG, rATG-T, & Rtx (3 ptns) or ALm (one ptn) were ttt with laparoscopic splenectomy. UO improved immediately, & SCr declined within 48 hs.

o   5 TR with living-donor RTx after Dsnz for a +ve CMX had an AMR. After rescue trials with Pph & IVIG failed, they underwent splenectomy followed by Pph + IVIG. Graft function recovered within 48 hs after splenectomy.




Experimental therapies:

C1 inhibitors: Activation of C pathway is crucial step in the pathogenesis of AMR. Binding of anti-HLA DSAs to C fraction C1q, the 1st component in activation of the C cascade, has been associated with poor graft outcome with severe phenotyping of AMR. These findings have provided the rationale for using proximal C inhibition via C1 INHs in ttt of AMR. C1 INHs have been approved by the FDA for ptns with hereditary angioedema. The admit of a plasma-derived C1 INH in ttt of active AMR was evaluated in a phase IIb, multicenter, RCT of 18 KTR with biopsy-approved, active AMR. Ptns were assigned to receive C1 INH 20,000 units or placebo EOD for 2 wks (total 7 doses) as adjunctive tttp to standard ttt with Pph, IVIG, & Rtx. Resolution of AMR was seen in 78 & 67 % of ptns ttt with C1 INH & placebo, resp. There was no significant difference between gs in post-ttt histopathology/graft survival on d. 20; however, a trend to sustained better graft function at d 90 was seen in C1 INH g.

Similar findings were seen in a prospective pilot study: of 6 KTR with active AMR & graft dysfunction not responding to Pph, IVIG, & Rtx. All ptns received C1 INHs Berinert (20 units/kg/d: 1, 2, & 3 & then twice wkly) + high-dose IVIG (2 g/kg/once per mo) for 6 mo; maintenance im/m:  MMF, Tac, & Pred. At 6 mo, all ptns showed improved eGFR compared to baseline. Kidney allograft biopsy at 6 mo revealed no significant change in histological features; however, C4d deposition was seen in only one of 6 ptns compared with 5 of 6 ptns at baseline. Moreover, of the 6 ptns who were +ve for a C1q-binding circulating DSA at initiation of the study, only one had +ve DSA at 6 mo. Further studies are needed to recognize efficacy/safety of proximal C inhibition in the ttt of active AMR.

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TREATMENT OF CH. AMR

ch. AMR, the most common cause of allograft failure, is more difficult to tttp as compared with active AMR considering the irreversible renal damage that already involved to the allograft. Despite evidence suggesting that ttt of AB-mediated injury requires a combined regimens to impede B cell evolution, maturation, & activity, it’s not clear that combined tttp is safe/efficacious in ch. AMR ptns. In all ptns with ch. AMR we use combined tttp of Gcrtcd & IVIG. Rtx could be added to the regimen if there’s evidence of active microvascular inflammation on renal allograft biopsy. Usually, we do not utilize Ecz or Bortz in ttt of ch. AMR. The suggested approach in ch. AMR is simulating that used in active AMR seen after the 1st y. post-Tx.  Like active AMR, there’s no high-quality evidence guiding the optimal tttp of ch. AMR, and the suggested approach is mainly linked to the observational trials:

o   Large observational study: 123 KTR with biopsy-approved, ch. AMR, 76 % of TR lost their grafts with average survival of 1.9 ys after ch. AMR Dgx. Ttt with Gcrtcd & IVIG can be linked to lowered risk of allograft loss. Ptns with surviving allografts showed more decline in DSA suggesting the need for more clinical trials to assess DSA in ptns with ch. AMR.

o   One study: 4 KTR with ch. AMR 1 & 27 ys post-Tx, ttt with a combined Rtx/IVIG showed better allograft function in all TR; DSA dropped in 2 of 4 ptns.

o   Retrosp. Review: 31 TR with ch. AMR, average allograft survival was higher among ptns ttt with Rtx compared to those ttt without Rtx.

One RCT of 25 ptns with ch. AMR found no difference in eGFR drop at one y between ptns ttt with combined IVIG (500 mg/kg/4 doses) & Rtx (375 mg/m2) and ptns ttt with placebo. However, the trial achieving only one-½ of its enrolled ptns and was underpowered to recognize any difference in its primary endpoint. Using Ecz in ttt of ch. AMR was assessed in a pilot, RCT: 15 TR with +ve DSA, deranged graft function, + histological AMR evidence. Ptns assigned in a 2:1 ratio to ttt with Ecz (10 ptns) or no Ecz (5 ptns)/6 mo, followed by 6 mo follow up. At 12 mo, no differences in allograft function or the expressed ENDATs, a molecular signature predicting AMR development, between the groups.

Bortz has NOT been shown to be efficacious in the tttp of ch AMR.

Toci: is a monoclonal AB that’s directed against the IL-6 receptor has been admitted for rheumatoid arthritis & juvenile idiopathic arthritis tttp. One study: evaluated Toci as rescue tttp in 36 KTR with ch. AMR failing the standard-of-care ttt with IVIG & Rtx, with/without PE. Toci was provided as 8 mg/kg monthly, maximum 800 mg/6-25 mo. Graft/ptn-survival rate in Toci-ttt ptns were 80 & 91 % at 6 ys post-ttt, resp. Significant decline in DSAs levels with stabilized graft function were reported at 2 ys. No significant SE/adverse events were reported. Toci is not routinely utilized in ch AMR tttp but may be considered a potential alternate for stabilizing allograft function.